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Bringing Informed Decision-Making to Cancer Screening

“Get screened” shouldn’t be the full message, says one cancer prevention expert.

Aliza Rosen

Screening for various cancers before a person experiences symptoms can help detect cancer in the early stages when treatment is often more effective. But there’s more to the message of “get screened” than most people realize, says Otis Brawley , MD, a Bloomberg Distinguished Professor with joint appointments in Epidemiology and the Sidney Kimmel Comprehensive Cancer Center, who emphasizes the importance of routine, high-quality screening with adequate follow-up.

For Cancer Prevention Awareness Month, Brawley talked with Public Health On Call host Stephanie Desmon about why it’s important for everyone to understand both the benefits and the risks of cancer screening in order to make informed decisions. This article is adapted from their conversation.

Cancer screening is more complex than just getting a test.

Many people think you just get the test, and if the test finds cancer, there is benefit. In fact, it’s far more complicated than that.

While family practice doctors and internal medicine doctors tend to be educated on it, it’s not something all doctors learn about in medical school. 

There are cancers—for example, in the prostate and breast—that a person will never be bothered by, because they will ultimately die from something totally unrelated.

Cervical cancer screening saves lives.

In the case of cervical cancer —detected early with a Pap smear or advanced HPV testing— screening clearly saves lives . Women should be screened starting in their 20s. Certain tests should only be done once women are in their 30s through their 60s.

Don’t just get a mammogram. Get routine, high-quality mammography.

Screening for breast cancer saves lives, and it’s recommended that most women start at age 45. However, the message so frequently is to get a mammogram, when the message should be to get into a program of routine, high-quality mammography.

For example, most mammogram vans do not offer the opportunity for previous mammograms to be looked at. High-quality mammography, in my opinion, means that a person’s mammograms from last year and the year before are compared to this year’s.

Colonoscopies aren’t the only way to screen for colorectal cancer.

With colorectal cancer screening , everybody thinks “colonoscopy, colonoscopy.” Colonoscopies save lives and they can be done every 10 years. There’s also stool blood testing, which can be done every year, and stool DNA tests, which can be done every three years. Starting at age 45, those things should be done with adequate follow-up .

Lung cancer screening saves lives, but it’s not without risks.

There are about 140,000 to 150,000 lung cancer deaths a year in the United States. If we had full-scale lung cancer screening , we know that we would prevent perhaps 10,000 of them, but we would actually cause 1,500 to 1,800 deaths because of the diagnostics .

In lung cancer screening, it’s common that a radiologist will see something on an image that could be lung cancer, but could also be an old fungal infection or a scar from a bacterial infection 60 years prior. The only way to figure out whether or not it’s lung cancer is a transthoracic needle biopsy, which involves a controlled stab of a needle through a person’s chest and into the lesion while the person is in a CT scanner. If you stab enough people, you’re going to potentially cause a collapsed lung, and it’s possible the person will have a heart attack.

It’s recommended that people with an extensive smoking history understand the potential risks and benefits, and then find a high-quality screening program. That means a hospital or clinic that has thoracic surgery, good radiology, and good pulmonary medicine.

Prostate cancer screening is controversial. Here’s why.

The approach to prostate cancer screening has changed dramatically over the last 20 years. Now, about half of all men with screen-detected prostate cancer are told that the next step should be observation. The majority of those men are never going to be treated because they don’t need to be cured.

Most professional organizations, including the U.S. Preventive Services Task Force and Medicare, recommend “fair balance,” meaning informed decision-making. There have been studies that show that prostate cancer screening doesn’t save lives, and at least one study that shows that it does save lives, but very few.

One study suggests that prostate cancer screening with a blood test and digital rectal exam will reduce risk of death by 20%. Here’s what that actually means:

If you screen 1,000 men in their 50s on a regular basis over 15 to 20 years, you will diagnose 100 of those 1,000 men with prostate cancer, and ultimately four will die. If you take 1,000 men of the same age, and you don’t screen them over that same period of time, you will diagnose about 60 with prostate cancer because of symptoms, and five will die. That five per 1,000 unscreened going to four per 1,000 screened is where the 20% reduction in risk of death comes from. But it’s at a cost of almost doubling the man’s risk of being diagnosed with prostate cancer.

After an abnormal screen, follow-up is essential.

One of the problems we find is people have an abnormal screen and then don't get the diagnostics or treatment. Women will get a mammogram, be told there’s an abnormality, and a repeat mammogram and additional testing may be needed. A larger portion of poorer women don’t return for that follow-up evaluation.

One study suggests that of the 45,000 or so women who die from breast cancer every year, approximately 10% die because they never got a mammogram. And somewhere around 20-25% die because they did not get adequate follow-up or treatment following an abnormal mammogram.

Not everyone has access to the same quality screening.

In the case of mammography in the U.S., the proportion of Black women and white women in their 50s and 60s who get screened is the same, about 60%. The problem is that Black women more often get screened in centers that don't have previous mammograms for comparison.

With lung cancer screening, we see middle- and upper-middle-class individuals going to high-quality centers and poorer people going to community hospitals that don't offer all the various specialties that ensure high-quality screening.

One famous study of colon cancer screening and treatment showed that poor people in California were going to overcrowded hospitals, and the quality of the screening and diagnosis was impacted. In the hospitals poor people went to, a pathologist had to deal with six patients a day, but in the hospitals where middle-class people with good insurance went, the pathologist only had to deal with two patients a day. So there was a difference in quality because the doctor spent more time analyzing the patients with better insurance.

Each person should make their own informed decisions around screening.

Cancer screening saves lives. But that doesn't mean the recommendation is for everyone to get it. It means that we should have a conversation and respect people’s concerns. Those who are concerned or hesitant to get screened, perhaps ought not to. Those who want to get screened ought to be able to get screened, and we should remove financial barriers for them to do so.

Aliza Rosen is a digital content strategist at the Johns Hopkins Bloomberg School of Public Health. 

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Science, health, and public trust.

April 27, 2022

Putting Cancer Screening in Perspective

By Paul Pinsky, Ph.D., Chief, Early Detection Research Group, NCI Division of Cancer Prevention; Philip Castle, Ph.D., M.P.H., Director, NCI Division of Cancer Prevention; Maureen Johnson, Ph.D., Executive Secretary, President’s Cancer Panel; and Samantha Finstad, Ph.D., Senior Health Science Policy Advisor, President’s Cancer Panel

It’s common wisdom that “catching the cancer early” is always a good thing. It can be a key factor in being able to survive cancer. You often hear, “luckily, they caught it early,” or the converse, “unfortunately, they didn’t detect it until it had spread” when people talk about friends or relatives with a cancer diagnosis. But the reality of cancer screening is not that simple.

The overall goal of cancer screening is to reduce cancer morbidity (illness) and mortality (death). There is no question that appropriate screening reduces illnesses and deaths due to cancer. Cervical and colorectal cancer incidence has declined in the last few decades by about 55% and 45%, respectively. Death rates have declined even more. These have been due primarily to routine screening.

Some types of screenings can detect cancer early (e.g., mammography for breast cancer and low-dose CT for lung cancer). Others can detect cancer early as well as detect cancer precursors, which can prompt action to prevent the development of cancer (e.g., colonoscopy screening for colorectal cancer and Pap smears and/or HPV testing for cervical cancer). Preventing cancer, even a curable cancer, is a large benefit in itself because it can reduce the many burdens to patients associated with a cancer diagnosis. 

But when communicating information about cancer screenings to the public, it’s important to discuss the benefits and the risks. Cancer screening will not necessarily benefit every patient who gets it. A patient could still succumb to cancer despite it being detected early. Others may survive even if their cancer was missed early on and caught at a later stage. And for some patients, screening can actually cause harms.

Screening may lead to the overdiagnosis of indolent (symptomless) cancers. These are cancers detected through screening that would never have become symptomatic in the patient’s lifetime. There is evidence of overdiagnosis associated with various types of screening, most notably PSA screening for prostate cancer. Overdiagnosis of cancer can lead to treatment, or overtreatment, and have serious side effects. For example, impotence and urinary incontinence are associated with prostate cancer surgery.

Screening can also lead to false positives—when people get a positive screening test but no cancer is found. Since screening tests are usually given to healthy people with a low risk of harboring cancer, the tests need to have a high specificity, or the ability to avoid too many false-positive results. A false-positive result can cause anxiety, require additional clinical visits and diagnostic procedures like imaging and biopsies, and lead to high costs for both the medical system and patient. For example, for mammography screening, around 8−12% of women will receive a false positive result at any given screening visit, and up to 45% will receive at least one false positive result over a ten year period of regular screening.

Since cancer screening is intended for those who have no signs or symptoms of cancer, it is important that the benefits strongly outweigh the risks. Cancer screening guidelines can change as new research shows which populations would benefit most from screening with the least harm. For example, more people became eligible for lung cancer screening in 2021, when the U.S. Preventive Services Task Force updated their eligibility recommendations, lowering the minimum age and the amount a person has smoked over their lifetime (or smoking pack-years).

For new screening approaches, establishing the high sensitivity of a test—the ability to find someone who does have cancer—is an important first step in determining its clinical utility. But it is only a first step. Researchers must also demonstrate that the benefits outweigh the harms. Such evidence generally requires a randomized clinical trial in which subjects are randomized to a screening and control arm. The primary outcome is typically mortality from the cancer in question. 

There is much discussion lately about the new “multi-cancer early detection” (MCED) tests. Also called liquid biopsies, these are blood tests that can detect multiple different cancer types simultaneously. To date, there has been limited research on the clinical utility of such tests—in other words, if they actually reduce illness and death. As these tests develop, it’s crucial to keep in mind that a sensitive test does not necessarily indicate clinical utility, or that the benefits of MCED screening would outweigh the harms.

While the benefits of appropriate screening are undeniable, it is important to acknowledge that harms can also be associated with screening; more is not always better. When describing cancer screening, make sure to refer to the current guidelines and clarify that screening isn’t for everyone. It should be done only for the right people at the right time.

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Cancer Screening Prevalence and Associated Factors Among US Adults

GUEST EDITORIAL — Volume 19 — April 21, 2022

Zhen-Qiang Ma, MD, MPH, MS 1 ; Lisa C. Richardson, MD, MPH 2 ( View author affiliations )

Suggested citation for this article: Ma Z, Richardson LC. Cancer Screening Prevalence and Associated Factors Among US Adults. Prev Chronic Dis 2022;19:220063. DOI: http://dx.doi.org/10.5888/pcd19.220063 external icon .

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Author information.

Cancer is the second leading cause of death in the US, exceeded only by heart disease. In 2018, 1,708,921 people were newly diagnosed and 599,265 people died of cancer (1). Although age-adjusted cancer incidence decreased 9.5% over the past 20 years, from 481.7 per 100,000 in 2009 to 435.8 per 100,000 in 2018, the number of people diagnosed with cancer increased, from 1,292,222 in 2009 to 1,708,921 in 2018 (1,2). The estimated national expenditure for cancer care in the US rose from $190.2 billion in 2015 to $208.9 billion in 2020, a 10% increase mainly due to the aging and growth of the US population (3,4). Costs will likely increase in future years as the population grows and ages and new and often more expensive treatments are adopted as standards of care.

Approximately 30% to 50% of cancers diagnosed today could be prevented by reducing exposure to tobacco smoke and other environmental carcinogens, maintaining healthy body weight, and receiving recommended cancer screenings and vaccinations (5,6). Cancer screening, which is different from diagnostic testing, can detect cancer at early stages before symptoms occur, when it can be more successfully treated. In addition to early detection, screening can prevent colorectal and cervical cancers by identifying precancerous lesions that can be removed before they become cancer (7–9). Thus, understanding screening patterns and factors associated with screening will help public health policy makers and practitioners improve cancer prevention programs further by implementing evidence-based policies and practices (10,11). This special collection of articles from Preventing Chronic Disease presents research on determinants of cancer screening, public health practices that increase cancer screening uptake in specific populations, and cancer screening trends.

Screening is considered the primary factor in the steady decline in colorectal cancer incidence over the past decade (12). Richardson and colleagues used data from the Behavioral Risk Factor Surveillance System to present a GIS (geographic information system) snapshot of US states and the District of Columbia that displays the percentage of US adults who reported no screening for colorectal cancer (13). The overall percentage screened decreased from 27.4% in 2012 to 21.6% in 2020, a 5.8 percentage=point decrease that represents almost 4 million people. The average statewide percentage of adults aged 50 to 75 years who were not up to date with colorectal cancer screening in 2020 was 69.4% and ranged from 58.4% in California to 79.6% in Maine. Twenty-two states did not meet the Healthy People 2020 objective of 70.5% of population screened for colorectal cancer. And most adults not up to date with screening had never been screened. Future research on colorectal cancer screening could focus on population subgroups and on new outreach methods directed at the unscreened in those subgroups. Successful interventions could then be disseminated among other population subgroups.

Although overall age-adjusted cancer incidence has been stabilizing over the past several decades, Weir and colleagues used the age-period-cohort generalized linear model to predict that total cancer incidence in the US will increase approximately 50% from 2015 to 2050, from 1.5 million to 2.3 million (2). The largest increase in cancer incidence will occur in people aged 75 years or older; prevention and early detection do work in older populations (14). With the US population aging and age as a nonmodifiable risk factor for cancer, prevention programs can implement evidence-based risk-reduction strategies to reduce behavioral risk factors such as smoking, drinking, and exposure to environmental carcinogens and chronic conditions such as obesity and type 2 diabetes. Cancer screening could also be treated as a prevention priority to detect precancerous lesions that can be removed, thereby preventing cancer, and to detect cancers at early, treatable stages. State and local health departments could also use the age-period-cohort model to estimate their local cancer incidence in their respective state and local areas and develop actionable plans with innovative strategies to help residents change their behaviors by making healthy lifestyle choices, including increasing screening rates. State and local health departments can also use the model to evaluate cancer prevention program outcomes by comparing the time trends and differentials of cancer incidences with or without interventions.

Screening can prevent thousands of cancer deaths. Modern mammography programs can reduce breast cancer mortality by more than 40% (15–17). The over-50% decrease in cervical cancer incidence and mortality over the past 3 decades is largely due to screening with the Papanicolaou (Pap) test, which can detect cervical cancer at an early stage as well as precancerous abnormalities (9). With appropriate evaluation, follow-up, and treatment, survival for women diagnosed with precancerous cervical lesions is almost 100% (18). Sharma and colleagues used a model-based approach in a cohort of 50-year-old participants and estimated that 10,179 deaths from breast cancer, 27,166 from cervical cancer, and 74,740 from colorectal cancer could be prevented if current screening levels were maintained. In addition, an extra 1,300 deaths from breast cancer, 3,400 from cervical cancer, and 11,000 from colorectal cancer could be averted with an increase of 10 percentage points above current screening rates (19). However, even with its proven benefits and US Preventive Services Task Force (USPSTF) recommendations, cancer screening is still suboptimal. The median prevalence of women aged 50 to 74 years who had a mammogram within the past 2 years was about 78% in 2020 and varied substantially, from 66% to 87% among states, differing by race and ethnicity, household income, access to health care, age, and education level (20). However, in 2020 approximately 20% of women aged 21 to 65 years had not been screened for cervical cancer in the past 3 years (20). Moreover, the national median prevalence of people aged 50 to 75 years who have been screened for colorectal cancer per USPSTF recommendations remains less than 70% (13). Again, screening rates differ substantially by state, age group, race and ethnicity, access to health care, health insurance, household income, and education level (20).

Many factors could affect cancer screening behavior, including sociodemographic characteristics, screening cost, health insurance, education, income, travel distance to and location of screening sites, knowledge of the disease, patient and clinician attitudes, and availability of adequate health care facilities (1,15–17,21,22). Therefore, investigating factors influencing screening participation is crucial to creating and implementing population-based cancer screening programs. One such program is the National Breast and Cervical Cancer Early Detection Program (NBCCEDP; www.cdc.gov/cancer/nbccedp/), which was authorized under the Breast and Cervical Cancer Mortality Prevention Act of 1990. The program provides breast and cervical cancer screening and diagnostic services to low-income, underinsured, and uninsured women. NBCCEDP focuses on factors at the interpersonal, organizational, community, and policy levels that influence screening and has served more than 5.9 million women with more than 15.4 million breast and cervical cancer screenings since its inception in 1991. NBCCEDP has expanded and now funds 70 award recipients — all 50 states, the District of Columbia, Puerto Rico, 5 US Pacific Island territories, and 13 American Indian and Alaska Native tribes or tribal organizations. Such programs directed at medically underserved populations should be expanded throughout the country.

Benavidez and colleagues used 2018 BRFSS data to study women who met breast, cervical, and colorectal cancer screening consistent with USPSTF recommendations and found that screening disparities persisted among socioeconomically disadvantaged groups, especially low-income women and women without health insurance (23). They also found that Hispanic women had higher breast and cervical cancer screening prevalence but lower colorectal cancer screening prevalence than non-Hispanic White women. In addition, some racial and ethnic groups and rural populations are disproportionately affected by most cancers. Kruse-Diehr and colleagues compared colorectal cancer deaths in Black populations with White populations in the historically segregated and economically distressed Mississippi Delta. They reported that segregation affected Black and White populations differently. Deaths from colorectal cancer among Black people were higher in mildly and severely segregated urban counties than in moderately segregated counties. Segregation had no effect on colorectal cancer death rates among Black populations in rural counties and was not associated with death rates among White populations (24). Bhimla and colleagues evaluated factors related to colorectal cancer screening among populations of Asian descent by neighborhood ethnic density and psychosocial factors, including knowledge about colorectal cancer, self-efficacy about screening, and perceived barriers to screening behaviors. Their study found that Vietnamese and Filipino Americans had significantly lower screening rates than Korean Americans (25). They also showed that Asian Americans who lived in neighborhoods with high Asian ethnic density were unlikely to complete the colorectal cancer screening process. These findings suggest that the people providing health education to populations with low colorectal cancer screening prevalence could benefit from a better understanding of the cultural norms and beliefs of those populations. Research on cultural characteristics is warranted to understand better why screening differences exist among different racial and ethnic populations. One successful study funded by the Centers for Disease Control and Prevention (CDC) showed that designing interventions for breast and cervical cancer for Muslim women could facilitate screening (26).

In an analysis of a large federally qualified health center in central Texas, Zhan and colleagues found that colorectal cancer screening prevalence was low among people who lived more than 20 miles from a primary care clinic. On the other hand, they found that screening prevalence was high among people who visited their primary care provider regularly. They also used geospatial cluster analysis to identify clusters of patients not up to date with colorectal cancer screening (27).

A randomized clinical trial showed that 20% fewer lung cancer deaths occurred in a group that received an invitation to annual low-dose computed tomography (LDCT) screening compared with a group invited to receive annual chest x-rays (22). Rohatgi and colleagues completed a quantitative evaluation of geographic access to LDCT lung cancer screening in Missouri and Illinois. They reported that rural residents had significantly lower access to LDCT than urban residents (28).

Where a person lives can profoundly affect short- and long-term health (29). Much research into this relationship incorporates locality and geospatial analysis with mixed-model approaches, which can be adopted by state and local health departments by using patient data. Although some geospatial research was done at the county level because of data constraints, geospatial analysis could be further developed for small neighborhoods where homogeneity can be found at the subcounty level. To answer this need, CDC developed PLACES (www.cdc.gov/places/) with the support of the Robert Wood Johnson Foundation and the CDC Foundation. PLACES uses small area estimation methods to provide community estimates on health conditions, prevention, health risks, and health status down to the zip code tabulation area (30). The PLACES tool can help us better understand why the uptake of cancer screening did not reach Healthy People 2020 targets. These data also allow public health professionals to identify populations for implementing proven interventions.

The Community Preventive Services Task Force ( Community Guide ) provides many evidence-based findings and recommendations about cancer screening in community settings (31). These recommendations can be adopted and modified for specific localities and populations. Haverkamp and colleagues mailed a fecal immunochemical test (FIT) to the eligible population served by 3 health care facilities in Arizona operated by American Indian tribes. They found that direct mail to eligible tribe members with instructions and a follow-up telephone call and/or home visit improved the screening compliance rate significantly (32). Simply mailing the FIT test kit with instructions and a telephone call reminder to eligible patients with regular office visits increased the test kit return rate almost threefold.

CDC supports many evidence-based public health interventions. Their National Comprehensive Cancer Control Program (NCCCP; www.cdc.gov/cancer/ncccp/) funds every US state, territory, and tribe or tribal organization to develop and implement evidence-based plans to control cancer. CDC recommends that state comprehensive cancer control plans include evidence-based recommendations and guidelines, such as those from the Community Guide and the USPSTF. These interventions include patient reminders, reducing structural barriers, provider reminders, provider assessment and feedback, small media programs, one-on-one education for cancer screening, multicomponent interventions, and interventions that engage community health workers (31). The inclusion of evidence-based interventions in cancer control plans is an area for improvement. Soori and colleagues evaluated current comprehensive cancer control plans for 50 states and the District of Columbia for inclusion of evidence-based breast cancer control recommendations and guidelines (33). They found that only 6% to 37% of plans included USPSTF recommendations for breast cancer interventions, and only about half included mammogram prevalence in the burden statement. A previous mixed-method study done by CDC found that developers of comprehensive cancer control programs were familiar with evidence-based interventions but needed assistance in implementing them and evaluating their success (34).

Increasing cancer screening will require the collective effort of policy makers, public health practitioners, researchers, and primary care providers. Using evidence-based, multicomponent interventions can increase screening among populations with low screening rates (35). Culturally tailored strategies could be developed to address the needs of socioeconomically disadvantaged and medically underserved groups (29,36). Research and evaluations of public health programs need to focus on the roots of barriers and develop innovative strategies to increase screening. Factors that affect cancer screening behaviors are intertwined. Resolving just one will not solve the whole screening issue. For example, cancer screening rates are generally low among people with low incomes or who lack health insurance (37,38). However, offering health insurance to the uninsured may not be sufficient to increase rates. Medicaid beneficiaries have health coverage for cancer screening, but they may not be able to afford the cost of transportation or loss of a day’s pay for a colonoscopy (31,39–41). The financial burden associated with transportation and loss of work should be considered and evaluated. Developing innovative cancer screening techniques that are portable, noninvasive, and low cost could also increase the uptake of cancer screening.

The ultimate goal of cancer screening is to reduce cancer incidence and mortality (36). Thus, cancer screening can be coupled with primary cancer prevention strategies to reduce cancer risks and to increase proper follow-up care and treatment, especially with the ongoing COVID pandemic in which preventive medical procedures and tests may be delayed or postponed. Public health needs to build the infrastructure to be better prepared so that cancer education, screening, and early treatment are minimally affected by the next pandemic, thereby saving lives.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. No copyrighted material, surveys, instruments, or tools were used in this article.

Correspondence: Zhen-Qiang (Marshal) Ma, MD, MPH, MS, Division of Community Epidemiology, Bureau of Epidemiology, Pennsylvania Department of Health, 625 Forster St, Rm 925, Harrisburg, PA 17120. Telephone: 717-547-3484. Email: [email protected] .

Author Affiliations: 1 Pennsylvania Department of Health, Harrisburg, Pennsylvania. 2 Centers for Disease Control and Prevention, Atlanta, Georgia.

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Essay: Raising awareness about prostate cancer

Other than skin cancer, prostate cancer is the most common cancer in men and is the second most common cause of cancer death in the United States.

The American Cancer Society estimates that in 2021 more than 248,000 American men will be diagnosed and more than 34,000 men will die of prostate cancer. Nearly 1 in 8 men will be afflicted by this disease in their lifetime and 1 in 41 men will die of prostate cancer.

Most commonly, prostate cancer manifests as a localized, silent disease, progressing slowly with minimal to no symptoms. Once the disease has spread out of the prostate to adjacent organs, lymph nodes or bones, symptoms become more prevalent. These include pain, urinary problems, neurologic symptoms, and more.

Data have shown that active screening can lead to early diagnosis. Studies with long-term follow-up have demonstrated an approximate 30 percent decrease in prostate cancer mortality when screening is implemented. In fact, the implementation of prostate cancer screening has been one of the main reasons for the decrease in prostate cancer-specific death by more than 50 percent from 1993 to 2017.

Screening for prostate cancer is simple and quick, performed with a digital rectal exam (DRE) assessing prostate size and contour and a blood test for prostate-specific antigen (PSA). PSA is a protein made by cells located in the prostate gland (both normal cells and cancer cells). The risk of being diagnosed with prostate cancer increases as the PSA blood level increases.

The National Comprehensive Cancer Network (NCCN) guidelines recommend that men over the age of 45 should discuss prostate cancer screening with their physicians. For men at increased risk (known family history, known genetic risk factors, or African ancestry) discussion about screening should start even earlier at age 40.

When prostate cancer is diagnosed at an early stage, and is still localized, the cure rate is incredibly high, with a nearly 100 percent five-year cancer-free survival rate. Once prostate cancer is diagnosed, various treatment options are available, ranging from “active surveillance” (frequent monitoring of the disease with no active treatment) to radiation or surgery and other therapeutic options.

Novel scientific discoveries, new treatment options and robust research published in the last decade have led to significant advances in the diagnosis and treatment of this common malignancy.

Despite the continuous increase in the incidence and prevalence of prostate cancer and a constant rising rate of cancer-specific death, not all men actively seek preventive care and undergo screening.

September is Prostate Cancer Awareness Month. During this time, various attempts are made across the country to raise awareness of this highly prevalent cancer and promote screening and early detection.

At Upstate Urology at the Mohawk Valley Health System (MVHS), we are organizing a free screening event at various dates and times throughout the month of September. These events are being scheduled so as to adhere to social distancing guidelines, with individual appointments being made.

It’s important that you don’t put off screenings during this time of COVID, and we encourage all men between the ages of 45-75 to use this opportunity to be screened for prostate cancer.

Visit mvhealthsystem.org/urology for more information.

As a urologist treating prostate cancer patients and as a son of a prostate cancer survivor, I hope our call is answered, and with your help, we will succeed in raising awareness and spreading the word.

Please join our important quest to fight this cancer by reaching out to more men and improving early detection rates.

Dr. Hanan Goldberg, MD, MSc, is assistant professor at SUNY Upstate Medical University and chief of Upstate Urology at the Mohawk Valley Health System (MVHS).

The Harms of Cancer Screening They Don't Warn You About

Hospitals and doctors fail to fully inform potential patients..

Posted October 3, 2022 | Reviewed by Gary Drevitch

• Cancer screening can lead to harm as well as provide benefit, but doctors and screening providers fail to warn about the risk..
• Advanced screening finds many earlier smaller cancers that are "overdiagnosed," and would never cause the patient any harm.
• The diagnosis "You have cancer" leads many to choose more aggressive and risky surgery than their particular case requires.
• Those surgeries cause harm, ranging from minor issues to death itself, and cost the health-care system billions of dollars.

October is Breast Cancer Awareness month. The world will turn pink. Recommendations for mammography will be everywhere. But few if any of those recommendations will include information about the harms that mammography can lead to. Yes, harms.

Decades of screening by ever-more perceptive advanced technologies have taught us that not all cancers kill. In fact, many tiny early cancers that screening can now detect never spread, or cause harm, or any symptoms at all. This is true for common types of breast, prostate, thyroid, skin, and lung cancer. They are confirmed as cancer under a microscope based on the size and shape and arrangement of their cells, but these cancers are “overdiagnosed," meaning that we’d never know we had them had screening not found them.

This overdiagnosis can sometimes lead to profound harm. Deeply frightened by the three awful words from our doctor — “You have cancer” — we understandably often pursue more aggressive and potentially harmful treatment than our clinical condition warrants. We have breasts and prostate glands and thyroid glands removed to rid ourselves of cancers that would never have caused any harm, by procedures that have side effects ranging from the minor to death itself. You'd think that doctors and hospitals and advocacy groups that encourage screening would also let us know about those risks, so we can be fully informed as we weigh the pros and cons of mammography.

Yet consider the new Breast Cancer Screening and Diagnosis information resource just published by the National Comprehensive Cancer Network , a group of 32 of the top cancer centers in the U.S. It offers clear and helpful information about breast cancer, and explains mammography and its benefits. But in its 51 pages, there is not a mention of the potential harm of mammography. The words "overdiagnosis” and "overtreatment" never appear. The problems are not even hinted at—even in the section titled “Risk assessment for screening." Nor are they alluded to in the section labeled “Questions to ask," which begins: “In shared decision making, you and your health care provider (HC) discuss the risk for developing breast cancer and agree to a screening schedule.” If you rely on this guide, the discussion of risk includes nothing about the potential harm mammograms can sometimes lead to; only the benefits.

One explanation for this failure to fully inform might be because the authors of the NCCN guidance either deny that overdiagnosis occurs, or don't think it’s that serious. They certainly know about it: Hundreds of research papers have firmly established that it’s a serious problem. So serious, in fact, that scientific panels in France and Switzerland have even suggested phasing out screening mammography altogether, since its life-saving benefits are real but modest (in the U.S., mammography saves between 1 and 2 women per 1,000 screened over 10 years) while the frequency of overdiagnosis and overtreatment leading to real harm is far greater. A recent study of Danish and Norwegian women also found that the harms of overdiagnosis may outweigh the benefits of mammography. The National Breast Cancer Coalition agrees: “Screening mammography of all women has demonstrated only a modest, if any, benefit in reducing breast cancer mortality and is associated with harms that may outweigh those benefits."

A less-benign interpretation would also note that the NCCN consists of institutions that profit from the screening and cancer care they provide. That could also be a part of why many cancer centers promote cancer screening. In fact, some hospitals provide screening free of charge — free screening that generates patients (customers) for those hospitals.

Imbalanced communication about screening that fails to note its risks is not only a problem with breast cancer. Many hospitals aren't informing men about the risks of prostate cancer screening any better than the NCCN does with mammography. A recent review of 607 U.S. cancer centers that recommend prostate cancer screening found that four in ten failed to mention anything about the potential harms of that screening. And one in four failed to suggest that men discuss the pros and cons of screening with their doctors, as recommended by the U.S. Preventive Services Task Force (USPSTF). Major cancer centers accredited by the National Cancer Institute were twice as likely as non-NCI accredited centers to fail to recommend shared decision-making . And eight in ten of all 607 centers also failed to inform men that the USPSTF recommends that testing stop at age 70.

A simpler explanation for all of this may be that society’s emotional relationship with the Emperor of All Maladies has yet to catch up to the progress we’ve made fighting the disease. A cancer diagnosis is no longer the death sentence many still believe it to be. As many as two-thirds of all cancers can now be treated as chronic diseases or cured altogether. Yet two-thirds of Americans, when asked, "What's the first word that comes to mind when you hear the word cancer?” answer "Death."

So we want every tool possible to give ourselves some sense of control against this dreaded threat. Which is why belief in screening is deeper than faith in many religions. Study after study finds that people choose cancer screening even when they are expressly told it’s more likely to harm them than help them. And study after study finds that doctors do the same thing the NCCN has done: Inform patients about the benefits of screening without fully informing them about its risks.

The problem of overdiagnosis of cancer is real, and its cumulative economic and human health costs are enormous. Research for my book due out next year, tentatively titled Rethinking Our Fear of Cancer: How excessive worry about a dread disease does great harm all by itself (in press, Johns Hopkins University Press) estimates that lumpectomies, mastectomies, or double mastectomies for overdiagnosed breast cancer conservatively cost the U.S. health-care system an estimated $2.5 billion. The overtreatment of prostate cancers that would never have caused any harm costs the health care system another $860 million annually.

Individual women considering a mammogram or men thinking about a PSA test don’t care about overall costs to the health care system. They want to know what’s advisable for them, which is what the NCCN booklet and cancer center screening recommendations are supposed to help with. Sadly, people relying on these communications for complete and balanced information to make choices about their health are not getting it. That failure to accurately and fully inform puts people at risk and contributes to significant harm.

David Ropeik is a retired Harvard Instructor, author, consultant, and public speaker on risk perception, risk communication, and risk management.

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Article Contents

Introduction, supplementary data, conflict of interest.

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Factors influencing the decision to attend screening for cancer in the UK: a meta-ethnography of qualitative research

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B Young, L Bedford, D Kendrick, K Vedhara, J F R Robertson, R das Nair, Factors influencing the decision to attend screening for cancer in the UK: a meta-ethnography of qualitative research, Journal of Public Health , Volume 40, Issue 2, June 2018, Pages 315–339, https://doi.org/10.1093/pubmed/fdx026

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This review aimed to better understand experiences of being invited to cancer screening and associated decision-making.

Qualitative evidence explaining UK cancer screening attendance decisions was systematically identified. Data were extracted and meta-ethnography used to identify shared themes, synthesize findings and generate higher level interpretations.

Thirty-four studies met inclusion criteria. They related to uptake of breast, cervical, colorectal, prostate, ovarian and lung cancer screening. Three primary themes emerged from the synthesis. ‘Relationships with the health service’ shaped decisions, influenced by trust, compliance with power, resistance to control or surveillance and perceived failures to meet cultural, religious and language needs. ‘Fear of cancer screening’ was both a motivator and barrier in different ways and to varying degrees. Strategies to negotiate moderate fear levels were evident. ‘Experiences of risk’ included the creation of alternative personal risk discourses and the use of screening as a coping strategy, influenced by disease beliefs and feelings of health and wellness.

The findings highlight the importance of the provider–patient relationship in screening uptake and enrich our understanding of how fear and risk are experienced and negotiated. This knowledge can help promote uptake and improve the effectiveness of cancer screening.

More than 50% of people in the UK born after 1960 will be diagnosed with cancer in their lifetime. 1 In order for screening to be effective in reducing cancer mortality, it is important that uptake is high. National Health Service (NHS) population screening tests for breast, cervical and colorectal cancer have uptake rates of 71%, 2 73% 3 and 52%, 4 respectively in England. Those who do not attend are more likely to be at higher risk; improving uptake is therefore a key public health strategy to reduce health inequalities in outcomes at every stage of the cancer patient pathway. 5 Ethnicity, social deprivation and gender are important determinants of cancer screening uptake. 6 Factors influencing screening uptake identified in quantitative research include practical barriers, such as difficulty making an appointment, forgetting to do so and dependency on others to carry out the activities of daily living. 7 , 8 Psychosocial motivators and barriers, including embarrassment, worry, anxiety and self-efficacy have also been identified. 9 , 10 Interventions to improve uptake targeting structural and system factors, such as invitation and reminder methods, and education have been demonstrated to be effective. 11 – 13

Public debate about communication of the benefits and harms of screening has led to a shift from the objective of maximizing uptake to the promotion of informed uptake. 14 A systematic review of interventions to promote informed choice about health screening found some evidence that greater informed choice does not reduce uptake but this was based on a limited number of studies. 15 A randomized controlled trial of information about overdetection in breast cancer screening found that greater knowledge about the potential harms of screening may reduce intentions to be screened. 16 Higher awareness of the risks of screening could contribute to a decline in the positive social attitudes to cancer screening which have generally been observed. 17 , 18 This highlights the importance of using an exploratory approach to investigate thoughts and experiences of recipients of cancer screening invitations to better understand why a proportion of individuals do not attend when invited.

The aim of this meta-ethnography was to systematically identify and synthesize qualitative evidence which explains cancer screening attendance decisions in the UK.

Eligibility criteria

Studies were eligible for inclusion if they utilized qualitative methodology and included evidence of factors influencing decisions to attend screening for cancer. We limited our search to UK studies because there are international differences in the organization and delivery of screening and a need for uptake strategies to consider health service context and cultural and societal norms. 6 At least one factor must have been described, either by a participant or the author, as having influenced the participant's prior real-life screening attendance decision.

Screening programmes eligible for inclusion were organised population screening and research trials of screening methods. Opportunistic screening, self-examination, second stage screening (e.g. a diagnostic test following an abnormal screen), genetic testing and family history counselling were all ineligible. Reports solely of the views of people other than the screening invitation recipient (e.g. healthcare practitioners) were ineligible. Research which reported screening attendance decisions exclusively in individuals with symptoms of the disease, a previous cancer diagnosis, physical or learning disabilities, or who had experienced sexual abuse were ineligible.

Several data sources were searched (see Supplementary data, Table S1 ), reference lists of included studies were searched for further relevant references and Web of Science was used to search for papers citing the included studies. Search results from each source were combined and duplicates removed. Titles and abstracts were screened for eligibility independently by B.Y. and L.B. A third researcher (R.d.N.) was available to resolve any disagreements. Full text papers were retrieved and the eligibility of each paper for inclusion was assessed by B.Y. and L.B. Papers assessed as eligible were then classified independently by both B.Y. and L.B. according to a typology of findings in qualitative research. 19 This addressed the problem that methodologies stated by qualitative study authors often do not accurately reflect those which are used. The typology outlines five categories which classify study findings as qualitative or not qualitative depending on the degree of data transformation (see Supplementary data, Table S2 ). Studies classified as ‘qualitative findings’ were included and others were excluded.

Study characteristics were extracted from included papers. Quotes and text from papers which met the criteria were extracted into a spreadsheet by B.Y., coded as first- or second-order constructs 20 and as primary or secondary data ( Supplementary data, Fig. S1 ).

Appraisal of included papers was conducted independently by both B.Y. and L.B. using the Critical Appraisal Skills Programme (CASP) tool for qualitative research. 21 The tool has 10 questions which assist in forming a judgement of the validity and value of reports. It was not used to numerically score papers on their quality. By taking into account the CASP tool, typology of findings, conceptual richness and relevance and contribution to the review question, papers were categorized as a key paper, satisfactory paper or fatally flawed. Such an approach allows the value and importance of qualitative studies in answering a research question to be tempered by the validity of the findings. 22 This categorization was used to guide the synthesis, allowing more emphasis to be placed on key papers.

The synthesis of findings involved interpretative analysis using meta-ethnography ( Supplementary data, Fig. S2 ). 23 Included papers were carefully read and the relationships between the concepts arising in the papers considered using a matrix of shared themes. Thematic coding was undertaken, firstly with data extracted from key papers and continued through all included studies. When a new theme was identified, the other papers were reviewed to check for the presence of the theme, forming a cyclical process. Studies were compared and contrasted via an interpretative reading of meaning of conceptual data. Third-order constructs 24 were developed by taking the first- and second-order constructs and analysing them thematically to form a new interpretation.

Summary of included studies

Thirty-six papers reporting 34 different studies were included in a ‘reciprocal synthesis’ 23 (Fig. 1 ). The characteristics and relevant findings of included studies are shown in Table 1 . Twenty-one papers had cancer screening uptake as the main focus of the reports. 25 – 45 The primary focus of other reports included wider knowledge and attitudes to cancer and prevention, 46 – 52 responses to information about screening, 53 – 56 experiences of screening test results 57 , 58 and risk management options which included screening. 59 , 60 Cervical, breast and colorectal cancer accounted for 29 of the 34 studies. Two related to prostate cancer, two to ovarian and one to lung cancer. Five papers were categorized as key papers 32 , 35 , 36 , 42 , 53 and the rest as satisfactory.

PRISMA flowchart.

Characteristics and relevant findings of included studies

a Same study as Armstrong 2005

Evidence synthesis

Three primary themes emerged from the analysis: first, screening attendance decisions were shaped by individuals’ relationships with the health service. Second, fear was a dominant influence on both decisions to attend and to not attend. Third, experiences of risk were expressed throughout the data. Additionally, a range of other factors interacted with these primary themes as described below. The distribution of themes across the 36 papers is shown in the Supplementary data, Table S3 . Illustrative quotes from study participants (P) and authors (A) are provided below and further supporting data excerpts are shown in the Supplementary data, Table S4 . A diagram of third-order constructs and their relationships is shown in Fig. 2 .

Diagram of primary third-order constructs and their relationships.

Relationship with health service

Responses to screening invitations were largely explained in terms of individuals’ relationship with the health service. There was a wide range of levels of trust evident in the data, ranging from those who interpreted the invitation as a command to be obeyed, to those who perceived it as an attempt at control to be resisted. Between these two extremes, individuals cited other aspects of the relationship which influenced their decision.

There was evidence that the NHS is seen as a higher power in the relationship: ‘Many interviewees referred to having a smear test as a “correct” form of behaviour: as the right/correct/proper thing for women to do. Notions of deviance were associated with non-attendance.’(A) 48 Some felt obliged to comply with the ‘system’ in order that they are taken seriously when presenting with other health problems in the future. 41 In this sense, they viewed trust as something to be demonstrated and maintained in both directions in the relationship. In contrast, others felt privileged to be invited to screening 56 and viewed it as the offer of a valuable service at no financial cost to them. 36

Immigrant populations with limited experience of the NHS lacked trust in its services and employees, sometimes opting to be screened in their home country where a stronger relationship existed with the healthcare provider. 40 Language problems inhibited them from asking questions and forming a trusting relationship. 38 There was distrust of interpreters provided by the NHS who were described as unqualified to translate using medical terminology. 44 There were perceptions from ethnic minority groups that screening services did not (or would not) meet their cultural and religious needs. ‘They just make you feel uncomfortable [for requesting a female nurse]. So that is why I don't go, if I got the test I would say no I don't want to go because of this thing.’(P) 25 Associations of cervical screening with promiscuity raised concerns about confidentiality in women who did not trust clinicians and receptionists to meet these needs. 45

Another aspect of the relationship which influenced decisions was the communication flowing from the health service to the individual containing information about screening and the potential harms and benefits. Different levels of knowledge about screening resulted from this information, but in those who did not attend there was often a deficit in knowledge and understanding about screening, which they were not motivated to overcome: ‘Throughout the focus groups the women expressed a lack of awareness about the need for cervical screening, resulting in the women ignoring an invite for cervical screening.’(A) 33 ‘Expressions such as ‘never knew anything about cancer before’; ‘I never knew’; ‘I didn't know what is cancer’ were common.’(A) 50 There were expectations that screening should take place in a clinical setting and that patients are the passive receiver of care from the screening provider. 35 The receipt of home testing kits for colorectal cancer, for example, was interpreted as unusual and impersonal. The detachment of screening from clinical settings was linked to non-uptake: ‘Self-testing at home … undermined the value and relevance of screening.’(A) 35 Invitations endorsed by general practitioners (GPs) carried additional weight and were revered, especially in those holding a biomedical view of the health service relationship in which the medical profession was seen as the sole decision-makers. 25

For women, the relationship with the health service was sometimes not perceived to be strong enough to entertain the prospect of attending screening, during which they would be required to reveal private parts of their body to a stranger. 45 There was a theme of control and surveillance experienced by women, within a discourse from the provider of the female body being a site of risk in need of medical observation, 48 or feelings their bodies were being used to fulfil quotas 45 or achieve other objectives. 55

Fears about cancer screening manifested as both a motivator and barrier to screening attendance. Four key sources of fear were screening invitations, the threat of cancer in the absence of screening, the threat of abnormal test results and screening methods.

The receipt of a cancer screening invitation was experienced as provoking varying levels of fear, often explaining avoidance or delay in participation. Non-attenders described being ‘terrified’ and ‘frightened to death’ by the invitation, 42 leading to a quick decision to not respond. Less extreme experiences of fear were carefully negotiated by talking to others and seeking more information about screening. An incentive to take up screening was anticipation that in doing so fear may be reduced. Fear of developing cancer in the absence of screening was a powerful motivator to attend which facilitated the overcoming of other perceived barriers to screening: ‘Fear appeared to be the main driving force behind the decision to have smear tests.’(A) 48

Implications of an abnormal screening test result were a principal source of fear in the data. This was interpreted as ‘fear of the unknown’ and fear of an inability to cope with a diagnosis and ‘the word cancer’ itself. 42 Fears about screening methods were commonly cited, either from previous experience or from anecdotes heard from others. These were anticipated as leading to other negative emotions including pain, discomfort and embarrassment.

Other sources of fear were the potential social inadequacy in the performance of an unfamiliar event under professional scrutiny, 36 anticipation of having to wait for screening results, a general fear of hospitals and medical procedures 42 and stigma associated with cancer or cancer risk. 50

Experiences of risk

Closely related to the first two themes was that of risk. Individuals were subject to external discourses of risk and also created their own ‘game of chance’. 36 The official discourse on screening from the health service was one which labels individuals as ‘at risk’, non-attenders as at even higher risk and attenders as at lower risk. There was, however, some resistance to this discourse, influenced by themes of beliefs about the disease and current health and wellness. For example, individuals who believed that an absence of symptoms and a feeling of wellness placed them at low risk cited this as a reason for either attending or not attending screening: ‘I'd almost be surprised if I did get it, I don't feel anything.’(P) 43 They felt they had either nothing to gain or nothing to lose by screening. Beliefs were expressed that risk of cancer was reduced by participation in screening. This may be a coping strategy to gain protection from the risk and uncertainty of the threat of cancer. Beliefs about cancer also influenced risk in minority ethnic groups, for example beliefs that talking about cancer or being in close proximity to someone with cancer can put one at risk. 50 This likely represents a culture in which cancer is a taboo subject and is avoided.

Main findings of this study

This meta-ethnography provides an insight into the thoughts and experiences which explained participants’ screening attendance decisions. Three primary themes emerged from the synthesis.

Individuals’ relationship with the health service was the most important factor, influenced by underlying dynamics of trust, power, control and authority. Some were compliant with screening requests, particularly when received from a known source. For example, invitations received from GPs were more trusted than those received from screening hubs. This is consistent with experimental research demonstrating that GP endorsement promotes higher uptake. 61 However, in a society where ever more areas of our lives are under routine surveillance, this synthesis found individuals can be sceptical of the requirement to adhere to a screening regime. Their resistance is interpreted as an attempt to maintain control over their own bodies and their right to decide when they are unwell and need medical attention. 48 A general distrust of those in power is a social dynamic that can include the NHS, which is viewed by some as an extension of the Government. 36

A further demonstration of the level of trust necessary in the relationship was the cultural and language needs which were seen as being unmet. Immigrant groups experience additional barriers due to a lack of familiarity with the NHS and limited knowledge of services. A fundamental aspect to the relationship with the screening provider is the information received and resulting knowledge and understanding. In screening, this communication typically occurs in writing and many of the nuances of communication that could contribute to a trusting relationship are lost. Home visits combined with an educational video have been shown to be particularly effective in promoting screening uptake in hard to reach groups, while written translated materials were ineffective. 62

According to our analysis, ultimately it was the sender's characteristics, rather than the content of the message itself, which were important. Interventions to modify invitation materials to address other barriers may therefore have limited potential to promote uptake beyond that which has already been achieved. 11 , 12 , 63 Improvements in uptake may be achieved by patient-oriented interventions targeting perceptions of the wider health service, rather than screening invitation materials or methods alone. For certain groups, there may be a benefit in including key community figures (e.g. local religious leaders) in communicating the health agenda. An extension of GP involvement in cancer screening could utilize an existing trusted relationship to promote uptake. For example, a banner on the invitation letter indicating endorsement from the patient's GP practice has been shown to increase uptake of colorectal screening. 64 Such interventions could lead to other desirable outcomes as a result of increased levels of trust in the relationship.

There are consistencies with other qualitative syntheses, which report cervical screening as an emotional experience 65 and fear as a barrier in colorectal screening. 66 Our finding of experiences of fear from a number of sources in cancer screening is consistent with patients’ reported experiences of seeking help for cancer symptoms. 67 , 68 The role of fear and its link with cancer worry and perceived susceptibility in cancer screening uptake has received much attention. Fear of a number of aspects of screening, including the hospital setting, pain from screening procedures, test results and their consequences, was strongly associated with non-attendance in a survey. 69 In a colorectal screening trial, desire for screening was higher in people who reported worrying about cancer, but individuals were less likely to attend if they had reported feeling uncomfortable at the thought of cancer. 70 It has been suggested that fear combined with high-efficacy messages promotes health behaviour change and fear with low-efficacy messages creates defensive responses. 71 The importance of response efficacy (the perception that a behaviour will alleviate a threat) in behaviour change has been demonstrated. 72 This relationship between fear and cancer screening attendance is complex and our findings provide an insight into the different ways fear is experienced and interpreted in this context. Specifically, the synthesis supports the theory that very high levels of fear about cancer screening, from sources including screening invitations, the perceived threat of cancer, abnormal test results or the screening methods, can promote avoidance. Some overcame their fear having been persuaded by another person to attend. Increasing familiarity and trust in relation to the health service might have a similar effect in enabling individuals to negotiate moderate levels of fear in deciding to attend screening.

The analysis showed how the experience of being identified as ‘at risk’ by the health service led to some resistance and the creation of alternative explanations based on a range of beliefs about the disease. Evidence shows a moderate level of perceived risk optimizes screening uptake, with high levels leading to avoidance and low levels a lack of motivation. 73 A meta-analysis of a range of behaviours suggests that this relationship between a threat and behaviour holds only when accompanied by high self- and response-efficacy. 74 Our study found individuals create their own perceptions of risk irrespective of the ‘official discourse’ and use screening as a coping strategy.

A better understanding of the complex determinants of uptake could lead to the identification of modifiable psychological variables as targets for intervention. Current screening invitation materials emphasize the recipient's choice in deciding whether or not to take part. To complement this, the perceived control an individual has over other aspects of the process could be promoted. Rather than screening being experienced as a mass surveillance programme in which people are systematically called and recalled by a computer, personalized aspects of screening could be enhanced and the element of individual control emphasized. The aims of ensuring that individuals have the knowledge to decide what they want to do and that they feel the communication is personalized could potentially be achieved in synergy. For example, interactive methods could be used in decision aids which address gaps in knowledge, tailored to individual levels of fear and perceived risk.

Our findings could also help in understanding why certain sociodemographic groups engage less with other health processes, as there may be common barriers generalizable beyond cancer screening. The findings could further contribute to understanding of delays in help-seeking when experiencing cancer symptoms.

What is already known on this topic

There is evidence that ethnic minorities, younger aged and economically deprived groups are less likely to attend cancer screening. Quantitative research has identified some practical and psychosocial factors influencing screening uptake but has not fully explained why a proportion of individuals do not attend. Qualitative studies have reported experiences of cancer screening uptake, focusing on specific groups and types of screening tests. Their findings have not been synthesized in a way that can be integrated with the existing hierarchy of evidence to inform future research, policy and practice.

What this study adds

A synthesis of evidence from a systematic review of qualitative studies has identified important themes which influence cancer screening uptake in the UK. A higher level interpretation of data demonstrated how an individual's relationship with the health service, their fear of cancer screening and their experiences of risk influence their response to a screening invitation. This review makes this important body of evidence more accessible to clinicians, policy-makers and researchers.

Limitations of this study

Reasons for taking part or not taking part in a cancer screening research trial may differ to those for routine NHS screening. As an example, altruistic reasons for participation were particularly evident in trials of ovarian and lung screening methods. 43 , 59 However, the majority of included studies related to NHS cervical, breast and colorectal screening. The studies were published over a wide time frame (1994–2016) and therefore the experiences of participants may not all necessarily reflect the current state of screening in the UK. Recall bias could have influenced the data because participants reported past experiences. Those who are least likely to engage in screening were probably underrepresented in the data since they might be less likely to take part in a research study on the topic.

This synthesis highlights important factors which underpin the uptake of cancer screening. It emphasizes the importance of the provider–patient relationship in promoting informed uptake and enriches our understanding of how fear and risk are experienced and negotiated in the screening attendance decision. Further research should use quantitative methods to explore in which groups the barriers identified are prevalent and the extent to which they are experienced. The qualitative literature could be examined further to draw out differences between screening programmes and population subgroups. Interventions could be piloted to promote a perception of personalized care, improved trust in the health service and prevent extreme levels of fear and perceived risk. As cancer screening invitations change in the future, due to the use of new screening methods and the growth in importance of concepts such as informed choice and risk stratification, there will be a continuing need to explore experiences of being invited to cancer screening.

Supplementary data are available at Journal of Public Health online.

This work received no specific grant from any funding agency.

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

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Questions Swirl Around Screening for Multiple Cancers With a Single Blood Test

• Review Assessing the Clinical Utility of Liquid Biopsies David J. Carr, MD; H. Gilbert Welch, MD, MPH JAMA Internal Medicine

It sounds almost too good to be true: a single blood test that can detect 50 different cancers or more before any symptoms appear.

But this is not science fiction. At least 2 multicancer detection (MCD) blood tests, also called multicancer early detection tests, are already on the US market, and many more are in development.

Such tests are designed to detect circulating tumor cells, cell-free tumor DNA, proteins, and other biomarkers that suggest cancer might be present somewhere in the body. However, what the results of MCD tests mean and how they should be used is not yet clear.

Cancer is the leading cause of death worldwide and is second only to heart disease in the US . Only 5 cancers—colorectal, lung, breast, cervical, and prostate—have recommended screening methods, at least for some populations. Malignancies that lack population screening methods are expected to account for about half of new cancer diagnoses this year, according to the American Cancer Society.

Interest in a multicancer screening test that could detect many of the approximately 200 other types of malignancies at an early stage is booming among consumers, policymakers, lawmakers, physicians, and scientists.

“Like anything in medicine, there are a lot of unknowns, but I think this is incredibly exciting,” gastroenterologist Anne Marie Lennon, MD, PhD, who recently became chair of medicine at the University of Pittsburgh Medical Center, said of MCD tests. Lennon previously was on the faculty at Johns Hopkins, where she codeveloped an MCD test that isn’t yet on the market.

The assays are meant to complement available screening for common cancers, not replace it. And as their developers emphasize, MCD tests don’t diagnose cancer. As with conventional cancer screening methods, a positive MCD test identifies individuals who need further evaluation to determine whether they have cancer, while a negative MCD test doesn’t necessarily mean cancer isn’t lurking somewhere.

“From the consumer perspective, these [MCD] tests are going to be very attractive,” Robert Volk, PhD, a decision scientist at the MD Anderson Cancer Center, told JAMA in an interview. “It’s a single blood test. It’s easy to do.”

Drawing a tube of blood may be easy. What comes after that is not.

“It’s safe to say that the technology is not well enough developed to be marketed,” Ruth Etzioni, PhD, a biostatistician at the Fred Hutchinson Cancer Center’s Public Health Sciences Division, said in an interview.

In fact, the 2 tests that have been commercialized in the US have not yet been approved or cleared by the US Food and Drug Administration (FDA). They are marketed as laboratory developed tests (LDTs), a category over which the FDA has exercised enforcement discretion for nearly half a century. The agency hasn’t enforced applicable regulatory requirements, specifically the demonstration of safety and effectiveness, for the majority of LDTs. Most laboratories that offer LDTs follow only the regulatory requirements of the Clinical Laboratory Improvement Amendments , which are intended to regulate their operations but not their tests.

“While these tests have the potential to improve care in selected indications, this must be proven, as they will add cost, complexity, and unintended adverse effects for patients,” concluded a recent JAMA Internal Medicine  review article about the use of tests to detect tumor DNA in a variety of situations, including MCD tests for population screening.

The Galleri MCD assay has not yet been greenlighted by the FDA, but more than 150 000 tests have been sold in the US and Canada since its commercial launch 2 years ago, according to Grail, the Menlo Park, California, company that developed and markets it. The company has also partnered with HCA Healthcare , the largest US health system, which is providing the Grail MCD test at select physician practices. In addition, Grail has established a network of more than 9000 prescribers in private practice across the US.

“[T]his is an opportunity to be at the forefront of a new age of cancer screening,” Chris Ott, MD, chief medical officer at HCA Healthcare Physician Services, said in a Grail press release last October.

However, there is still much uncertainty about the harms and benefits of MCD tests, suggesting that the forefront might not necessarily be the best place to be. Do MCD tests lead to improved cancer prognoses? Do they uncover tumors that were better left undetected? And do they cause unnecessary anxiety or provide false reassurance?

Setting the Stage

At least 3 MCD tests have a head start toward FDA approval or clearance.

The agency has designated the Grail test as well as MCD tests developed by Geneseeq , a Canadian company, and Burning Rock , based in Irving, California, as breakthrough devices , according to the companies. As the FDA puts it, breakthrough devices “provide for more effective treatments or diagnosis of life-threatening or irreversibly debilitating diseases or conditions,” justifying priority review by the agency.

The Gaithersburg, Maryland, company, 20/20 GeneSystems, that makes OneTest, the other MCD test available to buy in the US market, does not plan to seek FDA approval until it collects real-world data about its accuracy in detecting cancer from a statistically significant number of people, according to its website.

Last November, the FDA convened a meeting of the Molecular and Clinical Genetics Panel of its Medical Devices Advisory Committee to make recommendations on the design of MCD tests, including what end points could help assess probable risks and benefits.

And MCD tests are a major focus of the new Cancer Screening Research Network launched by the National Cancer Institute (NCI) in January of this year.

“The Cancer Screening Research Network is geared toward studying a variety of different technologies for the purpose of cancer screening,” oncologist Lori Minasian, MD, deputy director of the NCI’s Division of Cancer Prevention, explained in an interview. “Not every cancer sheds into the blood. There are some cancers that could be detected better in urine or sputum or breathalyzers.”

One of the first projects of the network, a central component of the Biden administration’s Cancer Moonshot , is the Vanguard study . This year, the study will begin enrolling 24 000 people aged 45 to 70 years to test 2 MCD assays and help lay the groundwork for a much larger randomized trial.

Vanguard will not be comparing the tests with each other, Minasian noted. “We’re not expecting a winner,” she said. “We’re expecting to better understand how to use these assays.”

Minasian said she couldn’t yet discuss which MCD assays will be tested in Vanguard. In interviews with JAMA , 20/20 GeneSystems Chief Executive Officer Jonathan Cohen said his company hopes that its test will be selected for Vanguard, while Grail President Joshua Ofman, MD, MSHS, said his company isn’t interested in participating. “We have so much more data already,” Ofman explained.

The 20/20 GeneSystems MCD test was developed using data from Taiwan, Chief Science Officer Michael Lebowitz, PhD, said in an interview. Physicians in that country have been offering tumor marker testing as part of annual physical examinations for a few years, Lebowitz said, and his company has had access to a database of information about the testing in 27 000 individuals.

Real-world data might not be enough to earn the FDA’s blessings, though. At last November’s FDA advisory committee meeting, panelists concluded that real-world data and evidence should be used to support clinical validation of MCD tests only in select situations, such as postmarket settings. Instead, the panelists advised that randomized trials be conducted to validate MCD tests.

At press time, the Grail test, which claims to detect more than 50 cancers, cost $949. The standard 20/20 GeneSystems test, which claims to detect more than 20 cancers, costs $189; a premium version, which tests for additional biomarkers, was available for $269; shipping for either 20/20 GeneSystems test was an additional $29.99.

Currently, neither public nor private insurance plans pay for MCD tests. Medicare covers screening tests only if the US Preventive Services Task Force recommends them with a grade “A” or grade “B,” which isn’t the case for either of the tests on the market. “Right now the evidence is nowhere near supporting a grade ‘A’ or grade ‘B’ recommendation” for MCD tests, Volk noted.

That issue might become moot. Legislation with broad bipartisan support has been introduced in the Senate and the House of Representatives that would give Medicare more leeway in covering MCD tests. The bills would authorize the federal insurance program for people aged 65 years or older to begin covering annual MCD tests as soon as the FDA approves or clears them, without waiting for the task force to deem them worthy.

Meanwhile, Grail announced last November that it is teaming with the Centers for Medicare & Medicaid Services to conduct a real-world study of the clinical impact of its test in as many as 50 000 Medicare beneficiaries. Medicare will cover the cost of the test and related and routine services for study participants, according to Grail. Trial participants will be compared with matched beneficiaries who received usual care but no testing.

Shifting the Stage

Research has shown that the recommended population cancer screening tests reduce mortality.

But no studies have been conducted to determine whether MCD tests lower cancer deaths. “We always have this mantra: it’s got to show that it reduces cancer mortality,” Etzioni, a member of the American Cancer Society’s panel on cancer early detection, said of cancer screening.

Developers argue that clinical trials with a mortality end point would be impractical. Such studies would require 15 to 20 years and a million participants to answer that question, Grail’s Ofman estimated. By the time such trials ended, he noted, the technology they evaluated would be obsolete.

That kind of thinking doesn’t sit well with Philip Castle, PhD, MPH, director of the NCI’s Division of Cancer Prevention and a member of the FDA’s Medical Devices Advisory Committee.

After all, the reason to screen is to reduce cancer incidence or cancer-related mortality, Castle pointed out at last November’s advisory committee meeting about MCD tests. “[W]e believe that mortality has to be the end point—cancer-specific mortality,” he told his fellow panelists, who did not all agree. “And for many cancers, there is not a proven surrogate end point that has been shown to correlate with mortality benefit.”

Castle’s colleague Minasian was more optimistic that questions about MCD tests’ harms and benefits could be answered with shorter-term outcomes. “If we design the studies well…there will be an opportunity to look at markers that could be used for surrogates for mortality,” she told JAMA .

Ofman and others have proposed that demonstrating MCD tests lead to earlier-stage cancer diagnoses is a reasonable surrogate for mortality. Earlier diagnosis alone benefits patients because it affords a better quality of life and less toxic therapies, Ofman said.

“Insisting on definitive proof of mortality benefit may have deadly consequences,” 20/20 GeneSystems’ Cohen said. “Many Americans may die unnecessarily.”

In an August 2023 article , a group of authors with financial ties to Grail or other MCD test developers called for more efficient randomized trials. These trials would possibly have “alternative primary endpoints to complement cancer mortality…so that populations can benefit sooner if such tests are shown to be effective,” they wrote.

Grail has organized and is funding a trial with the UK’s National Health Service (NHS) to determine whether its test leads to earlier cancer diagnoses. Over just 10 months in 2021 and 2022, Ofman noted, the trial reached its goal of enrolling more than 140 000 people aged 50 to 77 years. Those randomized to screening will receive the Grail test annually for 3 consecutive years. Grail is supplying the tests, while the NHS is providing follow-up care when needed.

Results won’t be known for a couple more years, at which point Grail will make its final submission to the FDA to support its application for approval, Ofman said. The NHS has said that it is committed to buying up to 1 million Grail tests if the initial trial results are promising. However, the health service hasn’t explained how it would define promising results.

In the public hearing portion of the November FDA meeting, Etzioni noted that earlier detection doesn’t always translate to reduced cancer mortality.

She pointed to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which enrolled approximately 202 000 postmenopausal women from the general population. Like previous ovarian cancer trials, UKCTOCS used a combination of the biomarker CA-125 in blood and transvaginal ultrasound. Participants were randomly assigned to annual CA-125 screening with transvaginal ultrasound as a second-line test, annual transvaginal ultrasound alone, or no screening.

After an average follow-up period of 11 years, no significant reduction in ovarian cancer mortality rates was seen in either of the screened groups compared with the no-screening group, the researchers reported in 2021.

“We need a screening strategy that can detect ovarian and tubal cancer in asymptomatic women even earlier in its course and in a larger proportion of women than the tests used in the trial,” the authors concluded. “Meanwhile, our results emphasize the importance of having ovarian and tubal cancer mortality as the primary outcome in screening trials.”

Experience is lacking in the use of downstaging—detecting cancers at an earlier stage—as an end point in screening trials, Etzioni said. “It’s not known how much of a reduction in late-stage cancers is enough to make a difference in cancer mortality rates,” she explained. In 2022, Etzioni coauthored a modeling study that concluded that stage shift appeared to be an unreliable predictor of mortality reduction for all the cancers that could be detected with MCD tests.

When Grail reports the findings of its UK trial, “there could be very positive headlines that there was a 10% reduction in advanced stage cancers,” Etzioni noted. “We really don’t know what that means. We don’t even know whether to call that a success or not.”

Positive or Negative—Now What?

Neither Grail nor 20/20 GeneSystems will ship their tests to consumers without a physician’s order. However, both companies make it simple to get tested without ever stepping into a clinician’s office.

They provide links on their websites to connect consumers to telemedicine prescribers and laboratories or urgent care centers where they can have blood drawn.

But a positive MCD test result “is the beginning, not the end,” Minasian emphasized. “One of the questions that we have been thinking through is what do you do with that positive test?” No research on that question has bet been published, she noted.

The Grail test assesses methylation patterns in cell-free DNA with the use of machine learning. Cancer cells have different methylation patterns than normal cells. The result is presented as a simple yes or no: either a cancer signal was detected, or it wasn’t. If a signal was detected, Grail has developed algorithms to narrow down its origin to a particular part of the body, such as the abdomen.

In a pilot study conducted in a US convenience sample of around 6700 people aged 50 years or older, the Grail test identified a cancer signal in 1.4% of participants, and 0.5%, or 1 in every 200 tested, were found to have cancer. The test’s first or second cancer signal origin prediction was accurate 97% of the time. However, 52% of the cancers detected were stage III or stage IV, not the early-stage tumors that MCD tests aim to find.

The 20/20 GeneSystems test looks for a handful of older cancer biomarkers, including the prostate-specific antigen (PSA) and cancer antigen 125 ( CA-125 ), which is not currently recommended for population screening. For $80, the test’s premium version adds 5 more biomarkers, including C-reactive protein, which is typically used to monitor inflammation in such conditions as infections, asthma, and autoimmune diseases, and CA 15-3, most commonly used to monitor metastatic breast cancer during therapy. The 20/20 GeneSystems test results are presented as the risk of cancer in the next 12 months.

“The biggest challenge is that these assays are looking at multiple different kinds of cancers,” Minasian pointed out. “You’re not looking at apples and oranges. You’re looking at apples, tomatoes, grapes, peas. They don’t behave the same way.”

And the tests alone can’t precisely pinpoint where in the produce section a cancer might be located, if it’s even present at all. That’s one reason Etzioni worries that a positive test result could lead to “a diagnostic odyssey.”

“My main concern is we might have an issue where the imaging test hasn’t caught up to the cancer test,” making it difficult to resolve the meaning of a positive result, Etzioni said. “If we’re going to take on these tests, we also have to understand imaging better than we do.”

CancerSEEK, an MCD test developed by Lennon and Johns Hopkins colleagues and acquired in 2021 by Exact Sciences Corporation, uses full-body positron emission tomography–computed tomography (PET-CT) scans to follow up on positive test results. “You really need to know where the cancers are,” Lennon said. “What is the quickest, least invasive, most cost-effective way of finding them?”

In 2020, she and her collaborators published the results of what they said was the first large prospective interventional clinical trial to evaluate an MCD test. The researchers incorporated an early version of their MCD test into the routine clinical care of 10 000 women with no history of cancer. In 26 of the women, 9 different types of cancer, including ovarian and uterine, were first detected by the MCD test. Fifteen of them underwent PET-CT imaging; the other 11 developed signs or symptoms that led to other types of imaging. Seventeen of the 26 had localized or regional disease.

The researchers extracted information from electronic medical records through November 2022 for an observational study of the longer-term health status of the 26 study participants with cancer first detected by the MCD test. After receiving treatment, half of them remained cancer free for an average of more than 4 years from their initial screening; 9 patients, all diagnosed at stage III or stage IV, were deceased, according to the study, presented last May in a poster session at the 2023 American Society of Clinical Oncology General Meeting.

Best to Let Sleeping Tumors Lie?

One concern is that MCD tests might detect slow-growing tumors that people would die with, not of, leading to unnecessary treatment and anxiety.

Neurosurgeon Daniel Orringer, of the New York University Grossman School of Medicine, compared the MCD tests with increasingly popular whole-body MRI scans , which can detect incidental cancers that never would have harmed a patient. Orringer coauthored a “ discovery study ” published last September about an MCD test that uses spectroscopy and machine learning algorithms to detect cancer. The test was developed by Dxcover , a company in Glasgow.

“Those whole-body MRI scans are detecting all kinds of lesions that are subclinical and asymptomatic,” he explained in an interview. Such findings leave physicians and patients scratching their heads, Orringer said. “Okay, what do we do with it?”

Physicians should approach MCD test findings the same way they approach whole-body MRI findings, he noted. “Something that we teach our residents and medical students: we treat the patient and not the scan. We’re going to treat the patient, and we’re not going to treat the result from a mail away test.”

Ofman, however, called the notion that MCD tests are likely to pick up tumors that never would have caused harm a misconception. “Slow-growing tumors that are unlikely to kill people are the same tumors that are not shedding into the blood,” Ofman explained.

MCD tests are “tuned” to be highly specific to reduce the risk of false-positive results, Etzioni noted. But these do still occur.

What if the Grail test detects a cancer signal that it predicts is coming from the ovary but nothing is seen on imaging? “The doctor may say, ‘It’s a false-positive, come back next year for a repeat Galleri test,’” Ofman explained. Or, he said, the physician might recommend repeating the imaging in 3 months. A third option would be retesting in 3 to 6 months, which Grail will provide for free, Ofman said.

The tests’ high specificity comes at a cost of sensitivity. “They are not informative if they’re negative,” Etzioni pointed out. “That’s because the tests haven’t been designed to rule out cancer. They’ve only been designed to rule in cancer.” She cautioned that “if you have a negative test you may be falsely reassured.”

Not Taught in Medical School

Physicians may be fielding questions from patients—perhaps after they saw a 20/20 GeneSystems ad in their Facebook feed—about whether they should get an MCD test.

“We are concerned that physicians don’t fully understand how to use these tests,” Minasian said. “Patients don’t understand the risks and benefits because they haven’t been systematically qualified.”

Both Grail and 20/20 GeneSystems say they offer support to physicians. Grail Chief Executive Officer Bob Ragusa noted in a January blog post that his company offers clinicians access to a cohort of physicians with experience with its MCD test, including experts from NCI-Designated Cancer Centers. Grail also operates an “early cancer detection board” with third-party experts who can consult on challenging cases.

On its website , 20/20 GeneSystems offers to connect US physicians with questions about its test with physicians in East Asia who are more familiar with using biomarkers for cancer screening.

Still, at MD Anderson, “What I hear from my clinical colleagues is a great deal of concern,” Volk said. “Who’s appropriate for these tests? When should these tests be done? How often should they be done?”

Volk said he’s particularly interested in the challenges that primary care physicians face when patients ask whether they should get an MCD test. He coauthored an article last April that detailed “core concepts for clinicians to share with patients,” most of which emphasized all the unknowns about the tests.

“It’s safe to assume that primary care clinicians are not ready to have those kinds of conversations,” Volk said. And as for patients who are curious about taking an MCD test, “We just don’t know at this time if this is a good idea or not.”

Published Online: March 15, 2024. doi:10.1001/jama.2024.1018

Conflict of Interest Disclosures: Dr Lennon reported that under a license agreement between Exact Sciences and the Johns Hopkins University, she and the school are entitled to royalty distributions associated with CancerSEEK technology; she also reported serving as a consultant for Exact Science. Dr Volk reported receiving research funding from the American Cancer Society (ACS); the Cancer Prevention and Research Institute of Texas; the National Cancer Institute; the National Heart, Lung, and Blood Institute; and the Patient-Centered Outcomes Research Institute and serving as coleader of the ACS National Lung Cancer Roundtable Shared Decision-Making Task Group. Dr Etzioni reported owning stock in Seno Medical, a privately held medical imaging company, and serving on the American Urology Association’s panel that issued the most recent prostate cancer screening guidelines. No other disclosures were reported.

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Rubin R. Questions Swirl Around Screening for Multiple Cancers With a Single Blood Test. JAMA. Published online March 15, 2024. doi:10.1001/jama.2024.1018

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Advances and Applications of Cancer Organoids in Drug Screening and Personalized Medicine

• Published: 27 March 2024

Cite this article

• Yujia Yang 1 , 2 ,
• Yajie Kong 1 , 2 ,
• Jinlei Cui 3 ,
• Yu Hou 1 , 2 ,
• Zhanjing Gu 1 , 2 &
• Cuiqing Ma   ORCID: orcid.org/0000-0001-9021-7040 1 , 2 , 3  

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In recent years, the rapid emergence of 3D organoid technology has garnered significant attention from researchers. These miniature models accurately replicate the structure and function of human tissues and organs, offering more physiologically relevant platforms for cancer research. These intricate 3D structures not only serve as promising models for studying human cancer, but also significantly contribute to the advancement of various potential applications in the field of cancer research. To date, organoids have been efficiently constructed from both normal and malignant tissues originating from patients. Using such bioengineering platforms, simulations of infections and cancer processes, mutations and carcinogenesis can be achieved, and organoid technology is also expected to facilitate drug testing and personalized therapies. In conclusion, regenerative medicine has the potential to enhance organoid technology and current transplantation treatments by utilizing genetically identical healthy organoids as substitutes for irreversibly deteriorating diseased organs. This review explored the evolution of cancer organoids and emphasized the significant role these models play in fundamental research and the advancement of personalized medicine in oncology.

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Organoid technology and applications in cancer research

Hanxiao Xu, Xiaodong Lyu, … Kongming Wu

The role of organoids in cancer research

Zhen Fang, Peijuan Li, … Leping Li

Organoids in cancer research

Jarno Drost & Hans Clevers

Data Availability

All required data included in text and supplementary. Any further any formation required is available with the corresponding author.

Code Availability

All required code included in text and supplementary.

Abbreviations

Microraft array

High-content screening

Cystic fibrosis

Embryonic stem cells

Induced pluripotent stem cells

Retinoblastoma

Pluripotent stem cells

Human pluripotent stem cells

S-adenosylmethionine

Paraxial mesoderm

Window-of-implantation

Colorectal cancer

Patient-derived organoids

Ovarian cancer

High-grade serous ovarian cancer

Pancreatic ductal adenocarcinoma

Protein arginine methyltransferase gene 5

Patient-derived xenografts

Diagnostic leukapheresis

Circulating tumor cell

Non-small cell lung cancer

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Acknowledgements

This work was supported by Hebei Medical University and funded by National Natural Science Foundation of China (No. 81971474, 8197061369 and 82201953), General Program of China Postdoctoral Science Foundation (No. 2021M701036), Hebei Key R&D Program Project Special Project for the Construction of Beijing-Tianjin-Hebei Collaborative Innovation Community (No. 22347702D), and Key Project of Natural Science Foundation of Hebei Province (C2021206011).

The work was supported by grants from the National Natural Science Foundation of China (No. 81971474, 8197061369 and 82201953), General Program of China Postdoctoral Science Foundation (No. 2021M701036), Hebei Key R&D Program Project Special Project for the Construction of Beijing-Tianjin-Hebei Collaborative Innovation Community (No. 22347702D), and Key Project of Natural Science Foundation of Hebei Province (C2021206011).

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Yujia Yang, Yajie Kong, Yu Hou, Zhanjing Gu & Cuiqing Ma

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Yang, Y., Kong, Y., Cui, J. et al. Advances and Applications of Cancer Organoids in Drug Screening and Personalized Medicine. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10714-6

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Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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The right way to talk with someone who has cancer

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Holidays and family celebrations are a joyous occasion for most people. But for someone with  cancer  or other serious illness, they can be a time of overwhelming anxiety and fear. And as family and friends get together, it's important to show that you care without coming across as insensitive.

Watch this "Mayo Clinic Minute" video to hear Lynne Vitagliano, a clinical social worker at Mayo Clinic, offer some helpful advice to make those uncomfortable conversations less awkward:

Many times, people mean well but don't know the right things to say to someone with cancer.

"Every person is different. So it would be hard to say that there's any one right question to ask or right thing to say. What I think is most important is to convey genuine care and concern," says Vitagliano. "Offer an invitation rather than a question. So to say something along the lines of, 'I've been thinking of you. I know a lot is going on in your life. I'm here if you'd like to talk.'"

Vitagliano says it's also important how you respond. And the best response is simply listening.

"Allow them to talk about their experience without feeling the need to kind of jump in with your own advice or suggestions," she says.

And it's important to show that you care without coming across as insensitive.

"We want to say something that we think is supportive. So we say, 'I'm sure it'll all turn out OK.' Well, we don't know that, and that's not necessarily true. And so, by saying that, it almost invalidates what they've shared with us," Vitagliano says. "It's not as supportive as saying, 'Wow, you've been through so much this year. And I'm just blown away by your strength. What can I do to help?'"

A version of this article was originally published on the Mayo Clinic News Network .

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