Accelerating progress to reduce the cancer burden through prevention and control in the United States

Abstract

Improvements in cancer prevention and control are poised to be main contributors in reducing the burden of cancer in the United States. We quantify top opportunities to accelerate progress using projected life-years gained and deaths averted as measures. We project that over the next 25 years, realistic gains from tobacco control can contribute 0.4-17 million additional life-years gained per intervention and 8.4 million additional life-years gained from improving uptake of screening programs over the lifetime of 25 annual cohorts. Additional opportunities include addressing modifiable risk factors (excess weight, alcohol consumption), improving methods to prevent or treat oncogenic infections, and reducing cancer health disparities. Investment is needed in the pipeline of new preventive agents and technologies for early detection to continue progress. There is also a need for additional research to improve the access to and uptake of existing and emerging interventions for cancer prevention and control and to address health disparities. These gains are undeniably within our power to realize for the US population.

In the reignited Cancer Moonshot, President Biden set inspirational goals to cut the age-adjusted cancer death rate in half in the next 25 years, reduce cancer disparities, and improve the experience of people and their families living with and surviving cancer, and by doing so, end cancer as we know it (1). How can this be achieved?

Cancer deaths can be averted by preventing cancer (ie, reducing incidence) or by earlier diagnosis and more effective treatment and survivorship care (ie, improving survival). Over the past 2 decades, the rate of new cases of cancer has declined after adjusting for the aging population. The 5-year survival following a cancer diagnosis has also improved. Taken together, there has been a decline in cancer mortality rates of approximately 28% over the past 20 years. Despite these advances, progress must be accelerated to reach the Cancer Moonshot goal by 2043 (2).

It is probably overly optimistic to assume that current trends in declining cancer incidence and mortality rates will continue. For example, the greatest gains in tobacco control have likely already been realized, although the long lag time means past efforts will impact cancer mortality into the future. In addition, new risks—such as increases in excess weight and alcohol consumption, changes in environmental hazards from climate change, and increases in early onset cancers—may offset progress in cancer prevention and control. Successfully navigating the future will require knowledge of new trends and forces, capacity to build on current and new insights, and innovative strategies to address these challenges.

Cancer prevention and control is poised to have a major role in reducing the US burden of cancer over the next 25 years. Basic epidemiological and biological research to understand the underlying etiology of cancer has identified numerous risk factors for cancer, many of which are modifiable. In the United States, approximately 45% of cancer deaths are attributable to 16 known modifiable risk factors (3). Cancer screening identifies those with a cancer precursor or cancer before signs or symptoms appear, potentially preventing cancer onset (interception) or diagnosing it at a clinically meaningful earlier stage (early detection). Uptake of existing screening strategies is suboptimal, and disparities exist in access to and use of these services including follow-up care. The capacity for cancer health-care delivery research and implementation science (4) has expanded to provide tools to address these challenges. In addition, novel screening modalities might expand the range of cancer sites that could be detected through screening or enable broader participation in screening programs. Finally, as suggested by Fineberg (5), novel policy strategies such as paying health-care providers and patients to participate in preventive services could increase their uptake.

Recent insights have paved the way for innovative research on interventions designed to address and reduce known health disparities. Cancer health disparities have been identified and characterized through surveillance and epidemiological research. Individuals in groups that experience any cancer health disparities are more likely to experience multiple health disparities (ie, be exposed to the harmful effects of smoking, alcohol consumption, overweight or obesity, poor diet, limited physical exercise, and environmental carcinogens) and to be marginalized and underserved in the US health-care system. A recent study highlighted the economic burden of health disparities in the United States (6).

We can now leverage this foundation of knowledge, capacity, and opportunity to accelerate progress and realize the promise of current and emerging opportunities to reduce cancer and cancer-related mortality risk. While the cancer control continuum spans all components of cancer care from prevention to survivorship, here we focus particular attention on aspects of cancer prevention and control that reduce cancer risk and incidence. We discuss the present trends and opportunities for the greatest impact over the 25 years from 2021 to 2045, and we describe long-term investments that are needed to achieve greater impact beyond 2045.

Opportunities to reduce the burden of cancer by reducing cancer risk and incidence

Reduce exposure to modifiable risk factors

Tobacco

Tobacco use continues to be the greatest contributor to cancer deaths despite decades of efforts in tobacco control. Over approximately 50 years, from 1964 to 2012, tobacco control produced 157 million life-years gained from all causes (7), and 800 000 lung cancer deaths averted from 1975 to 2000 (8). Smoking still causes 30% of cancer deaths (3). Nearly 40% of smoking-attributable deaths from all causes are due to cancer (9). Five-year relative survival for lung cancer remained below 16% between 1975 and 2003 indicating few treatment advances.

Past efforts in tobacco control will produce an estimated 73.5 million life-years gained and 4.1 million lung cancer deaths averted over the next 25 years (10) (Supplementary Material, available online). Additional gains from future efforts can be estimated using the Tobacco Control Policy tool (tobaccopolicyeffects.org). For instance, increasing cigarette taxes by $1.00 could produce an additional 174 000 deaths averted and 3.3 million life-years gained from all causes by 2045 (Table 1), if it is reasonable to assume that the future impact of a policy change can be estimated by the past impact.

Table 1.

Deaths averted and life-years gained for tobacco control policies initiated in 2021 and effects through 2045 for the entire adult US population and including all causes of death

Tobacco control intervention	Assumption	Deaths averted (all causes)	Life-years gained (all causes)
Raise cigarette taxesa	Increase by $1.00 from a current average of $6.50 to $7.50 per pack	174 411	3.3 million
Increase smoke-free air lawsa	Increase coverage from 75% to 100% in workspaces, restaurants, and bars	68 579	1.4 million
Increase tobacco control expendituresa	Increase annual expenditures from 20% to 40% of the amount recommended by the Centers for Disease Control and Prevention (approximately $3.3 billion)	27 532	500 000
Add graphic health warningsa	Reduce smoking initiation by 5% and increase smoking cessation by 25%	75 877	400 000
Food and Drug Administration proposed rule on menthol	Rule implemented	650 000	11 million (15)
Food and Drug Administration proposed rule on nicotine standard	Rule implemented	1.7 million	17 million (17)

^aWe used the Tobacco Control Policy tool (tobaccopolicyeffects.org) to estimate the projected impact of specific tobacco control policies for the entire adult US population beginning in 2021 through 2045. Results from each policy were modeled individually, not in combination with each other. Other model assumptions were not modifiable by the user and are described on the website.

Changes to public policy are effective in tobacco control (11). The US Food and Drug Administration, which is authorized within the United States to regulate tobacco products, is considering 2 proposed rules: prohibition of menthol as a characterizing flavor in cigarettes (12) and reducing nicotine levels in cigarettes to nonaddictive levels (13). Menthol may increase cancer risk by easing inhalation of smoke and encouraging people to smoke more frequently. In other jurisdictions with a menthol flavor ban, 24% smokers successfully quit their use of tobacco products (14). A menthol ban could translate to an additional 11 million life-years gained from all causes by 2060 (15), with 4 million life-years gained from all causes among the non-Hispanic Black population (16). The US Food and Drug Administration has delayed a final decision on a menthol flavor ban. Apelberg et al. (17) estimated a median of 17 million additional life-years gained from all causes from a policy to reduce nicotine in combustible tobacco products to nonaddictive levels (17).

These statistics compare favorably with estimates from research on cancer treatment. The National Cancer Institute’s National Clinical Trials Network treatment studies produced 14.2 million life-years gained from 1980 to 2020 and projected an additional 10 million life-years gained by 2030 (18).

Excess weight

Another major modifiable risk factor is excess body weight. Excess weight currently accounts for 7.8% of cancer deaths (3), however, the attributable fraction will increase as the population prevalence of excess weight increases. The prevalence of excess weight (19) is more than 50% of the US adult population, and minoritized groups are disproportionately impacted, especially non-Hispanic Black adults and low-income adults. Obesity is associated with 13 cancers (20). Sustained reduction in weight can reduce cancer risk within 10 years (21).

A study from the United Kingdom estimated that excess body weight could have the largest population attributable fraction for cancer as soon as 2043 for women (22). In the US population, excess weight causes nearly one-half million excess deaths from all causes per year, and a loss in life expectancy of more than 2 years (23). Lessons from tobacco control suggest that we need societal and system strategies to support individual-level behavior change, focus on industry influences and messaging, and address behaviors when habits form in youth and young adults.

There is limited evidence that increased cancer risks can be reversed by reducing excess weight. For instance, bariatric surgery for weight loss reduces the risk of cancer (24-26). Observational studies show that sustained reduction in weight and increases in physical activity (27) reduce cancer risk (21). Weight-loss pharmaceuticals, incretin mimetics (eg, glucagon-like peptide-1), reduce weight (28) in those with type 2 diabetes and those with chronic obesity. However, there is not sufficient experience in nondiabetic individuals to determine the impact on cancer risk. Individuals regain weight after stopping treatment (29), so treatment may need to continue long term or be combined with behavioral modification. Finally, high treatment cost and coverage policies that are inconsistent and opaque may lead to health disparities (30,31). Further evidence is needed to understand if, how, and for whom these drugs reduce cancer risks.

Alcohol

Alcohol consumption accounts for 5.6% of cancer deaths (3). The prevalence of alcohol consumption (32) is more than 50% of the adult US population. Alcohol is associated with at least 5 types of cancer, and there is a dose response with increased risk of cancer with higher levels of alcohol consumption. Sustained cessation or reduction in alcohol consumption reduces risk after 5 years (33) for oral cancer and esophageal cancer, with limited or inadequate evidence for other cancer sites.

Per capita alcohol consumption in the United States has increased since 1995 and rose sharply in 2020 (34). “Best buys” for alcohol control strategies include increasing taxes on alcoholic beverages, reducing alcoholic beverage availability, and restricting promotion of alcoholic products (35). Approximately one-half of US adults are unaware of the relationship between alcohol consumption and cancer risk (36). Going forward, we must address awareness and social norms about alcohol consumption as part of a comprehensive approach.

Oncogenic infections

Infections by human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV and human herpesvirus-8, and Helicobacter pylori account for 2.7% of deaths (3). Several advances have reduced cancer incidence, including vaccines (for HPV and HBV), antiviral treatment (for HCV and HIV and human herpesvirus-8), and antibiotics (for H. pylori). Uptake of available vaccinations, preventive therapy, or treatment for oncogenic infections is suboptimal (Table 2). Despite the long latency period from initial infection to cancer, it is possible to impact cancer mortality within 25 years. For instance, H. pylori treatment reduces risk of gastric cancer within 8 years (37). Among HIV-infected homosexual men treated with combination antiretroviral therapy, the median latency period before developing Kaposi sarcoma was 6.5 years (38), indicating that it is possible to impact cancer mortality within 25 years.

Table 2.

Current uptake of preventive interventions that reduce cancer risk from oncogenic infections

Infectious agent	Associated cancer(s)	Intervention	Current uptake	Annual number of cancer cases	Population attributable fractiona (3)
Human immunodeficiency virus/human herpesvirus-8	Kaposi sarcoma	Pre-exposure prophylaxis (with highly active antiretroviral therapy)	30.1% (87)	901	76.5%
Human papillomavirus	Cervical, anal, penile, vulvar, vaginal, and oropharyngeal	Vaccination	62.6%b (88)	46 711	74.3%
Hepatitis B virus	Liver cancer	Vaccination	40.3% (ages 19-49 years); 19.1% (ages 50 years and older) (47)	41 210	6.6%
Hepatitis C virusc		Antiviral treatment	83 000 per year initiate treatment		24.2%
Heliobacter pylori c	Gastric cancer	Antibiotic treatment plus proton pump inhibitor	68.2%-75% (37,89)	26 500	31.2%

^aPopulation averages that do not account for differences in subgroups that contribute to health disparities.

^bPercentage of adolescents aged 13-17 years who had received at least 3 doses of the human papillomavirus vaccine and those with 2 doses when the first dose was initiated at age younger than 15 years and there were at least 5 months minus 4 days between the first and second dose.

^cThese may be underassessed, given the lack of population screening for these oncogenic infections.

Substantial reductions of HPV and HCV as a cause of cancer are possible but not without sustained effort to deliver treatments and interventions to more people. Although HPV vaccination has not yet been observed to reduce the incidence of cervical cancer in the United States, probably because of slow and low uptake, we anticipate that it will, given recent reports from Finland, Denmark, Sweden, England, and Scotland that HPV vaccination substantially reduces the incidence of cervical cancer (39-43). Maintaining the status quo for screening and vaccination could eliminate cervical cancer (defined as ≤4 new cases per 100 000 women-years) by 2040 and potentially sooner with improved efforts (44).

In 2015, it was estimated that 260 000 people need to initiate treatment each year to achieve HCV elimination in the United States by 2030 (45), but this is now likely an underestimate. In addition, new HCV infections are increasing. Interventions to improve uptake of HCV screening and HCV treatment are needed (46).

HBV vaccination rates among adults are low (47), and improved coverage in adults would provide herd protection and prevent mother-to-child transmission (48). There are substantial racial and ethnic disparities in HBV vaccination coverage, HBV prevalence, and management and treatment of chronic HBV infection (49-52). Improving uptake of interventions to prevent or treat infections will require meeting the needs and addressing barriers for all groups. A national vaccination registry could help improve coverage by helping identify and target unvaccinated individuals and groups of individuals who would benefit from recommended vaccinations.

Improve cancer screening strategies

For US Preventive Services Task Force (USPSTF)–recommended screening strategies for breast, colorectal, and cervical cancer, 25%-30% of eligible individuals remain unscreened (53). Approximately one-half of the cervical cancers in the United States are diagnosed in this subgroup of women who have received little or no screening (54). Uptake is even lower for lung cancer screening, which started in 2013, with 70% or more of eligible individuals remaining unscreened. Disparities in cancer screening are associated with race and ethnicity, lower economic status, low health literacy, and geographical barriers.

Table 3 (and Supplementary Tables 1-3, available online) shows the projected life-years gained from modest assumptions about improved screening rates, including a 10-percentage-point increase for each of colorectal, breast, and cervical cancer screening, and an increase for lung cancer screening to 80% (to be comparable with the other longer-standing programs). Increasing uptake of existing screening modalities would provide 8.4 million additional life-years gained for cohorts reaching the minimum age of screening eligibility in 2021-2045 over their remaining lifetime, and more if a smoking cessation program is added to lung cancer screening.

Table 3.

Model-estimated number of cancer deaths averted and life-years gained from increased uptake of US Preventive Services Task Force–recommended screening for cohorts reaching the minimum age of screening eligibility in 2021-2045 over their remaining lifetime

Cancer screening	Screening rate, 2019-2021b	Hypothetical improved screening rate	Percentage-point increase in screening ratec	Total over the lifetime of 25 annual cohorts (2021-2045)a
				Cancer deaths averted	Life-years gained
Lung	13%	80%	67	110 000	1.5 million
Lung and smoking cessation program	13%	80%	67	150 000	4.6 million
Colorectal	69%	80%	11	360 000	4.4 million
Breast	76%	86%	10	50 000	1.0 million
Cervical	73%	83%	10	40 000	1.5 million

^aMean (lung and colorectal cancer models) or median (breast cancer models) estimate across Cancer Intervention and Surveillance Modeling Network models for a given cancer site; analyses for cervical cancer screening were performed with only 1 model. Additional information is provided in the Supplementary Tables 1-3 (available online).

^bColorectal, breast, and cervical cancer screening rates (in accordance with contemporary US Preventive Services Task Force screening recommendations) are the average of the rates reported in the 2019 and 2021 National Health Interview Surveys (71); lung cancer screening rates are from the 2019 Behavioral Risk Factor Surveillance System survey (90).

^cIncrease necessary to bring screening rates to at least 80%, with a minimum increase of 10 percentage points.

Current screening strategies could be enhanced by using precision-prevention, especially for cancers where screening identifies a lot of indolent disease, such as prostate and breast. Such approaches use risk factor information to guide who should be screened, how frequently, when to perform more invasive diagnostic procedures, and type of treatment. Risks are updated as new information becomes available. A risk-based approach uses predetermined clinical action thresholds, which will promote “equal care for equal risk.” This approach has been adopted for cervical cancer screening and management guidelines (55,56). Furthermore, screening is a multistep process, and interventions are needed to ensure that patients receive needed follow-up care after a positive screen. Too often, these subsequent steps are missed, and systems for follow-up care and coordination that monitor all steps and intervene to minimize loss to follow-up will improve health outcomes from screening programs. This is another opportunity for precision strategies that address differing risks for failing to complete the entire process.

Some of the deadliest cancers (eg, pancreatic and ovary) do not have proven methods for screening to detect precursors and/or early detection of cancer. A multicenter study of individuals at high risk of pancreatic cancer demonstrated that annual endoscopic ultrasound surveillance reduces advanced stage cancer and improves cancer survival (57). Modest improvements in stage at diagnosis with screening may have the potential for clinically significant impact on averting cancer deaths.

Reduce health disparities

Cancer control interventions contribute differently to reductions in health disparities depending on how the disparity manifests. Mandelblatt et al. (58) summarized findings from statistical models for the US Black population compared with the overall US population across 5 cancer sites—breast, cervical, colorectal, lung, and prostate. Although the USPSTF recommendation for prostate cancer screening indicates that the decision is individual risk and preference sensitive, Black men have earlier presentation, more aggressive disease, and higher mortality than White men and may benefit from precision screening approaches. When the disparity is primarily related to cancer incidence, the percentage of mortality disparities that are explained by 4 components (incidence, screening, screening test modality, and timeliness of follow-up) is very high, such as for male and female lung cancer (88%-90%). This suggests that interventions to improve risk reduction (eg, smoking cessation) and screening processes would have a high impact on reducing disparities in these instances. Further modeling is needed to address knowledge gaps on the impacts of interventions to reduce health disparities, to address excess weight and alcohol consumption, and to reduce or treat oncogenic infections.

Novel approaches are needed to reach those at higher risk, including marginalized, rural, and persistently poor populations. Self-sampling, self-testing, and point-of-care testing could bridge some access gaps. At-risk groups may experience health disparities for multiple conditions that share common causes related to social determinants of health (59). Strategies to bundle interventions may be an efficient way to address multiple care gaps (60,61). Portable interventions delivered to the home may benefit members of the entire household or community. Access to screening tests is not sufficient, and the follow-up process and management remains an even greater challenge (62-65). Community health workers (66) and patient navigators (67) are proven, cost-effective services to increase follow-up care. Without a billable code for these services, integration of frontline clinicians into the medical home has been limited. Medical deserts especially impact rural health, and additional strategies may be needed in these areas to ensure adequate follow-up and management.

Invest in long-term research priorities

The landscape of cancer will evolve as we make progress on known risk factors. For instance, if trends in smoking cessation are maintained, by 2065, never smokers will account for 50% of lung cancer deaths, an increase from approximately 10% now (10). Novel risk factors for lung cancer among never smokers include climate change, which is driving changes in exposure to air pollution due to wildfires, specifically to particulate matter measuring no more than 2.5 µm (PM_2.5). Hill et al. (68) showed a relationship between PM_2.5 levels and EGFR–driven lung cancer incidence in ecological correlation analyses from cohort studies in 3 countries. This relationship appears after as few as 3 years of exposure to high levels of air pollutants (68). EGFR–positive lung cancer currently represents only 10%-15% of lung cancer in the United States, but this observation suggests that this proportion could grow.

Infrastructure and investment will drive future etiological discoveries and understanding carcinogenesis and natural history that inform future cancer prevention strategies. Our deep understanding of the etiology and carcinogenesis of several cancers, such as cervix and colon, have driven the advancement of prevention and control strategies. We suggest 2 priority areas—the exposome and precancer biology—but there are others. At present, exposome measurement is expensive, uneven across the population, and in many cases, uncharacterized. The exposome is complex and unstable over a person’s lifetime. New exposures require new data sources and measures. The critical timing of exposure can vary from preconception to end of life. Novel technologies are needed for standardized and longitudinal measurement of the exposome at scale (69). Robust, ubiquitous, and inexpensive measurement systems will advance our knowledge of emerging risk factors for cancer. We speculate that the changing exposome may explain the rise in early onset cancers.

Premalignant and in situ carcinoma are states of abnormal cells that often, but not always, precede the development of malignancy. A greater understanding of the key initiation steps and cancer precursors will provide a rational basis for novel prevention and interception strategies, respectively.

Social determinants of health contribute to disease risk and poorer health outcomes. There is not yet a standardized way to measure social needs for individuals at the point of care or social risks in the community (70). Systematic capture of this information will enable the development of interventions that can be deployed in real time to achieve better health outcomes and to address health disparities. Increasing diversity of our scientific workforce and research participants and greater involvement of communities will be important strategies to advance this work.

National surveillance for cancer screening and modifiable risk factors needs to be modernized to monitor patterns of care delivery and lifestyle changes at a population level. This will enable identification of gaps and subsequent development of interventions to close gaps and address health disparities. Our current best population-level surveillance for cancer screening relies on self-reported data on an annual survey (the National Health Interview Survey) (71). Routine capture of data from health systems and other sources could enable broad data capture closer to real time and in greater detail. Not only would automated systems support surveillance and monitoring but they could also be redeployed by health-care systems to support interventions to address care gaps.

Tumor-specific neoantigens are recognized and modulated by the immune system (72). Vaccination with tumor-specific neoantigens can stimulate existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities via epitope spreading (73). However, tumor interaction with the immune system (immunoediting) can change the antigenicity of emerging tumors and lead to immune evasion and progression (74). Hence, early stage tumor-specific neoantigens are promising targets for use in cancer preventive vaccines with minimal risk of side effects including autoimmunity and immune tolerance. Vaccine strategies that target neoantigens found in high-risk populations, such as Lynch syndrome, are under evaluation in clinical trials (75). We need to expand the catalogue of neoantigens for other high-risk groups and common neoantigens arising sporadically from somatic mutations to target for cancer interception and treatment of early cancers.

Diagnostics, including screening tests and monitoring technologies, play an essential role in health care. Approximately 70% of all medical decisions are informed by at least 1 laboratory test (76), and the Essential Diagnostics List catalogs these tests (77). Underserved populations face substantial barriers in accessing diagnostics and recommended follow-up care. This gap could be addressed using innovations including over-the-counter diagnostics, self-sampling, portable diagnostics, digital health technologies (eg, wearables), and advances in testing methodology. A research-and-development pipeline and ecosystem is needed to sustain research for diagnostics and to increase access and equity.

Efficiency is crucial to achieve a screening program for individually rare cancer sites, such as bundling into a single intervention. This efficiency could potentially be achieved through blood-based screening tests for multicancer detection. This approach is based on liquid-biopsy technology developed for guiding cancer therapy. However, it is not known if and who will benefit (ie, reduced cancer mortality). Potential harms of multicancer detection tests include reduced participation in USPSTF-recommended cancer screening, which for colorectal and cervical screening prevents cancer onset (interception). To date, the sensitivity varies greatly between tests and by tissue and organ, and multicancer detections primarily find advanced-stage rather than early stage cancer (78). Routinely repeating testing will increase the false-positive probability. Other questions include performance characteristics and clinical effectiveness in diverse populations and high-risk populations (eg, hereditary cancer syndromes, cancer survivors). Without access to proven effective multicancer detection tests and follow-up care, these tests may exacerbate, not diminish, health disparities (79,80).

Discussion

Cancer is an ongoing pandemic in the United States, with 600 000 related deaths [almost twice the number of deaths due to COVID in the United States in 2020 (81)]. New efforts in prevention and control to reduce cancer risk and incidence are poised to be main contributors to reducing the burden of cancer in the United States. This can be achieved in part by leveraging knowledge of new population trends and forces, growing research capacity, and innovative strategies to address these challenges. We recommend using population modeling and knowledge of current trends to quantify potential impacts of prevention and control strategies and to prioritize future initiatives based on evidence for interventions with the greatest potential to reduce mortality. Knowledge gaps remain, and to fully articulate priorities, additional modeling analyses will need to be conducted to quantify potential impacts for interventions where this modeling has not yet been performed. We are poised to accelerate progress in the near term by improving delivery of already existing interventions (Table 4).

Table 4.

Recommended strategies to accelerate progress to reduce the cancer burden through prevention and control in the United States

Recommended strategies	Additional detailed strategies
Tobacco cessation	Table 1
Reduce excess weight	—a
Reduce consumption of alcohol	—a
Improve uptake of preventive interventions for oncogenic infections	Table 2
Improve uptake of recommended cancer screening	Table 3
Reduce health disparities	—a

^aStrategies are noted in the text where no quantification of impact is summarized in the manuscript.

As excess weight and alcohol consumption increase, it will be critical to stabilize or reverse these patterns, and population strategies are needed given the high population prevalence of these risk factors. Interventions to address these common risk factors will have population-level impacts beyond cancer, because of their association with other common causes of death. Sustained reduction in weight or alcohol consumption and increases in physical activity (27) can reduce cancer risk within 10 years (21), indicating that these efforts are critical for achieving the Cancer Moonshot goal.

Several limitations should be considered related to this commentary. Although we primarily focused on common cancers, rare cancer types represent 27% of all cancers and 25% of all cancer-related deaths (82). We used population averages that do not fully describe the heterogeneity in cancer risks across the US population. We are unlikely to be successful with uniform efforts, and we need more attention to subpopulations that experience health disparities.

Although we did not address quality of life, we recognize that mortality measures fail to consider outcomes that are meaningful for cancer survivors and their families. Indeed, the Cancer Moonshot goals include “improving the experience of people and their families living with and surviving cancer.” There are currently 18.1 million cancer survivors in the United States, and this number is expected to increase to 26 million by 2040 (83). Early diagnosis and prevention may reduce, or even eliminate, the amount of treatment needed, improve quality of life, and reduce the financial burden of cancer on patients.

It is also important to recognize that mortality benefits of preventive and control interventions at different stages in the natural history will be realized on different time horizons. To highlight these different time frames, a new lexicon for cancer prevention has been suggested: cancer prophylaxis to prevent carcinogenic initiation, cancer interception to interrupt progression from precursor to invasive cancer, and cancer mitigation to detect and/or treat early cancer before it becomes clinically aggressive (84). Cancer prophylaxis will take the longest time to glean its benefit as it impacts the earliest step in the natural history of disease. Cancer interception, interrupting progression of cancer precursors, has a shorter timeline for realizing those benefits than preventing initiation for a given cancer. Thus, combining HPV-based screening (interception) with HPV vaccination (prophylaxis) could accelerate the elimination of cervical cancer faster than HPV vaccination alone (44). Cancer mitigation, finding and treating cancer early enough to avert death, will yield mortality benefits relatively quickly, but perhaps at the cost of greater morbidity.

Our analysis focused on the burden of cancer in the United States, which does not reflect the cancer burden worldwide. For instance, oncogenic infections account for only 2.7% of cancer deaths in the United States, however, they account for approximately 16% of cancer deaths globally. Similar opportunities for prevention and control have been identified in the European Union (85) and globally (86). It is likely that innovations in prevention and control will have substantial impact on cancer mortality in low- and middle-income countries, where cancer treatment services are limited because of cost and access.

Shiels et al. (2) showed that current trends in cancer mortality will not achieve the objective of the Cancer Moonshot (1). Excess weight and alcohol consumption are increasingly important causes of cancer that could leave us well short of that goal. Research in and commitment to cancer prevention and control is needed to address current gaps and inequalities. It is undeniably within our power to realize the Cancer Moonshot goals for the US population and to reduce the global burden of cancer.

Data availability

Most data underlying this article were not new data generated or analyzed for this commentary. The new data underlying this article are available in the article and in its online supplementary material.

Author contributions

Katrina Goddard, PhD (Conceptualization; Visualization; Writing—original draft; Writing—review & editing), Eric J. Feuer, PhD (Conceptualization; Visualization; Writing—original draft; Writing—review & editing), Asad Umar, DVM, PhD (Conceptualization; Visualization; Writing—original draft; Writing—review & editing), and Philip E. Castle, PhD (Conceptualization; Visualization; Writing—original draft; Writing—review & editing).

Funding

All authors are employees of the National Cancer Institute, National Institutes of Health.

Conflicts of interest

The authors declare no conflicts of interest or financial disclosures.