Cancer Screening

Function

Breast Cancer 

Breast cancer is the most common cancer among women and the second most common cause of cancer death in the United States. Female breast cancer incidence was on a declining trend before 2004 but has since increased at an average of 0.4% per year. After an initial incidence reduction in the early 2000s following the cessation of hormone replacement therapy, the period from 2004 to 2014 showed an increase in incidence, which may partially be attributed to the obesity epidemic. 

As mammography rates remained constant during this period, the recent rise in breast cancer incidence cannot be attributed to increased detection through mammography. However, due to breast cancer screening, most cases are diagnosed at stage I, which has a 5-year survival rate of 100%.[6] From 1989 to 2015, breast cancer mortality dropped by 39%. The mortality rate among women aged 50 and older has continued to decline since 2007, while it has remained steady for women aged 50 or younger.[7] Widely accepted breast cancer screening modalities include mammography, breast magnetic resonance imaging (MRI), digital breast tomosynthesis (DBT), breast ultrasound, and breast self-examinations.

According to the United States Preventive Services Task Force (USPSTF) guidelines, women aged 50 to 74 are recommended to undergo biennial mammography. For women aged 40 to 49, the decision to screen should be individualized, as the reduction in breast cancer deaths is smaller compared to the rate of false-positive results and unnecessary biopsies.[8] Frequent screening also increases the risk of overdiagnosis and overtreatment. This contrasts with the American Cancer Society (ACS) guidelines, which strongly recommend annual mammography beginning at age 45, and a discussion of the pros and cons with women aged 40 to 44.

The ACS also recommends transitioning to biennial screening or continuing annual screening in women aged 55 or older. Women should not discontinue screening mammography after age 75 if their general health is good and their life expectancy is 10 years or longer. According to the USPSTF guidelines, evidence is insufficient regarding the benefits and risks of mammograms in women aged 75 or older. The same applies to women with negative mammograms due to dense breasts, as well as the use of DBT, breast ultrasound, breast MRI, and other modalities.  

According to ACS guidelines published in 2007, annual mammography with MRI is recommended for women at increased risk of breast cancer. This group includes women with a known BRCA mutation, as well as those with a first-degree relative with a BRCA mutation. Additionally, women with a 20% to 25% or higher lifetime risk of breast cancer, as predicted by breast cancer risk-estimation models, are included. Screening protocols would include pedigree analysis of first- and second-degree relatives on both paternal and maternal sides, individuals treated for Hodgkin disease with chest irradiation before age 30, women with Cowden, Li-Fraumeni, and Bannayan-Riley-Ruvalcaba syndromes, and the first-degree relatives of all these patients. The ACS guideline for women at increased risk is currently being updated.

Cervical Cancer

Cervical cancer is the second leading cause of cancer death among women aged 20 to 39.[9] Cervical cancer was diagnosed in 569,847 women globally and had a mortality of 311,365 in 2018.[10] In the United States, the ACS projects 13,820 new cases of invasive cervical cancer and 4360 deaths from the disease in 2024. According to the World Health Organization (WHO), approximately 660,000 new cases of cervical cancer are expected globally in 2022, with approximately 350,000 deaths.

Persistent HPV infection is the primary cause of cervical cancer. According to NHIS 2013 data, approximately 80% of women aged 21 to 65 received Pap tests in the last 3 years. The HPV vaccine protects against 9 types of HPV, preventing about 90% of cervical, anal, vulvar, and vaginal cancers. However, vaccination rates among adolescent girls and boys remain low, at 37.6% and 13.9%, respectively. Cervical cancer screening tests include the Pap test, the Pap test with HPV co-testing, and high-risk HPV (hrHPV) testing alone.

As per USPSTF guidelines, women aged 21 to 29 should undergo cervical cytology every 3 years. For women aged 30 to 65, screening options include cervical cytology alone every 3 years, hrHPV co-testing every 5 years, or hrHPV testing alone every 5 years. The USPSTF advises against cervical cancer screening in women aged 21 or younger, those who have had a hysterectomy with cervix removal and no history of high-grade precancerous lesions or cervical cancer (ie, cervical intraepithelial neoplasia or CIN of grade 2 or 3), and women aged 65 and older with adequate prior screening and not at high risk for cervical cancer.[11]

The screening recommendations, as per the joint guidelines of the ACS, American Society of Clinical Pathology (ASCP), and American Society of Colposcopy and Clinical Pathology (ASCCP), align closely with those of the USPSTF, advocating against screening before age 21. For women with atypical squamous cells of undetermined significance (ASC-US) and a negative HPV test result, the guideline suggests repeating the screening test in 3 years. HPV vaccination status does not influence cervical cancer screening practice. Screening can be discontinued after age 65 if women have had 3 consecutive negative cytology tests or 2 consecutive negative co-test results in the last 10 years before discontinuing screening, with the latest test performed within the past 5 years. Women with ASC-US and HPV-negative results should be considered for screening discontinuation. Once screening is ceased, it should not be restarted for any reason, even in women with new sexual partners. Following the spontaneous resolution or appropriate management of CIN 2, CIN 3, and adenocarcinoma in situ, routine screening should continue for at least 20 years, even if this extends beyond age 65.

Lung Cancer

Lung cancer is the number one leading cause of cancer death. The ACS estimates new lung cancer cases and deaths in the US in 2024 to be 234,590 and 125,070, respectively. The National Lung Screening Trial (NLST), conducted in 2011, is one of the largest multicenter randomized lung cancer screening studies worldwide. NLST assessed the reliability of low-dose lung computed tomography (LDCT) in lung cancer screening. Mortality from lung cancer was the primary endpoint. The study concluded that LDCT screening reduced lung cancer mortality by 20%. The NLST findings formed the basis of the USPSTF recommendation for lung cancer screening. However, concerns persist due to the NLST's limited representation of the Black American population, accounting for only 4%, and its failure to address differences in smoking behaviors among racial groups.[12]

According to USPSTF guidelines, adults aged 55 to 80 who are currently smoking or have a 30-pack-year history of smoking and have quit within the last 15 years should undergo annual LDCT screening. Screening should be discontinued once the individual has not smoked for 15 years, has a limited life expectancy, or is unable to undergo curative lung surgery due to health problems.[13] The ACS recommendation is similar to that of the USPSTF but applies to individuals aged 55 to 74. As with the USPSTF recommendation, current smokers should receive evidence-based smoking cessation counseling. Patients should also participate in an informed, shared decision-making process regarding the benefits, harms, and limitations of LDCT screening and have access to a high-quality lung cancer screening and treatment center. Past studies have shown that fully implementing screening in the target population, as described in the NLST trial, could prevent 12,250 lung cancer deaths annually.[14]

Colorectal Cancer

CRC is the second most common cause of cancer-related death in the United States. According to data from the National Institutes of Health, new CRC cases are estimated to reach 147,950, with CRC-related deaths predicted to reach 53,200. CRC screening options include an annual high-sensitivity fecal immunochemical test (FIT), an annual guaiac-based fecal occult blood test (g-FOBT), a multitarget stool DNA test every 3 years, colonoscopy every 10 years, flexible sigmoidoscopy every 5 years, and computed tomography (CT) colonography every 5 years.

The ACS CRC screening guidelines were updated in 2018. Over the past 2 decades, CRC incidence and mortality have decreased, primarily due to effective screening practices. Adults aged 45 and older with an average risk of CRC should undergo screening using either a high-sensitivity stool-based test or a structural (visual) examination based on patient preference and test availability. Positive results from non-colonoscopy screening tests should be promptly followed up with a colonoscopy as part of the screening process. The ACS strongly recommends that adults aged 50 and older begin screening with the methods mentioned above. Adults with average risk and good health with a life expectancy of more than 10 years can continue screening for CRC until age 75. CRC screening decisions should be individualized for adults aged 76 to 85 based on patient preferences, health status, life expectancy, and prior screening history. Individuals aged 85 and older may discontinue CRC screening. 

High-risk patients include people with a family history of CRC or an advanced adenoma in a first-degree relative before age 60 or 2 first-degree relatives at any age. These patients should undergo colonoscopy every 5 years, starting 10 years before the youngest relative's diagnosis or at age 40, whichever is earlier. Individuals with a single first-degree relative diagnosed with CRC at age 60 or older or with an advanced adenoma may consider average-risk screening options starting at age 40.[15] Colonoscopy is the gold standard screening tool for CRC.[16] This modality allows for the detection and resection of precancerous and cancerous lesions. Adverse event rates are low, with colonic perforation occurring in 0.010% to 0.067% of screening/surveillance colonoscopies and 0.022% to 0.268% of diagnostic colonoscopies.[17]

Stool-Based Tests

g-FOBT detects blood in stool based on the peroxidase activity of heme. The test is noninvasive, inexpensive, and has the highest quality of evidence from randomized controlled trials. However, because the test relies on simple oxidation, dietary peroxidases (eg, from plants), heme from red meat, or antioxidants (eg, vitamin C) can confound results. The g-FOBT has a low positive predictive value (PPV) of 3% to 10% but a good negative predictive value of 94%.[18]

FIT uses human globin antibodies, minimizing the likelihood of cross-reaction with dietary meat. FIT specifically detects colonic blood, unaffected by upper gastrointestinal globin, which may be contaminated by digestive proteolytic enzymes. A recent systematic review and meta-analysis demonstrated FIT's high accuracy in detecting CRC, with an overall accuracy of 95%, sensitivity of 79%, and specificity of 94%.

Stool deoxyribonucleic acid (DNA) testing uses Cologuard—the first multitarget stool DNA test approved by the US Food and Drug Administration (FDA) in August 2014 for CRC screening. Cologuard detects abnormal DNA present in stool samples from individuals with malignancies. Comparative studies between FIT and stool DNA testing indicate higher sensitivity but lower specificity and increased false-positive rates for the latter.[19] As per USPSTF guidelines, screening should commence at age 50, utilizing stool-based tests (gFOBT, FIT, and FIT-DNA) or direct visualization tests (colonoscopy every 10 years, sigmoidoscopy every 5 years, or CT colonography every 5 years, if combined with annual FIT).

The Septin9 (SEPT9) DNA serology test recently gained FDA approval for CRC screening. However, a systematic review found its sensitivity for detecting CRC to be less than 50%. This test does not feature among the recommended screening tests for colon cancer.[20] For patients aged 75 or older, the USPSTF guidelines agree with the ACS recommendations, which strongly discourage routine screening colonoscopies beyond age 85. According to the USPSTF, no conclusive evidence from head-to-head trials supports one screening method over another, with ongoing studies like the CONFIRM trial comparing colonoscopy with FIT for reducing CRC mortality. USPSTF hasn't yet evaluated evidence on screening high-risk populations. 

SEPT9 is a PCR serology test that detects hypermethylated SEPT9 DNA in the tumor DNA that has been shed into the bloodstream from all intestinal anatomical sites. The FDA approved Epi proColon (also recognized as the methylated SEPT9 or mSEPT9 assay) for CRC screening in April 2016, marking the first approval of its kind for blood-based CRC screening. A prospective multicenter study comparing Sept9 testing with FIT showed similar sensitivity (73% versus 68%) but substantially lower specificity (81% versus 97%). However, studies have noted that offering a noninvasive test for CRC screening improved compliance with testing. For instance, in a study, 97% of individuals who declined colonoscopy were willing to do a noninvasive test, and 83% of the study participants were willing to undergo the SEPT9 test.[21]

Prostate Cancer

Prostate cancer ranks as the second leading cause of cancer-related deaths in men globally, following lung cancer. The ACS reported in 2022 that prostate cancer accounted for 1,466,680 new cases and 396,792 deaths worldwide. The ACS also anticipates approximately 299,000 new cases globally in 2024, with 35,250 deaths projected in the United States alone. The incidence and mortality rates are substantially higher in Black Americans than in Whites or the general male population in the United States.[22] Incidence and mortality also increase with advancing age, with the mean age at diagnosis being 66.[23]

The 2010 ACS guideline recommends that men with at least a 10-year life expectancy should have the option to discuss prostate cancer screening with their healthcare provider. This discussion should include information about the uncertainties, benefits, and risks associated with serum prostate-specific antigen (PSA) testing, with or without a digital rectal exam (DRE), to make an informed decision. Men at higher risk, including those with a family history of prostate cancer (father or brother diagnosed with prostate cancer before age 65), Agent Orange exposure, and Black American men, should be educated about prostate cancer screening from age 45. Men at considerably higher risk (eg, prostate cancer diagnosed before age 65 in multiple family members) should start receiving screening information from age 40.[24]

When men face difficulty making decisions, healthcare providers may involve the patient's family. The decision should be made considering the patient's overall health, preferences, comorbidities, life expectancy, and willingness to pursue treatment if diagnosed with prostate cancer. Asymptomatic men with a life expectancy of less than 10 years, determined by age and health, typically should not undergo prostate cancer screening. For men opting for prostate cancer screening following an informed, objective discussion of the pros and cons (shared decision-making), the following measures are recommended:[25]

• The PSA test should be utilized with or without a DRE. However, in men with hypogonadism, PSA with a DRE should be combined due to PSA's reduced sensitivity in this group.
• The interval between screenings can be extended to every 2 years for men whose PSA level is less than 2.5 ng/mL and yearly for men with a PSA level of 2.5 ng/mL or higher.
• A referral for further evaluation or biopsy is recommended if the PSA level is 4.0 ng/mL or higher in men who are at average risk for prostate cancer. A second PSA level should be obtained 30 days after the initial test for verification before considering further investigation or a possible biopsy.
• If the PSA levels range between 2.5 and 4.0 ng/mL, the healthcare provider should assess the individual's risk factors for developing high-grade prostate cancer and decide, through a thorough shared decision-making discussion with the patient, whether to make a referral for further diagnostic evaluation.

Factors that enhance the risk of prostate cancer are Black race, advancing age, family history of prostate cancer, Agent Orange exposure, presence of a known BRCA2 mutation, Lynch syndrome, elevated age-specific PSA level, low free % PSA, and abnormal DRE results. A history of prior negative biopsies reduces the risk. Patients who decline further evaluation, biopsies, or treatment, even in the presence of clinically significant cancer, are not ideal candidates for prostate cancer screening. The 2018 USPSTF guidelines on prostate cancer screening suggest discussing screening's advantages and drawbacks in men up to age 70. However, several oncology and urology experts have raised concerns about this recommendation. They argue that, based on US Social Security Actuarial tables, average American men in good health do not reach a median 10-year life expectancy until age 77. Moreover, these experts note that the USPSTF panel lacked representation from urologists or oncologists and tended to overstate screening's risks while minimizing its benefits.

The American Urological Association suggests shared decision-making discussions for men aged 70 to 80 regarding ongoing screenings, as per consensus. Continuing the screening of men aged 80 and older is generally not recommended. However, exceptions can be made for patients who understand the risks but wish to continue screening regardless. Please see StatPearls' companion resource, "Prostate Cancer Screening," for further information.

Issues of Concern

The ACS projects approximately 1.9 million newly diagnosed cancer cases and 609,360 cancer deaths in the United States in 2022. The cancer death rate increased until 1991, then steadily declined through 2017, resulting in a 29% overall decrease and approximately 2.9 million fewer deaths than if peak rates had continued. This improvement was largely due to long-term reductions in death rates for lung, colorectal, breast, and prostate cancers. However, the decline in breast and CRC cases slowed for women and stopped for prostate cancer from 2008 to 2017. In contrast, lung cancer cases in men declined more rapidly, from 3% annually between 2008 and 2013 to 5% annually between 2013 and 2017. Despite this trend, lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined.

Even though CRC screening has improved compared to past rates, specific populations significantly lag in screening practices, including:

• The uninsured, unhoused, migrants, and undocumented individuals with no accessible source of healthcare
• People who have not visited a physician for a year due to financial, legal, personal, logistical, dementia, or mental issues
• Non-Hispanic Asians

Considerable confusion about appropriate cancer screening remains, especially where guidelines are conflicting and changing, such as for prostate cancer. Potential harms from screening include false-positive tests, resulting in cancer overdiagnosis and overtreatment. False-positive results also cause undue anxiety and subject patients to invasive diagnostic testing. One strategy to avoid these problems is to target screening to high-risk individuals, making cancer screening more cost-effective and balancing the benefit-to-harm trade-off.

The ACS reports that colorectal, lung, and prostate cancers account for an estimated 48% of all cancers expected to be diagnosed in men in 2024. For women, the 3 most common malignancies are breast, lung, and colorectal, which will constitute an estimated 51% of all new female cancer diagnoses in 2024. Overall, the cancer mortality rate in the United States continues to decline slowly, although the incidence is increasing, with 2 million new cases expected to be diagnosed in 2024. Worldwide, the overall cancer incidence is also rising, with diagnoses expected to reach a yearly incidence of 29.9 million and 15.3 million deaths by 2040.

Clinical Significance

Cancer screening is initiated in an otherwise healthy population when the cancer risk is substantial enough to justify the potential risks of overdiagnosis and overtreatment. Cervical cancer screening has significantly decreased both the incidence and mortality rates of the condition. Cancer mortality in the United States decreased by 25% from 1990 to 2015. A significant decline has been noted in mortality rates for CRC (47% in men and 44% in women) and breast cancer (39% in women), trends partially attributed to the introduction of cancer screening for these diseases.[26] In addition, improved treatments for lung cancer have also helped.

Early-stage breast, cervical, and CRCs have a 5-year survival rate ranging from 84% to 93%. However, various studies have noted that certain population subsets are not aware of the benefits of cancer screening. Community outreach programs that increase cancer awareness and motivate people to discuss cancer risk and screening with a doctor will be tremendously beneficial.[27] An estimated 611,720 cancer deaths are expected to occur in the United States in 2024.

Enhancing Healthcare Team Outcomes

Certain organizations, including the USPSTF and ACS, periodically review the available evidence and update their recommendations as more trials demonstrate the real survival and mortality benefits of cancer screening and early diagnosis. Primary healthcare providers should stay updated with changing screening guidelines. Primary care physicians are critical in determining screening eligibility, engaging in informed decision-making discussions, and coordinating care with specialists. Additionally, issues regarding insurance and affordability should be addressed at the institutional level and by nonprofit organizations, while patients should be guided to appropriate resources when available. Handouts distributed in clinics, pharmacies, and common public places, such as grocery stores, have significantly increased public awareness. Healthcare providers must now ensure they make appropriate recommendations for screening patients based on published guidelines, patient age, preferences, comorbidities, life expectancy, and risk factors.