Multidimensional Approach Is Required to Diagnose and Surveil Breast Cancer

The US Preventive Services Task Force (USPSTF) revised its guidelines for breast cancer screening in April 2024, lowering the recommended starting age to 40 and advising biennial screenings until age 75.¹ This adjustment has been praised as a positive step forward, although many organizations still advocate for more frequent screenings without an upper age limit.

In 2009, the USPSTF shifted from recommending annual or biennial screening for all women over the age of 39 to biennial screenings for women aged 40 to 74, citing concerns over the risks associated with unnecessary procedures and treatments for false positives and overdiagnosis. Conversely, the American Cancer Society recommends annual screening starting at 45 years, with the option to transition to biennial screening at 5 years, and continuing as long as women in good health are expected to live at least 10 more years.

Additionally, the American Cancer Society recommends screening can begin as early as age 40.¹ Similarly, the American College of Radiology (ACR), National Comprehensive Cancer Network, National Consortium of Breast Centers, American Society of Breast Surgeons (ASBrS), and Society of Breast Imaging (SBI) all advocate for annual screening starting at age 40, with no upper age limit barring severe health conditions.¹ The ACR recommendations highlight the importance of risk assessment starting at age 25 to tailor screening strategies based on individual risk profiles. Recommendations made by these different organizations are summarized in the table below.

The rationale for advocating for earlier and more frequent breast cancer screening stems from several critical factors. Breast cancer can manifest at any age, raising the need for vigilance across all demographics and individualization of screening protocols for each patient and risk profile.

Higher breast density poses a well-known risk, underscoring the need for targeted supplemental screening in cases of extreme density. Moreover, given the aggressive nature of certain cancer types, a 2-year interval between screenings is insufficient for timely detection for adequate treatment. Additionally, there is no clear recommendation on the optimal timing for cessation of breast cancer screening.

Addressing these and other challenges through research efforts and healthcare policy initiatives likely will lead to improved delivery of care to all women.

Limitations of Current Evidence

Due to the lack of randomized clinical trials investigating women younger than age 39 and older than age 75, the USPSTF is unable to recommend for or against breast cancer screening in these age groups.2 The situation is similar for frequency of screening, risk-based approaches, and supplementary investigations in individuals with dense breasts. Without high-quality clinical trials, the basis for the recommendations relies on trial emulations and statistical modeling. The potential for type II errors underscores the importance of cautious decision-making to avoid unintended harm to women.

The only trials assessing screening frequencies were conducted more than 2 decades ago, and since then, the incidence of breast cancer has continued to rise.² The USPSTF uses modeling data to balance the benefits of screening (reduced mortality and increased life years) against harms (false positives). However, these models may not comprehensively consider factors like morbidity, disability, and financial costs.

In contrast to other organizations, the USPSTF takes a more conservative stance, awaiting more conclusive evidence before updating recommendations. Several ongoing randomized trials may provide such evidence, which could potentially influence future screening strategies.

High-Risk Populations

Younger women with dense breasts often face faster growing, more aggressive breast tumors, suggesting that shorter screening intervals would be beneficial for this group by promoting early cancer detection. When the screening intervals in British Columbia, Canada, were changed from annual to biennial, a study performed in 2008 demonstrated that these claims may have been overstated.³

In contrast, a Swedish study indicated a mortality benefit in women aged 40 to 49 with a screening interval of 12 months, implying that optimal screening intervals may vary by age group.³ This variability suggests that less-frequent screenings might be prudent for older women to minimize potential harms, similar to recommendations made by the American Cancer Society. 

Currently, notification of breast density during mammography is mandatory in 38 states and the District of Columbia.² Starting in September 2024, the US Food and Drug Administration will require mammography centers to inform patients of their breast density, the increased cancer risk in higher-density breasts, the challenges to detecting cancer in different breast densities, and the potential need for additional tests to screen for cancer.²

Despite the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial showing that the addition of magnetic resonance imagining (MRI) may lower the rate of interval cancers,⁴ the evidence was insufficient for the USPSTF to make recommendations for supplementary investigations due to lack of data regarding morbidity, mortality, or cancer detection.² Nonetheless, some groups advocate for annual MRI screenings for high-risk women, although insurance approval remains a significant barrier.⁵

The Japan Strategic Anti-Cancer Randomized Trial (J-START)⁶ and the Adjunct Screening with Tomosynthesis or Ultrasound in Women with Mammography-Negative Dense Breasts (ASTOUND)⁷ trials highlight that ultrasound can enhance cancer detection rates when added to mammography.⁸

Breast cancers that are not detected by mammography are more likely to be invasive, and certain guidelines recommend using ultrasound as the primary screening tool instead of mammography in patients with dense breasts, such as in Asian populations.⁹ However, ultrasound also can increase false positives and, consequently, unnecessary biopsies. Ongoing technological advancements aim to address these challenges.

Despite breast cancer being most prevalent among nonHispanic White women, mortality rates are the highest in Black women⁸ who face higher risks of marker-negative cancers and often present with advanced stage diagnoses.⁸ This disparity is associated with systemic inequities, such as residential segregation, harmful environmental exposures, and limited access to timely healthcare.

Addressing this disparity requires a comprehensive approach starting with improved access to screening and treatment, as well as addressing the various other contributing social determinants of health. Modeling studies have found that screening Black women annually and other women biennially would reduce the disparity in mortality; however, biennial screening is more favorable in terms of benefits and harms.¹

Achieving the targets set by Healthy People 2030 for breast cancer screening will require an increase in the number of women screened and those receiving evidence-based preventive care. Healthcare policy is one method of alleviating obstacles to breast cancer screening. Such barriers to screening may disproportionately affect Black women and other vulnerable groups, and tackling them may reduce disparities in breast cancer mortality.

The SCREENS for Cancer Act was passed by the US House Energy and Commerce Health Subcommittee in 2023. This act reauthorizes the National Breast and Cervical Cancer Early Detection Program, which provides screening, diagnostic, and treatment services to low-income, uninsured, and underinsured populations. Furthermore, the Find It Early Act proposed by Reps. Rosa DeLauro and Brian Fitzpatrick, and supported by the ACS, would ensure all health insurance plans cover screening and diagnostic breast imaging without cost sharing, which may lead to an increase in supplementary investigations for high-risk patients.

Emerging Screening Modalities

Various innovations have been devised to augment traditional imaging techniques in breast cancer detection and surveillance. Ultrasound elastography, for example, identifies malignant tissue based on its stiffness relative to its surrounding tissues, potentially enabling earlier detection of smaller tumors and reducing unnecessary biopsies in some cases.⁹

Contrast-enhanced ultrasound can enhance visualization of the vasculature, aiding in the detection of malignancies by way of increased vascularity.⁹ Automated whole-breast ultrasound, optoacoustic imaging, and ultrasound transmission tomography are other modalities that may enhance ultrasound screening compared to traditional handheld ultrasonography. Radiomics is another novel approach that leverages machine learning and artificial intelligence to evaluate imaging results that may provide valuable additional information to enhance diagnosis.¹

Liquid biopsies are emerging techniques that use ELISA (enzyme-linked immunosorbent assay) and mass spectrometric analysis of proteins in biological fluids to evaluate genomic profiles and can be used to monitor treatment response, resistance, and the presence of other malignancies.¹⁰ Human epidermal growth factor receptor, carcinoembryonic antigen, the oncogenic protein RS/DJ-1, and circulating cytokeratin fragments may be detected using serum samples.¹⁰

Both digital mammography and digital breast tomosynthesis (DBT) are endorsed by the USPSTF. However, DBT must be supplemented with synthetic or traditional digital mammography.² Mammography has a sensitivity of 67.8% and a specificity of 75.0%, while DBT has a sensitivity of 90.8% and a specificity of 96.5% with the disadvantage of doubling the radiation exposure.¹⁰ DBT can reduce the masking effect seen in dense breasts and detect smaller tumors.¹¹

Other proteins such as apolipoprotein C1, carbonic anhydrase 1, and neural cell adhesion molecule L1-like protein may be expressed in different quantities in those with breast cancer compared to otherwise healthy women.¹⁰ Similarly, S100A8, S100A9, and galectin-3-binding protein are ocular proteins whose quantitative levels may vary in the presence of breast cancer, detected by analyzing tear samples.¹²

In addition to addressing the need for more robust studies investigating risk-based approaches, screening intervals, and supplementary investigations, it is evident that advancements in noninvasive tests with high specificity would be most beneficial in reducing the harm from false-positive screening results. These advancements would support more frequent screening in wider age groups.

Screening modalities such as the abbreviated breast MRI protocol being investigated in the FAST trial,¹³ contrast-enhanced spectral mammography being studied in the Contrast-enhanced Mammography, Early detection biomarkers, Risk assessment, and Imaging Technologies (C-MERIT) study,¹⁴ and the Rapid Access to Contrast-Enhanced spectral mammogRaphy (RACER) study,¹⁵ blood-based detection of circulating tumor cells (TriNetra)¹⁶ and tear-based screening assays (Melody^®)¹⁷ are some of the investigational screening modalities in various stages of development.

Risk-based approaches to screening are being investigated in the Women Informed to Screen Depending On Measures of Risk (WISDOM) and Tomosynthesis Mammographic Imaging Screening Trial (TMIST) studies.^8,18,19 Additionally, the TMIST trial is comparing DBT and digital mammography to determine which one is superior for detection of early breast cancer. Various methods and approaches to risk assessment also are under investigation, including salivary genetic tests, questionnaires, and various outreach and educational interventions.

These advancements highlight the multidimensional approach required to diagnose and surveil breast cancer by leveraging cutting-edge technology to enhance accuracy, reduce invasiveness, and improve overall patient outcomes.

Innovative approaches like conducting mammograms in the workplace have improved screening use in Japan,²⁰ and intensive case management has yielded promising results in inner-city populations in the US.²¹ Educational and outreach programs using mobile mammography units, text messaging, and chatbots are other approaches to increase screening rates. These initiatives aim to make screening more accessible and convenient for diverse populations, ultimately improving early detection and outcomes in breast cancer care.

While breast cancer screening guidelines vary among organizations, several clinical trials investigating improved imaging techniques, liquid biopsies, and risk-based approaches may provide the necessary evidence for the USPSTF to update its guidelines. In an effort to increase breast cancer screening and detection rates, several policies have been proposed with bipartisan support. Keeping up with current guidelines, emerging techniques, and healthcare policy initiatives will allow surgeons and allied professionals to better advocate for patients.

Dr. Kaiser Sadiq, originally from India, earned his medical degree from JIPMER, a prestigious Indian medical school. He then obtained Educational Commission for Foreign Medical Graduates certification and completed several clinical rotations at US institutions, including the University of California San Diego and University of Miami. Dr. Kaiser is an active member of the RAS-ACS Membership, Education, Communications, and Global Surgery committees and is preparing to apply for general surgery residency.

References

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