Abstract

Breast cancer remains one of the most prevalent and life-threatening cancers worldwide, necessitating reliable screening and monitoring strategies. Mammography, the gold standard for breast cancer screening, remains indispensable for early detection and monitoring. However, emerging technologies such as cell-free DNA (cfDNA) testing offer a promising complementary approach, especially in risk stratification, early detection, and monitoring recurrence. This article explores how cfDNA testing can complement traditional mammography and discusses the integration of both modalities in personalized screening schedules for high-risk and breast cancer patients.

Introduction

Mammography has long been the cornerstone of breast cancer screening, widely used for early detection of tumors, including those that are too small to be felt by physical examination. Despite its effectiveness, mammography has limitations, such as false positives and negatives, especially in dense breast tissue, as well as the inability to detect cancer at the genetic or molecular level.

 In contrast, cell-free DNA testing, often referred to as a "liquid biopsy," analyzes fragmented DNA from tumor cells circulating in the bloodstream. This approach has gained attention for its potential to detect genetic mutations and monitor the presence of minimal residual disease (MRD). By combining cfDNA with mammography, clinicians can offer a more comprehensive screening and monitoring strategy, potentially improving the detection and treatment of breast cancer.

The Role of Mammography in Breast Cancer Screening

Mammograms are widely recommended for breast cancer screening based on established guidelines. For women of average risk, regular screening typically begins at age 40-45, with annual mammograms suggested for those aged 45-54, and biennial screening for those 55 and older. Mammograms are especially effective at detecting structural abnormalities in the breast, such as lumps or microcalcifications, even before they become clinically palpable.

For women at high risk—due to factors such as family history, genetic mutations (e.g., BRCA1, BRCA2), or previous breast cancer history—screening may start earlier (in the 30s) and may involve more frequent imaging or the addition of breast MRI to enhance sensitivity.

While mammograms are instrumental in early detection, they are not without limitations:

(i) They can miss tumors, especially in dense breast tissue.

(ii) They can result in false positives, leading to unnecessary follow-up procedures.

(iii) They do not assess the genetic makeup of tumors, which can influence treatment decisions and predict recurrence.

The Role of Cell-Free DNA Testing in Breast Cancer

Cell-free DNA testing is an emerging non-invasive method of detecting breast cancer by analyzing DNA fragments shed by tumors into the bloodstream. This genetic material, known as circulating tumor DNA (ctDNA), can reveal key mutations or alterations associated with cancer, such as those in the BRCA genes, p53, or others. Liquid biopsy is already being utilized for other cancers, and its use in breast cancer detection is advancing rapidly.

Key Functions of Cell-Free DNA Testing in Breast Cancer

Risk Assessment: Cell-Free DNA testing can identify genetic mutations or alterations that may predispose individuals to breast cancer, such as mutations in the BRCA1 or BRCA2 genes. This can help identify individuals at higher risk, allowing for earlier and more targeted screenings.

Early Detection: While still under investigation, cfDNA testing could potentially detect breast cancer earlier than imaging, particularly in cases where the tumor is too small or subtle to be seen on a mammogram. The plasma levels of cfDNA were significantly higher in patients with breast cancer than in patients with benign tumors  (1,2).

Monitoring Treatment Response and Recurrence: For breast cancer patients undergoing treatment, cfDNA tests can be used to monitor how well the treatment is working. cfDNA is a promising biomarker for predicting treatment response and disease outcomes in Breast Cancer patients undergoing neoadjuvant chemotherapy (NAC) (3). A reduction in ctDNA levels suggests a positive treatment response, while rising levels may indicate recurrence or minimal residual disease. 

Detecting Micrometastasis: cfDNA testing can help in detecting small amounts of cancer cells that have spread to other parts of the body, something that mammography cannot detect, especially in the early stages of metastasis.

How Cell-Free DNA Testing Can Complement Mammograms?

While mammography remains the gold standard for structural breast cancer detection, cfDNA testing offers distinct advantages in understanding the genetic landscape of a patient's cancer, helping to personalize treatment and detect recurrence at earlier stages. Below are ways in which cfDNA can complement mammography:

Improved Early Detection: Mammography is effective at detecting structural changes in the breast, but it can miss smaller or more diffuse cancers, particularly in dense tissue. cfDNA testing, on the other hand, might detect the presence of genetic material from cancerous cells before they form palpable lumps or visible abnormalities. This could lead to earlier detection, especially in high-risk individuals or those with dense breasts.

Refining Risk Assessment: Cell-Free DNA testing can help refine risk predictions in patients with a family history or genetic predisposition. For example, identifying genetic mutations such as BRCA1 or BRCA2 mutations through cfDNA analysis can lead to more targeted screening plans, including earlier or more frequent mammograms or the addition of other imaging techniques like breast MRI.

Monitoring Treatment Response and Residual Disease: For breast cancer patients undergoing treatment, cfDNA testing can be used to monitor how well the tumor is responding to therapySerial plasma ctDNA monitoring is effective in predicting the progression of a disease and evaluating how well a patient is responding to current therapy (4). If ctDNA levels fall, this indicates that the cancer is likely responding to treatment. Rising ctDNA levels, on the other hand, can indicate recurrence, prompting earlier follow-up imaging (such as mammograms or MRIs). This approach can help avoid unnecessary imaging when cfDNA results suggest no recurrence.

Guiding Therapy Decisions: cfDNA testing can identify specific genetic mutations that can guide the use of targeted therapies. For example, if ctDNA testing identifies a mutation that is susceptible to a specific targeted therapy, this can help personalize the treatment plan. This would be in addition to structural imaging like mammography to assess the tumor's size and spread.

Assessment of Biomarkers using cfDNA: Up to 40% of cases of breast cancer are thought to have PIK3CA mutations [5]. Naturally, PIK3CA has been thoroughly studied as a potential therapeutic target due to its role in oncogenesis [6]. According to published research, liquid biopsies have the potential to be a trustworthy method for determining whether breast cancer has PIK3CA mutations (7 & 8). ESR1 mutations are prognostic of adverse outcomes because they can be found in ctDNA with a median of 6.7 months before the disease actually progresses (9). Thus far, phase II clinical trials (10,11,12) have conducted systematic ctDNA-based HER2 mutation testing to assess the effectiveness of neratinib in the treatment of previously treated locally advanced/metastatic HER2-mut BC (either alone or in combination with fulvestrant, depending on the HR status, ER-negative or ER +respectively).

Suggestive Screening and Follow-Up Schedule for Breast Cancer Patients

Conclusion

Mammography remains an essential tool for breast cancer screening, especially in early detection of tumors and monitoring treatment effectiveness. However, cfDNA testing, as a non-invasive method of detecting genetic mutations and monitoring cancer recurrence, offers significant complementary value. By integrating cfDNA testing with mammography, clinicians can offer a more personalized, precise, and comprehensive approach to breast cancer detection and management. As cfDNA testing technology continues to evolve, its role in early detection, monitoring of residual disease, and informing treatment decisions is expected to grow, enhancing the overall effectiveness of breast cancer care.