Breast cancer has surpassed lung cancer, in terms of being the most diagnosed cancer. According to the World Health Organization report, 2.3 million women globally were diagnosed with breast cancer in 2020 alone (1). Furthermore, approximately 60 -80% of breast cancer patients are hormone receptor-positive (HR+), which unlike other breast cancer types, are known for their high recurrence rates especially in late adjuvant setting. 

The commonly available clinicopathologic tools for breast cancer screening are insufficient to determine patients at high risk of late recurrence. Detection of minimal residual disease (MRD) via plasma circulating tumor DNA (ctDNA) is one promising prognostic tool in high-risk breast cancer recurrence. Accurate detection of MRD can help oncologists to decide the optimal course of adjuvant therapy and maximize the duration of disease-free status with minimal toxicityin patients. Breast cancer patients have higher levels of ctDNA than healthy individuals; ctDNA can thus be used for screening and early detection of resistance mutations in advanced disease. Further, ctDNA clearance in early breast cancer is associated with increased rates of complete pathological response after neoadjuvant treatment. The detection of ctDNA in late adjuvant setting can facilitate early identification and treatment of MRD, thereby preventing or delaying recurrence.

A prospective study was conducted in 83 patients with high-risk HR+ stage II-III breast cancer, 5 or more years from diagnosis by researchers from Dana Farber Cancer Institute and Harvard Medical School, USA in collaboration with Astra Zeneca and Inivata Ltd to evaluate the relationship between MRD detection and patient characteristics and to study if there exists any association between MRD status and distant and local recurrence of the disease (2). 

About 90% of patients received chemotherapy, either neoadjuvant (22.7%) or adjuvant (77.3%). There were 38.6% of patients who had breast conserving surgery and radiation while remaining 61.4% had mastectomy done with (90%) or without (10%) radiation therapy. All patients received endocrine therapy and 45.8% of patients remained on adjuvant endocrine therapy at last follow-up timepoint (median clinical follow-up: 10.4 years).

The study demonstrated that about 10% of patients were MRD positive for more than 5 years from disease diagnosis without any clinical evidence of metastatic recurrence. ctDNA analysis identified MRD in all cases of distant recurrences with a median lead time of approximately 1 year. Further, the recurrence free survival of MRD- positive patients was worse than MRD-negative patients. However, ctDNA analysis could not identify MRD in local recurrence.

Although there are several limitations to this study including small sample size, the results of this study are important as clinical utility of MRD assays is not yet clearly established. This is the first study on plasma ctDNA analysis for MRD detection in late adjuvant HR+ breast cancer, which itself is a major understudied cancer type responsible for more than 40,000 deaths in the US alone. With several clinical studies now undermining MRD detection in treatment interventions, the findings of this study may thus help in characterisation and incorporation of ctDNA detection in prospective clinical studies.

References:

1.https://www.who.int/news-room/fact-sheets/detail/breast-cancer. Last accessed on 25 Aug 2022.

2.Lipsyc-Sharf M, de Bruin EC, Katheryn Santos BS, McEwen R, Daniel Stetson MS, Ashka Patel BS, et al. Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor– Positive, Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer. Journal of Clinical Oncology. 2022 Aug;40(22).