Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

Marla Lipsyc-Sharf, MD; Elza C. de Bruin, PhD; Katheryn Santos, BS; Robert McEwen, PhD; Daniel Stetson, MS; Ashka Patel, BS; Gregory J. Kirkner, MPH; Melissa E. Hughes, MSc; Sara M. Tolaney, MD, MPH; Ann H. Partridge, MD, MPH; Ian E. Krop, MD, PhD; Charlene Knape, MT; Ute Feger, PhD; Giovanni Marsico, PhD; Karen Howarth, PhD; Eric P. Winer, MD; Nancy U. Lin, MD; Heather A. Parsons, MD, MPH


J Clin Oncol. 2022;40(22):2408-2419. 

In This Article

Abstract and Introduction


Purpose: To examine the prevalence and dynamics of circulating tumor DNA (ctDNA) and its association with metastatic recurrence in patients with high-risk early-stage hormone receptor–positive breast cancer (HR+ BC) more than 5 years from diagnosis.

Methods: We enrolled 103 patients with high-risk stage II-III HR+ BC diagnosed more than 5 years prior without clinical evidence of recurrence. We performed whole-exome sequencing (WES) on primary tumor tissue to identify somatic mutations tracked via a personalized, tumor-informed ctDNA test to detect minimal residual disease (MRD). We collected plasma at the time of consent and at routine visits every 6–12 months. Patients were followed for clinical recurrence.

Results: In total, 85 of 103 patients had sufficient tumor tissue; of them, 83 of 85 (97.6%) patients had successful whole-exome sequencing. Personalized ctDNA assays were designed targeting a median of 36 variants to test 219 plasma samples. The median time from diagnosis to first sample was 8.4 years. The median follow-up was 10.4 years from diagnosis and 2.0 years from first sample. The median number of plasma samples per patient was two. Eight patients (10%) had positive MRD testing at any time point. Six patients (7.2%) developed distant metastatic recurrence, all of whom were MRD-positive before overt clinical recurrence, with median ctDNA lead time of 12.4 months. MRD was not identified in one patient (1.2%) with local recurrence. Two of eight MRD-positive patients had not had clinical recurrence at last follow-up.

Conclusion: In this prospective study, in patients with high-risk HR+ BC in the late adjuvant setting, ctDNA was identified a median of 1 year before all cases of distant metastasis. Future studies will determine if ctDNA-guided intervention in patients with HR+ BC can alter clinical outcomes.


Breast cancer is the most commonly diagnosed cancer worldwide.[1] Most breast cancers, nearly 80%, are hormone receptor–positive (HR+).[2] Unlike other subtypes of breast cancers in which risk of recurrence decreases 5 years after diagnosis, the recurrence risk for HR+ breast cancer remains steady from 5 years to at least 20 years with some patients experiencing recurrence three decades after diagnosis.[3,4] In some high-risk patients, breast cancer–specific mortality over 5 years after diagnosis exceeds 30%.[5] For patients with late recurrences, 10-year breast cancer–specific mortality approaches 50%.[6] Although about 6% of patients with breast cancer are diagnosed with de novo metastatic breast cancer, most are diagnosed with earlier-stage disease and treated with curative-intent local and systemic therapy.[7] Of more than 150,000 patients currently living with metastatic breast cancer, approximately three quarters initially presented with early-stage disease.[8]

Most distant recurrences of HR+ breast cancers occur more than 5 years after initial diagnosis.[4,9] Distant recurrence after resection of primary tumor arises from residual disease not detected in current practice via imaging, laboratory tests, or clinical assessment. The benefits of adjuvant chemotherapy and hormonal therapy in preventing recurrence are well-established, demonstrating the importance of treating residual disease.[3,10,11] Adjuvant treatment for patients with HR+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer is tailored on the basis of assessment of recurrence risk using clinical features and tumor molecular testing before or at the time of surgery. In routine clinical practice, recurrence risk is not reliably reassessed after the perioperative period.[12]

Detection of minimal residual disease (MRD) via plasma circulating tumor DNA (ctDNA) is associated with high risk of breast cancer recurrence, yet little is known about ctDNA in the late adjuvant setting in HR+ breast cancer.[13–19] In one cohort of 49 patients up to 4 years after definitive treatment, including 34 with HR+/HER2– disease, investigators identified ctDNA in 16 of 18 patients with relapsed breast cancer with lead time up to 2 years.[14] In another cohort of 84 patients from the I-SPY-2 trial, including 29 HR+/HER2– patients, detection of ctDNA after neoadjuvant chemotherapy was associated with similarly high risk of metastatic recurrence.[15]

Some patients with high-risk HR+ breast cancer remain on adjuvant endocrine therapy (ET) for up to 10 years or longer, although the impact of treatment beyond 5 years is modest.[20,21] Accurate detection of MRD has the potential to inform whether to continue, change, or stop adjuvant therapy to maximize duration of disease-free status while minimizing therapy toxicity in patients for whom optimal benefit may have already been achieved.[22] As patients with HR+ breast cancer remain at risk for many years, it is possible that ctDNA detection in the late adjuvant setting could facilitate early identification and treatment of MRD, preventing or delaying recurrence. A foundational understanding of ctDNA characteristics in this population is necessary to inform the role of ctDNA in interventions to improve personalized adjuvant treatment and patient outcomes. Here, we report a prospective investigation of ctDNA dynamics and clinical outcomes in 83 patients in the late adjuvant setting—defined here as 5 years or more after diagnosis—of high-risk, early-stage HR+ breast cancer.