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Cell-Free DNA Assay Can Identify Microsatellite Instability–High Status in Advanced Breast Cancer

Key findings

  • This study evaluated the ability to detect microsatellite instability–high (MSI-H) status in patients with metastatic breast cancer using a plasma-based genotyping assay (Guardant360)
  • Among the 6,718 patients who had at least one gene mutation detected, MSI-H was relatively rare, noted in 42 patients (0.63%) but detectable in cell-free DNA
  • Compared with non–MSI-H tumors, MSI-H breast cancers demonstrated a significantly higher number of genomic alterations, even when analysis was limited to samples with ≥5% maximum variant allele fraction
  • Clinical data were available on 11 patients; seven had received various immune checkpoint inhibitors for a median of 92 days (range, 29–273 days)
  • With the small sample size, variety of regimens used, and the mixture of lines of therapy, this study does not provide information about which patients with MSI-H metastatic breast cancer may benefit from immunotherapy but does demonstrate a signal of efficacy

Pembrolizumab is now approved for treatment of advanced solid tumors with microsatellite instability–high (MSI-H) status and/or mismatch repair deficiency. MSI-H status is typically determined through tumor tissue genotyping.

Plasma-based genotyping ("liquid biopsy") is being explored as complementary testing, principally because it's less invasive and can be repeated easily throughout the disease course.

Researchers at the Massachusetts General Cancer Center have demonstrated that plasma-based genotyping can identify MSI-H status in patients with advanced breast cancer. A study led by Neelima Vidula, MD, a breast medical oncologist, with additional co-authors from the Mass General Cancer Center (Dejan Juric, MD, director of the Termeer Center for Targeted Therapies, and Aditya Bardia, MD, MPH, director of Precision Medicine in the Center for Breast Cancer), and colleagues from across the country was published in npj Breast Cancer.


The researchers retrospectively reviewed data on consecutive U.S. patients with metastatic breast cancer who underwent cell-free circulating tumor DNA (cfDNA) analysis with Guardant360 (Guardant Health, Redwood City, CA) between September 27, 2018 and March 12, 2020. Guardant360 analyzes single nucleotide variants in up to 74 genes.

6,718 patients had at least one alteration detected in cfDNA. Of those 42 (0.63%) had MSI-H.

Patient Characteristics

All 42 patients were female, median age 61 (range, 39–92). Comparing the MSI-H and non–MSI-H cohorts (P<0.0001 for all):

  • Median number of genomic alterations per sample overall—11 vs. 3
  • Median number of genomic alterations per sample when maximum variant allele fraction was limited to ≥5%—11 vs. 4
  • Median maximum mutant allelic fraction—16.8% vs. 2.6%

Response to Immunotherapy

The team contacted the physicians who ordered the tests of the 42 patients with MSI-H, and clinical data were received for 11 of them. Seven patients had received various immune checkpoint inhibitors for a median of 92 days (range, 29–273 days). Two patients remained on immunotherapy and chemotherapy for more than 245 days.

The small sample size, the variety of regimens used and the mixture of lines of therapy preclude any definitive conclusions about which patients with metastatic breast cancer who have cfDNA-detected MSI-H may benefit from immunotherapy, but provides a potential signal of efficacy in this setting.

of patients with metastatic breast cancer with at least one genomic alteration detected by plasma-based genotyping had microsatellite instability–high status

days was the median duration of checkpoint inhibitor immunotherapy in patients with metastatic breast cancer who had microsatellite instability–high status

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Related topics


Dejan Juric, MD and colleagues have provided proof of concept that a single genetic event—in this study, loss of PTEN expression in estrogen receptor–positive, HER2-negative advanced breast cancer—can cause cross-resistance to multiple targeted therapies and affect subsequent lines of treatment.


Aditya Bardia, MD, MPH, is the first author of the report of the phase 3 ASCENT trial, which showed a significant survival benefit for sacituzumab govitecan compared with standard chemotherapy in patients with relapsed/refractory metastatic triple-negative breast cancer.