Hormone Receptor–Positive Breast Cancer Sensitive to Pembrolizumab: Evidence of the Pathogenicity of the MLH1 Variant 1835del3
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A woman with estrogen/progesterone receptor–positive, ERBB2-negative metastatic breast cancer developed progressive disease despite treatment with multiple hormonal and chemotherapeutic modalities. She carried a germline variant of MLH1 (1835del3), also known as c.1835_1837del and v612del, the pathogenicity of which has not been conclusively determined. MLH1 staining was not seen on immunohistochemical staining of her tumor tissue. The patient experienced a >5-year dramatic response to 4 doses of pembrolizumab. Family studies revealed multiple other relatives with the MLH1 1835del3 variant, as well as multiple relatives with colon cancer. The one relative with colon cancer who underwent genetic testing demonstrated the same variant. Laboratory studies revealed that the patient’s tumor showed loss of heterozygosity (LOH) in the MLH1 region, high levels of microsatellite instability, and a high tumor mutational burden. LOH in the MLH1 region, along with the remarkable clinical response to pembrolizumab treatment and the presence of the same MLH1 variant in affected relatives, supports the hypothesis that the MLH1 1835del3 variant is pathogenic. Given the patient’s family history, this likely represents an uncommon presentation of Lynch syndrome. Physicians should be alert to evaluate patients for targetable genetic variants even in unlikely clinical situations such as the one described here.
Submitted January 10, 2023; final revision received April 11, 2023; accepted for publication May 11, 2023. Published online August 29, 2023.
Disclosures: J.R. Whiteaker has disclosed serving as a consultant for CellCarta. A.G. Paulovich has disclosed serving as a consultant for CellCarta and having an ownership interest in Precision Assays LLC. The remaining authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: This work was funded by Kaplan Cancer Research Fund and in part by the National Cancer Institute of the National Institutes of Health, under the NCI Beau Biden National Cancer Moonshot (Task Order No. HHSN26100025, Applied Proteogenomics Organizational Learning and Outcomes, under Contract No. HHSN261201500003I), the NCI Clinical Proteomic Tumor Analysis Consortium (grant numbers U01CA214114 and U01CA271407), and the NCI Research Specialist program (grant number R50CA211499).
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