Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient

Abstract

Background: In the field of breast cancer tumor biology, triple-negative breast cancer patients are the main focus of current clinical trials exploring the use of immune checkpoint inhibitors due to higher frequencies of somatic mutations, neoantigens, and resulting tumor-specific T-cell reactivity. Case Report: Here, we present the case of a 66-year-old woman with metastatic luminal breast cancer that rapidly responded to monotherapy with pembrolizumab, a monoclonal anti-PD-1 antibody. This patient obtained a partial clinical response within the first cycle of treatment and an ongoing durable complete remission after 12 weeks. Except for a transient immune-related thyreoiditis, there were no side effects observed offering remarkable quality of life to the patient. To evaluate the underlying mechanisms, we performed immunohistochemistry, explored the mutational landscape by whole-exome sequencing, and identified potential T-cell epitopes by prediction of neoantigens with high affinity binding to one of the patient's HLA. Briefly, we found a strong infiltration of CD8+ T cells without staining for PD-L1 in the tumor stroma. Exome sequencing revealed an enormous frequency of somatic and tumor-specific alterations, mainly C>T/G>A transitions. The mutational pattern was further linked to genome instability and deficient mismatch repair supported by the loss of MSH6 protein expression and therefore leading to susceptibility to immune checkpoint blockade. Conclusion: Within the overall goal to establish operating procedures for breast cancer immunotherapy, we propose to re-evaluate testing for deficient mismatch repair and to further intensify the search for biomarkers predictive for the success of immune checkpoint modulation including all tumor biologic subtypes of breast cancer.

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

“…Using our assay, we identified 31 MMR-deficient cases out of 1635 that had data for all four MMR biomarkers (MSH2, MSH6, MLH1 and PMS2). Despite its relative rarity in breast cancer, this population is important as MMR-deficient cancers have been highly responsive to immune therapies such as PD-1 or CDK4/6 checkpoint inhibitors [1,13,[33][34][35]. The 1.9% frequency of MMR deficiency in our study corroborates well with the genomic findings reported from the Sanger Centre, who on the basis of mutational signatures derived from whole genome sequencing of 640 cases, identified 11 cases (1.7%) as MMR-deficient [19].…”

Prognosis of Tumor Microenvironment in Luminal B-Type Breast Cancer

“…Previous study [ 47 ] analyzed 1861 advanced melanoma patients and showed that anti-CTLA4 antibody (ipilimumab) could greatly prolong patients' long-term survival. Recently, anti-PD1 antibody (nivolumab) has been found to be ineffective against metastatic renal cell carcinoma, advanced squamous cell carcinoma, non-small-cell lung cancer, melanoma, or luminal-like breast cancer [ 48 , 49 ]. Therefore, there is a need for developing novel biomarkers predictive of whether cancer patients could benefit from checkpoint immunotherapy.…”

Immunotherapy in Breast Cancer Patients: A Focus on the Use of the Currently Available Biomarkers in Oncology

“…A recent study demonstrated that dMMR can be used as a prognostic and likely predictive biomarker, but without being interchangeable with MSI as in other tumor types [98]. Additionally, a case study of a woman with metastatic, ER + , HER2breast cancer, showed durable complete remission after treatment with pembrolizumab [102]. Although dMMR cases are infrequent in breast cancer, there is an urgent need to identify and select even that fairly low proportion of patients who could benefit from immunotherapy.…”