Durable Complete Response With Immune Checkpoint Inhibitor in Breast Cancer With High Tumor Mutational Burden and APOBEC Signature

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Increasing data support the importance of preexisting host immune response and neoantigen burden for determining response to immune checkpoint inhibitors (ICIs). In lung cancer and melanoma, tumor mutational burden (TMB) has emerged as an independent biomarker for ICI response. However, the significance of TMB in breast cancer, particularly in the context of PD-L1 negativity, remains unclear. This report describes a patient with HER2-negative breast cancer with high TMB and an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) trinucleotide signature; her disease was refractory to multiple lines of treatments but achieved durable complete response using ICIs and capecitabine. Additional analysis of the tumor revealed a low amount of stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 negativity, reflecting a poor preexisting host immune response. In collaboration with Foundation Medicine, comprehensive genomic profiling from 14,867 patients with breast cancer with the FoundationOne test was evaluated. Using the cutoff of ≥10 mutations/megabase (mut/Mb) for high TMB, PD-L1 positivity and TMB-high populations were not significantly overlapping (odds ratio, 1.02; P=.87). Up to 79% of TMB-high tumors with >20 mut/Mb were PD-L1–negative. Our study highlights that despite having low TILs and PD-L1 negativity, some patients may still experience response to ICIs.

Submitted September 10, 2019; accepted for publication January 30, 2020.

Author contributions: Obtained FoundationOne data: Sokol. Obtained pathology images: Nassar. Manuscript preparation: Chumsri. Manuscript editing: Sokol, Soyano-Muller, Parrondo, Reynolds, Thompson. Final approval of manuscript: Sokol, Soyano-Muller, Parrondo, Reynolds, Thompson.

Disclosures: Dr. Sokol has disclosed that he is employed by Foundation Medicine and that he owns stock in Roche. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the Breast Cancer Research Foundation (BCRF-17-161).

Correspondence: Saranya Chumsri, MD, Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224. Email: chumsri.saranya@mayo.edu
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