01.16 Hypermutation in Breast Cancer: A Potential Marker for Immunotherapy?

H. M. Poushay1, M. Asaoka1, K. Takabe1  1Roswell Park Cancer Institute,Department Of Surgical Oncology,Buffalo, NY, USA

Immunotherapy has revolutionized treatment of many cancers, although its role in breast cancer treatment has yet to be well-established. Immune checkpoint inhibitors (ICIs) have demonstrated significant therapeutic responses across a variety of cancers, and may prolong overall survival in tumors with high mutation loads. One such ICI is the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitor, which targets the PD-1/PD-L1 pathway, resulting in restoration of the immune system’s anti-tumor response. To investigate the potential role of ICIs in the treatment of breast cancer, we sought to compare hypermutated breast cancers to non-hypermutated breast cancers. We hypothesized that hypermutated breast cancers would have increased heterogeneity, leading to an increased presence of tumor-infiltrating lymphocytes (TILs), which has been shown to portend favorable response to immunotherapy.  We also hypothesized that the hypermutated group would have higher cytolytic activity and PD-1/PD-L1 activity; the latter has also been suggested as a predictor of cancer response to PD-1/PD-L1 inhibitor therapy.


Genomic and clinical data of 1065 breast cancer patients were obtained from The Cancer Genome Atlas (TCGA) and the Pan-Cancer Atlas.

We defined hypermutated tumors as those with non-silent mutation rate greater than 3.0.

Cytolytic activity (CYT), T cell receptor (TCR) diversity, and tumor infiltrating immune cell composition were calculated by CIBERSORT. Categorical variables were compared by Fisher's exact test (p<0.05 considered significant).


Of the 1065 patients, 114 (10.7%) were identified as having hypermutated tumors. The incidence of hypermutation was more frequent in older patients (age ≥50 vs. <50; 12.1% vs. 7.4%; p=0.03; odds ratio [OR]=1.7), in ER-negative compared to ER-positive tumors (18.6% vs. 8.8%; p <0.01; OR=2.4), but was not associated with cancer stage (p=0.485) or HER2 receptor status (p=0.079). Intra-tumor heterogeneity was higher in hypermutated tumors (p=0.014). Activated CD4 T-cells (p<0.001), macrophage M1 (p<0.001) and gamma delta T-cells (p<0.001) were higher in hypermutated tumors, whereas immune restraining regulatory T cells were lower (p=0.004). Reflecting the infiltration of immune activating cells, gene expression associated with TILs (p<0.001) and TCR diversity (p<0.001) were higher in the hypermutated group. Expression of immune checkpoint molecules PD-1 (p<0.001) and PD-L1 (p<0.001) were increased in the hypermutated tumor group. Finally, immune cytolytic activity was higher in the hypermutated group (p<0.001).


The results support our hypothesis that hypermutation breast cancer tumors have increased heterogeneity and cytolytic activity, and increased PD-1/PD-L1 activity. Given these findings, further study is warranted to investigate the potential role of ICIs in breast cancer treatment in selected breast cancer patients.