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Frequency, Mutational Patterns, and Genomic Profile of Hypermutated Breast Cancer

High tumour mutational burden more common in metastatic tumours
17 Jan 2020
Tumour Immunology;  Translational Research
Breast Cancer

A group of researchers from Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Harvard Medical School, Brigham and Women's Hospital in Boston, US found that high tumour mutational burden is present in 5% of all breast cancers and is more common in metastatic tumours. While different mutational signatures are present in hypermutated tumours, APOBEC activity is the most common process. Patients with hypermutated breast cancers may represent a subgroup more likely to benefit from immune checkpoint inhibitors. The findings are published online on 9 January 2020 in the Annals of Oncology.

Somatic mutations are main source of tumour specific neoantigens, which are a key target of antitumor immunity. High tumour mutational burden is associated with high neoantigen burden, high T-cell infiltration, and high response rates to immune checkpoint inhibitors across different tumour types. However, only a small subset of patients with metastatic breast cancer have benefited from PD-1/PD-L1 inhibitors.

The authors wrote in the study background that prevalence of hypermutated breast cancer is not well described. Evaluating other predictive biomarkers may help increase the number of breast cancer patients who benefit from immune checkpoint inhibitors. Recently, the IMPASSION130 study showed a benefit of atezolizumab plus nab-paclitaxel therapy in patients with metastatic triple-negative breast cancer with ≥1% PD-L1 expression on tumour-infiltrating immune cells.

Hypermutated breast cancers analysis

In this latest research study, the authors evaluated the prevalence, pathological characteristics, mutational patterns, and genomic profiles of hypermutated breast cancers by analyzing publicly available genomic data from 3969 breast cancer tumour samples. The prevalence of hypermutated breast cancer was determined among patients' samples that underwent whole exome sequencing or gene panel sequencing.

The samples were classified as having high tumour mutational burden if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high tumour mutational burden, the mutational patterns and genomic profiles were determined. A subset of patients was treated with immune checkpoint inhibitors.

The median tumour mutational burden was 2.63 mut/Mb. The median tumour mutational burden significantly varied according to the tumour subtype (HR-negative/HER2-negative >HER2-positive >HR-positive/HER2-negative, p < 0.05) and sample type (metastatic > primary, p = 2.2 × 10−16).

Hypermutated tumours were found in 198 patients (5%), with enrichment in metastatic versus primary tumours (8.4% versus 2.9%, p = 6.5 × 10−14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumours. Three patients with hypermutated breast cancer (including two with a dominant APOBEC activity signature and one with a dominant MMRd signature) treated with pembrolizumab-based therapies derived an objective and durable response to therapy.

The authors concluded that their findings demonstrate that 5% of breast cancers have high tumour mutational burden, with enrichment in metastatic tumours. These tumours are associated with a higher neoantigen burden and increased T-cell infiltration. Different mutational signatures are present in this population with APOBEC activity being the most common.

Preliminary data suggest that hypermutated breast cancers are likely to benefit from immune checkpoint inhibitor therapy, independent of underlying mutational process.

The study was supported by the NCI Breast Cancer SPORE, Susan G. Komen, The V Foundation, The Breast Cancer Alliance, The Cancer Couch Foundation, Twisted Pink, Hope Scarves, Breast Cancer Research Foundation, ACT, the Fashion Footwear Association of New York and the Friends of the Dana-Farber Cancer Institute.


Barroso-Sousa R, Jain E, Cohen E, et al. Prevalence and mutational determinants of high tumor mutation burden in breast cancerAnnals of Oncology; Published online 9 January 2020. https://doi.org/10.1016/j.annonc.2019.11.010

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