Prevalence and mutational determinants of high tumor mutation burden in breast cancer

R Barroso-Sousa; E Jain; O Cohen; D Kim; J Buendia-Buendia; E Winer; N Lin; S M Tolaney; N Wagle

doi:10.1016/j.annonc.2019.11.010

Prevalence and mutational determinants of high tumor mutation burden in breast cancer

Ann Oncol. 2020 Mar;31(3):387-394. doi: 10.1016/j.annonc.2019.11.010. Epub 2020 Jan 9.

Authors

R Barroso-Sousa¹, E Jain², O Cohen², D Kim², J Buendia-Buendia², E Winer³, N Lin³, S M Tolaney³, N Wagle⁴

Affiliations

¹ Department of Medical Oncology; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, USA.
² Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, USA; Broad Institute of MIT and Harvard, Cambridge, USA.
³ Department of Medical Oncology; Harvard Medical School, Boston, USA; Department of Medicine, Brigham and Women's Hospital, Boston, USA.
⁴ Department of Medical Oncology; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, USA; Broad Institute of MIT and Harvard, Cambridge, USA; Harvard Medical School, Boston, USA; Department of Medicine, Brigham and Women's Hospital, Boston, USA. Electronic address: nikhil_wagle@dfci.harvard.edu.

PMID: 32067680
DOI: 10.1016/j.annonc.2019.11.010

Abstract

Background: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer.

Patients and methods: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB 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 TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors.

Results: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10^-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (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 tumors. 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.

Conclusion: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

Keywords: APOBEC; breast cancer; immunotherapy; mismatch repair deficiency; mutational signatures; tumor mutational burden.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / drug therapy
Breast Neoplasms* / epidemiology
Breast Neoplasms* / genetics
Exome Sequencing
Genomics
Humans
Mutation
Prevalence

Grants and funding

P50 CA168504/CA/NCI NIH HHS/United States