MMR-deficient breast cancer tumors can be pinpointed using mutational signature analysis

By Liz Meszaros, MDLinx
Published September 14, 2017

Key Takeaways

Mutation patterns may be helpful in identifying mismatch repair (MMR)-deficient breast cancer tumors, which may then be targeted with PD-1 immune checkpoint inhibitor treatment, according to research published in Cancer Research.

MMR-deficient tumors have 10 to 100 times more mutations compared with tumors with intact MMR pathways.

“Our research demonstrates the value of using mutation patterns to identify MMR deficiency in unselected breast cancer cases,” said Serena Nik-Zainal, MD, PhD, Cancer Research UK (CRUK) Advanced Clinician Scientist and Honorary Consultant in Clinical Genetics at the University of Cambridge and Wellcome Trust Sanger Institute, Genome Research Limited in Cambridge, United Kingdom. “These findings are important because a subset of patients may be responsive to immunotherapies such as PD-1 checkpoint blockade as has been demonstrated with MMR deficiency in colorectal and other cancers.”

For this study, Dr. Nik-Zainal and colleagues used mutational signatures, or patterns of mutagenesis, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset in 640 patients. To identify defects responsible for MMR deficiency, they searched also for mutations in multiple genes with a known association with MMR deficiency, including MLH1, MSH2, MSH6, PMS2, PMS1, SETD2, MYH11, EPCAM, TGFBR2, MLH3, and MUTYH MLH1, MSH2, MSH6, PMS2, PMS1, SETD2, MYH11, EPCAM, TGFBR2, MLH3, and MUTYH.

In all, 11 of the 640 tumors harbored MMR deficiency in varying amounts. In addition to base substitution mutational signatures specific to MMR deficient tumors, they also found an average of 20,870 small insertions/deletions in the 11 MMR-deficient breast cancer tumors compared with only a fraction, 270 on average, in the non-MMR-deficient tumors.

“We found variations of mutations, including single base substitutions and small insertions/deletions,” explained Dr. Nik-Zainal. “By looking at multiple signals, we identified a subset of tumors that would not have been detected as MMR-deficient using current clinical criteria for the assessment of breast cancer,” she said.

Because of its high sensitivity and specificity for classifying tumors, mutational signature analysis may be a better biomarker for future clinical trials, noted Dr. Nik-Zainal.

“In some recent pharmaceutical trials, the protocols used single biomarkers and startlingly different cut-off points to measure PD-L1 expression for tumor classification, which may explain the different results in progression-free survival outcomes,” she explained. “With mutational signature analysis that investigates multiple mutations, we can see a direct readout of the pathway that has gone wrong. Our method might outperform the use of a single biomarker.”

The previously published whole genome sequencing data was sponsored by the following organizations: the European Community’s Seventh Framework Programme; the Breast Cancer Somatic Genetics Study (BASIS); Wellcome Trust; Institut National du Cancer (the French National Cancer Institute); and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. The mutational signature analysis was sponsored by CRUK and Wellcome Trust.

Dr. Nik-Zainal is a consultant for Artios Pharma Ltd. She has filed five patent applications with the UK Intellectual Property Office for various clinical applications of mutational signatures.

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