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Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes. Breast cancer research and treatment Lenz, L., Neff, C., Solimeno, C., Cogan, E. S., Abramson, V. G., Boughey, J. C., Falkson, C., Goetz, M. P., Ford, J. M., Gradishar, W. J., Jankowitz, R. C., Kaklamani, V. G., Marcom, P. K., Richardson, A. L., Storniolo, A. M., Tung, N. M., Vinayak, S., Hodgson, D. R., Lai, Z., Dearden, S., Hennessy, B. T., Mayer, E. L., Mills, G. B., Slavin, T. P., Gutin, A., Connolly, R. M., Telli, M. L., Stearns, V., Lanchbury, J. S., Timms, K. M. 2023

Abstract

A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of =?42, though recent studies have explored the utility of a lower threshold (GIS?=?33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER?+?BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer.Ovarian cancer and breast cancer (ER?+?BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes.A total of 560 ovarian cancer, 805 ER?+?BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER?+?BC (p?=?0.015), but not TNBC (p?=?0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of =?42 and =?33 were significant predictors of response to platinum therapy.This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER?+?BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

View details for DOI 10.1007/s10549-023-07046-3

View details for PubMedID 37589839