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Harvard Medical School

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Clin. Cancer Res., Nov 01 2022, 28 (21) | https://doi.org/10.1158/1078-0432.CCR-22-0749 Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

Felipe Batalini ^1,2,3,†, Doga C. Gulhan ^4,†, Victor Mao⁴, Antuan Tran ⁴, Madeline Polak ^1,5, Niya Xiong ^1,6, Nabihah Tayob ^1,6, Nadine M.Tung ^1,2, Eric P. Winer ^1,5, Erica L. Mayer ^1,5, Stian Knappskog⁷, Per E. Lønning ⁷, Ursula A. Matulonis ^1,8, Panagiotis A. Konstantinopoulos ^1,8, David B. Solit ⁹, Helen Won ⁹, Hans P. Eikesdal ⁷, Peter J. Park ^4,*, and Gerburg M. Wulf ^1,2,*

¹Harvard Medical School, Department of Medicine, Boston, Massachusetts.
²Beth Israel Deaconess Medical Center, Division of Medical Oncology and Cancer Research Institute, Boston, Massachusetts.
³Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁴Harvard Medical School, Department of Biomedical Informatics, Boston, Massachusetts.
⁵Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts.
⁶Dana-Farber Cancer Institute, Department of Data Sciences, Boston, Massachusetts.
⁷University of Bergen, Department of Clinical Science, Bergen, Norway.
⁸Dana-Farber Cancer Institute, Department of Gynecologic Oncology, Boston, Massachusetts.
⁹Memorial Sloan Kettering Cancer Center, New York, New York.

^†F. Batalini and D.C. Gulhan contributed equally as the co-first authors in this article.
^*Corresponding authors: correspondence to Peter J. Park or Gerburg M. Wulf

Abstract

Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.

Experimental design: We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973).

Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score.

Conclusions: Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.

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