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Supplementary Table from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

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posted on 2023-04-01, 00:02 authored by Felipe Batalini, Doga C. Gulhan, Victor Mao, Antuan Tran, Madeline Polak, Niya Xiong, Nabihah Tayob, Nadine M. Tung, Eric P. Winer, Erica L. Mayer, Stian Knappskog, Per E. Lønning, Ursula A. Matulonis, Panagiotis A. Konstantinopoulos, David B. Solit, Helen Won, Hans P. Eikesdal, Peter J. Park, Gerburg M. Wulf
Supplementary Table from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Stand Up To Cancer (SU2C)

Stiftelsen Kristian Gerhard Jebsen (KGJF)

AstraZeneca (AstraZeneca PLC)

Pfizer UK

Helse Vest (WNRHA)

Kreftforeningen (NCS)

Norwegian Research Council

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ARTICLE ABSTRACT

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. 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). 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. 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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