Mutational signature 3 detected from clinical panel sequencing is associated with responses to olaparib in breast and ovarian cancers Journal Article

   

Authors:	Batalini, F.; Gulhan, D. C.; Mao, V.; Tran, A.; Polak, M.; Xiong, N. Y.; Tayob, N.; Tung, N. M.; Winer, E. P.; Mayer, E. L.; Knappskog, S.; Lønning7, P. E.; Matulonis, U. A.; Konstantinopoulos, P. A.; Solit, D. B.; Won, H.; Eikesdal, H. P.; Park, P. J.; Wulf, G. M.
Article Title:	Mutational signature 3 detected from clinical panel sequencing is associated with responses to olaparib in breast and ovarian cancers
Abstract:	Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCAJ/ 2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signa-ture 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 demon-strated 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 BRCAJ/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.
Keywords:	monotherapy; carboplatin; genomic instability; brca1; therapy; repair; phase-ii; maintenance; deficiency; landscape
Journal Title:	Clinical Cancer Research
Volume:	28
Issue:	21
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2022-11-01
Start Page:	4714
End Page:	4723
Language:	English
ACCESSION:	WOS:000884839800001
DOI:	10.1158/1078-0432.Ccr-22-0749
PROVIDER:	wos
PMCID:	PMC9623231
PUBMED:	36048535
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/200861