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

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, 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

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.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Cohort 1 details and comparison of different HRD detection methods. A, Clinical and genomic characteristics for each sample (small numbers at the bottom represent the individual study ID of each participant), grouping based on RECIST best overall response criteria. Clinical characteristics include the different cancer types and number of prior treatments. Different intervals of PFS are shown in the third row. Genomic characteristics include BRCA1/2 mutation status, Sig3+ classification by SigMA from panel and WES data, and the GIS calculated from WES. The lighter fill color of BRCA1/2mut indicates lack of LOH. B, 2 × 2 table of Sig3 status identified from WES and panel concordance is 81%. C, 2 × 2 table of GIS calculated with scarHRD versus Sig3 status from panel data. D, Mutations of BRCA1/2 versus Sig3 status. One patient had both a BRCA1 and BRCA2 mutation. Tx, therapy; WT, wild type.
Figure 2.
Figure 2.
Survival analysis according to (A and B) Sig3 status using panel data (median survival: 5.6 vs. 7.7 months in Sig3− and Sig3+ samples, respectively) and WES (median survival: 5.0 vs. 8.5 in Sig3− and Sig3+ samples respectively); C, GIS (median survival: 5.6 months vs. 7.0 months in GIS+ and GIS− samples, respectively); D,BRCA1/2mut or WT (median survival: 5.5 months vs. 7.3 months in WT vs. BRCA1/2mut samples, respectively). Cox multivariate regression including (E) Sig3 status or (F) GIS. Age, ECOG, and stage as covariates did not have significant HR and were not included as covariates. “Prior lines” refers to the number of previous lines of therapy in the metastatic setting.
Figure 3.
Figure 3.
Survival analysis according to (A) ATR amplification (median PFS 5.0 months vs.10.9 months, respectively, for samples with ATR amplification and those without). B, Cox model same as in Fig. 2E but with the additional covariate of ATR amplification. HRD is defined as panel-Sig3+ and/or BRCA1/2mut. “Prior N Tx” refers to number of prior lines of therapy.
Figure 4.
Figure 4.
Fraction of samples that are Sig3+ (top), the proportion of samples with germline BRCA1/2mut for Sig3+ and Sig3− groups (middle), and pie charts showing the fraction of samples that are Sig3+ germline BRCA1/2 WT in TNBCs from PETREMAC trial (A) and TCGA ovarian cancers and the major clinical subtypes of breast cancer (B). The fraction of samples that are Sig3+ but not germline BRCA1/2mut are shown below the pie charts in red and the fractions are indicated below. Pink: Sig3+ and germline BRCA1/2mut, Green: Sig3− and germline BRCA1/2mut, and Blue Sig3− and germline BRCA1/2 WT. C, HR-gene alterations in patients from the PETREMAC trial. D, ORR from patients from the PETREMAC trial according to panel-Sig3 classification and etiology of Sig3. Error bars denote the SE. The number of samples and the responders are denoted in parenthesis. WT, wild type.

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