Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Wijngaart, Hanneke van der; Hoes, Louisa R.; Henegouwen, Jade M. van Berge; Velden, Daphne van der; Zeverijn, Laurien J.; Roepman, Paul; Werkhoven, Erik van; Leng, Wendy W.J. de; Jansen, Anne M.L.; Mehra, Niven; Robbrecht, Debbie G.J.; Labots, Mariëtte; Groot, Derk Jan A. de; Hoeben, Ann; Hamberg, Paul; Gelderblom, Hans; Voest, Emile E.; Verheul, Henk M.W.

doi:10.1158/1078-0432.ccr-21-1104

Cited by 19 publications

(11 citation statements)

References 58 publications

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“…Different platinum-resistant BRCA1 methylated models show significant BRCA1 gene expression, associated with a low percentage of BRCA1 methylation and increased levels of RAD51 foci upon cisplatin treatment, supporting incomplete promoter methylation as potential mechanism of platinum resistance in these tumours. This is in accordance with recent studies demonstrating that biallelic BRCA1/2 inactivation was required for response to PARP inhibitors and platinum [31][32][33] .…”

Section: Discussionsupporting

confidence: 93%

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

et al. 2023

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The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.

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Section: Discussionsupporting

confidence: 93%

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

et al. 2023

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“…The primary endpoints of this study, as previously described [ 25 , 28 , 29 ], were clinical benefit (CB) and safety. CB was defined by confirmed complete or partial response (CR; PR) or stable disease (SD) for at least 16 weeks, according to RECIST 1.1. or RANO criteria and measured at least two times, at least 28 days apart in a particular cohort.…”

Section: Methodsmentioning

confidence: 99%

“…In DRUP, as previously described [ 25 , 28 , 29 ], cohorts are monitored using a Simon-like two-stage “admissible” monitoring plan to identify cohorts with evidence of activity [ 33 ]. If no CB is observed in any of the first enrolled 8 patients in the cohort, the cohort will be closed.…”

Section: Methodsmentioning

confidence: 99%

“…The null hypothesis and alternative hypothesis to be tested are defined as clinical benefit rate (CBR) of 10% versus ≥ 30%. This design has 85% power to reject the null hypothesis of a CBR of 10% when the true CBR is 30%, with a one-sided alpha error rate of 7.8% [ 29 ]. Cohorts with a response rate of ≥ 30% are considered potentially successful and may proceed to stage III in DRUP to validate and confirm results earlier found [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

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Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours

et al. 2023

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Background In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. Patients and methods Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. Results Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. Conclusion Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Trial registration Clinical trial registration: NCT02925234. First registration date: 05/10/2016.

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“…Third, the interplay between somatic mutations and (possible) germline DNA alterations is becoming increasingly important in targeted therapies, e.g. carriers of germline BReast CAncer genes (BRCA) mutations without biallelic loss of function do not respond to Poly(ADP-Ribose) Polymerase (PARP) inhibitors [12,13] and wholegenome sequencing (WGS) potentially offers insight into both tumor and germline. Fourth, there is an increasing demand for more complex biomarkers like signatures for homologous repair deficiency (HRD), microsatellite instability (MSI), and tumor mutational load, which increasingly guide therapeutic decisions and can act as valid proxies of epigenetic inactivation of druggable pathways [1,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Feasibility of whole‐genome sequencing‐based tumor diagnostics in routine pathology practice

Samsom

Schipper

Roepman

et al. 2022

The Journal of Pathology

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The current increase in number and diversity of targeted anticancer agents poses challenges to the logistics and timeliness of molecular diagnostics (MolDx), resulting in underdiagnosis and treatment. Whole‐genome sequencing (WGS) may provide a sustainable solution for addressing current as well as future diagnostic challenges. The present study therefore aimed to prospectively assess feasibility, validity, and value of WGS in routine clinical practice. WGS was conducted independently of, and in parallel with, standard of care (SOC) diagnostics on routinely obtained tumor samples from 1,200 consecutive patients with metastatic cancer. Results from both tests were compared and discussed in a dedicated tumor board. From 1,200 patients, 1,302 samples were obtained, of which 1,216 contained tumor cells. WGS was successful in 70% (854/1,216) of samples with a median turnaround time of 11 days. Low tumor purity (<20%) was the main reason for not completing WGS. WGS identified 99.2% and SOC MolDx 99.7% of the total of 896 biomarkers found in genomic regions covered by both tests. Actionable biomarkers were found in 603/848 patients (71%). Of the 936 associated therapy options identified by WGS, 343 were identified with SOC MolDx (36.6%). Biomarker‐based therapy was started in 147 patients. WGS revealed 49 not previously identified pathogenic germline variants. Fresh‐frozen, instead of formalin‐fixed and paraffin‐embedded, sample logistics were easily adopted as experienced by the professionals involved. WGS for patients with metastatic cancer is well feasible in routine clinical practice, successfully yielding comprehensive genomic profiling for the vast majority of patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Cited by 19 publications

References 58 publications

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours

Feasibility of whole‐genome sequencing‐based tumor diagnostics in routine pathology practice

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