Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Abstract Background: Recent data demonstrate that patients with early-stage triple negative breast cancer (TNBC) benefit from escalating adjuvant treatment with capecitabine. However, since a substantial proportion of patients does not benefit, predictive biomarkers to select those individuals upfront are needed. Over half of all TNBCs have a BRCA1-like DNA copy number signature similar to the profile found in germline BRCA1-mutated breast cancers and indicative for homologous recombination deficiency. We evaluate this signature as a predictive biomarker for capecitabine benefit in archived specimens of the randomized controlled FinXX trial. Additionally, we compared the concordance of our DNA-based BRCA1-like classifier with the RNA-based NanoString BRCAness signature. Methods: Early-stage TNBC patients were randomized between adjuvant capecitabine-containing chemotherapy (TX+CEX: capecitabine plus docetaxel, followed by cyclophosphamide, epirubicin and capecitabine) and conventional adjuvant chemotherapy (T+CEF: docetaxel, followed by cyclophosphamide, epirubicin, and fluorouracil). Breast tumor BRCA1-like status was determined on low coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridization algorithm. We used interaction analysis in proportional hazards models to evaluate whether benefit of adjuvant capecitabine-containing versus conventional chemotherapy differs between BRCA1-like and non-BRCA1-like tumors in early-stage TNBC patients.Results: For 129 (63.9%) of the 202 TNBC patients the BRCA1-like status could be determined. Thirty-five recurrences and 32 deaths occurred during a median follow-up of 10.7 years. The capecitabine effect on recurrence-free survival did not significantly differ between the 68 patients (52.7%) with a BRCA1-like tumor (HR 0.66, 95% CI 0.24-1.81) and others (HR 0.23, 95% CI 0.08-0.70, P interaction = 0.17), also after adjustment for clinico-pathological variables. Conclusions: In the FinXX trial, the BRCA1-like status was not associated with a differential benefit from capecitabine-containing adjuvant chemotherapy compared to conventional chemotherapy in the TNBC subgroup. Based on this study, it is unlikely that the BRCA1-like classifier can be used to distinguish patients who do and do not benefit from capecitabine-enriched standard adjuvant chemotherapy.

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Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

10.1101/681114 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zsofia Sztupinszki ◽

Miklos Diossy ◽

Marcin Krzystanek ◽

Judit Borcsok ◽

Mark Pomerantz ◽

...

Keyword(s):

Prostate Cancer ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Next Generation Sequencing Data ◽

Parp Inhibition ◽

Sequencing Data ◽

Mutational Signatures ◽

Homologous Recombination Deficiency ◽

Platinum Based Chemotherapy ◽

Inhibitor Treatment

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

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Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer

npj Breast Cancer ◽

10.1038/s41523-018-0066-6 ◽

2018 ◽

Vol 4 (1) ◽

Cited By ~ 14

Author(s):

Zsofia Sztupinszki ◽

Miklos Diossy ◽

Marcin Krzystanek ◽

Lilla Reiniger ◽

István Csabai ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Homologous Recombination ◽

Snp Array ◽

Next Generation Sequencing Data ◽

Next Generation ◽

Sequencing Data ◽

Homologous Recombination Deficiency ◽

Generation Sequencing

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PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

Journal of Clinical Medicine ◽

10.3390/jcm8040435 ◽

2019 ◽

Vol 8 (4) ◽

pp. 435 ◽

Cited By ~ 29

Author(s):

Man Keung ◽

Yanyuan Wu ◽

Jaydutt Vadgama

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Anticancer Agents ◽

Excision Repair ◽

Parp Inhibitor ◽

Predictive Biomarkers ◽

Parp Inhibitors ◽

Homologous Recombination Deficiency ◽

Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

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High dose neo-adjuvant chemotherapy in triple-negative breast cancer with evidence of homologous recombination deficiency (HRD)

Annals of Oncology ◽

10.1093/annonc/mdz240.013 ◽

2019 ◽

Vol 30 ◽

pp. v61-v62

Author(s):

S.B. Vliek ◽

E. Van Werkhoven ◽

I. Mandjes ◽

T. Westphal ◽

E.H. Lips ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Homologous Recombination ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

High Dose ◽

Homologous Recombination Deficiency ◽

Neo Adjuvant Chemotherapy

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Evaluation of homologous recombination deficiency (HRD) status with pathological response to carboplatin +/- veliparib in BrighTNess, a randomized phase 3 study in early stage TNBC.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.519 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 519-519 ◽

Cited By ~ 11

Author(s):

Melinda L. Telli ◽

Otto Metzger ◽

Kirsten Timms ◽

Brent Evans ◽

Diana Vogel ◽

...

Keyword(s):

Homologous Recombination ◽

Early Stage ◽

Pathological Response ◽

Phase 3 ◽

Homologous Recombination Deficiency

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A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3025 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3025-3025

Author(s):

Deqiang Wang ◽

Deyu Chen ◽

Bo Shen ◽

Xiaofeng Chen ◽

Mingzhe Xiao ◽

...

Keyword(s):

Gastric Cancer ◽

Adjuvant Chemotherapy ◽

Mismatch Repair ◽

Patient Selection ◽

Early Stage ◽

Predictive Biomarkers ◽

Mismatch Repair Gene ◽

Poor Overall Survival ◽

Repair Gene ◽

The Impact

3025 Background: Radical surgery with subsequent adjuvant chemotherapy was effective treatment for early-stage gastric cancer (GC) patients. Unfortunately, after optimal multimodality therapy, up to 30% to 40% of patients undergoing resection will relapse within 5 years. There are no validated prognostic and predictive biomarkers for GC patients who receive adjuvant chemotherapy, and current patient selection is based mainly on postoperative pathological staging. Defective mismatch repair (MMR) or microsatellite instability (MSI) may affect GC outcome. Polymorphisms of MMR genes with a low-penetrant effect can cause heterogeneous MMR capability among individuals. It is not known about the impact of these polymorphisms on GC outcome. Methods: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. Results: In the discovery set, both the rs2303428 TC+CC and the rs11797 GA+AA genotypes significantly correlated with poor overall survival (OS; P < 0.05). In the validation set, we confirmed the prognostic association for the rs2303428 TC+CC genotype (P = 0.036) but not for the rs11797 GA+AA genotype (P = 0.737). Furthermore, the prognostic role of the rs2303428 TC+CC genotype was observed in non-cardia (P = 0.005) but not in cardia GC (P = 0.934). The multivariate model showed that the rs2303428 TC+CC genotype was an independent predictor for OS in non-cardia patients (HR = 1.54; 95% CI: 1.02-2.32; P = 0.040). Moreover, fluoropyrimidines-based adjuvant chemotherapy significantly improved OS (HR = 0.29; 95% CI: 0.15-0.58; P < 0.001) for non-cardia patients with the rs2303428 TC+CC genotype but not for those with the rs2303428 TT genotype. The rs2303428 genotypes were not associated with MSI frequency. Conclusions: The rs2303428 TC+CC genotype may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients independent of MSI. To our knowledge, our study is the first to report the prognostic and predictive roles of MMR genotype in GC. Although prospective validation is necessary, our findings have the potential to improve patient selection for adjuvant chemotherapy and spare large numbers of GC patients’ unnecessary therapy.

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Copy number variation analysis increases the diagnostic yield in muscle diseases

Neurology Genetics ◽

10.1212/nxg.0000000000000204 ◽

2017 ◽

Vol 3 (6) ◽

pp. e204 ◽

Cited By ~ 6

Author(s):

Salla Välipakka ◽

Marco Savarese ◽

Mridul Johari ◽

Lydia Sagath ◽

Meharji Arumilli ◽

...

Keyword(s):

Muscular Dystrophy ◽

Copy Number ◽

Diagnostic Yield ◽

Dystrophin Gene ◽

Final Diagnosis ◽

Next Generation Sequencing Data ◽

Comparative Genomic ◽

Sequencing Data ◽

Single Nucleotide Variants ◽

Muscle Diseases

Objective:Copy number variants (CNVs) were analyzed from next-generation sequencing data, with the aim of improving diagnostic yield in skeletal muscle disorder cases.Methods:Four publicly available bioinformatic analytic tools were used to analyze CNVs from sequencing data from patients with muscle diseases. The patients were previously analyzed with a targeted gene panel for single nucleotide variants and small insertions and deletions, without achieving final diagnosis. Variants detected by multiple CNV analysis tools were verified with either array comparative genomic hybridization or PCR. The clinical significance of the verified CNVs was interpreted, considering previously identified variants, segregation studies, and clinical information of the patient cases.Results:Combining analysis of all different mutation types enabled integration of results and identified the final cause of the disease in 9 myopathy cases. Complex effects like compound heterozygosity of different mutation types and compound disease arising from variants of different genes were unraveled. We identified the first large intragenic deletion of the titin (TTN) gene implicated in the pathogenesis of a severe form of myopathy. Our work also revealed a “double-trouble” effect in a patient carrying a single heterozygous insertion/deletion mutation in the TTN gene and a Becker muscular dystrophy causing deletion in the dystrophin gene.Conclusions:Causative CNVs were identified proving that analysis of CNVs is essential for increasing the diagnostic yield in muscle diseases. Complex severe muscular dystrophy phenotypes can be the result of different mutation types but also of the compound effect of 2 different genetic diseases.

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