Implications of BRCA1 and BRCA2 mutations for the efficacy of paclitaxel monotherapy in advanced ovarian cancer

Tan, David S.P.; Yap, Timothy A.; Hutka, Margaret; Roxburgh, Patricia; J, Ang; Banerjee, Susana; Grzybowska, Ewa; Gourley, Charlie; Gore, Martin; Kaye, Stan B.

doi:10.1016/j.ejca.2012.11.016

Cited by 23 publications

(20 citation statements)

References 27 publications

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“…In a small study of recurrent platinum sensitive ovarian cancer patients, BRCA1/2 mutation carriers demonstrated a significant response to repeat carboplatin with dose dense paclitaxel regimens, compared to sporadic patients, suggesting that this drug combination is particularly effective in BRCA1/2 -related disease [28], and potentially by extension to HR deficient tumors. In addition, a study examining the role of taxane monotherapy in germline BRCA1/2 mutation carriers with relapsed ovarian cancer found a significant survival benefit in patients with initially platinum-sensitive disease compared to those with platinum-resistant disease [29]. Both the pre-clinical and clinical data support our finding that EOC tumors with BRCA1 (and other HR gene) mutations have an increased sensitivity to paclitaxel as compared to tumors without such mutations.…”

Section: Discussionsupporting

confidence: 77%

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

Jean

Katsaros

et al. 2016

Oncotarget

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PURPOSETo investigate the impact of somatic mutations in homologous recombination (HR) genes on the chemotherapeutic response and survival of patients with epithelial ovarian cancer (EOC).EXPERIMENTAL DESIGNWe performed targeted massively parallel sequencing of tumor DNA from 158 patients with EOC. We associated adjuvant chemotherapy and clinical outcome with mutations in selected genes, focusing on those encoding HR proteins.RESULTSHR mutations were found in 47 (30%) tumors. We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had HR mutations compared to those without (median OS of 49.6 months (95% CI 29.9-57.7) vs. 43.3 months (95% CI 31.9-75.47), p = 0.87). However, when stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs. platinum +/− cyclophosphamide (median OS of 90 months (95% CI 50-NA) vs. 29.5 months (95% CI 17.7-50.5), p = 0.0005).CONCLUSIONSPrevious studies demonstrating a survival advantage for EOC patients with somatic HR mutations have been conducted with almost universal use of both platinum and paclitaxel. Our study is the first to our knowledge to compare cohorts with somatic HR gene mutations treated with and without paclitaxel containing platinum regimens. The survival benefit attributed to the platinum sensitivity of HR deficient ovarian cancers may depend upon the combined use of paclitaxel.

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Section: Discussionsupporting

confidence: 77%

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

Jean

Katsaros

et al. 2016

Oncotarget

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“…There has been a suggestion that OC expressing high BRCA1 mRNA levels may benefit from addition of taxanes to platinum, while those with low levels do not, though these data are yet to be confirmed in a comprehensive cohort of OC 92. It has been shown that BRCA -linked OC can benefit from paclitaxel monotherapy in both the platinum-sensitive and platinum-resistant relapsed disease settings (response rate 60%, 9 of 15 patients and 33%, 3 of 9 patients, respectively); however, meaningful comparison of taxane monotherapy efficacy between BRCA -linked and BRCA wild-type OC has not been conducted 93. Critically, the existing data have examined BRCA -associated OC as a single entity.…”

Section: Chemosensitivitymentioning

confidence: 98%

Distinct implications of different BRCA mutations: efficacy of cytotoxic chemotherapy, PARP inhibition and clinical outcome in ovarian cancer

Hollis¹,

Churchman²,

Gourley³

2017

OTT

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Approximately a fifth of ovarian carcinoma (OC) is associated with inherited germline mutations, most commonly in the DNA repair genes BRCA1 or BRCA2 (BRCA). BRCA1- and BRCA2-associated OCs have historically been described as a single subgroup of OC that displays a distinct set of characteristics termed the “BRCAness” phenotype. The hallmarks of this phenotype are superior clinical outcome and hypersensitivity to platinum-based chemotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors. However, growing evidence suggests that BRCA1- and BRCA2-associated OCs display distinct characteristics, most notably in long-term patient survival. Furthermore, recent data indicate that the site of BRCA1 mutation is important with regard to platinum and PARP inhibitor sensitivity. Here, we summarize the body of research describing the BRCAness phenotype and highlight the differential implications of different BRCA mutations with regard to clinicopathologic features, therapy sensitivity and clinical outcome in OC.

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“…It is essential to acknowledge that some breast cancer studies do not support this concept [61]. Furthermore, paclitaxel monotherapy is effective in relapsed ovarian cancer in BRCA1 mutation carriers [62], although this study did not consider possible restoration of BRCA1 function during the prior therapy [25]. Recently Burness et al [63] communicated 2 cases of BRCA1-associated chemonaive breast cancers, which demonstrated complete response to the paclitaxel monotherapy.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic and targeted therapy for hereditary cancers

Iyevleva

Imyanitov

2016

Hered Cancer Clin Pract

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There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.

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Implications of BRCA1 and BRCA2 mutations for the efficacy of paclitaxel monotherapy in advanced ovarian cancer

Cited by 23 publications

References 27 publications

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

Distinct implications of different BRCA mutations: efficacy of cytotoxic chemotherapy, PARP inhibition and clinical outcome in ovarian cancer

Cytotoxic and targeted therapy for hereditary cancers

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