Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients

Vencken, P.M.L.H.; Kriege, Mieke; Hoogwerf, D.; Beugelink, S.; Burg, M.E.L. van der; Hooning, Maartje J.; Berns, Els M.J.J.; Jager, Agnes; Collée, Margriet; Burger, Curt W.; Seynaeve, Caroline

doi:10.1093/annonc/mdq628

Cited by 188 publications

(188 citation statements)

References 25 publications

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“…234 Several studies have revealed ovarian cancer patients with BRCA1 as well as BRCA2 germline mutations to have a better chance of responding to platinumbased therapy as compared with patients wild type for BRCA1/2 in the primary setting as well as on tumour relapse. 233,[235][236][237][238] Most interestingly, there is experimental (BRCA2) but also results in human tumours (BRCA1 and BRCA2) revealing secondary mutations, restoring BRCA1/2 protein function, to be associated with acquired resistance toward platinum compounds. [239][240][241][242] The fact that mutations affecting both BRCA1 and BRCA2 seem to confer sensitivity to platinum compounds and to PARP inhibitors (see below) clearly implicates the Fanconi complex in drug sensitivity to these compounds.…”

Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…30 Since that time, Soslow et al 23 validated the significance of different histologic patterns by describing variant morphologies (SET) in tumors with BRCA germline mutations that are associated with a better prognosis and a better response to chemotherapy. 3,4,[12][13][14][15][16][17][18][19] We previously reported on a separate cohort of high-grade serous carcinomas, showing an association between BRCA-positivity and variant histology (SET-like), younger age, a lower frequency of serous tubal intraepithelial carcinoma, and trends toward improved survival. 24 In this current study, we found that mutations in homologous recombination genes were 6 times more likely to be associated with nonclassic high-grade serous carcinoma histology (70%) than with classic high-grade serous carcinoma histology (28%) (P o0.001), and BRCA1 mutations were 10 times more likely to be associated with nonclassic high-grade serous carcinoma histology (P o 0.001) than classic histology.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 The reliance on alternative end-joining repair pathways subsequently renders homologous recombination-deficient tumors more sensitive to chemotherapy as well as to PARPi. 3,4,[12][13][14][15][16][17][18][19] Only one PARPi has been FDA approved for the treatment of ovarian cancer, olaparib, and this is only in the setting of BRCA mutation and at least three prior lines of chemotherapy. Our findings further support the work of Pennington et al, 21 suggesting that a broader population of women with ovarian cancer may benefit from PARPi therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Although most high-grade serous carcinomas are associated with a poor prognosis, some patients with the disease have significantly better outcomes. [3][4][5] Germline mutations in BRCA1 and BRCA2 account for the majority of inherited cases of high-grade serous carcinomas, and the recognition of these germline mutations has led to the widespread use of prophylactic bilateral salpingo-oophorectomies to …”

mentioning

confidence: 99%

“…[6][7][8][9] Homologous recombination-deficient high-grade serous carcinomas (including BRCA1/2 mutations) depend on alternative, error-prone mechanisms for doublestrand break repair, such as the Polθ/PARP1-mediated alternative end-joining pathway for DNA repair, 10,11 and subsequently have been shown to have increased sensitivity to platinum chemotherapy and to poly ADP-ribose polymerase inhibitors (PARPi), and improved overall survival. 3,4,[12][13][14][15][16][17][18][19] Studies from The Cancer Genome Atlas Research Network (TCGA) demonstrated that nearly one-third of ovarian high-grade serous carcinomas had BRCA1-/2 alterations, which included 20% with either germline or somatic mutations in BRCA1/2 and an additional 11% with BRCA1 epigenetic silencing via hypermethylation. 20 Interestingly, they found that improved survival was limited to high-grade serous carcinomas with mutations in BRCA1/2, and was not seen in high-grade serous carcinomas with epigenetically silenced BRCA1.…”

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confidence: 99%

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Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

et al. 2016

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Extrauterine high-grade serous carcinomas can exhibit various histologic patterns including (1) classic architecture that is papillary, micropapillary and infiltrative and (2) solid, endometrioid, and transitional (ie, SET) patterns. Although the SET pattern has been associated with germline BRCA mutations, potential molecular underpinnings have not been fully investigated. DNA was isolated from 174 carcinomas of the fallopian tube, ovary, or peritoneum. Targeted next-generation sequencing was performed and single-nucleotide and copy number variants were correlated with morphologic subtype. Overall, 79% of tumors were classified as high-grade serous carcinoma (n = 138), and the most common mutations in high-grade serous carcinomas were TP53 (94%), BRCA1 (25%), BRCA2 (11%), and ATM (7%). Among chemotherapy-naive high-grade serous carcinomas, 40 cases exhibited classic morphology and 40 cases had non-classic morphology (SET or ambiguous features). Mutations in homologous recombination pathways were seen across all tumor histotypes. High-grade serous carcinomas with homologous recombination mutations were six times more likely to be associated with nonclassic histology (P = 0.002) and were significantly more likely to be platinum sensitive and have improved progression-free survival (PFS) (P = 0.007 and P = 0.004, respectively). In a multivariate analysis adjusted for age, homologous recombination mutation status and increased copy number variants were independently associated with improved PFS (P = 0.008 and P = 0.005, respectively). These findings underscore the potential significance of variant morphologic patterns and comprehensive genomic analysis in high-grade serous carcinomas with potential implications for pathogenesis, as well as response to targeted therapies. Extrauterine Müllerian carcinomas (ovarian, fallopian tube, and peritoneal) are the eighth most common malignancy in women and the fifth most common cause of death from cancer among women in the United States. 1 The 5-year survival for highgrade serous carcinoma, the most common and most lethal of all pelvic Müllerian carcinomas, is approximately 40%. 2 These tumors are difficult to detect in early stage and thus frequently present with metastatic disease. Although most high-grade serous carcinomas are associated with a poor prognosis, some patients with the disease have significantly better outcomes. [3][4][5] Germline mutations in BRCA1 and BRCA2 account for the majority of inherited cases of high-grade serous carcinomas, and the recognition of these germline mutations has led to the widespread use of prophylactic bilateral salpingo-oophorectomies to

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Unwrapping the Implications of BRCA1 and BRCA2 Mutations in Ovarian Cancer

Hyman¹,

Spriggs²

2012

JAMA

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Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients

Abstract: Compared with sporadic EOC patients, both BRCA1- and BRCA2-associated patients have improved outcomes after primary therapy, including chemotherapy.

Cited by 188 publications

References 25 publications

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

Unwrapping the Implications of BRCA1 and BRCA2 Mutations in Ovarian Cancer

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