American Journal of Obstetrics and Gynecology
Original ResearchGynecologyBRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study
Introduction
After its first discovery, deficiency in homologous recombination due to deleterious BRCA1/2 gene mutations has been progressively recognized not only as a predictor of ovarian cancer susceptibility, but also as a prognostic factor.1, 2 In fact, an increased response rate to platinum-based chemotherapy,3 a longer progression-free survival (PFS),4, 5, 6 and a higher benefit of neoadjuvant chemotherapy (NACT)7, 8 have been reported in high-grade serous ovarian cancer (HGSOC) patients with significant BRCA1/2 mutations, compared with women showing wild-type BRCA genotype.
Furthermore, the presence of deleterious BRCA1/2 mutations has been associated with a higher incidence of parenchymal disease at the time of relapse,9 thus suggesting that BRCA mutational status may also influence disease presentation. However, despite this encouraging evidence, scanty data are currently available regarding the correlation between BRCA mutational status and disease presentation at the time of diagnosis.10
In this context, it has also to be considered that tools to properly select newly diagnosed HGSOC patients suitable for complete primary debulking surgery (PDS) vs NACT are urgently needed; and the incorporation of BRCA testing into established surgical algorithm11, 12, 13, 14 may represent a future intriguing horizon in the era of precision medicine.
For these reasons, we evaluate the correlation between disease presentation at diagnosis and BRCA germline mutational status in a large series of advanced HGSOC patients. Survival outcome according to initial treatment strategy and BRCA mutational status has been also analyzed in the effort to evaluate whether integrated approaches may be proposed in the future.
Section snippets
Patients
We selected from our electronic database all women submitted to BRCA testing at the gynecologic oncology units of the Policlinico Gemelli Foundation of the Catholic University and La Sapienza University of Rome showing the following criteria: newly diagnosed HGSOC patients, International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV disease, at least 18 months of follow-up time.
Indications for gene testing slightly changed over the time accrual from positive familiar history only
Clinicopathological features
In all, 324 women with advanced ovarian cancer, admitted at our institutions, received BRCA testing from January 2013 through January 2016, and among these patients, 273 fulfilled inclusion criteria (high-grade serous histology, and a follow-up time of at least 18 months) and were included in the final analysis. Median time from diagnosis to BRCA testing was 15 months without differences according to BRCA mutational status. Clinically relevant BRCA1/2 germline mutations were observed in 107
Comment
In the precision medicine era, the incorporation of personalized approaches in the clinical management of HGSOC should be considered as the primary goal to be achieved.21 Over the last 2 decades, several efforts have been made to identify the hallmarks of ovarian cancer,22 thus making available a plethora of potentially useful biomarkers to stratify prognosis and establish personalized therapies. However, despite these encouraging results no molecular signatures have successfully entered
References (25)
- et al.
Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients
Ann Oncol
(2011) - et al.
BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study
Gynecol Oncol
(2016) - et al.
Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage müllerian cancer
Gynecol Oncol
(2015) - et al.
High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation
Cancer Lett
(2015) - et al.
Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma
Gynecol Oncol
(2012) - et al.
Introduction of staging laparoscopy in the management of advanced epithelial ovarian, tubal and peritoneal cancer: impact on prognosis in a single institution experience
Gynecol Oncol
(2013) - et al.
Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof of a concept
Gynecol Oncol
(2015) - et al.
Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment
Gynecol Oncol
(2011) - et al.
A preliminary quality control (QC) for next generation sequencing (NGS) library evaluation turns out to be a very useful tool for a rapid detection of BRCA1/2 deleterious mutations
Clin Chim Acta
(2014) - et al.
Targeting the hallmarks of ovarian cancer: the big picture
Gynecol Oncol
(2016)
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2021, Gynecologic OncologyCitation Excerpt :However, in this study gBRCA mutation status had a significant impact on PFS and OS. A recent report by Petrillo et al. showed higher tumor load and a more diffuse intraperitoneal tumor spread in patients with gBRCA than in non-gBRCA patients measured on the basis of the laparoscopic predictive index (6). Therefore, they reported that significantly more complex surgical procedures were necessary in gBRCA patients than in non-gBRCA patients to achieve complete macroscopic tumor resection.
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2021, Seminars in Cancer BiologyCitation Excerpt :Interestingly, according to the Cancer Genome Atlas (TCGA) project data, up to 51 % of HGSOC cases are characterized by defective HRR pathway [146]. Considering that BRCA1 and BRCA2 are largely restricted to the HGSOC subtype and are mainly a risk factor for this histotype -notably 25 % HGSOC harbor somatic and germline BRCA1/2 mutations [147] - the subsequent homologous recombination deficiency (HRD) promotes platinum sensitivity due to an accumulation of double-strand breaks after platinum chemotherapy. In addition, mBRCA patients can also be sensitive to other DNA damage-inducing regimens, such PARP inhibitors, because of the deficiency in HRR.
The authors report no conflict of interest.
Cite this article as: Petrillo M, Marchetti C, De Leo R, et al. BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study. Am J Obstet Gynecol 2017;217:334.e1-9.