BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study

doi:10.1016/j.ajog.2017.05.036

American Journal of Obstetrics and Gynecology

Volume 217, Issue 3, September 2017, Pages 334.e1-334.e9

https://doi.org/10.1016/j.ajog.2017.05.036 Get rights and content

Background

In the last decades, there have been several efforts to clarify the role of BRCA mutational status in women with advanced ovarian cancer, demonstrating its role in cancer development, as well as the prognostic significance of BRCA genotype.

Objective

Our aim is to evaluate the correlation between BRCA mutational status and disease presentation in a large series of advanced high-grade serous ovarian cancer patients.

Study Design

This is a retrospective multicenter study including a consecutive series of newly diagnosed high-grade serous ovarian cancer patients with International Federation of Gynecology and Obstetrics stage IIIC-IV disease, at least 18 months of follow-up time, and tested for BRCA 1/2 germline mutation status. Disease presentation was analyzed using the following variables: laparoscopic predictive index value, incidence of bulky lymph nodes, and ovarian masses. Progression-free survival was defined as the months elapsed from initial diagnosis (staging laparoscopy) and recurrent disease or last follow-up.

Results

In all, 324 high-grade serous ovarian cancer patients received BRCA testing, and 273 fulfilled inclusion criteria. BRCA1/2 germline mutations were observed in 107 women (39.2%). No differences were documented according to BRCA mutation status in terms of International Federation of Gynecology and Obstetrics stage, CA125 levels, or presence of ascites. In patients with BRCA1/2 mutations we observed a higher incidence of peritoneal spread without ovarian mass (25.2% vs 13.9%; P value = .018) and of bulky lymph nodes (30.8% vs 17.5%; P value = .010) compared with women showing BRCA1/2 wild type genotype. Furthermore, women with BRCA1/2 mutations showed high peritoneal tumor load (laparoscopic predictive index value ≥8; 42.1% vs 27.1%; P value = .016) more frequently. Focusing on survival, no differences in term of median progression-free survival were observed among women treated with primary debulking surgery and neoadjuvant chemotherapy in the group of patients with BRCA1/2 mutations (P value = .268). On the other hand, in women showing BRCA wild type genotype, median progression-free survival after primary debulking surgery was 8 months longer compared with patients treated with neoadjuvant chemotherapy approach (26 vs 18 months; P value = .003).

Conclusion

Women with BRCA1/2 mutations show at diagnosis higher peritoneal tumor load and increased frequency of bulky lymph nodes compared to patients without germline BRCA mutations. Primary debulking surgery seems to ensure a longer progression-free survival in women with BRCA wild type genotype compared to neoadjuvant chemotherapy. BRCA testing might be a reliable tool to personalize treatment in patients with high-grade serous ovarian cancer, thus giving novel points of discussion to the ongoing debate regarding the best initial treatment approach.

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

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In the era of target therapy and personalized medicine, BRCA mutational status has a major influence on survival in ovarian cancer patients. Our aim is to verify if the poorer prognosis of elderly ovarian cancer patients can be related to the biology of the tumor beyond their own morbidities and/or suboptimal treatments.
This is a retrospective single-institution study evaluating prognosis of patients with a diagnosis of ovarian cancer and known BRCA status. We collected clinical and surgical characteristics and the distribution of BRCA mutational status according to age groups.
1840 patients were included in the analysis. The rate of BRCA mutated decreased over age-range from 49.7% in patients aged <50 years to 18.8% in ≥80 years old women. The prognostic role of BRCA status on survival is maintained when focusing on the elderly population, with improved Disease Free Survival (27.2 months vs 16.5 months for BRCA mutated and wild type respectively, p = 0.001) and Cancer Specific Survival (117.6 months vs 43.1 months for BRCA mutated and wild type respectively, p = 0.001) for BRCAmut compared to BRCAwt patients. In the multivariable analysis, among elderly women, upfront surgery and BRCA mutation are independent factors affecting survival.
Elderly patients experiment a poorer prognosis due to multiple factors that include both their medical condition and comorbidities, under-treatment and most importantly disease characteristics. We found that beyond disparities, BRCA mutation is still the strongest independent prognostic factor affecting both the risk of recurrence and death due to disease.
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To assess incidence and oncologic outcomes in women with advanced epithelial ovarian cancer (EOC) with inguinal lymph node metastasis (ILNM) at diagnosis.
An IRB-approved, retrospective single-institution cohort study was performed in women with stage III/IV EOC from 2009 to 2017. Patients with inguinal lymphadenopathy (defined as >1 cm in short axis) clinically or radiographically were identified. The impact of ILNM on progression-free survival (PFS) and overall survival (OS) were assessed.
Of the 562 women with advanced EOC, 18 (3.2%) had ILNM at diagnosis, accounting for 25.7% of all patients with stage IVB disease (n = 70). Five patients (27.7%) had a known genetic predisposition for EOC, including BRCA1 (11.1%, n = 2), BRCA2 (11.1%, n = 2) and BRIP1 (5.6%, n = 1). The majority of patients underwent optimal primary cytoreductive surgery (CRS), including debulking of inguinal nodal metastasis (83.3%, n = 15), with 50% (n = 9) having no gross residual disease after surgery. There was no difference in PFS (19.9 vs. 19.9 vs. 17.2 months, p = 0.84) or OS (137.2 vs. 52.9 vs. 67.6 months, p = 0.29) in women with stage III/IV with ILNM, stage III/IV without ILNM, and stage IVB disease without ILNM, respectively. Progression-free survival was improved in women with ILNM who underwent an optimal resection to no macroscopic disease vs. non-optimal resection (27.4 vs. 14.3 months, p = 0.019). Median overall survival at the time of analysis did not reach statistical significance (137.2 vs. 57.3 months, p = 0.24).
In this retrospective cohort study, 3.2% of women with advanced EOC presented with ILNM at diagnosis. Although ILNM did not portend worse clinical outcomes compared to all Stage III/IV and Stage IVB patients, respectively, resection to no gross residual disease was associated with improved PFS.
Combining surgery and medical treatments for ovarian cancer: Is there an optimal strategy?
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L’objectif de cette revue est d’évaluer le positionnement optimal de la chirurgie de cytoréduction et des traitements médicaux périopératoires lors de la prise en charge initiale et lors de la rechute des carcinomes épithéliaux ovariens de stades avancés. Lors de la prise en charge initiale, une chirurgie première doit être proposée si l’absence de résidu tumoral est envisageable au prix d’une chirurgie raisonnable (gestes de résection à envisager et leurs complications mais également en fonction de l’état général de la patiente). Dans les recommandations actuelles, trois à quatre cycles de chimiothérapie néoadjuvante sont proposés avant une chirurgie d’intervalle aux patientes non éligibles à une chirurgie première. La réalisation d’une chirurgie d’intervalle tardive (par exemple après ≥ cinq à six cycles de chimiothérapie) ne constitue pas un standard thérapeutique et doit être proposée uniquement en cas de mauvaise réponse tumorale après trois à quatre cycles et lorsqu’une chirurgie complète semble faisable. Lors de la première récidive tumorale chez des patientes platino-sensibles, une chirurgie de cytoréduction première peut être envisagée si l’absence de résidu tumoral est envisageable. On peut s’appuyer sur des scores prédictifs (score AGO ; score i-model) permettant de sélectionner les patientes. En absence de données robustes, il ne peut être préconisé de réaliser une chirurgie de cytoréduction lors de la première récidive chez les patientes platino-résistantes ou bien en situation de récidive ultérieure. Néanmoins, l’obtention d’une chirurgie complète dans ces situations cliniques semble apporter un bénéfice en survie globale et sa réalisation doit reposer au cas par cas sur un avis d’équipes spécialisées.
The objective of this review is to evaluate the optimal positioning of cytoreduction surgery and perioperative medical treatments in the initial management and relapse of advanced-stage epithelial ovarian carcinoma. In the initial management, primary surgery should be proposed if the absence of tumor residue is feasible with reasonable surgery (extensive surgical resections to be considered and their complications, but also the general condition of the patient). Guidelines recommend 3 to 4 cycles of neoadjuvant chemotherapy before interval surgery for patients not eligible for primary surgery. Late interval surgery (i.e. after ≥ 5–6 cycles of chemotherapy) is not a standard of care and should only be proposed in case of poor tumor response after 3–4 cycles and when complete interval surgery seems feasible. At first tumor recurrence in platinum-sensitive patients, a primary cytoreduction surgery can be considered if complete surgery can be managed. Predictive scores (AGO score; i-model score) can be used to select eligible patients. Given the lack of strong evidence, performing cytoreduction surgery at first recurrence in platinum-resistant patients or in the event of subsequent recurrence cannot be recommended. Nevertheless, obtaining a complete surgery in these clinical situations seems to provide a benefit in terms of overall survival and its application should be based on the expertise of specialized teams.
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Citation 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.
We evaluated the clinical impact of germline (g)BRCA1/2-mutation on initial disease presentation, surgical implications, surgical morbidity and survival in patients with advanced epithelial ovarian cancer (EOC) undergoing debulking surgery (DS).
Data of all consecutive EOC patients with stage III/IV, high-grade serous disease and known gBRCA1/2 status (gBRCA; non-gBRCA), who underwent DS at our department between 01/2011 and 06/2019 were analyzed. Associations between gBRCA-status and severe postoperative complications and survival were analyzed.
gBRCA-status was determined in 50.1% (612/1221) of all patients. gBRCA was present in 21.9% (134/612). Significant differences were observed in terms of median age (p = 0.001) and histology (high-grade serous histology gBRCA: 98.5%, non-gBRCA 76.2%; p < 0.001). gBRCA-status had no impact on intraoperative disease presentation, surgical complexity or complete resection rate (gBRCA: 74.4%, non-gBRCA: 69.0%; p = 0.274). gBRCA-status was not predictive for severe postoperative complication (gBRCA: 12.0%, non-gBRCA: 19.1%; p = 0.082). Median PFS and OS was 31/22 and 71/53 months in patients with/without gBRCA-mutation, respectively. gBRCA was a significant prognostic factor for PFS (HR 0.57 p < 0.001) and for OS (HR 0.64, p = 0.048) after adjusting for established prognostic factors.
gBRCA-status had no impact on initial disease presentation, surgical results or postoperative complications. gBRCA patients have a significantly longer PFS but the impact on the long term prognosis is unclear. Complete resection remains the most important prognostic factor in patients with EOC independent of gBRCA-status.
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Citation 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.
Ovarian cancer (OC) remains a fatal malignancy because most patients experience recurrent disease, which is resistant to chemotherapy. The outcomes for patients with platinum-resistant OC are poor, response rates to further chemotherapy are low and median survival is lower than 12 months. The complexity of platinum-resistant OC, which comprises a heterogeneous spectrum of diseases, is indeed far from being completely understood. Therefore, comprehending tumors’ biological behaviour to identify reliable biomarkers, which may predict responses to therapies, is a demanding challenge to improve OC management. In the age of precision medicine, efforts to overcome platinum resistance in OC represent a dynamic and vast field in which innovative drugs and clinical trials rapidly develop. This review will present the exceptional biochemical environment implicated in OC and highlights mechanisms of chemoresistance. Furthermore, innovative molecules and new therapeutic opportunities are presented, along with currently available therapies and ongoing clinical trials.

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: 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.

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Original ResearchGynecologyBRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study

Background

Objective

Study Design

Results

Conclusion

Introduction

Section snippets

Patients

Clinicopathological features

Comment

Ann Oncol

Gynecol Oncol

Gynecol Oncol

Cancer Lett

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Clin Chim Acta

Gynecol Oncol

Mod Pathol

Mod Pathol

Original Research
Gynecology
BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study