|Ahead of print publication
BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines – Place for platinum reinduction
Michal Zikan1, Livia Vecerova2, Olga Dubova1, Borek Sehnal1, Jana Soukupova3
1 Department of Obstetrics and Gynecology, Charles University – First Faculty of Medicine and Bulovka University Hospital, Prague, Czech Republic
2 Department of Radiology, Charles University – Third Faculty of Medicine and Bulovka University Hospital, Prague, Czech Republic
3 Department of Biochemistry and Experimental Oncology, Charles University – First Faculty of Medicine, Prague, Czech Republic
|Date of Submission||01-Jun-2021|
|Date of Decision||12-Aug-2021|
|Date of Acceptance||12-Aug-2021|
|Date of Web Publication||11-Nov-2022|
Department of Obstetrics and Gynecology, Charles University – First Faculty of Medicine and Bulovka University Hospital, Budinova 67/2, 181 00 Prague 8
Source of Support: None, Conflict of Interest: None
Context: Ovarian carcinoma is a malignancy with the highest mortality among gynecological cancers. Mutations in BRCA1/2 genes are believed to be a favorable prognostic factor and that, in general, the biological behavior of ovarian cancer in BRCA-positive individuals differs from others. However, some clinically relevant issues (i.e., prediction of response to chemotherapy and treatment of platinum-resistant BRCA-positive patients) remain unclear.
Aims: (1) The aim of this study was to examine the prevalence of germline BRCA mutations in unselected recurrent ovarian cancer patient population, (2) analyze whether biological behavior of BRCA-positive tumors differs from others, and (3) analyze the effect of platinum reinduction in platinum-resistant BRCA-positive patients.
Settings and Design: This was a single-institution retrospective analysis.
Subjects and Methods: Consecutive recurrent ovarian cancer patients from years 2012 to 2020 were included; their BRCA1/2 mutational status was analyzed and correlated with progression-free survival (PFS), type of treatment, and response to treatment.
Statistical Analysis Used: Statistical significance of differences between and among patients was tested for continuous variables by the Mann–Whitney U-test or the Kruskal–Wallis test; a maximum likelihood Chi-square test was used for categorical variables.
Results: Two hundred and forty-three recurrent ovarian cancer patients were included. The median follow-up was 37 months. Pathogenic mutation in BRCA1 or BRCA2 gene was found in 18.1% of patients. There was no difference in PFS comparing BRCA-positive to BRCA-negative patients (median PFS: 10.2 vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002). BRCA-positive platinum-resistant patients reinduced with platinum achieved a median PFS of 8 months (compared to those receiving nonplatinum treatment, median PFS: 4 months, P = 0.062).
Conclusions: Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.
Keywords: BRCA1/2 gene mutation, ovarian cancer, platinum-based chemotherapy
|How to cite this URL:|
Zikan M, Vecerova L, Dubova O, Sehnal B, Soukupova J. BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines – Place for platinum reinduction. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=361024
| > Introduction|| |
Despite the more precise classification of tumor subtypes and the introduction of targeted treatment into ovarian cancer treatment, this cancer has a poor outcome, specifically in advanced stages with a 5-year survival of <25%. Although majority of patients respond to initial platinum-based chemotherapy with or without antiangiogenic targeted treatment, relapses occur in most patients leading to clinical platinum resistance which is fatal.
Data are increasing during the time to support the finding that the biological behavior of ovarian cancer in BRCA-positive individuals differs from others and that these tumors are rather platinum sensitive. It is also generally assumed that germline BRCA mutations are found exclusively in patients with platinum-sensitive disease.
The aim of this retrospective study was (1) to examine the prevalence of germline BRCA mutations in unselected (platinum-sensitive plus platinum-resistant) recurrent ovarian cancer patient population, (2) analyze whether biological behavior of cancer in BRCA-positive patients differs from others, and (3) focus on the possibility of platinum reinduction in platinum-resistant BRCA-positive patients with recurrent disease.
| > Subjects and Methods|| |
Consecutive recurrent ovarian cancer patients diagnosed and treated between 2012 and 2020 at our institution were identified in our database. As a standard diagnostic procedure, they underwent a mutational analysis of BRCA1 and BRCA2 genes to identify potential germline mutations. Frozen whole peripheral blood of these patients was collected after consultation with a geneticist, and all patients gave informed consent for blood sampling and mutational analysis of BRCA genes. The local ethical review board approved the project.
BRCA1 and BRCA2 mutational analysis was done in peripheral blood by next-generation sequencing and MLPA. Sequencing reads were aligned by Novoalign v2.08.03 to the human reference (hg19). Variants were identified using GATK and Pindel and choroidal neovascularization (CNV) using CNV score. Germline variants were classified according to the recommendations of the ENIGMA consortium. All pathogenic/likely pathogenic mutations were confirmed by Sanger sequencing and CNVs by MLPA.
Clinical data (regimens of chemotherapy, response to chemotherapy, progression-free survival [PFS], and overall survival [OS]) were extracted from the institutional electronic system [Table 1].
Standard descriptive statistics were applied to describe primary data; continuous variables were expressed as arithmetic mean and standard deviations, supplemented by median and minimum–maximum ranges; absolute and relative frequencies of categories were used to describe categorical variables. Statistical significance of differences between and among patients was tested for continuous variables by the Mann–Whitney U-test or the Kruskal–Wallis test; a maximum likelihood Chi-square test was used for categorical variables. A value of P<0.05 was considered as the level of statistical significance in all analyses. Analyses were performed using SPSS 21 (IBM Corporation, Armonk, New York, USA, 2021).
| > Results|| |
In the database, 254 recurrent ovarian cancer patients were identified. Two hundred and forty-three recurrent ovarian cancer patients in initial Stages IIC-IV were included in the analysis; 11 were excluded due to lack of clinical data or mutational analysis [Figure 1]. The median follow-up was 37 months. None of these patients received PARP inhibitor as a part of primary treatment.
Prevalence of germline BRCA mutations in unselected ovarian cancer patients
Clinically relevant, pathogenic mutation in BRCA1 or BRCA2 gene (Class IV or V) was found in 44/243 patients (18.1%). Twenty-nine of 44 mutation carriers (65.9%) developed platinum-sensitive disease defined as PFS >6 months from each and last platinum-based chemotherapy, and due to the course of the disease, they are candidates for platinum-based systemic treatment. Fifteen of 44 mutation carriers (34.1%) developed platinum-resistant disease defined as PFS <6 months from each and last platinum-based chemotherapy.
The biological behavior of cancer in BRCA-positive and BRCA-negative patients
There was no difference in PFS initial treatment comparing BRCA-positive patients to BRCA-negative patients (median PFS: 10.2 months vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002).
Platinum reinduction systemic treatment in platinum-resistant BRCA-positive patients
Seven of 15 BRCA-positive platinum-resistant patients (46.7%) were reinduced with platinum after one nonplatinum chemotherapy line [Table 2], and they achieved a PFS median of 8 months (compared to others in this group with a median PFS of 4 months, P = 0.062).
|Table 2: Chemotherapy regimens in BRCA-positive platinum-resistant patients|
Click here to view
| > Discussion|| |
Our study described the prevalence of BRCA1/2 gene mutation in our population of recurrent ovarian cancer patients. We studied the difference in PFS in BRCA mutation carriers and noncarriers and a possibility for platinum reinduction to achieve PFS prolongation in BRCA mutation carriers with platinum-resistant disease.
Nearly 80% of patients with advanced high-grade ovarian carcinoma relapse despite surgical and systemic treatment and die of disease. A high proportion (14%–18%) of ovarian carcinomas arises due to germline mutations in either BRCA1 or BRCA2 gene. Our study found a germline mutation of either BRCA1 or BRCA2 in 18.1% of our recurrent ovarian cancer patients. Although BRCA mutation carriers develop a platinum-sensitive recurrence in the majority of cases, in our study, a substantial proportion of mutation carriers (34.1%) suffered from the platinum-resistant disease.
Harboring a BRCA gene mutation in ovarian cancer patients is believed to be linked with beneficial survival in both PFS and OS. We confirmed this in our group of patients among BRCA mutation carriers developing platinum-sensitive disease only, not if comparing all carriers versus noncarriers.
While the standard first-line chemotherapy is platinum based, the optimal treatment for recurrent disease in which platinum-based chemotherapy failed is not clear. There is a plurality of available chemotherapies and very heterogeneous response to relapse treatments. Based on known BRCA gene mutation effects on tumor cell biology and clinical experience, our study emphasizes the possibility of platinum reinduction even for BRCA mutation carriers in whom the previous platinum-based line (s) failed. Moreover, we report a notable trend for PFS improvement in this group of patients compared to those who received nonplatinum treatment.
A limited number of BRCA-positive platinum-resistant patients is a weakness of this study. However, we included patients consecutively, and our data reflect on clinical reality. Our study may also give a real-life view on the prevalence of BRCA germline-positive patients among recurrent ovarian cancer cohort and offer the management option for BRCA-positive and platinum-resistant patients.
| > Conclusions|| |
Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.
This work was supported by the Ministry of Health of the Czech Republic Grant AZV NV17-32030A.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Vergote I, Denys H, De Greve J, Gennigens C, Van De Vijver K, Kerger J, et al.
Treatment algorithm in patients with ovarian cancer. Facts Views Vis Obgyn 2020;12:227-39.
Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, et al.
Sequence variant classification and reporting: Recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 2008;29:1282-91.
Bhoola S, Hoskins WJ. Diagnosis and management of epithelial ovarian cancer. Obstet Gynecol 2006;107:1399-410.
Gadducci A, Guarneri V, Peccatori FA, Ronzino G, Scandurra G, Zamagni C, et al.
Current strategies for the targeted treatment of high-grade serous epithelial ovarian cancer and relevance of BRCA mutational status. J Ovarian Res 2019;12:9.
Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al.
Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012;307:382-90.
Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, et al.
Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 2002;20:463-6.
Morgan RJ Jr., Alvarez RD, Armstrong DK, Burger RA, Castells M, Chen LM, et al.
Ovarian cancer, version 3.2012. J Natl Compr Canc Netw 2012;10:1339-49.
Ushijima K. Treatment for recurrent ovarian cancer-at first relapse. J Oncol 2010;2010:497429.
Ledermann JA, Kristeleit RS. Optimal treatment for relapsing ovarian cancer. Ann Oncol 2010;21 Suppl 7:vii218-22.
[Table 1], [Table 2]