BRCA-associated Ovarian Cancer Research Articles

Mitomycin C in the treatment of early triple-negative locally advanced BRCA-associated breast cancer

Rationale. BRCA1 associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. At the same time, carcinomas that develop in carriers of BRCA1 mutations are characterized by extremely high sensitivity to DNA-damaging chemotherapy. Mitomycin C alone or in combination with platinum agents has already demonstrated promising results in the treatment of BRCA-associated ovarian cancer (OC) and metastatic breast cancer. In this article, we present the results of a retrospective study aimed at comparing standard neoadjuvant chemotherapy regimens (NACT) with mitomycin-based regimens for primary locally advanced BRCA1-associated TNBC.The aim of the study is to determine the effectiveness of the combination of mitomycin and platinum compounds during neoadjuvant therapy in patients with primary locally advanced BRCA1 – associated TNBC.Materials and methods. The study included 89 patients diagnosed with primary locally advanced BRCA1-associated TNBC. Patients were divided into three groups depending on the therapy: 1) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel (n = 48) (AC + T), 2) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel and carboplatin (n = 27) (AC + TCbP), 3) mitomycin C plus platinum followed by 12 weekly injections of paclitaxel (n = 14) (MR + T). Pathological complete response (pCR) rates were compared.Results. The pCR rate in the MP+T group was 10/14 (71%). In patients with BRCA1-associated breast cancer who received AC + T and AC + TCbP regimens as NACT, the pCR rate was 17/48 (35%) and 19/27 (70%), respectively. The difference in pCR rate between mitomycin-containing therapy and the standard AC + T regimen was statistically significant (p = 0.03); the frequency of regressions was comparable to the frequency in the AC + TCbP group. During the 20-month follow-up period, no relapses were observed in the MR + T group. Relapses were more frequent in the AC + T group compared with the AC + TCbP group (16/48 (33%) vs 1/27 (4%), p = 0.003, Fisher’s exact test). The toxicity profile of the mitomycin-containing regimen included hematologic adverse events, the most common of which were anemia and leukopenia. Compared to standard regimens, nausea was significantly less pronounced. No patients reported alopecia with this regimen.Conclusions. The addition of mitomycin C to neoadjuvant therapy for BRCA1-associated TNBC may be a promising treatment option for this category of patients and merits further study.

BRCA-associated ovarian cancer in the russian patient population. Analysis of the non-interventional study Ovatar

Purpose: To evaluate the proportion of BRCA1 / 2 mutations in patients with serous and endometrioid cancer of the ovary, fallopian tube, and peritoneum in Russia, to evaluate the percentage of germinal and somatic mutations, to identify the spectrum of mutations in BRCA1 / 2 genes, to evaluate clinical and morphological features of the BRCA-associated ovarian cancer (OC).Patients and methods: The study enrolled patients of 18 years and older with newly diagnosed serous and endometrioid cancer of the ovary, fallopian tube, and peritoneum. Biological material (blood, tumor tissue) was collected, followed by molecular genetic analysis. The method of mutations detecting in the blood were: allele-specific PCR, high-resolution melting (HRM), Sanger sequencing method. Advanced genetic testing included the use of generation sequencing (NGS) and multiplex amplification of ligated probes (MLPA). The collection of clinical data, family history, clinical and morphological characteristics of the tumor was performed.Results: 500 patients were included in the study, the evaluation of BRCA1 / 2 mutations was performed in 496 patients (99,2 %). The frequency of BRCA1 / 2 mutations in the Russian patient population was 28,4 % (n = 141 / 496). The incidence of germinal mutations was 23,5 % (n = 117 / 141), and somatic — 4,8 % (n = 24 / 141). Frequent mutations in the Russian population were identified in 50 % of cases. When analyzing the ethnicity of patients in the Russian Federation BRCA-associated OC was most common in Russian (83,6 %, n = 118 / 141), Ukrainian (4,2 %, n = 6 / 141) and Tatar (3,5 %, n = 5 / 141) women. A family history of cancer was detected in 44 % of patients (n = 62 / 141) with BRCA1 / 2 mutations.Conclusions: Due to the high frequency of germinal and somatic BRCA1 / 2 mutations in the Russian patients it is recommended to conduct the advanced testing methods not only in blood samples but also in tumor tissue.

Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival

ObjectiveTo define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC. MethodsWe included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015–12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset. ResultsOf 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1–6.0] vs. 1.2 mut/Mb [0.6–2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01). ConclusionsOCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.

A case report of long-term successful use of maintenance therapy with PARP inhibitors in the primary treatment of advanced brca-associated ovarian cancer

Background. Ovarian cancer is the third most common cancer of the female reproductive system after cervical and uterine cancer and is diagnosed at stage III–IV in 2 out of 3 cases. Maintenance therapy with PARP inhibitors signifcantly prolongs disease-free and overall survival. The purpose of the study was to demonstrate long-term remission in a patient with advanced ovarian cancer using maintenance therapy with PARP inhibitors (olaparib). Description of the clinical case. A 54-year-old female patient with verifed stage IV ovarian cancer, peritoneal carcinomatosis and left-sided pleurisy received combined modality treatment, including 2 courses of neoadjuvant chemotherapy with paclitaxel/carboplatin, cytoreductive surgery and 6 courses of postoperative chemotherapy with docetaxel/cisplatin. The patient was diagnosed with a somatic BRCA2 gene mutation (c.3708delA), which was detected by tumor DNA sequencing. The patient received maintenance therapy with olaparib for 38 months, resulting in no evidence of disease progression. Conclusion. This clinical case demonstrates the feasibility of using maintenance therapy with PARP inhibitors in a patient with initially disseminated platinum-sensitive ovarian cancer. Olaparib maintenance therapy provides stable long-term remission with no signs of adverse events and determined effect on quality of life of the patient.

Analysis of olaparib efficacy in patients with serous ovarian cancer

Modern treatment of ovarian cancer is impossible without understanding the carcinogenesis and the structure of malignant epithelial ovarian tumors and carrying out molecular genetic testing for homologous recombination deficiency. The choice of maintenance therapy depends on the presence of a mutation in the BRCA1/2 genes and the HRD status of the tumor. Targeted drugs, such as bevacizumab and olaparib, are used in the treatment of ovarian cancer. The aim of the work is to determine the effectiveness of olaparib in first-line maintenance therapy and in the treatment of platinum-sensitive recurrence of ovarian cancer. A retrospective study included 67 patients with high-grade serous ovarian cancer stages I–IV who were prescribed olaparib in first-line maintenance therapy or in maintenance therapy for the treatment of disease progression, provided a complete or partial response to platinum-containing chemotherapy in the period from 2016 to 2022. The median life expectancy of the patients receiving first-line maintenance treatment coincides with the median time to progression; only one patient died due to the progression of the disease, and the rest are alive. The median time to progression in the group of patients with maintenance therapy of relapses was 23.0 ± 1.5 months, and the median life expectancy was 24.7 ± 2.3 months. When comparing the patients of the first group, depending on the term of surgical treatment performed, the median life expectancy was statistically higher with primary cytoreduction and constituted 46.0 months, while in the interval cytoreduction group, it was 25.0 months (p = 0.018). When comparing the patients of the second group, depending on the mutation in the BRCA1 and BRCA2 genes, the median life expectancy was statistically higher in the patients with a mutation in the BRCA2 gene — by 38.6 months (p = 0.020). The addition of olaparib to the treatment of BRCA-associated ovarian cancer in first-line maintenance therapy and in the treatment of platinum-sensitive relapses of the disease makes it possible to increase the median time to progression and median life expectancy.

Germline variants in non-BRCA1/2 homologous recombination-related genes and ovarian cancer: Analysis of tumor phenotype and survival.

5565 Background: BRCA1/2-associated ovarian cancer (OC) exhibits homologous recombination (HR)-deficiency (HRD) and a better prognosis than BRCA1/2-wildtype (WT) OC. However, it is unclear if patients with germline pathogenic variants (gPV) in other HR-related genes have a similar tumor phenotype. We sought to define OC molecular features from patients with gPV in other HR genes and analyze survival compared to patients with BRCA1/2 and WT OC. Methods: We identified patients with OC treated at our institution who underwent tumor-normal sequencing using MSK-IMPACT targeting 341-505 cancer-related genes with germline analysis of ≥76 genes from 7/2015-12/2020. Biallelic inactivation was inferred via assessments of loss of heterozygosity (LOH) at gPV in non- BRCA1/2 HR-related genes ( ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D). Clinical characteristics were compared to patients with BRCA1/2-associated and WT OC using non-parametric tests. Progression-free (PFS) and overall-survival (OS) were calculated from date of pathologic diagnosis using the Kaplan-Meier method. Left truncation at date of MSK-IMPACT consent was applied. Whole-exome sequencing (WES) was performed in a subset of OCs. Results: Of 882 patients with OC, 56 (6.3%) had gPV in non- BRCA1/2 HR-related genes compared to 95 (10.8%) patients with BRCA1-associated OC (58 germline, 37 somatic) and 59 (6.7%) patients with BRCA2-associated OC (40 germline, 19 somatic). Patients with a deleterious genetic alteration were diagnosed with OC at younger age and more likely to have high-grade serous histology compared to the WT group (p &lt; 0.01). High rates of biallelic alterations were observed amongst gPV in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10), and WES was performed in a subset (n = 27) of tumors from these patients with adequate tumor purity (&gt;30%). We observed a higher tumor mutational burden (TMB), median 2.5 (1.1-6.0) vs. 1.2 (0.6-2.6) mut/Mb, and enrichment of HRD mutational signatures in tumors associated with PALB2 and RAD51B/C/D compared with BRIP1 (p &lt; 0.01), although markers of telomeric-allelic imbalance (TAI), large-scale state transitions (LST) and fraction of genome altered (FGA) were similar. PFS and OS varied by gene group with best survival in BRCA1/2-associated OC, even after adjustment for clinical covariates in multivariable models (p &lt; 0.01). Although we observed heterogeneity in PFS and OS for those with gPV in other HR-related genes by biallelic status and HRD phenotype, none had significantly better survival than those with WT OC. Conclusions: OCs associated with gPV in non- BRCA1/2 HR-related genes represent a heterogenous group. OCs in those with gPV in PALB2 and RAD51B/C/D preferentially harbored biallelic alterations and displayed an HRD phenotype.

Experience in the use of olaparib poly (ADP-ribose) polymerase inhibitors in maintenance therapy of BRCA-associated ovarian cancer

Aim to study the frequency of BRCA1/2 gene mutations , the efficacy of ovarian cancer therapy depending on the presence of BRCA1/2 mutations as well as the efficacy of olaparib maintenance therapy in BRCAassociated ovarian cancer.Material and Methods. The retrospective analysis included 355 patients with high-grade, stage I–IV serous ovarian cancer. The examination for a mutation in the BRCA1/2 gene was carried out within the framework of the program “Improvement of molecular genetic diagnostics in the Russian Federation in order to increase the effectiveness of antitumor treatment”.Results. Mutations in the BRCA1/2 genes were detected in 98 out of 355 (27.6 %) patients. Mutations of the BRCA1+ gene were detected in 62 out of 230 patients with ovarian cancer of stages IIIC–IV (27.0 %), the BRCA2 gene – in 9 out of 230 (3.9 %). In ovarian cancer of stages III–IV, BRCA gene mutations were absent in 159 of 230 (69.1 %) patients. The median time to progression in stages III–IV of the disease with a mutation in the BRCA1 gene was 22.0 months, in the BRCA2 gene – 27.0 months, in patients without mutations in the BRCA1/2 genes – 17.0 months, median life expectancy – 70.0; 65.0 and 45.0 months, respectively. Patients with serous ovarian carcinoma of high-grade I–IV stages with the presence of mutations in the BRCA1/2 genes were divided into two groups. The first group (6 out of 26 patients, 23.1 %) consisted of patients with stage IIIC–IV high-grade serous ovarian carcinoma, who received olaparib as maintenance therapy after the 1st line of chemotherapy, the second group (20 out of 26 patients, 76.9 %) were patients with stage I–IV high-grade serous ovarian carcinoma, who received olaparib in maintenance mode after 2 or more lines of chemotherapy.Conclusion. The presence of BRCA1/2 gene mutations significantly increased the median life expectancy of patients with stage IIIC–IV serous ovarian cancer, and primary cytoreduction significantly improved both overall survival and survival to progression in this group of patients. Maintenance therapy with olaparib is more appropriate after the 1st line of treatment than after subsequent ones.

Лептоменингеальный канцероматоз при BRCA1-ассоциированном раке яичников

Leptomeningeal carcinomatosis (LMC) in ovarian cancer is a rare complication of malignant gynecological disease, which is characterized by the spread of tumor cells through the cerebrospinal fluid to the membranes surrounding the brain and spinal cord. The cause of rare involvement of central nervous system (CNS) meninges in ovarian cancer is unclear. To date, there are no clinical guidelines for the management of this category of patients, and treatment of LMC in ovarian cancer is based on treatment protocols for meningeal carcinomatosis in other nosologies and on selected clinical observations presented in the world literature and personal experience. This article presents a clinical case of a patient with BRCA1-associated ovarian cancer and lesions of CNS meninges and parenchyma and our own experience in the treatment of this pathology. The treatment consisted of systemic anti-cancer therapy in combination with radiation therapy. Survival time after diagnosis of CNS metastases and treatment was 8 months. Key words: ovarian cancer, meningeal carcinomatosis, brain metastases, cytological examination, cerebrospinal fluid

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor.

Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34. These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.

&lt;i&gt;BRCA&lt;/i&gt;-associated ovarian cancer: a review of the current literature

Ovarian cancer is a heterogeneous disease and is the leading cause of mortality among all gynecological malignancies. The disease is characterized by a high frequency of germline and somatic mutations in BRCA1/2 suppressor genes, which, according to various sources, occur in 10–27 % of all ovarian cancer cases. Determination of mutations in BRCA1 / 2 genes is a mandatory diagnostic criteria and includes performing next generation sequencing. Knowledge of the disease mutational status is important not only in the case of determining treatment plan, but also in the case of prevention of the other malignant neoplasms. The purpose of this review is to summarize the current data on the disease characteristics, diagnosis and treatment of BRCA-associated ovarian cancer. Also, the article presents data from a non-interventional multicenter OvATAR study to assess the prevalence of germline and somatic mutations in BRCA1 / 2 genes in the Russian patient population.

A clinical case of repeat use of PARP inhibitors in a patient with &lt;i&gt;mBRCA&lt;/i&gt;-associated ovarian cancer

Backgraound. High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer. The prevalence of BRCA1/2 germline mutations is the highest in HGSOC. patients with germline BRCA gene mutations are more likely to respond to platinum-based chemotherapy. Clinical trials demonstrate the effectiveness of PARP inhibitors in the treatment of BRCA-associated ovarian cancer. Re-administration of PARP inhibitors after response to platinum-based chemotherapy demonstrates an increase in progression-free survival rates regardless of BRCA status. it is important for understanding the development of molecular mechanisms of resistance to platinum drugs and PARP inhibitors, as well as for developing new treatment strategies and tools to overcome resistance. Case description. This clinical case of BRCA-associated hereditary ovarian cancer demonstrates the efficacy and good tolerability of PARP inhibitor maintenance therapy following the treatment of the first relapse, as well as the efficacy of re-administration of PARP inhibitors following the treatment of the second relapse. The short-course of re-treatment with PARP inhibitors was accompanied by the development of multidrug resistance. the overall survival time was 112 months. Conclusion. The presence of mutations in BRCA1/2 genes is a promising justification for the administration of maintenance therapy with PARP inhibitors. Re-administration of PARP inhibitor maintenance therapy for relapsed ovarian cancer is currently being considered as a possible therapeutic option. deciphering the molecular mechanisms of resistance to PARP inhibitors is of paramount importance for the development of new treatment strategies and tools to overcome chemoresistance, re-sensitization of the tumor to platinum-based drugs or PARP inhibitors.

Genetic, clinic and histopathologic characterization of BRCA-associated hereditary breast and ovarian cancer in southwestern Finland

We have analyzed the histopathological, clinical, and genetic characteristics in hereditary breast and ovarian cancer patients of counselled families from 1996 up to today in the southwestern Finland population. In this study we analyzed the incidence of different BRCA1 and BRCA2 pathogenic variants (PV). 1211 families were evaluated, and the families were classified as 38 BRCA1 families, 48 BRCA2 families, 689 non-BRCA families and 436 other counselled families (criteria for genetic testing was not met). In those families, the study consisted of 44 BRCA1 breast and/or ovarian cancer patients, 58 BRCA2 cancer patients, 602 non-BRCA patients and 328 other counselled patients. Breast cancer mean onset was 4.6 years earlier in BRCA1 carriers compared to BRCA2 (p = 0.07, a trend) and ovarian cancer onset almost 11 years earlier in BRCA1 families (p < 0.05). In BRCA families the onset of ovarian cancer was later than 40 years, and BRCA2-origin breast cancer was seen as late as 78 years. The BRCA PV (9%) increases the risk for same patient having both ovarian and breast cancer with a twofold risk when compared to non-BRCA group (4%) (95% CI p < 0.05). Triple-negativity in BRCA1 (42%) carriers is approximately 2.6 times vs more common than in BRCA2 carriers (16%) (p < 0.05). The risk ratio for bilateral breast cancer is approximately four times when compared BRCA2 (17%) and other counselled patients’ group (4%) (p < 0.05). 27% southwestern BRCA2-families have a unique PV, and correspondingly 39% of BRCA1-families. The results of this analysis allow improved prediction of cancer risk in high-risk hereditary breast and ovarian families in southwestern Finland and improve long term follow-up programs. According to the result it could be justified to have the discussion about prophylactic salpingo-oophorectomy by the age of 40 years. The possibility of late breast cancer onset in BRCA2 carriers supports the lifelong follow-up in BRCA carriers. Cancer onset is similar between BRCA2 carries and non-BRCA high-risk families. This study evaluated mutation profile of BRCA in southwestern Finland. In this study genotype–phenotype correlation was not found

Risk-Reducing Options for High-Grade Serous Gynecologic Malignancy in BRCA1/2.

Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancy. Breast Cancer Susceptibility Gene 1 (BRCA 1) and Breast Cancer Susceptibility Gene 2 (BRCA 2) germline mutations confer an estimated 20 to 40 times increased risk of OC when compared to the general population. The majority of BRCA-associated OC is identified in the late stage, and no effective screening method has been proven to reduce mortality. Several pharmacologic and surgical options exist for risk-reduction of gynecologic malignancy in BRCA 1/2 mutation carriers. This review summarizes up-to-date research on pharmacologic risk-reducing interventions, including the oral contraceptive pill, acetylsalicylic acid/nonsteroidal anti inflammatory drugs (ASA/NSAID) therapy, and denosumab, and surgical risk-reducing interventions, including risk-reducing bilateral salpingo-oophorectomy, salpingectomy with delayed oophorectomy, and hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy.

Приобретенная платинорезистентность BRCA1-ассоциированного рака яичника после неоадъювантной химиотерапии

Objective of the Paper: To individualise the treatment programme for patients with advanced BRCA-associated ovarian cancer. Key points. Ovarian cancer is a highly aggressive disease characterized by low overall survival rates. The search for molecular markers, predictors of the effectiveness of drug therapy, is an urgent area of research. The article describes a clinical case of a fundamentally new approach to the combined treatment of a patient with BRCA1-associated advanced ovarian cancer. Conclusion. Molecular testing proved tumor resistance, which evolved during neoadjuvant therapy, so adjustment of the drug regimen was required. A comprehensive approach in the assessment of molecular genetic status and tumor prevalence allows to individualize the treatment program for patients with advanced BRCA-associated ovarian cancer. Keywords: ovarian cancer, chemoresistance, mutations in BRCA genes.

Poly(ADP-Ribose) Polymerase Inhibitor Inhibition in Ovarian Cancer: A Comprehensive Review.

The emergence of clinical trial data for poly(ADP-ribose) polymerase inhibitors (PARPi), in BRCA-associated ovarian cancer (epithelial ovarian cancer [EOC]) in 2009 (Lancet 2010;376:245-251) unleashed a rapid series of additional asset development and clinical trial activation across all lines of EOC treatment, ultimately leading to 8 new approvals of 3 different PARPi in EOC since 2014. Monotherapy iPARPi were approved as frontline maintenance treatment for all patients with EOC who respond to platinum-based chemotherapy irrespective of biomarker (niraparib) and for BRCA-associated cancers (olaparib) (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf). Combination of olaparib and bevacizumab was approved as maintenance for patients in response to platinum-based and bevacizumab containing frontline therapy whose tumor is characterized as homologous recombination deficient and as approved test by the Food and Drug Administration, inclusive of BRCA-associated cancers (N Engl J Med 2019;381:2416-2428). Niraparib, olaparib, and rucaparib were also approved as maintenance treatment following response to platinum-based therapy in the recurrent setting irrespective of biomarker (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf). All 3 PARPi were also approved as treatment in lieu of chemotherapy for patients with BRCA-associated cancers in third line and beyond (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1;https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf) and platinum-sensitive homologous recombination deficient in the fourth line and beyond (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf), as well as the National Comprehensive Cancer Network listed in combination with bevacizumab for treatment of patients with platinum-sensitive recurrent disease (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf). Ongoing clinical trials in all lines of treatment are evaluating combinations of therapies to improve efficacy among biomarker negative tumors as well as overcome acquired PARPi resistance due to prior use.

The correlation between BRCA status and surgical cytoreduction in high-grade serous ovarian carcinoma

<h3>Objectives:</h3> BRCA-associated ovarian cancers are biologically unique, as evident by differential molecular and clinical behaviour of these tumor as compared to sporadic ovarian cancers. It is unclear if these biological differences translate to favorable outcomes at the time of primary cytoreduction. The aim of this study is to compare the amount of residual disease after primary cytoreduction in <i>BRCA</i> mutated and wildtype populations, and to assess whether <i>BRCA</i> status is an independent predictor of optimal cytoreduction. <h3>Methods:</h3> We conducted a retrospective analysis of patients with high-grade serous (HGSC) ovarian cancers with known germline and somatic <i>BRCA</i> mutation status, treated with primary cytoreductive surgery from 2000 to 2017. Post-operative <i>BRCA</i> germline and somatic testing was conducted in all cases. We compared the complete, optimal and suboptimal cytoreduction rates between the <i>BRCA</i> positive and the <i>BRCA</i> negative cohorts and built a predictive model to assess whether the <i>BRCA</i> status was associated with the amount of residual disease after controlling for confounding variables. <h3>Results:</h3> Of 355 women with HGSC ovarian cancers treated with primary cytoreduction, 144 harbored germline or somatic <i>BRCA</i> mutations (41%) and 211 were <i>BRCA</i> wildtype (59%). <i>BRCA</i> positive women tended to be younger (54 vs 59; p<0.001), but there were no differences between the two groups in preoperative CA-125 levels, disease burden (measured by disease score), surgical complexity score, stage distributions, length of surgery, intraoperative or postoperative complications. Comparing residual disease burden at the end of primary cytoreduction, the <i>BRCA</i> positive group had a higher rate of complete cytoreduction to no residual disease (0mm) [75% vs 54%], and a lower rate of optimal cytoreduction (1-9mm) [16% vs 34%] or suboptimal cytoreduction (≥10mm) [9% vs. 12%] (p<0.001). In our predictive model, after accounting for length of surgery, CA-125 level, stage distributions, disease scores and surgical complexity scores, <i>BRCA</i> positive status was predictive of complete cytoreduction to 0mm residual disease with odds ratio (OR) of 4.78 (95% CI 2.32-9.85; p<0.001). Subgroup analysis restricted to patients with stage III/IV HGSC showed similar results, with <i>BRCA</i> positive status having OR of 5.2 (95% CI 2.44-11.09; p<0.001) for complete primary cytoreduction. <h3>Conclusions:</h3> <i>BRCA</i> status is predictive of complete and optimal cytoreduction at the time of primary surgical cytoreduction in patients presenting with newly diagnosed ovarian cancer. This positive correlation should be taken into consideration when deciding between primary cytoreductive surgery or neoadjuvant chemotherapy in women with this disease.

Abstract 878: Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study

Abstract Background: Oral contraceptive use is associated with a significantly reduced risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. To date, there have been no prospective analyses of this relationship, and the impact of other types of contraception (e.g. intrauterine device (IUD), implant, patch, injection) on BRCA-associated ovarian cancer risk is unknown. The goal of this study is to prospectively evaluate the relationship between types of contraception and ovarian cancer incidence in women with a BRCA1 or BRCA2 mutation. Methods: The longitudinal study included 3,298 eligible BRCA1/2 mutation carriers. Self-reported information regarding contraceptive use, including medication name, start year, end year, duration of use and method of administration were collected by biennial questionnaire. Women were classified according to history of contraceptive use (ever/never), duration of use, contraceptive method, calendar year of initiation and time since last use. Time-dependent Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer associated with each contraceptive method. Results: There were 84 incident ovarian cancer cases diagnosed over a mean follow-up period of 5.1 years. There was no significant association between ever use of an IUD (HR: 0.78; 95% CI: 0.28-2.14) and risk of ovarian cancer compared to IUD never users. Ongoing analyses will focus on the relationships between other contraceptive methods, formulations and duration of use on ovarian cancer risk, further stratified by histology and site of origin. Conclusions: Preliminary findings from this prospective analysis suggest that IUD use may not be protective among BRCA1/2 mutation carriers. Ongoing results will elucidate the impact of contraceptive formulation and method on ovarian cancer risk to inform clinical recommendations surrounding the use of contraceptive agents for chemoprevention in high risk women. Citation Format: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos. Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 878.

Clinical case of gastric cancer in patient with hereditary BRCA-associated ovarian cancer

The detection of tumor-like formations in the area of the uterine appendages during dispensary observation in patients who have undergone treatment for malignant neoplasms of the gastrointestinal tract often suggests metastatic lesions of the ovaries (Krukenberg metastasis). It is very important to collect anamnestic data, namely the fact of hereditary burden. It is recognized that one of the main indications for molecular genetic testing for the detection of mutations in the BRCA1, BRCA2 genes is hereditary burden, that is, the presence of a family history of cancer. Oncological burden of personal history, implying the development of polyneoplasias, is less often taken into account by oncologists, although it is one of the most important characteristics of hereditary ovarian cancer. Most often, with BRCA-associated ovarian cancer, breast cancer, pancreatic cancer occurs in the patient herself (polyneoplasia) or in close female and male relatives. The risk of developing stomach cancer is extremely low in patients with mutations in the BRCA1 genes. Stomach cancer is characterized by mutations in other genes. The article presents a rare case of multiple primary metachronous gastric cancer and BRCA1-associated ovarian cancer. In a patient who underwent radical treatment for stomach cancer, after 3 years, a relapse in the region of the esophageal-gastric anastomosis was revealed. Regarding the recurrence, extirpation of the gastric transplant with esophagogastroanastomosis with one-stage reconstruction – colon plastic surgery was performed in a planned manner. 10 years after the second operation, the patient was diagnosed with ovarian cancer. Taking into account the obtained postoperative historesponse for the ovary (serous adenocarcinoma), aggravated family and personal history, the patient underwent a molecular genetic study in order to identify germline mutations in the BRCA1 and BRCA2 genes by the polymerase chain reaction method. For the detection of mutations, a standard diagnostic panel was used, which makes it possible to analyze the mutations most common in the Russian Federation. According to the results of the study, the patient was found to have a 5382insC mutation in the BRCA1 gene. The patient is a candidate for PARP inhibitors, which are widely used as maintenance therapy not only for hereditary ovarian cancer, but also have found application in the treatment of patients with identified somatic mutations in the BRCA1 and BRCA2 genes, which will increase life expectancy and improve treatment results.

Overview of recent advances in metastatic triple negative breast cancer.

Metastatic triple negative breast cancer (TNBC) has an aggressive phenotype with a predilection for visceral organs and brain. Best responses to chemotherapy are predominately in the first line. Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC. However, a recent trial in a similar population showed no benefit for atezoli-zumab and paclitaxel which led to a Food and Drug Administration alert. Two phase III trials (OLYMPIAD and BROCADE3) demonstrated a benefit in progression free survival (PFS) but not overall survival in patients with BRCA-associated metastatic TNBC treated with Olaparib or Talazoparib respectively. For those treated with Talazoparib, the time to deterioration in health related-quality of life was also longer compared to chemotherapy. The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity. There are no head-to-head comparisons of a poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinums. There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCA-associated ovarian cancer. Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway, protein kinase B, mammalian target of rapamycin or utilising antibody drug conjugates. This review focusses on recent and emerging therapeutic options in metastatic TNBC. We searched PubMed, clinicaltrials.gov and recent international meetings from American Society of Clinical Oncology, San Antonio Breast Cancer Conference and the European Society of Medical Oncology.

The latest first-line treatment options for ovarian cancer: focus on maintenance therapy

Ovarian cancer is one of the leading causes of death from gynecologic cancers in Russia: in 2018, 7616 women died from this disease and the proportion of patients who is under observation for 5 years or more was only 3.4%, which probably indicates very low 5-year survival. At the same time, there was is a tremendous paradigm shift in the treatment of BRCA-associated ovarian cancer. A number of large phase III trials have been published on the use of PARP inhibitors in this subtype of the disease. Their results demonstrated a marked reduction in the risk of disease progression or death with PARP inhibitors after first-line therapy for advanced ovarian cancer. Here we present a comparative analysis of the efficacy of various PARP inhibitors in BRCA-associated ovarian cancer. The relative risk reduction in disease progression or death for olaparib, niraparib and veliparib was 70%, 60% and 56%, respectively and advantage of using these drugs noted in all patient subgroups. Comparative analysis of the safety of various PARP inhibitors was carried out as well, the risks of developing various toxicity were assessed. Based on a comparison of published data on their safety profile, it was concluded that olaparib is the safest drug of this class, especially in the context of therapy on an outpatient basis. Possible ways to optimize the use of PARP inhibitors in disseminated ovarian cancer have been analyzed.