Origin of Residual Tumor Masses in BRCA1/2-Driven Ovarian Carcinomas Treated by Neoadjuvant Chemotherapy: Selection of Preexisting BRCA1/2-Proficient Tumor Cells but Not the Gain of Second ORF-Restoring Mutation.

INTRODUCTION: Tubo-ovarian carcinomas (OCs) are highly sensitive to platinum-based neoadjuvant chemotherapy (NACT) but almost never demonstrate complete pathologic response. METHODS: We analyzed paired primary and residual tumor tissues from 30 patients with hereditary BRCA1/2-driven OCs (BRCA1: 17; BRCA2: 13), who were treated by carboplatin/paclitaxel NACT (median number of cycles: 3, range: 3-6). BRCA1/2 and TP53 genes were analyzed by the next-generation sequencing. The ratio between TP53 mutation-specific versus wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample, and the ratio between BRCA1/2-mutated and wild-type reads was used to estimate the presence of cells with the loss or retention of heterozygosity (LOH or ROH, respectively). RESULTS: All 30 OCs had BRCA1/2 LOH in primary tumor and carried somatic TP53 mutation. Twenty-eight OCs had sufficient tumor cell cellularity in the post-NACT tissue to evaluate the ratio between mutated and wild-type BRCA1/2 alleles. Five (18%) out of 28 informative tumor pairs showed transition from LOH to ROH during NACT presumably affecting all or the vast majority of residual tumor cells. There were no signals of the emergence of a second open reading frame-restoring BRCA1/2 mutation. CONCLUSION: Chemonaive BRCA1/2-driven carcinomas may contain a fraction of tumor cells with preserved BRCA1/2 heterozygosity. NACT can cause a selection of pre-existing BRCA1/2-proficient tumor cells, without gaining secondary reversal BRCA1/2 mutations.

Effects of Endocrine Interventions Targeting ERα or PR on Breast Cancer Risk in the General Population and Carriers of BRCA1/2 Pathogenic Variants.

There is evidence suggesting that endocrine interventions such as hormone replacement therapy and hormonal contraception can increase breast cancer (BC) risk. Sexual steroid hormones like estrogens have long been known for their adverse effects on BC development and progression via binding to estrogen receptor (ER) α. Thus, in recent years, endocrine interventions that include estrogens have been discussed more and more critically, and their impact on different BC subgroups has increasingly gained interest. Carriers of pathogenic variants in BRCA1/2 genes are known to have a high risk of developing BC and ovarian cancer. However, there remain open questions to what extent endocrine interventions targeting ERα or the progesterone receptor further increase cancer risk in this subgroup. This review article aims to provide an overview and update on the effects of endocrine interventions on breast cancer risk in the general population in comparison to BRCA1/2 mutation carriers. Finally, future directions of research are addressed, to further improve the understanding of the effects of endocrine interventions on high-risk pathogenic variant carriers.

Mastectomy with Reconstruction Including Robotic Endoscopic Surgery (MARRES): a prospective cohort study of the Korea Robot-Endoscopy Minimal Access Breast Surgery Study Group (KoREa-BSG) and Korean Breast Cancer Study Group (KBCSG).

BACKGROUND: Robotic nipple-sparing mastectomy (RNSM) has emerged as a new treatment option for breast cancer and risk-reducing mastectomy (RRM) for women who have a high risk of pathogenic variants. Even though several studies have reported that RNSM is a feasible procedure, some argue that it should only be performed by specialized surgeons, and data on oncologic outcomes and patient-reported outcomes (PROs) are limited. Recently, the United States Food and Drug Administration and several surgeons warned that robotic breast surgery should be performed only by specialized surgeons and recommended that the benefits, risks, and alternatives of all available treatment options be discussed with patients so they can make informed treatment decisions. The Korea Robot-Endoscopy Minimal Access Breast Surgery Study Group (KoREa-BSG) has been established to evaluate, standardize, and teach this state-of-the-art procedure. We have designed a multicenter prospective cohort study entitled Mastectomy with Reconstruction Including Robot Endoscopic Surgery (MARRES) to report surgical, PRO, and oncologic outcomes. METHODS: MARRES is a multi-institution cohort study prospectively collecting data from patients undergoing mastectomy and reconstruction. The patient inclusion criteria are adult women older than 19 with breast cancer or a high risk of breast cancer (patients with BRCA1/2, TP53, PALB2 mutations, etc.), who have scheduled therapeutic or RRM and want immediate reconstruction. Surgical outcomes, including pre- and postoperative photos, oncologic outcomes, cost-effectiveness, and PRO, are collected. The primary endpoints are postoperative complication rates within 30 postoperative days and the Clavien-Dindo grade of postoperative complications within 180 postoperative days. The secondary endpoints are 5-year postoperative recurrence-free survival and cancer incidence rate (for those who underwent RRM), patient satisfaction with reconstruction expectations preoperative (baseline) and results within 6 to 12 postoperative months, surgeon satisfaction with postoperative results in 6 postoperative months, and cost-effectiveness of the definitive surgery. Patient recruitment will be completed in April 2025, and the target number of enrolled patients is 2000. DISCUSSION: This study will provide evidence about the surgical outcomes, oncologic outcomes, and patient satisfaction with RNSM and endoscopic nipple-sparing mastectomy (NSM), compared with conventional NSM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04585074. Registered April 8, 2020.

Prevalence of BRCA1 and BRCA2 pathogenic variants in 8627 unselected patients with breast cancer: stratification of age at diagnosis, family history and molecular subtype.

PURPOSE: Comprehensively analyzing the prevalence of BRCA1/2 germline pathogenic variants (PVs) in a large cohort of unselected Chinese patients with breast cancer has great clinical importance. METHODS: Germline pathogenic variants in full-length BRCA1/2 genes were determined through next-generation sequencing and/or Sanger sequencing assays in 8627 unselected Chinese patients with breast cancer who were treated at the Breast Center of Peking University Cancer Hospital. The prevalence of BRCA1/2 PVs was further stratified by age at diagnosis, family history of cancer and molecular subtype. RESULTS: We found that the overall prevalence of BRCA1/2 PVs was 6.0% in the entire cohort, 2.4% in BRCA1 and 3.7% in BRCA2. The prevalence of BRCA1/2 PVs in patients with early-onset breast cancer (age at diagnosis ≤ 40 years) was significantly higher than that in patients over the age of 40 (9.7% vs. 5.1%). The prevalence rates of BRCA1/2 PVs in patients with a family history of breast, ovarian, pancreatic, and prostate cancer were 19.5%, 39.0%, 11.1%, and 12.8%, respectively. Moreover, the number of relatives affected by breast cancer was associated with a higher prevalence of BRCA1/2 PVs. Molecular subtypes were associated with the prevalence of BRCA1/2 PVs. Patients with the triple-negative phenotype had the highest prevalence of BRCA1/2 PVs (13.3%) among the three molecular groups, followed by the HR + and HER2- group (5.9%), and the lowest was in the HER2 + group (2.5%). CONCLUSION: Our study provides the most comprehensive information to date on the prevalence of BRCA1/2 PVs in unselected Chinese patients with breast cancer.

Real-world patient-reported outcomes and physician satisfaction with poly (ADP-ribose) polymerase inhibitors versus chemotherapy in patients with germline BRCA1/2-mutated human epidermal growth factor receptor 2-negative advanced breast cancer from the United States, Europe, and Israel.

BACKGROUND: In clinical trials, poly (ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy resulted in significantly improved progression-free survival, manageable adverse event profiles, and favorable patient-reported outcomes (PROs) in patients with human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and germline BRCA1/2 mutations (gBRCA1/2mut). The objective of this study was to evaluate PROs and physician satisfaction with treatment in patients with gBRCA1/2mut HER2- ABC receiving PARPi or physician's choice of chemotherapy in a multi-country, real-world setting. METHODS: This retrospective analysis used data from the Adelphi Real World ABC Disease Specific Programmes in the United States, European Union, and Israel. PROs were assessed at a single timepoint using the EuroQol 5-Dimensions 5-Level (EQ-5D-5L) scale, Cancer Therapy Satisfaction Questionnaire (CTSQ), and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) and the breast cancer-specific module (QLQ-BR23). Baseline PROs were not assessed. Physician satisfaction with treatment scores was dichotomized to a 0/1 variable (0 = very dissatisfied/dissatisfied/moderately satisfied; 1 = satisfied/very satisfied). Scores were compared using inverse-probability-weighted regression adjustment, controlling for multiple confounding factors. RESULTS: The study included 96 patients (PARPi, n = 38; platinum/non-platinum-based chemotherapy, n = 58). Patients receiving PARPi versus chemotherapy reported significantly better scores on the EQ-5D-5L Health Utility Index. On the EORTC QLQ-C30 functional scales, patients receiving PARPi reported significantly better scores (mean ± SE) for physical functioning (80.0 ± 2.4 vs 71.9 ± 3.4; p < 0.05) and social functioning (82.0 ± 6.2 vs 63.6 ± 3.7; p < 0.05) and, on the symptom scales, reported significantly better scores for constipation (1.9 ± 1.8 vs 18.7 ± 3.2; p < 0.001), breast symptoms (0.4 ± 3.9 vs 13.3 ± 2.6; p < 0.01), arm symptoms (2.6 ± 1.3 vs 11.4 ± 2.4; p = 0.001), and systemic therapy side effects (13.5 ± 1.8 vs 29.4 ± 2.3; p < 0.001). In contrast, patients receiving chemotherapy scored significantly better on the nausea/vomiting scale (18.3 ± 2.8 vs 34.5 ± 5.1; p < 0.01). Patients receiving PARPi reported numerically better satisfaction scores on the CTSQ scales. Physicians were more likely to be satisfied/very satisfied with PARPi versus chemotherapy (95.4% ± 7.3% vs 40.8% ± 6.2%; p < 0.001). CONCLUSIONS: The PRO findings in this real-world population of patients with gBRCA1/2mut HER2- ABC complement those from the pivotal clinical trials, providing further support for treatment with PARPi in these patients.

Surgical Menopause and Bilateral Oophorectomy: Effect of Estrogen-Progesterone and Testosterone Replacement Therapy on Psychological Well-being and Sexual Functioning; A Systematic Literature Review.

BACKGROUND: Besides experiencing vasomotor symptoms, after surgical menopause and bilateral salpingo-oophorectomy (BSO), women experience moderate to severe psychological and sexual symptoms. AIMS: To systematically review and meta-analyze the effect of systemic hormone replacement therapy (sHRT) on psychological well-being and sexual functioning in women after surgical menopause and BSO. METHODS: Medline/Pubmed, EMBASE and PsychInfo were systematically searched until November 2021. Randomized controlled trials investigating the effect of sHRT on psychological well-being and/or sexual functioning in surgically menopausal women and women after BSO were eligible for inclusion. Two independent authors performed study selection, risk of bias assessment and data extraction. Standardized mean differences (SMDs) were calculated. OUTCOMES: Primary outcomes for psychological well-being were defined as overall psychological well-being, depression, and anxiety. Primary outcomes for sexual functioning were defined as overall sexual functioning, sexual desire, and sexual satisfaction. All outcomes were assessed on short (≤12 weeks) or medium term (13-26 weeks). RESULTS: Twelve studies were included. Estradiol had a beneficial effect on depressed mood on short term 3-6 years after surgery or 2 years (median) after surgery with high heterogeneity (SMD: -1.37, 95%CI: -2.38 to -0.37, P = .007, I2 79%). Testosterone had a beneficial effect on overall sexual functioning on short to medium term 4.6 years (mean) after surgery (SMD 0.38, 95%CI 0.11-0.65, I2 0%) and on sexual desire on medium term at least 3-12 months after surgery (SMD 0.38, 95%CI 0.19-0.56, I2 54%). For most studies, risk of bias was uncertain. CLINICAL IMPLICATIONS: Estradiol may beneficially affect psychological symptoms after surgical menopause or BSO and testosterone might improve sexual desire and overall sexual functioning. STRENGTHS AND LIMITATIONS: This review only included patient-reported outcomes, thereby reflected perceived and not simply objective symptoms in surgically menopausal women and women after BSO. The small number of studies highly varied in nature and bias could not be excluded, therefore our results should be interpreted with great caution. CONCLUSION: Independent randomized controlled clinical trials investigating the effects of estrogen-progesterone and testosterone on psychological and sexual symptoms after surgical menopause are needed. PROSPERO REGISTRATION NUMBER: CRD42019136698. Stuursma A, Lanjouw L, Idema DL, et al. Surgical Menopause and Bilateral Oophorectomy: Effect of Estrogen-Progesterone and Testosterone Replacement Therapy on Psychological Well-being and Sexual Functioning: A Systematic Literature Review. J Sex Med 2022;19:1778-1789.

Real-world multi-country study of BRCA1/2 mutation testing among adult women with HER2-negative advanced breast cancer.

Aim: We assessed real-world patient demographics and BRCA1/2 mutation testing rates among adult women with HER2-negative advanced breast cancer (ABC). Methods: Oncologists across the USA and in France, Germany, Italy, Spain and the UK provided medical chart data in 2015 and 2017. Results: Overall, 28% of patients received BRCA1/2 mutation testing. Untested patients were more likely to be aged ≥45 years, have hormone receptor-positive/HER2-negative ABC and have no known family history of breast/ovarian cancer. BRCA1/2 mutation testing rates were significantly lower in the European countries, women aged ≥45 years, women without a known family history of breast/ovarian cancer, and women with hormone receptor-positive/HER2-negative ABC versus advanced triple-negative breast cancer. Conclusion: BRCA1/2 mutation testing rates were low, and disparities were observed in patient characteristics among BRCA1/2 mutation-tested versus untested patients.

This study investigated the use of BRCA1/2 genetic testing in women with breast cancer in the USA and Europe. This is important, as mutations in this gene are known to influence cancer progression, with many treatments now available for patients with these mutations. Doctors collected data from patient medical records in both 2015 and 2017. The results show the BRCA1/2 testing rates were low, with only 28% of patients tested. Patients who did not have a test were older, had hormone receptor-positive/HER2-negative cancer and did not have a family history of cancer. Testing rates were also lower in Europe than in the USA. Improved BRCA1/2 testing rates could identify patients at risk and aid physicians and their patients in their choice of treatment, improving outcomes.

PARP Inhibition and Beyond in BRCA-Associated Breast Cancer in Women: A State-Of-The-Art Summary of Preclinical Research on Risk Reduction and Clinical Benefits.

In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome.

Impact of the addition of carboplatin to anthracycline-taxane-based neoadjuvant chemotherapy on survival in BRCA1/2-mutated triple-negative breast cancer.

Whether adding carboplatin to standard neoadjuvant chemotherapy improves survival in BRCA1/2-mutated triple-negative breast cancer (TNBC) is unknown. In this retrospective study, we aimed to explore the efficacy of anthracycline-taxane (A-T)-based or anthracycline-taxane/carboplatin (A-TP)-based neoadjuvant chemotherapy in BRCA1/2-mutated TNBC. A total of 1585 operable primary breast cancer patients were treated with either neoadjuvant A-T (n = 886) or A-TP regimen (n = 699). BRCA1 and BRCA2 germline mutations were determined in all subjects. Pathological complete response (pCR), recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and overall survival (OS) were estimated. Of the entire cohort, 102 patients (6.4%) carried a pathogenic BRCA1/2 germline mutation. After a median follow-up of 81 months, no significant differences in survival between the A-T and A-TP arms were found in the entire cohort. However, among 288 TNBC patients, BRCA1/2 mutation carriers had significantly better survival when treated with the A-TP regimen than with the A-T regimen (5-year RFS: 82.6% vs 47.9%; P = .024; 5-year DRFS: 88.5% vs 46.9%; P = .010; 5-year OS: 88.2% vs 49.9%; P = .036). Multivariate analyses revealed that the A-TP regimen was a significantly favourable factor for RFS and DRFS and showed a trend towards better OS when compared with the A-T regimen in BRCA1/2-mutated TNBC (RFS: adjusted hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.06-0.91, P = .035; DRFS: HR, 0.17; 95% CI, 0.03-0.80; P = .025; OS: HR, 0.29; 95% CI, 0.06-1.49; P = .14). Our study suggested that BRCA1/2-mutated TNBC patients gain a survival benefit when carboplatin is added to standard A-T-based neoadjuvant chemotherapy.

Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers.

BACKGROUND: Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)-involved in tumorigenesis and obesity-related diseases-are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC. METHODS: The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors. RESULTS: At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = - 0.435; CI - 0.653 to - 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061-0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: - 37.9, p = 0.097/0.080) in multivariate analysis. CONCLUSION: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Physical activity and Mediterranean diet as potential modulators of osteoprotegerin and soluble RANKL in gBRCA1/2 mutation carriers: results of the lifestyle intervention pilot study LIBRE-1.

PURPOSE: Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations. METHODS: Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups. RESULTS: The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = - 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871). CONCLUSION: Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.

The preventive effect of breastfeeding against ovarian cancer in BRCA1 and BRCA2 mutation carriers: A systematic review and meta-analysis.

OBJECTIVE: A recent study showed that even a few months of breastfeeding is associated with a significant decrease in the risk of ovarian cancer in the general population. This study aimed to perform a systematic review and meta-analysis to determine the significance of the length of the breastfeeding period on ovarian cancer risk in BRCA1/2 mutation carriers. METHODS: PubMed, EMBASE, and Cochrane databases were searched up to June 1, 2021. We included case-control and cohort studies that contained information on breastfeeding and the risk of ovarian cancer in BRCA1/2 mutation carriers. Odds ratios (OR) were meta-analytically pooled using a fixed-effects model.dd RESULTS: Five studies, including one cohort study and four case-control studies, were included in this meta-analysis. Of the 14,601 BRCA1/2 mutation carriers, the overall pooled OR of ever having performed breastfeeding in patients who had ovarian cancer was 0.767 (95% confidence interval [CI], 0.688-0.856) and 0.817 (95% CI, 0.650-1.028) for patients with BRCA1 and BRCA2 mutation, respectively. Breastfeeding for >1 year acted as a protective factor in both BRCA1 [OR: 0.787 (95% CI, 0.682-0.907)] and BRCA2 [OR: 0.567 (95% CI, 0.400-0.802)] mutation carriers. No significant heterogeneity was present (I2 = 0%), and the funnel plot was also properly distributed, showing no publication bias. CONCLUSIONS: Breastfeeding is a preventive, modifiable factor for ovarian cancer in BRCA1/2 mutation carriers. Ever having performed breastfeeding was significantly preventive for ovarian cancer in the BRCA1 mutation carriers, however a period of 1 year or more of breastfeeding is required for a reduced ovarian cancer risk in BRCA2 mutation carriers.

Breast cancer incidence in BRCA mutation carriers with ovarian cancer: A longitudal observational study.

OBJECTIVES: We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. METHODS: Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. RESULTS: The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9-90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11-168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. CONCLUSION: The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Development of decision aids for female BRCA1 and BRCA2 mutation carriers in Germany to support preference-sensitive decision-making.

BACKGROUND: Women with pathogenic BRCA1 and BRCA2 mutations possess a high risk of developing breast and ovarian cancer. They face difficult choices when considering preventive options. This study presents the development process of the first decision aids to support this complex decision-making process in the German healthcare system. METHODS: A six-step development process based on the International Patient Decision Aid Standards was used, including a systematic literature review of existing decision aids, a topical medical literature review, preparation of the decision aids, focus group discussions with women with BRCA1/2 mutations, internal and external reviews by clinical and self-help experts, and user tests. All reviews were followed by iterative revisions. RESULTS: No existing decision aids were transferable to the German setting. The medical research revealed a need to develop separate decision aids for women with BRCA1/2 mutations (A) without a history of cancer (previvors) and (B) with a history of unilateral breast cancer (survivors). The focus group discussions confirmed a high level of approval for the decision aids from both target groups. Additionally, previvors requested more information on risk-reducing breast surgery, risk-reducing removal of both ovaries and Fallopian tubes, and psychological aspects; survivors especially wanted more information on breast cancer on the affected side (e.g. biological parameters, treatment, and risk of recurrence). CONCLUSIONS: In a structured process, two target-group-specific DAs for previvors/survivors with BRCA1/2 mutations were developed to support decision-making on risk-adapted preventive options. These patient-oriented tools offer an important addition to existing specialist medical care in Germany.

Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors. METHODS: Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel. RESULTS: Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98). CONCLUSIONS: Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.

[Hereditary breast and ovarian cancer syndrome: Diagnosis and therapeutic implications]. / Syndrome héréditaire de prédisposition au cancer du sein et de l'ovaire : diagnostic et implications thérapeutiques.

Patients who carry the BReast Cancer 1 or 2 (BRCA) gene mutations have an underlying hereditary predisposition for breast and ovarian cancers. These deleterious genetic mutations are the most common ones implicated in hereditary breast and ovarian cancers. Oncogenetic counselling plays a key role in identifying patient for BRCA testing and for mutation identification. BRCA1/2 carriers have to be followed up regularly and may justify breast and/or adnexal prophylactic surgery, according to the French National Cancer Institute guidelines (INCa). Poly- (DNA-riboses) polymerases inhibitors, notably olaparib, have a major role in the management of epithelial ovarian cancer in patients with BRCA mutation and many studies are ongoing to expand their indications in a near future.

Risk of ipsilateral breast tumor recurrence in primary invasive breast cancer following breast-conserving surgery with BRCA1 and BRCA2 mutation in China.

PURPOSE: BRCA1/2 germline mutations are associated with a high risk of breast cancer, which may preclude mutation carriers from breast-conserving surgery (BCS). This study retrospectively examined whether mutation status influenced the rate of ipsilateral breast tumor recurrence (IBTR) after BCS  in Chinese women. METHODS: Patients who underwent BCS were enrolled in carriers group and non-carriers group according to their BRCA1/2 mutation status in the study. The correlations were analyzed between IBTR incidence and BRCA1/2 mutation. The IBTR cases were further separated into new primary tumor (NP) and true local recurrences (TR). The risk factors of NP were studied in multivariate analysis. RESULTS: 1947 consecutive Chinese women with primary invasive breast cancer were selected. 103 patients were identified as BRCA1/2 mutation carriers and 1844 were non-carriers. BRCA1/2 mutation carriers were younger (P < 0.001) with more often negative HER-2 expression (P = 0.01) and tumor size over 2 cm (P = 0.04) than non-carriers. The median follow-up for all patients was 80 months. The rate of IBTR was 3.9% in mutated carriers and 2.0% in non-carriers, respectively (P = 0.16). In IBTR cases, NP incidence was 3.9% in carrier group and 0.6% in non-carrier group, respectively (P < 0.01). After adjustment of all clinical-pathological factors, BRCA1/2 mutation was the only statistical risk factor of NP incidence (HR = 6.29, P = 0.002), while positive lymph node was nearly statistically significant (HR = 2.70, P = 0.06). CONCLUSIONS: BCS may be a rational option for Chinese BRCA1/2 mutation carriers. High NP incidence in mutation carriers should be paid close attention in the future.

Cytology material is equivalent to tumor tissue in determining mutations of BRCA 1/2 genes in patients with tubo-ovarian high grade serous carcinoma.

BACKGROUND: High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples. METHODS: Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared. RESULTS: Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples. CONCLUSION: There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients. TRIAL REGISTRATION: The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038 .

Psychological aspects, risk and protective factors related to BRCA genetic testing: a review of the literature.

PURPOSE: The primary aim of the present study was to conduct a systematic review of short-, intermediate- and long-term psychological effects, such as anxiety, depression and distress, on individuals undergoing genetic testing to determine BRCA1 and BRCA2 gene mutation. The different instruments used for the measurement of each construct were reported. In addition, risk and protective factors associated with psychological outcomes of genetic tests were explored. METHODS: Bibliographic databases were searched for studies published over the period 1998-2018. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method, 21 articles were selected for the current review. RESULTS: Overall, the collected data revealed rather diverse results, although most studies reported higher levels of distress, anxiety and depression in carriers, as compared to non-carriers. The two genders were not equally represented, with men constituting only 6% of the sample. Risk factors and protective factors that may influence psychological outcomes and adjustment to genetic tests are highlighted and discussed in this review. CONCLUSIONS: The increased risk of developing cancer associated with positive genetic testing results may be experienced as traumatic by many patients, although not all individuals with positive genetic testing results will experience increased distress. Hence, future studies should consider specific risk factors in order to select those who are more likely to be in need of psychological support. Finally, it is necessary to increase the number of male samples to better understand the male experience related to genetic testing outcomes.

Review of Immune Therapies Targeting Ovarian Cancer.

OPINION STATEMENT: The rise of immunotherapy is the greatest advance in oncology to occur over the last several years, but applications in gynecologic malignancies lag behind other tumors. The term "immunotherapy" envelops monoclonal antibodies as receptor mediators, including immune checkpoint inhibitors (ICPI), cancer vaccines, and adoptive immunotherapies alone or in combination with other therapeutic approaches. The purpose of this review is to summarize the status of immunotherapy trials in ovarian cancer and to specifically highlight data published in the last 1-2 years.