Concordance Between Genomic Alterations Detected by Tumor and Germline Sequencing: Results from a Tertiary Care Academic Center Molecular Tumor Board.

OBJECTIVE: The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results. METHODS: A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status. RESULTS: A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin. CONCLUSIONS: Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.

Proliferation of the Fallopian Tube Fimbriae and Cortical Inclusion Cysts: Effects of the Menstrual Cycle and the Levonorgestrel Intrauterine Contraceptive System.

BACKGROUND: The objectives of this study were (i) to explore whether differences in cell proliferation may help explain why most high-grade serous ovarian cancers (HGSOC) arise in the fallopian tube fimbriae (FTF) rather than in ovarian cortical inclusion cysts (CIC); (ii) to compare premenopausal and postmenopausal FTF proliferation as a reason why the age incidence of HGSOC increases at a slower rate after menopause; and (iii) to compare FTF proliferation in cycling women and women using the levonorgestrel intrauterine contraceptive system (Lng-IUS) to see whether proliferation on the Lng-IUS was lower. METHODS: We studied 60 women undergoing a salpingo-oophorectomy. We used Ki67, paired-box gene 8 (PAX8, Müllerian marker), and calretinin (mesothelial marker) to study FTF and CIC proliferation. RESULTS: FTF Ki67%+ was greater in the follicular than in the luteal phase (4.9% vs. 1.5%; P = 0.003); postmenopausal Ki67%+ was 1.7%. Ki67%+ in PAX8 negative (PAX8-) CICs was extremely low. Proliferation in PAX8+ CICs did not vary by menstrual phase or menopausal status. Follicular Ki67%+ was 2.6-fold higher in FTF than PAX8+ CICs. FTF Ki67%+ from 10 women using the Lng-IUS was not lower than in cycling women. CONCLUSIONS: Overall FTF Ki67%+ is greater than overall CIC Ki67%+. Overall FTF Ki67%+ in postmenopausal women is lower than in premenopausal women. The Lng-IUS is not associated with lower FTF Ki67%+. IMPACT: Ki67%+ provides an explanation of the preponderance of FTF-derived HGSOCs, and of the slower increase of HGSOCs after menopause. The Lng-IUS may not be associated with a protective effect against HGSOCs.

Universal screening for Lynch syndrome in uterine cancer patients: A quality improvement initiative.

OBJECTIVE: To determine the feasibility and effectiveness of a quality improvement initiative (QI) to adopt universal screening for Lynch syndrome in uterine cancer patients at an institution that previously employed age-based screening. METHODS: Prior to the initiative, tumors of patients with uterine cancer diagnosed at age ≤ 60 years were screened for mismatch repair deficiency (MMR) and microsatellite instability (MSI). The QI process change model adopted universal testing of all uterine cancer specimens and implemented provider training, standardized documentation, and enhanced use of the electronic medical record (EMR). We compared screening rates, results of screening, follow up of abnormal results, and final diagnoses from the pre- and post-implementation periods. RESULTS: Pre- and post-implementation screening rates for women age ≤ 60 years at the time of diagnosis were 45/78 (57.7%) and 64/68 (94.5%), respectively. The screening rate for all patients with uterine cancer increased from 73/190 (38.4%) to 172/182 (94.5%). The rate of abnormal screening results increased from 15/190 (7.9%) to 44/182 (24.0%) cases. Genetics referral rates among screen positives increased from 3/15 (20.0%) to 16/44 (36.4%). Germline diagnoses increased from 2/190 (1.1%) with two Lynch syndrome diagnoses to 4/182 (2.2%) including three Lynch syndrome diagnoses and one BRCA1 germline diagnosis. The number of patients errantly not screened decreased from at least 32 patients to 3 patients after the intervention. CONCLUSIONS: Adherence to screening guidelines significantly improved after interventions involving provider education, optimal use of the EMR, and simplification of screening indications. These interventions are feasible at other institutions and translatable to other screening indications.

Management of high, moderate, and low penetrance ovarian cancer susceptibility mutations: an assessment of current risk reduction practices.

OBJECTIVE: Limited information exists regarding risk reduction strategies for women with moderate and low penetrance ovarian cancer susceptibility mutations. We sought to assess current risk reduction practice patterns for carriers of these mutations through a survey of members of the Society of Gynecologic Oncology. METHODS: Society of Gynecologic Oncology members were emailed a survey consisting of two vignettes: (1) a 35-year-old premenopausal woman; (2) a 55-year-old postmenopausal woman with comorbidities. Each vignette contained sub-scenarios in which the patient had either a BRCA1 (relative risk (RR)=30-60), RAD51C (RR=5.0), or ATM (RR=1.5-2.0) mutation. Respondents were queried about their preferred management approach. Summary statistics were performed to describe results of the survey. We used χ2 testing for statistical analyses, comparing results according to mutation type and demographic information. RESULTS: A total of 193 (15%) of 1284 Society of Gynecologic Oncology members responded. For the premenopausal woman, 99%, 80%, and 40% would perform a risk reducing salpingo-oophorectomy prior to menopause in the setting of a BRCA1, RAD51C, and ATM mutation, respectively. For the postmenopausal woman, 98%, 85%, and 42% would proceed with risk reducing salpingo-oophorectomy in the setting of a BRCA1, RAD51C, and ATM mutation, respectively. Response distribution for carriers of RAD51C and ATM mutations were different from BRCA1 in both vignettes (p<0.001). CONCLUSIONS: Respondents were more likely to perform risk reducing salpingo-oophorectomy, in the setting of a BRCA1, RAD51C, and ATM mutation, earlier and more frequently in the setting of a BRCA1 mutation. However, there was a lack of consensus about management of the moderate and low penetrance mutations, suggesting that more data regarding age specific risks and appropriate risk reduction strategies for these alterations are needed.

Risk-Reducing Salpingo-Oophorectomy and Breast Cancer Risk Reduction in the Gynecologic Oncology Group Protocol-0199 (GOG-0199).

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) has been associated with approximately 50% breast cancer risk reduction among women with a pathogenic variant in BRCA1 or BRCA2 (BRCA1/2), a finding that has recently been questioned. METHODS: We estimated incidence rates of breast cancer and all cancers combined during 5 years of follow-up among participants selecting RRSO or ovarian cancer screening (OCS) among women with a BRCA1/2 pathogenic variant or strong breast and/or ovarian cancer family history. Ovarian or fallopian tube or peritoneal cancer incidence rates were estimated for the OCS group. Breast cancer hazard ratios (HRs) for time-dependent RRSO were estimated using Cox regression with age time-scale (4943 and 4990 women-years in RRSO and OCS cohorts, respectively). All statistical tests were two-sided. RESULTS: The RRSO cohort included 925 participants, and 1453 participants were in the OCS cohort (381 underwent RRSO during follow-up), with 88 incident breast cancers diagnosed. Among BRCA1/2 pathogenic variant carriers, a non-statistically significant lower breast cancer incidence was observed in the RRSO compared with the OCS cohort (HR = 0.86, 95% confidence interval = 0.45 to 1.67; P = .67). No difference was observed in the overall population or among subgroups stratified by prior breast cancer history or menopausal status. Seven fallopian tube and four ovarian cancers were prospectively diagnosed in the OCS cohort, and one primary peritoneal carcinoma occurred in the RRSO cohort. CONCLUSIONS: These data suggest that RRSO might be associated with reduced breast cancer incidence among women with a BRCA1/2 pathogenic variant, although the effect, if present, is small. This evolving evidence warrants a thorough discussion regarding the impact of RRSO on breast cancer risk with women considering this intervention.

Prospective follow-up of quality of life for participants undergoing risk-reducing salpingo-oophorectomy or ovarian cancer screening in GOG-0199: An NRG Oncology/GOG study.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) and ovarian cancer screening (OCS) are management options for women at increased risk of ovarian cancer. Long-term effects of these interventions on quality of life (QOL) are not well understood. METHODS: GOG-0199 is a prospective cohort study of women at increased ovarian cancer risk who chose either RRSO or OCS as their risk management intervention. At study entry, 6, 12, 24 and 60 months of follow-up, participants completed the QOL questionnaire, which included the Medical Outcome Study Short Form-36, the Impact of Events Scales, the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, the Functional Assessment of Cancer Therapy - Endocrine Subscale, and the Sexual Activity Questionnaire. QOL measures were compared between the RRSO and OCS cohort at baseline and over time. RESULTS: Five-hundred-sixty-two participants in the RRSO cohort and 1,010 in the OCS completed the baseline and at least one follow-up questionnaire. At baseline, participants selecting RRSO reported lower health-related QOL (HRQOL), greater ovarian cancer-related stress, greater anxiety, and more depressive symptomatology, which improved during follow-up, especially for ovarian cancer-related stress. Screening was not found to adversely impact HRQOL. Hormone-related menopausal symptoms worsened and sexual functioning declined during follow-up in both cohorts, but more so among participants who underwent RRSO. CONCLUSIONS: HRQOL improved after surgery among women who chose RRSO and remained stable among participants undergoing screening. The adverse effects of RRSO and screening on short-term and long-term sexual activity and sexual functioning warrant consideration in the decision-making process for high-risk women.

The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome.

PURPOSE: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. METHODS: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. RESULTS: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. CONCLUSION: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium.

PURPOSE: Advances in germline genetics, and related therapeutic opportunities, present new opportunities and challenges in prostate cancer. The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group was established to address genetic testing for men with prostate cancer, especially those with advanced disease undergoing testing for treatment-related objectives and clinical trials. METHODS: The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group met monthly to discuss the current state of genetic testing of men with prostate cancer for therapeutic or clinical trial purposes. We assessed current institutional practices, developed a framework to address unique challenges in this population, and identified areas of future research. RESULTS: Genetic testing practices in men with prostate cancer vary across institutions; however, there were several areas of agreement. The group recognized the clinical benefits of expanding germline genetic testing, beyond cancer risk assessment, for the goal of treatment selection or clinical trial eligibility determination. Genetic testing for treatment selection should ensure patients receive appropriate pretest education and consent and occur under auspices of a research study whenever feasible. Providers offering genetic testing should be able to interpret results and recommend post-test genetic counseling for patients. When performing tumor (somatic) genomic profiling, providers should discuss the potential for uncovering germline mutations and recommend appropriate genetic counseling. In addition, family members may benefit from cascade testing and early cancer screening and prevention strategies. CONCLUSION: As germline genetic testing is incorporated into practice, further development is needed in establishing prompt testing for time-sensitive treatment decisions, integrating cascade testing for family, ensuring equitable access to testing, and elucidating the role of less-characterized germline DNA damage repair genes, individual gene-level biologic consequences, and treatment response prediction in advanced disease.

Observations on the origin of ovarian cortical inclusion cysts in women undergoing risk-reducing salpingo-oophorectomy.

AIMS: Evidence suggests that up to 70% of high-grade serous ovarian carcinomas (HGSCs) arise potentially from fallopian tube fimbriae, and that many of the remaining cases arise from within the ovary in cortical inclusion cysts (CICs) with a Müllerian phenotype (Müllerian-CICs). It has been proposed that Müllerian-CICs arise either from metaplasia of mesothelial ovarian surface epithelium (OSE) entrapped within the ovary after ovulation or from normal tubal cells entrapped postovulation. However, this proposal is controversial. We therefore conducted a study of CICs in women, most of them BRCA1/2 mutation carriers, undergoing risk-reducing salpingo-oophorectomy at our institution from 2000 to 2014. METHODS AND RESULTS: We used immunohistochemistry for PAX8, a Müllerian marker, and calretinin, a mesothelial marker to classify CIC cells. In 499 CICs from 59 women, 72.3% were positive for PAX8 (PAX8+ ): ≥10% of CIC cells positive; 43.5% positive for calretinin (calretinin+ ). The proportion of PAX8+ CICs increased from 62.9% in premenopausal to 80.5% in postmenopausal patients. The proportion of calretinin+ CICs decreased from 52.6% to 35.6%, respectively. There was significant overlap of PAX8 and calretinin positivity: 82 (16.4%) CICs were PAX8+ /calretinin+ ; 43 (40.2%) of these 82 demonstrated PAX8+ /calretinin+ in the same cells. CONCLUSIONS: These results, and the increased ratio of PAX8+ to calretinin+ CICs from premenopausal to postmenopausal, show that many PAX8+ CICs probably arise from metaplasia of OSE-derived CICs. The proportion of PAX+ /calretinin- CICs arising from OSE-derived CICs is unclear, but our results strongly support the proposal that many Müllerian-CICs arise from OSE via metaplasia.

Cost Effectiveness of Risk-Reducing Mastectomy versus Surveillance in BRCA Mutation Carriers with a History of Ovarian Cancer.

BACKGROUND: The appropriate management of breast cancer risk in BRCA mutation carriers following ovarian cancer diagnosis remains unclear. We sought to determine the survival benefit and cost effectiveness of risk-reducing mastectomy (RRM) among women with BRCA1/2 mutations following stage II-IV ovarian cancer. DESIGN: We constructed a decision model from a third-party payer perspective to compare annual screening with magnetic resonance imaging (MRI) and mammography to annual screening followed by RRM with reconstruction following ovarian cancer diagnosis. Survival, overall costs, and cost effectiveness were determined by decade at diagnosis using 2015 US dollars. All inputs were obtained from the literature and public databases. Monte Carlo probabilistic sensitivity analysis was performed with a $100,000 willingness-to-pay threshold. RESULTS: The incremental cost-effectiveness ratio (ICER) per year of life saved (YLS) for RRM increased with age and BRCA2 mutation status, with greater survival benefit demonstrated in younger patients with BRCA1 mutations. RRM delayed 5 years in 40-year-old BRCA1 mutation carriers was associated with 5 months of life gained (ICER $72,739/YLS), and in 60-year-old BRCA2 mutation carriers was associated with 0.8 months of life gained (ICER $334,906/YLS). In all scenarios, $/YLS and mastectomies per breast cancer prevented were lowest with RRM performed 5-10 years after ovarian cancer diagnosis. CONCLUSION: For most BRCA1/2 mutation carriers following ovarian cancer diagnosis, RRM performed within 5 years is not cost effective when compared with breast cancer screening. Imaging surveillance should be advocated during the first several years after ovarian cancer diagnosis, after which point the benefits of RRM can be considered based on patient age and BRCA mutation status.

High-Grade Serous Ovarian Cancer: Associations between BRCA Mutation Status, CT Imaging Phenotypes, and Clinical Outcomes.

Purpose To investigate the associations between BRCA mutation status and computed tomography (CT) phenotypes of high-grade serous ovarian cancer (HGSOC) and to evaluate CT indicators of cytoreductive outcome and survival in patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 108 patients (33 with BRCA mutant and 75 with BRCA wild-type HGSOC) who underwent CT before primary debulking. Two radiologists independently reviewed the CT findings for various qualitative CT features. Associations between CT features, BRCA mutation status, cytoreductive outcome, and progression-free survival (PFS) were evaluated by using logistic regression and Cox proportional hazards regression, respectively. Results Peritoneal disease (PD) pattern, presence of PD in gastrohepatic ligament, mesenteric involvement, and supradiaphragmatic lymphadenopathy at CT were associated with BRCA mutation status (multiple regression: P < .001 for each CT feature). While clinical and CT features were not associated with cytoreductive outcome for patients with BRCA-mutant HGSOC, presence of PD in lesser sac (odds ratio [OR] = 2.40) and left upper quadrant (OR = 1.19), mesenteric involvement (OR = 7.10), and lymphadenopathy in supradiaphragmatic (OR = 2.83) and suprarenal para-aortic (OR = 4.79) regions were associated with higher odds of incomplete cytoreduction in BRCA wild-type HGSOC (multiple regression: P < .001 each CT feature). Mesenteric involvement at CT was associated with significantly shorter PFS for both patients with BRCA-mutant HGSOC (multiple regression: hazard ratio [HR] = 26.7 P < .001) and those with BRCA wild-type HGSOC (univariate analysis: reader 1, HR = 2.42, P < .001; reader 2, HR = 2.61; P < .001). Conclusion Qualitative CT features differed between patients with BRCA-mutant HGSOC and patients with BRCA wild-type HGSOC. CT indicators of cytoreductive outcome varied according to BRCA mutation status. Mesenteric involvement at CT was an indicator of significantly shorter PFS for both patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. © RSNA, 2017 Online supplemental material is available for this article.

Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing salpingo-oophorectomy for prophylaxis against serous/serous-like uterine cancers in BRCA1 mutation carriers.

OBJECTIVE: To estimate the survival benefit and cost-effectiveness of performing hysterectomy during risk-reducing salpingo-oophorectomy (RRSO) for BRCA1 mutation carriers. METHODS: Based on a recent prospective cohort study indicating an elevated incidence of serous/serous-like uterine cancers among BRCA1 mutation carriers, we constructed a modified Markov decision model from a payer perspective to inform decisions about performance of hysterectomy during RRSO at age 40. We assumed patients had previously undergone a risk-reducing mastectomy and had a residual risk of death from breast or ovarian cancer. Disease-specific survival, age-adjusted competing hysterectomy rates, and deaths from other causes were incorporated. Costs of risk-reducing surgery, competing hysterectomy, and care for serous/serous-like uterine cancer were included. RESULTS: A 40year old woman who undergoes RRSO+Hysterectomy gains 4.9 additional months of overall survival (40.38 versus 39.97 undiscounted years) compared to RRSO alone. The lifetime probabilities of developing or dying from serous/serous-like uterine cancer in the RRSO group are 3.5% and 2%, respectively. The RRSO alone strategy has an average cost of $9013 compared to $8803 for RRSO+Hysterectomy, and is dominated (less effective and more costly) when compared to RRSO+Hysterectomy. In an alternative analysis, delayed hysterectomy remains a cost-effective prevention strategy with an ICER of less than $100,000/year for up to 25years following RRSO at age 40. CONCLUSIONS: The addition of hysterectomy to RRSO in a 40year old BRCA1 mutation carrier results in a mean gain of 4.9 additional months of life and is cost-effective.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.

Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations.

IMPORTANCE: The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial. OBJECTIVE: To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy. DESIGN, SETTING, AND PARTICIPANTS: This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression. MAIN OUTCOMES AND MEASURES: Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database. RESULTS: Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors. CONCLUSIONS AND RELEVANCE: Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.

Invasion Patterns of Metastatic Extrauterine High-grade Serous Carcinoma With BRCA Germline Mutation and Correlation With Clinical Outcomes.

Characteristic histopathologic features have been described in high-grade serous carcinoma associated with BRCA abnormalities (HGSC-BRCA), which are known to have relatively favorable clinical outcomes. The aim of this study was to evaluate the clinical significance of invasion patterns in metastatic HGSC-BRCA cases. Of the 37 cases of advanced-stage HGSC with known BRCA1 or BRCA2 germline mutation retrieved from our institutional files, 23 patients had a germline mutation of BRCA1 and 14 had a BRCA2 mutation. The pattern of invasion at metastatic sites was recorded and classified as a pushing pattern (either predominantly or exclusively), an exclusively micropapillary infiltrative pattern, or an infiltrative pattern composed of papillae, micropapillae, glands, and nests (mixed infiltrative pattern). Histologic evaluation of metastases was performed without knowledge of genotype or clinical outcome. Clinical data were abstracted from medical records. Median age was 56 years (range, 31 to 73 y). All patients presented at stage IIIC or IV and underwent complete surgical staging followed by chemotherapy. All 37 HGSC-BRCA cases showed either pushing pattern metastases (30; 81%) or infiltrative micropapillary metastases (7; 19%). No HGSC-BRCA case exhibited metastases composed solely of mixed infiltrative patterns. Among the 7 infiltrative micropapillary cases, 6 had a BRCA1 germline mutation versus 1 with a BRCA2 mutation. The median time of follow-up was 26 months (range, 13 to 49 mo). All 7 patients with infiltrative micropapillary metastases either experienced recurrence or died of disease (5 recurrences and 2 deaths), which was significantly worse than what was seen in patients with predominantly pushing pattern metastases, of whom 16 of 30 (53%) experienced recurrence (n=14) or died of disease (n=2) (P=0.03). In conclusion, the recognition of different invasion patterns of metastatic extrauterine HGSC-BRCA has prognostic implications. The infiltrative micropapillary pattern is associated with poor outcomes and is more frequently seen in BRCA1-associated HGSC than in BRCA2 cases.