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.

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.

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.

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.

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.

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.

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.

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.

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.

Rare de novo germline copy-number variation in testicular cancer.

Although heritable factors are an important determinant of risk of early-onset cancer, the majority of these malignancies appear to occur sporadically without identifiable risk factors. Germline de novo copy-number variations (CNVs) have been observed in sporadic neurocognitive and cardiovascular disorders. We explored this mechanism in 382 genomes of 116 early-onset cancer case-parent trios and unaffected siblings. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were indeed found in 7% of 43 testicular germ cell tumor trios; this percentage exceeds background CNV rates and suggests a rare de novo genetic paradigm for susceptibility to some human malignancies.

IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.

Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families.

BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis.

Invasion patterns of metastatic high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency.

High-grade serous carcinomas of the uterine adnexa with BRCA1 deficiency (high-grade serous carcinomas-BRCA) have recently been described to demonstrate characteristic histopathological features. We hypothesize that metastatic high-grade serous carcinomas-BRCA cases exhibit characteristic morphological features as well. We studied 102 high-grade serous carcinomas with known BRCA1 and BRCA2 genotype from the archives of the Department of Pathology at Memorial Sloan-Kettering Cancer Center. The primary site morphological characteristics of these cases were reported previously; we now focus solely on tumor morphology in sites other than the uterine adnexa (ie, metastatic sites). The study group consisted of the following case types: 13 BRCA1 germline mutations; 5 BRCA1 somatic mutations; 10 BRCA1 promoter methylation; 4 BRCA2 germline mutations; 1 BRCA2 somatic mutation; 11 lacking BRCA1 or BRCA2 abnormality; 58 cases lacking BRCA1 or BRCA2 germline mutation. Two observers independently scored invasion patterns and microscopic tumor architecture while blinded to genotype. Concordance between observers and correlations between metastatic patterns and the following indices were studied: genotype, primary site tumor characteristics, and BRCA1 immunohistochemistry. Concordance between observers was excellent (κ values >0.9). All cases with BRCA1 or 2 abnormalities showed either pushing pattern metastases (76%) or infiltrative metastases composed only of micropapillae (24%). In contrast, all cases lacking BRCA1 or 2 abnormalities showed infiltrative metastases that contained combinations of papillary, glandular, and, rarely, cribriform and micropapillary architecture (P<0.0001 for comparison with pushing metastasis and P<0.001 for comparison with purely micropapillary architecture). Morphological assessment of metastatic carcinomas, a highly reproducible exercise, accurately correlated with BRCA1 status in every case, unlike morphological assessment of primary site adnexal high-grade serous carcinomas or BRCA1 immunohistochemistry. Metastatic high-grade serous carcinomas-BRCAs exhibit characteristic morphological features that appear more sensitive and specific for BRCA mutations than two other morphologically based prediction systems and should be easier to apply in practice. These findings should be validated prospectively in an independent cohort.

Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer.

BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC.

Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC).

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC. MATERIALS/METHODS: We retrospectively reviewed the medical records of consecutive patients with a germline BRCA1/2 mutation or a high-risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients had peritoneal washings collected. All surgical specimens were assessed using the sectioning and extensively examining the fimbria protocol, with immunohistochemistry when indicated. p53 signature lesions and secretory cell outgrowths were excluded. RESULTS: Of 593 patients who underwent RRSO, isolated STIC was diagnosed in 12 patients (2%). Five patients (42%) were BRCA1 positive, 5 patients (42%) were BRCA2 positive, and 2 patients (17%) had high-risk family history. Preoperatively, all patients with STIC had normal CA-125 levels and/or pelvic imaging results. Seven patients underwent hysterectomy and omentectomy, 6 patients (46%) had pelvic node dissections, and 5 patients (39%) had para-aortic node dissections. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 28 months (range, 16-44 months), no recurrences have been identified. CONCLUSIONS: Among the cases of isolated STIC after RRSO reported in the literature, the yield of surgical staging is low, and short-term clinical outcomes are favorable. Peritoneal washings are the most common site of disease spread. Individualized management is warranted until additional data become available.

Incorporating information regarding preimplantation genetic diagnosis into discussions concerning testing and risk management for BRCA1/2 mutations: a qualitative study of patient preferences.

BACKGROUND: Studies have shown that BRCA1/2 mutation carriers are interested in learning about reproductive options such as preimplantation genetic diagnosis (PGD) to prevent passing their risk onto their children. However, attitudes vary widely, and the procedure raises complex ethical and psychosocial issues. This complexity, plus the highly technical nature of PGD, makes it difficult to integrate PGD information into genetic counseling sessions that already cover probabilistic, emotionally charged risk information. METHODS: A total of 33 carriers of the BRCA1/2 mutation who were of reproductive age and had previously undergone genetic counseling viewed a tutorial regarding PGD and were interviewed concerning their attitudes toward PGD and preferences about how to include PGD information in genetic counseling. RESULTS: The majority of participants preferred to be briefly informed of the availability of PGD information, and to receive written materials regarding PGD, but with the option of deferring detailed discussion if they already believed themselves to be overloaded or perceived that PGD was not immediately relevant to their risk management and/or childbearing plans. For some individuals, the stress of testing temporarily interfered with information processing, producing states of cognitive avoidance ("in a fog," or "tuning out"). Some preferred to discuss PGD with a physician with whom they had an ongoing relationship (eg, obstetrician/gynecologist, primary care provider, or oncologist). CONCLUSIONS: Providers offering cancer genetic testing may consider indicating the availability of PGD information to their patients, while attending to the patients' level of interest and ability to absorb information. Research is needed to link patient responses to information overload with psychosocial outcomes (eg, distress, and quality of decision-making). Continuing medical education is needed to support providers in facilitating informed decisions regarding PGD.

Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer.

BACKGROUND: Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown. METHODS: A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed-to-expected (O:E) mutation prevalence was calculated for the entire group. RESULTS: Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first-, second-, or third-degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15). CONCLUSIONS: BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence.

Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer.

BACKGROUND: Multiple observational studies have suggested that breast cancer gene (BRCA)-associated ovarian cancers have improved survival compared with BRCA-negative ovarian cancers. However, most of those studies combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether BRCA1-associated and BRCA2-associated ovarian cancers were associated with different outcomes. METHODS: This was a single-institution, retrospective analysis of patients who had a new diagnosis of histologically confirmed stage III or IV serous ovarian, fallopian tube, or primary peritoneal cancer between January 1, 1996 and February 1, 2011 and who underwent BRCA mutation testing on 1 of 2 institutional review board-approved follow-up studies. Patients who had been tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from including patients who were referred for genetic testing because of long survival. RESULTS: Data from 190 patients (143 BRCA-negative patients, 30 BRCA1-positive patients, and 17 BRCA2-positive patients) were analyzed. During the study period, 73 deaths were observed (60 BRCA-negative patients, 10 BRCA1-positive patients, 3 BRCA2-positive patients). The median follow-up for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90.7%, and 100% of BRCA-negative patients, BRCA1-positive patients, and BRCA2-positive patients were alive, respectively. On univariate analysis, age, BRCA2 mutations, debulking status, and type of first-line therapy (intravenous or intraperitoneal) were significant predictors of overall survival. On multivariate analysis, BRCA2 mutations (hazard ratio, 0.20; 95% confidence interval, 0.06-0.65; P = .007), but not BRCA1 mutations (hazard ratio, 0.70; 95% confidence interval, 0.36-1.38; P = .31), predicted for improved overall survival compared with BRCA-negative patients. When carriers of BRCA2 mutations were directly compared with carriers of BRCA1 mutations, BRCA2 mutations appeared to confer improved overall survival (hazard ratio, 0.29; 95% confidence interval, 0.08-1.05; P = .060), although this finding did not reach significance. CONCLUSIONS: The current data suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA-negative or having a BRCA1 mutation in high-grade serous ovarian cancer. This finding may have important implications for clinical trial design.