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Susan M Domchek - One of the best experts on this subject based on the ideXlab platform.

  • patient reported outcomes in patients with a germline BRCA Mutation and her2 negative metastatic breast cancer receiving olaparib versus chemotherapy in the olympiad trial
    European Journal of Cancer, 2019
    Co-Authors: Mark E Robson, Nadine Tung, Susan M Domchek, Elzbieta Senkus, Norikazu Masuda, Suzette Delaloge, Anne C Armstrong, Kathryn J Ruddy, Wendy Bannister, C Goessl
    Abstract:

    Abstract Background The phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA Mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). Methods Patients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. Results Overall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus −3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of ‘improvement’ in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). Conclusion HRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.

  • risk factors for sexual dysfunction in BRCA Mutation carriers after risk reducing salpingo oophorectomy
    Menopause, 2019
    Co-Authors: Jessica L Chan, Suneeta Senapati, Lauren N C Johnson, Laura Digiovanni, C Voong, Samantha Butts, Susan M Domchek
    Abstract:

    OBJECTIVE The aim of the study was to identify risk factors for sexual dysfunction in BRCA Mutation carriers who have undergone risk-reducing salpingo-oophorectomy (RRSO). METHODS A cross-sectional study was performed. BRCA1/2 Mutation carriers with and without RRSO were surveyed to determine sexual function (Female Sex Function Index [FSFI]), demographics, medical history, sleep quality, depression, and anxiety scores. Characteristics of patients with the lowest quartile of FSFI scores (<14 ± 8.8) were analyzed to identify risk factors for the most severe phenotype. RESULTS In the 804 women surveyed, 764 underwent RRSO. Of the 529 (69%) carriers with completed FSFI questionnaires in the RRSO cohort, sexual dysfunction was reported in 77.3%. Poor sleep (P = 0.002), hot flashes (P = 0.002), lack of current systemic hormone therapy (HT) use (P = 0.002), depression (P < 0.001), and anxiety (P = 0.001) were associated with sexual dysfunction. In adjusted analyses, depression (adjusted odds ratio [aOR] 2.4, 95% CI, 1.4-4.1) and hot flashes (aOR 1.9, 95% CI, 1.2-3.0) remained significantly associated with sexual dysfunction. Depression was also a significant risk factor for the most severe degree of sexual dysfunction (OR 2.1, 95% CI, 1.3-3.5) and had the greatest impact on Arousal and Satisfaction domain scores of the FSFI. Current systemic HT use seemed to decrease the risk for sexual dysfunction (aOR 0.6, 95% CI, 0.4-1.0). CONCLUSIONS Sexual dysfunction is highly prevalent in BRCA Mutation carriers after RRSO. Depression seems to be a significant risk factor for sexual dysfunction in this patient population and may be under-recognized and undertreated. Patient and provider education on sexual side effects after surgery and risk factors for sexual dysfunction is necessary to decrease postoperative sexual distress. HT may be associated with improved sexual function after surgery.

  • olaparib for metastatic breast cancer in patients with a germline BRCA Mutation
    The New England Journal of Medicine, 2017
    Co-Authors: Mark E Robson, Nadine Tung, Susan M Domchek, Elzbieta Senkus, Norikazu Masuda, Suzette Delaloge, Anne C Armstrong, C Goessl, Sarah Runswick, Pierfranco Conte
    Abstract:

    BackgroundOlaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA Mutation. MethodsWe conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA Mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. ResultsOf the 302 patients who underwent randomization, 205 were assigned to receive...

  • rucapanc an open label phase 2 trial of the parp inhibitor rucaparib in patients pts with pancreatic cancer pc and a known deleterious germline or somatic BRCA Mutation
    Journal of Clinical Oncology, 2016
    Co-Authors: Susan M Domchek, Ravit Geva, Robert R Mcwilliams, Robert H Vonderheide, Steven R. Alberts, Andrew Eugene Hendifar, Robert A. Wolff, Andrew V Biankin, Ron Epelbaum, Heidi Giordano
    Abstract:

    4110Background: Pts with PC have a poor prognosis and limited treatment options. Around 9% of pts with PC have a germline or somatic BRCA Mutation. Recent studies showed that rucaparib effectively treats pts with platinum-sensitive, relapsed, high-grade ovarian carcinoma and a BRCA Mutation. RUCAPANC investigated the efficacy and safety of rucaparib in pts with PC and a known deleterious BRCA Mutation. Methods: RUCAPANC (NCT02042378) enrolled pts with PC with measurable, relapsed disease who received 1–2 prior chemotherapy regimens in the locally advanced/metastatic setting. Pts received oral rucaparib (600 mg twice daily) until disease progression. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Safety was also evaluated. Results: Nineteen pts were treated; 3 pts are ongoing. Median age was 57 years (range 41–75), 58% were male, 68% received ≥ 2 prior chemotherapy regimens (including adjuvant treatment), 79% were ECOG Performance Status of 1, and 79% had a BRCA2Mutation by local te...

  • abstract b102 a phase 2 open label study of the parp inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA Mutation
    Cancer Research, 2015
    Co-Authors: Susan M Domchek, Rachna T Shroff, Lawrence Leichman, Ravit Geva, Robert R Mcwilliams, Steven R. Alberts, Andrew Eugene Hendifar, Robert A. Wolff, Ron Epelbaum, Andrew M Allen
    Abstract:

    Background: Despite the recent progress made with front-line treatment for advanced pancreatic cancer (PC), most patients (pts) will either relapse or be refractory to treatment. Others may not even be eligible due to the toxicity profile of the available options or due to clinical deterioration. Once the disease progresses following front-line treatment, there is no accepted standard of care. Treatment options are clearly needed for patients with refractory disease. Approximately 5% of unselected PC pts, 10% of PC patients of Ashkenazi Jewish descent, and up to 19% of familial PC cases, harbor a germline BRCA Mutation. Though less well characterized to date, somatic BRCA Mutations also appear to play a significant role in PC. Clinical data have shown that pts with BRCA-mutant (BRCAmut) tumors, including those with PC, respond to treatment with a PARP inhibitor (PARPi). Early data suggest that other genomic characteristics may be surrogate biomarkers of homologous recombination deficiency (HRD) and define a larger group of responders than just BRCA Mutation(s) alone. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with HRD due to a BRCA Mutation or other homologous recombination pathway defect. Rucaparib has a desirable PK profile, is well tolerated, and has demonstrated clinical activity (RECIST and/or CA-125 responses) in patients with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Three studies are currently ongoing in ovarian cancer and a trial in BRCAmut pancreatic cancer is now planned. The clinical activity of PARPi, including rucaparib, in BRCAmut PC, combined with the paucity of active 2nd-line therapies, support evaluation of rucaparib in PC pts with a BRCA Mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous monotherapy rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) who are known to harbor a deleterious BRCA Mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed / progressive disease confirmed by radiologic assessment, or are no longer able to tolerate chemotherapy due to toxicity, and radiologic assessment confirms stable or progressive disease. Other key inclusion criteria include measurable disease, ECOG Performance Status 0 or 1, and adequate organ function. Pts with endocrine tumors or who received prior PARPi treatment are excluded. Pts will take 600 mg BID rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then for survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th patient enrolled has sufficient disease assessment data available. If robust activity is observed in the BRCAmut PC population, the trial may be broadened to include PC pts with HRD due to other than a BRCA Mutation. The trial will be open to enrollment at clinical sites in the US and Israel in 2Q 2014. Citation Format: Susan M. Domchek, Robert McWilliams, Andrew Hendifar, Rachna T. Shroff, Lawrence Leichman, Ron Epelbaum, Ravit Geva, George Kim, Steven R. Alberts, Robert A. Wolff, Andrew Allen, Heidi Giordano, Mitch Raponi, Jeff Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide. A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA Mutation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B102.

Steven A. Narod - One of the best experts on this subject based on the ideXlab platform.

  • Factors associated with use of hormone therapy after preventive oophorectomy in BRCA Mutation carriers.
    Menopause (New York N.Y.), 2020
    Co-Authors: Javier César Mejía-gómez, Beth Y Karlan, Nadine Tung, Steven A. Narod, Jacek Gronwald, Ping Sun, Leigha Senter, Wendy Wolfman, Rochelle Demsky, Joanne Kotsopoulos
    Abstract:

    OBJECTIVE Bilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 Mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA Mutation carriers who underwent preventive oophorectomy before natural menopause. METHODS Eligible participants were identified from a longitudinal study of BRCA Mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups. RESULTS A total of 793 women with a BRCA1 or BRCA2 Mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy. CONCLUSIONS The uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 Mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.

  • effects of bilateral salpingo oophorectomy on menopausal symptoms and sexual functioning among women with a BRCA1 or BRCA2 Mutation
    Gynecologic Oncology, 2019
    Co-Authors: Elizabeth Hall, Kelly A. Metcalfe, Amy Finch, Steven A. Narod, Ping Sun, Michelle Jacobson, Barry Rosen, Joanne Kotsopoulos
    Abstract:

    Abstract Introduction Prophylactic bilateral salpingo-oophorectomy (BSO) is recommended at an early age to BRCA Mutation carriers to prevent ovarian cancer. It is critical to evaluate the impact of BSO on non-cancer outcomes, including quality of life (QOL), menopausal symptoms and sexual functioning. Methods BRCA Mutation carriers who elected to undergo a BSO completed three questionnaires prior to surgery and then again approximately one and three years following surgery which included: 1) medical history questionnaire, 2) Menopause-Specific Quality of Life Intervention questionnaire and 3) Sexual Activity Questionnaire. The change in quality of life, menopausal symptoms and sexual functioning before and after oophorectomy was determined using a paired t-test and stratified by menopausal status at surgery. Results We included 140 BRCA Mutation carriers with an average follow-up of 3.5 years following BSO. Among 93 women who were premenopausal, oophorectomy was associated with an increase in menopausal symptoms (vasomotor, physical) (P  Conclusions This study demonstrates that 3.5 years after oophorectomy, BRCA Mutation carriers experience a significant worsening of menopausal symptoms and a decline in sexual functioning, particularly among those who underwent surgery prior to natural menopause. The use of HRT mitigated some but not all the effects. Overall, women who were premenopausal at surgery did not experience a decline in their QOL.

  • impact of prophylactic bilateral salpingo oophorectomy on bone health in BRCA Mutation carriers a prospective cohort study
    Journal of Clinical Oncology, 2018
    Co-Authors: Elizabeth Hall, Amy Finch, Steven A. Narod, Barry P. Rosen, Joanne Kotsopoulos, Joan Murphy, Islay Thompson, Angela M Cheung
    Abstract:

    1566Background: Women who inherit a deleterious Mutation in BRCA1 or BRCA2 face a high lifetime risk of ovarian cancer. Prophylactic bilateral-salpingo oophorectomy (PBSO) is recommended prior to natural menopause; however, the impact of abrupt hormonal withdrawal on bone health in this high-risk population is not known. We conducted a longitudinal study to evaluate the impact of PBSO on bone mineral density (BMD) in BRCA Mutation carriers. Methods: The study population included women who underwent PBSO at the University Health Network (Toronto, Canada) between January 2000 and May 2013. Eligibility criteria included having a BRCA Mutation, at least one ovary prior to surgery, and no personal cancer history other than breast cancer. Information regarding medical history, medication use, and lifestyle factors was collected via questionnaire. BMD measurements using dual x-ray absorptiometry were collected at baseline (prior to surgery) and follow-up. The % change in BMD from baseline to follow-up was calcul...

  • BRCA Mutation status is not associated with increased hematologic toxicity among patients undergoing platinum based chemotherapy for ovarian cancer
    International Journal of Gynecological Cancer, 2017
    Co-Authors: Steven A. Narod, Ping Sun, Joanne Kotsopoulos, Karla Willows, Sandra Trat, Raymond H Kim, Alexandra Volenik, Jeff Boyd
    Abstract:

    Objective Women with an inherited BRCA1 or BRCA2 Mutation may have an impaired ability to repair chemotherapy-induced damage as a result of a state of haploinsufficiency and may experience greater treatment-related toxicity. The objective of this study was to compare the hematologic adverse effect profiles associated with platinum-based chemotherapy in ovarian cancer patients with and without germline BRCA Mutations. Methods We conducted a retrospective analysis of patients treated for high-grade serous ovarian cancer at Princess Margaret Cancer Center, Toronto, Ontario between January 2000 and December 2015. We included only women with known BRCA Mutation status and who received first-line platinum-based chemotherapy. We compared 3 primary measures of myelosuppression (ie, hemoglobin levels, platelet counts, and neutrophil counts) before each cycle of chemotherapy in patients with and without a BRCA Mutation. Results We included 130 BRCA Mutation carriers and 302 noncarriers who met the eligibility criteria. There were no significant differences in baseline hemoglobin levels, neutrophil counts, or platelet counts between the groups (P ≥ 0.31). We found no significant difference in 3 measures of hematologic toxicity (ie, neutropenia, anemia, or thrombocytopenia) based on BRCA Mutation status across all chemotherapy cycles (P ≥ 0.06). Although BRCA Mutation carriers were more likely to experience an absolute neutrophil count below 1.0 × 109/L than noncarriers (P = 0.02), this did not translate to an increased frequency of dose reduction or dose delay. Discussion Among women with ovarian cancer, hematologic toxicity does not appear to be more frequent in BRCA Mutation carriers than in noncarriers. This is reassuring for clinicians treating ovarian cancer patients with respect to dosing regimens. These findings do not support the hypothesis that a haploinsufficiency phenotype exists with respect to the repair of chemotherapy-induced double-strand DNA breaks in this high-risk population.

  • The expected benefit of preventive mastectomy on breast cancer incidence and mortality in BRCA Mutation carriers, by age at mastectomy.
    Breast cancer research and treatment, 2017
    Co-Authors: Vasily Giannakeas, Steven A. Narod
    Abstract:

    Preventive breast surgery is offered to unaffected BRCA Mutation carriers to prevent breast cancer incidence and mortality. The clinical benefit of preventive mastectomy can be measured in several ways, including extension of life expectancy (mean years of life gained) and by estimating the probability of surviving until age 80. We sought to estimate the expected benefit of a preventive mastectomy at various ages, using these indices of mortality, by simulating hypothetical cohorts of women. The age-specific annual risks of developing breast cancer were used to estimate the actuarial risk of developing breast cancer by age 80 for women with a BRCA1 or BRCA2 Mutation. The probability of developing breast cancer before age 80 was then modified to include competing causes of death, including from ovarian cancer. The mortality rate from breast cancer after a diagnosis of breast cancer was set at 2% annually for the first 10 years and then 1% annually for years ten to twenty. The incidence rate and mortality rate from ovarian cancer were based on published literature. We assumed that preventive mastectomy was associated with complete protection against subsequent breast cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) until age 80, according to the age at mastectomy. The actuarial risk of developing breast cancer until age 80 was estimated to be 70.8%. The actual risk (incorporating competing risks) was 64.0%. The probability of being alive at age 80 by having a mastectomy at age 25 increased by 8.7% (from 42.7 to 51.3%). The estimated benefit declined with age at mastectomy; for surgery done at age 50 the improvement in survival to age 80 was much more modest (2.8% at age 80, from 42.7 to 45.5%). Among BRCA Mutation carriers, the mortality benefit of preventive mastectomy at age 25 is substantial, but the expected benefit declines rapidly with increasing age at surgery.

Joanne Kotsopoulos - One of the best experts on this subject based on the ideXlab platform.

  • an evaluation of memory and attention in BRCA Mutation carriers using an online cognitive assessment tool
    Cancer, 2021
    Co-Authors: William D. Foulkes, Susan Armel, Joanne Kotsopoulos, S Kim, Louise Bordeleau, Wendy Mckinnon, Seema Panchal, Stephanie A Cohen
    Abstract:

    BACKGROUND The objective of this study was to evaluate the impact of various surgical, hormonal, and lifestyle factors on memory and attention in women with a BRCA1 or BRCA2 Mutation. METHODS BRCA Mutation carriers enrolled in a longitudinal study were invited to complete an online brain health assessment tool designed to screen for cognitive deficits. Four measures of memory and executive attention were assessed individually, and an overall score was compiled adjusting for age. Exposures, including preventive surgery, hormone use, and lifestyle factors, were captured by questionnaire. Performance on each of the 5 subtasks was analyzed according to various exposures. Analysis of covariance was used to compare overall scores. RESULTS In total, 880 women completed the online cognitive assessment. The average age of the participants was 54 years (range, 23-86 years). The mean overall test score was 54.4 (range, 0-93). The individual subtask scores declined with age at test completion (P < .0001) and increased with level of education (P ≤ .01). Women who underwent a preventive oophorectomy had a significantly higher overall score compared with women who did not undergo this surgery (55.5 vs 50.5; P = .01). Reconstructive breast surgery was also associated with a higher overall score (56.5 vs 52.3; P = .005). Chemotherapy and hormone-replacement therapy were not predictive of the overall score. CONCLUSIONS These findings are reassuring to high-risk women who undergo early surgical menopause for their cancer predisposition. Further studies are needed to evaluate cognitive function over time when memory deficits become more prevalent.

  • Factors associated with use of hormone therapy after preventive oophorectomy in BRCA Mutation carriers.
    Menopause (New York N.Y.), 2020
    Co-Authors: Javier César Mejía-gómez, Beth Y Karlan, Nadine Tung, Steven A. Narod, Jacek Gronwald, Ping Sun, Leigha Senter, Wendy Wolfman, Rochelle Demsky, Joanne Kotsopoulos
    Abstract:

    OBJECTIVE Bilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 Mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA Mutation carriers who underwent preventive oophorectomy before natural menopause. METHODS Eligible participants were identified from a longitudinal study of BRCA Mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups. RESULTS A total of 793 women with a BRCA1 or BRCA2 Mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy. CONCLUSIONS The uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 Mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.

  • Does preventive oophorectomy increase the risk of depression in BRCA Mutation carriers
    Menopause (New York N.Y.), 2019
    Co-Authors: Joanne Kotsopoulos, Jan Lubinski, Henry T. Lynch, William D. Foulkes, Susan L Neuhausen, Jacek Gronwald, Leigha Senter, Jeanna M. Mccuaig, Jeffrey N. Weitzel, Nadine Tung
    Abstract:

    OBJECTIVE BRCA Mutation carriers are advised to undergo bilateral salpingo-oophorectomy to prevent ovarian cancer. The abrupt hormonal withdrawal associated with early surgical menopause has been shown to increase the risk of depression and anxiety among women in the general population. The impact in women with a BRCA1 or BRCA2 Mutation is not known. METHODS We undertook a matched prospective study of BRCA Mutation carriers to evaluate the impact of oophorectomy on self-reported initiation of antidepressant use. We identified women with no personal history of cancer or depression and prospectively evaluated the frequency of self-reported medication use after surgery. Each exposed participant (oophorectomy) was randomly matched to a control participant (no oophorectomy) according to year of birth (within 3 years), BRCA Mutation type (BRCA1 or BRCA2), and country of residence (Canada, United States, Poland). A total of 506 matched sets were included. We estimated the odds ratio (OR) and 95% confidence intervals (CIs) of antidepressant use (ever/never) following preventive oophorectomy in the entire study population and stratified by age at oophorectomy and by use of hormone therapy. RESULTS Oophorectomy was not associated with more frequent antidepressant use among BRCA Mutation carriers (OR = 0.46; 95% CI 0.22-0.96). We observed reductions in the odds of antidepressant medication use among women who underwent oophorectomy before the age of 50 years (OR = 0.33; 95% CI 0.14-0.78) and among those who initiated hormone therapy use after oophorectomy (OR = 0.35; 95% CI 0.14-0.90). Findings were similar when the analysis was based on self-reported depression (rather than antidepressant use). CONCLUSIONS Although based on a small number of women, these findings suggest that oophorectomy does not increase psychological distress among women at an elevated risk of ovarian cancer.

  • effects of bilateral salpingo oophorectomy on menopausal symptoms and sexual functioning among women with a BRCA1 or BRCA2 Mutation
    Gynecologic Oncology, 2019
    Co-Authors: Elizabeth Hall, Kelly A. Metcalfe, Amy Finch, Steven A. Narod, Ping Sun, Michelle Jacobson, Barry Rosen, Joanne Kotsopoulos
    Abstract:

    Abstract Introduction Prophylactic bilateral salpingo-oophorectomy (BSO) is recommended at an early age to BRCA Mutation carriers to prevent ovarian cancer. It is critical to evaluate the impact of BSO on non-cancer outcomes, including quality of life (QOL), menopausal symptoms and sexual functioning. Methods BRCA Mutation carriers who elected to undergo a BSO completed three questionnaires prior to surgery and then again approximately one and three years following surgery which included: 1) medical history questionnaire, 2) Menopause-Specific Quality of Life Intervention questionnaire and 3) Sexual Activity Questionnaire. The change in quality of life, menopausal symptoms and sexual functioning before and after oophorectomy was determined using a paired t-test and stratified by menopausal status at surgery. Results We included 140 BRCA Mutation carriers with an average follow-up of 3.5 years following BSO. Among 93 women who were premenopausal, oophorectomy was associated with an increase in menopausal symptoms (vasomotor, physical) (P  Conclusions This study demonstrates that 3.5 years after oophorectomy, BRCA Mutation carriers experience a significant worsening of menopausal symptoms and a decline in sexual functioning, particularly among those who underwent surgery prior to natural menopause. The use of HRT mitigated some but not all the effects. Overall, women who were premenopausal at surgery did not experience a decline in their QOL.

  • impact of prophylactic bilateral salpingo oophorectomy on bone health in BRCA Mutation carriers a prospective cohort study
    Journal of Clinical Oncology, 2018
    Co-Authors: Elizabeth Hall, Amy Finch, Steven A. Narod, Barry P. Rosen, Joanne Kotsopoulos, Joan Murphy, Islay Thompson, Angela M Cheung
    Abstract:

    1566Background: Women who inherit a deleterious Mutation in BRCA1 or BRCA2 face a high lifetime risk of ovarian cancer. Prophylactic bilateral-salpingo oophorectomy (PBSO) is recommended prior to natural menopause; however, the impact of abrupt hormonal withdrawal on bone health in this high-risk population is not known. We conducted a longitudinal study to evaluate the impact of PBSO on bone mineral density (BMD) in BRCA Mutation carriers. Methods: The study population included women who underwent PBSO at the University Health Network (Toronto, Canada) between January 2000 and May 2013. Eligibility criteria included having a BRCA Mutation, at least one ovary prior to surgery, and no personal cancer history other than breast cancer. Information regarding medical history, medication use, and lifestyle factors was collected via questionnaire. BMD measurements using dual x-ray absorptiometry were collected at baseline (prior to surgery) and follow-up. The % change in BMD from baseline to follow-up was calcul...

Michael Friedlander - One of the best experts on this subject based on the ideXlab platform.

  • tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA Mutation in the randomized phase iii solo1 trial
    Gynecologic Oncology, 2021
    Co-Authors: Nicoletta Colombo, Ana Oaknin, Alexandra Leary, Giovanni Scambia, Michael Friedlander, A Floquet, Kathleen N Moore, Alla Lisyanskaya, Gabe S Sonke, Charlie Gourley
    Abstract:

    OBJECTIVES In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA Mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. METHODS Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). RESULTS Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily. CONCLUSIONS Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients.

  • patient centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA Mutation receiving maintenance olaparib or placebo solo1 a randomised phase 3 trial
    Lancet Oncology, 2021
    Co-Authors: Michael Friedlander, Nicoletta Colombo, Ana Oaknin, Giovanni Scambia, Kathleen N Moore, Alla Lisyanskaya, Gabe S Sonke, Charlie Gourley, Byounggie Kim, Susana Banerjee
    Abstract:

    Summary Background In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA Mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. Methods SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0–1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA Mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov , NCT01844986 . Findings Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9–42·9) for olaparib and 41·2 months (32·2–41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI −0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of −3·00, 95% CI −4·78 to −1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20–31·63] vs placebo 17·58 [15·05–20·18]; difference 12·17 months [95% CI 9·07–15·11], p Interpretation The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. Funding AstraZeneca and Merck Sharp & Dohme.

  • final overall survival os results from solo2 engot ov21 a phase iii trial assessing maintenance olaparib in patients pts with platinum sensitive relapsed ovarian cancer and a BRCA Mutation
    Journal of Clinical Oncology, 2020
    Co-Authors: Andres Poveda, Jonathan A Ledermann, Michael Friedlander, Jacob Korach, A Floquet, Rebecca Asher, Richard T Penson, Tomasz Huzarski, Sandro Pignata, Alessandra Baldoni
    Abstract:

    6002Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA Mutation ...

  • 885pdhealth related quality of life hrqol during olaparib maintenance therapy in patients with platinum sensitive relapsed serous ovarian cancer psr soc and a BRCA Mutation BRCAm
    Annals of Oncology, 2014
    Co-Authors: Jonathan A Ledermann, Michael Friedlander, Charlie Gourley, P Harter, I Vergote, G J S Rustin, Clare L Scott, W Meier, Ronnie Shapirafrommer, Tamar Safra
    Abstract:

    ABSTRACT Aim: Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with PSR SOC, and subsequent analysis has shown that patients with a BRCAm receive greater treatment benefit (Ledermann et al Lancet Oncol 2014). As preserved HRQoL may support chronic administration in the maintenance setting, the effect of olaparib on HRQoL was evaluated in this randomized, double-blind Phase II trial (NCT00753545). Methods: Patient-reported HRQoL and disease-related symptoms were evaluated using the Functional Assessment of Cancer Therapy Ovarian (FACT-O) questionnaire, FACT/NCCN Ovarian Symptom Index (FOSI) and Trial Outcome Index (TOI). Patients completed the FACT-O questionnaire at baseline and every 28 days until progression. Individual symptom severity over 7 days was measured using the five-item Likert scale; physical, social/family, emotional, functional wellbeing and specific concerns to ovarian cancer patients were assessed. The TOI of the FACT-O was the primary HRQoL endpoint. FOSI is the sum of a subset of eight symptom-related items. Results: Of patients randomized to olaparib (n = 136) or placebo (n = 129), BRCA Mutation status data were available for 254/265 (96%), of whom 136/254 (53.5%) had a known deleterious/suspected deleterious germline or somatic BRCA Mutation. Most patients reported a best response of ‘improved’ or ‘no change’ on TOI (Table); this trend was also seen in other HRQoL measures. There were no statistically significant differences in improvement rates or time to worsening of TOI, FOSI and Total FACT-O. Overall BRCAm BRCAwt Olaparib Placebo Olaparib Placebo Olaparib Placebo TOI N = 115 N = 111 N = 64 N = 53 N = 49 N = 54 Improved * 23 (20.0) 20 (18.0) 16 (25.0) 10 (18.9) 7 (14.3) 10 (18.5) No change† 72 (62.6) 67 (60.4) 38 (59.4) 30 (56.6) 32 (65.3) 36 (66.7) Worsened†† 16 (13.9) 20 (18.0) 7 (10.9) 10 (18.9) 9 (18.4) 8 (14.8) Non-evaluable 4 (3.5) 4 (3.6) 3 (4.7) 3 (5.7) 1 (2.0) 0 BRCAwt, BRCA wild type, includes patients with no known BRCAm or a variant of unknown significance. * Best response of improved defined as two visit responses of 'improved' a minimum of 21 days apart without an intervening visit response of 'worsened'. †Defined as two visit responses of 'no change' or a response of 'no change' and a response of 'improved' a minimum of 21 days apart without an intervening visit response of 'worsened'. No change is defined as a change from baseline of greater than -7 but less than +7.††Defined as a visit of 'worsened' without a response of 'improved' or 'no change' within 21 days. Worsened is defined as a change from baseline of less than or equal to -7. Conclusions: HRQoL was not negatively impacted during maintenance therapy with olaparib. Phase III trials are enrolling. Disclosure: J.A. Ledermann: Travel grants from AstraZeneca; P. Harter: Received a grant from AstraZeneca; C. Gourley: Served on advisory boards for, and received travel grants from, AstraZeneca; G.J.S. Rustin: Served on advisory boards for AstraZeneca, Oxigene, Roche, Amgen, Boehringer Ingelheim and Clovis; C. Scott: Received travel grants from AstraZeneca; A. Fielding, S. Spencer, B. Bennett and D. Parry: Employee of AstraZeneca and stock ownership. All other authors have declared no conflicts of interest.

  • olaparib maintenance therapy in patients with platinum sensitive relapsed serous ovarian cancer a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial
    Lancet Oncology, 2014
    Co-Authors: Jonathan A Ledermann, Michael Friedlander, Charlie Gourley, P Harter, G J S Rustin, Clare L Scott, W Meier, Ronnie Shapirafrommer, Ignace Vergote, Tamar Safra
    Abstract:

    Summary Background Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA Mutation. Methods We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA Mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545. Findings Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA Mutation. Of patients with a BRCA Mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3–not calculable] vs 4·3 months [3·0–5·4]; HR 0·18 [0·10–0·31]; p BRCA , although the difference between groups was lower (7·4 months [5·5–10·3] vs 5·5 months [3·7–5·6]; HR 0·54 [0·34–0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64–1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45–1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63–1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [ BRCA and the overall population. Interpretation These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA Mutation have the greatest likelihood of benefiting from olaparib treatment. Funding AstraZeneca.

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  • Factors associated with use of hormone therapy after preventive oophorectomy in BRCA Mutation carriers.
    Menopause (New York N.Y.), 2020
    Co-Authors: Javier César Mejía-gómez, Beth Y Karlan, Nadine Tung, Steven A. Narod, Jacek Gronwald, Ping Sun, Leigha Senter, Wendy Wolfman, Rochelle Demsky, Joanne Kotsopoulos
    Abstract:

    OBJECTIVE Bilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 Mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA Mutation carriers who underwent preventive oophorectomy before natural menopause. METHODS Eligible participants were identified from a longitudinal study of BRCA Mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups. RESULTS A total of 793 women with a BRCA1 or BRCA2 Mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy. CONCLUSIONS The uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 Mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.

  • Risk of breast cancer after a diagnosis of ovarian cancer in BRCA Mutation carriers: Is preventive mastectomy warranted?
    Gynecologic oncology, 2017
    Co-Authors: Jacob Mcgee, Beth Y Karlan, Jan Lubinski, Vasily Giannakeas, Jacek Gronwald, Barry P. Rosen, John R. Mclaughlin, Harvey A. Risch, Ping Sun, William D. Foulkes
    Abstract:

    Abstract Objective Preventive breast surgery and MRI screening are offered to unaffected BRCA Mutation carriers. The clinical benefit of these two modalities has not been evaluated among Mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA Mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. Methods First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA Mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA Mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. Results Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA Mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. Conclusions Among BRCA Mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer.

  • occult and subsequent cancer incidence following risk reducing surgery in BRCA Mutation carriers
    Gynecologic Oncology, 2016
    Co-Authors: M Zakhour, Jenny Lester, Beth Y Karlan, Yael Danovitch, B J Rimel, Christine Walsh, Ilana Cass
    Abstract:

    Abstract Objective To report the frequency and features of occult carcinomas and the incidence of subsequent cancers following risk-reducing salpingo-oophorectomy (RRSO) in BRCA Mutation carriers. Methods 257 consecutive women with germline BRCA Mutations who underwent RRSO between January 1, 2000 and December 31, 2014 were identified in an Institutional Review Board approved study. All patients were asymptomatic with normal physical exams, CA 125 values, and imaging studies preoperatively, and had at least 12months of follow-up post-RRSO. All patients had comprehensive adnexal sectioning performed. Patient demographics and clinico-pathologic characteristics were extracted from medical and pathology records. Results The cohort included 148 BRCA1 , 98 BRCA2 , 6 BRCA not otherwise specified (NOS), and 5 BRCA1 and 2 Mutation carriers. Occult carcinoma was seen in 14/257 (5.4%) of patients: 9 serous tubal intraepithelial carcinomas (STIC), 3 tubal cancers, 1 ovarian cancer, and 1 endometrial cancer. Three patients (1.2%) with negative pathology at RRSO subsequently developed primary peritoneal serous carcinoma (PPSC), and 2 of 9 patients (22%) with STIC subsequently developed pelvic serous carcinoma. 110 women (43%) were diagnosed with breast cancer prior to RRSO, and 14 of the remaining 147 (9.5%) developed breast cancer following RRSO. Median follow-up of the cohort was 63months. Conclusion In this cohort, 5.4% of asymptomatic BRCA Mutation carriers had occult carcinomas at RRSO, 86% of which were tubal in origin. The risk of subsequent PPSC for women with benign adnexa at RRSO is low; however, the risk of pelvic serous carcinoma among women with STIC is significantly higher.

  • breast cancer following ovarian cancer in BRCA Mutation carriers
    JAMA Surgery, 2014
    Co-Authors: Alexandra Gangi, Ilana Cass, Beth Y Karlan, B J Rimel, Christine Walsh, Daniel Paik, Galinos Barmparas, Catherine Dang, Farin Amersi
    Abstract:

    Importance BRCA Mutation carriers are at increased risk of developing breast cancer. However, the incidence of breast cancer after a diagnosis of epithelial ovarian cancer (EOC), one of the tubal/peritoneal cancers collectively referred to as pelvic serous carcinomas, is not well known. Optimal breast cancer surveillance and detection for these patients have also not been well characterized. Objectives To determine the incidence of breast cancer after a diagnosis of EOC and to evaluate the need for breast cancer surveillance for these patients. Design, Setting, and Participants A retrospective database review of 364 patients who underwent BRCA Mutation testing for EOC (stages I-IV) between 1998 and 2012 at an academic medical center with gynecologic and breast cancer centers. Main Outcomes and Measures Incidence of breast cancer and methods of surveillance. Results Of 364 patients, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 Mutation. The mean age of patients at diagnosis of EOC was 49.5 years (range, 28-89 years). Of the 135 patients, 12 (8.9%) developed breast cancer. The median time from diagnosis of EOC to diagnosis of breast cancer was 50.5 months. Annual mammography was performed for 80 patients (59.3%), with annual magnetic resonance imaging of the breasts performed for 60 patients (44.4%). Thirteen patients (9.6%) underwent a bilateral prophylactic mastectomy at a median of 23 months following EOC diagnosis. Breast cancer was most commonly diagnosed by mammography for 7 of the 12 patients (58.3%), 3 (25.0%) of whom had a palpable mass and 2 (16.7%) of whom had incidental breast cancer detected during a prophylactic mastectomy. Seven patients with breast cancer (58.3%) underwent a bilateral mastectomy. All patients had early-stage breast cancer (stages 0-II). Four patients (33.3%) received adjuvant chemotherapy. At a median follow-up of 6.3 years, 4 of the 12 patients (33.3%) died of recurrent EOC after a diagnosis of breast cancer. The overall 10-year survival rate for the entire cohort of 135 patients was 17.0%. Conclusions and Relevance The risk of metachronous breast cancer is low in patients with known BRCA Mutations and EOC. A majority of these cases of breast cancer at an early stage are detected by use of mammography. Despite the small number of patients in our study, these results suggest that optimal breast cancer surveillance for patients with BRCA -associated EOC needs to be reevaluated given the low incidence of breast cancer among these high-risk patients. Confirmation of our findings from larger studies seems to be indicated.

  • a cautious view of putative precursors of serous carcinomas in the fallopian tubes of BRCA Mutation carriers
    Gynecologic Oncology, 2014
    Co-Authors: Ilana Cass, Denise Barbuto, Jenny Lester, Ann E Walts, Beth Y Karlan
    Abstract:

    Abstract Objective To compare the frequency and distribution of candidate precursors of serous carcinoma in the fallopian tubes of BRCA Mutation carriers to BRCA non-Mutation carriers (controls) at risk-reducing bilateral salpingo-oophorectomy (RRSO). Methods 78 BRCA carriers (52 BRCA1, 26 BRCA2) and 23 controls underwent RRSO. Fallopian tubes were serially cross-sectioned, and adnexa were entirely submitted and examined by two gynecologic pathologists blinded to BRCA Mutation status. The presence and location of serous tubal intraepithelial carcinoma (STIC), p53 overexpression (≥6 consecutively stained nuclei), Ki67 overexpression, atypia/low grade dysplasia and epithelial hyperplasia were compared between BRCA carriers and controls. Patient age was dichotomized: ≤50 and >50years. Results 9 (12%) BRCA carriers had occult carcinoma: 8 STIC and 1 stage IC tubal carcinoma with STIC. No occult carcinomas or STIC was seen in controls. STIC involved the distal tube in all cases and was multifocal in three cases. STIC was more common in women >50 (p=0.06). P53 overexpression was common in BRCA carriers (30%) and controls (43%) (p=0.5) and did not correlate with age. Only 5/9 (55%) of STIC exhibited p53 overexpression. 2 patients had Ki67 overexpression: both BRCA1 carriers with STIC. No difference in the frequency of atypia/low grade dysplasia or hyperplasia was observed between BRCA carriers and controls. Conclusions STIC is the dominant precursor of serous fallopian tube carcinoma in BRCA carriers. There is insufficient evidence to support p53 overexpression alone as a putative precursor. Atypia/low grade dysplasia and epithelial hyperplasia are not pre-neoplastic lesions of serous fallopian tube carcinoma.