Clinicogenetic care of women of BRCA mutation carrier women: prevention, diagnosis and therapy

Predictive genetics opens a considerable perspective in the diagnostics as well as the treatment of breast and ovarian cancer. Current recommendations and guidelines for the management of BRCA 1 and BRCA 2 mutation carriers are not based on controlled randomized trials, but on expert opinions. The existing options of prevention, early diagnosis and treatment must be clearly interpreted to the patient. In the context of a dedicated genetic counseling the participation of all involved professionals (geneticist, oncologist, surgeon, gynecologist) is required. The decision-making process concerning the possibilities of prevention, diagnosis and treatment is always deeply influenced by the patient’s own experience with the cancer occurred in the family, as well as by her values and expectations of life. The focused multidisciplinary approach, with the application of results from prospective studies in cohorts of BRCA mutation carriers allow the concerned individuals to benefit from this kind of approach of medical treatment. Orv. Hetil., 2011, 152, 913–918.

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Pathologic findings at risk-reducing salpingo-oophorectomy in germline BRCA mutation carriers: Optimal age of bilateral RRSO.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13046 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13046-e13046

Author(s):

Yong-Man Kim ◽

Shin-Wha Lee ◽

Young-jae Lee

Keyword(s):

Medical Center ◽

Metastatic Cancer ◽

Brca Mutation ◽

Brca1 Mutation ◽

Premalignant Lesions ◽

Mutation Carriers ◽

Brca 1 ◽

Brca Mutation Carriers ◽

Germline Brca Mutation ◽

Risk Reducing

e13046 Background: Most BRCA1/2 carriers do not undergo risk-reducing salpingo-oophorectomy (RRSO) by the recommended age of 40. Methods: We retrospectively reviewed breast cancer patients identified as BRCA mutation carriers who underwent RRSO at Asan Medical Center, Seoul, Korea, from 2013 to 2015. Both fallopian tubes of all cases were examined according to the SEE/FIM protocol and immunohistochemically (IHC) staining was performed when a precursor lesion was suspected. Results: RRSO was performed in 55 patients. The median age at RRSO was 44 years (32–73 years). Of the 36 patients with IHC staining, 7 showed p53 overexpression, 1 showed Ki-67 overexpression, 2 showed serous tubal intraepithelial carcinoma, 2 showed occult cancer, and 1 showed metastatic cancer of breast origin. All occult invasive cancer cases were tubal origin and detected in patients older than 40 years. The detection rate of premalignant lesions or cancer was 21.8% (12/55). Among patients who underwent RRSO under the age of 40, premalignant lesions were found only in BRCA 1 mutation carriers (40.0% vs 0%). In BRCA 2 mutation carriers, premalignant lesions were only detected in those older than 40 years of age, indicating the possible faster occurrence of premalignant lesions in BRCA1 mutation carriers. Conclusions: Many patients still tend to delay RRSO until after they are 40 years old. Our findings support the significance of RRSO before the age of 40 in germline BRCA mutation carriers, especially in BRCA 1 mutation carriers.

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Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer

British Journal of Cancer ◽

10.1038/bjc.2016.41 ◽

2016 ◽

Vol 114 (7) ◽

pp. 723-730 ◽

Cited By ~ 85

Author(s):

Yvette Drew ◽

Jonathan Ledermann ◽

Geoff Hall ◽

Daniel Rea ◽

Ros Glasspool ◽

...

Keyword(s):

Ovarian Cancer ◽

Stable Disease ◽

Multicentre Trial ◽

Brca Mutation ◽

Advanced Breast ◽

Phase 2 ◽

Mutation Carriers ◽

Brca 1 ◽

Brca Mutation Carriers ◽

Dose Levels

Abstract Background: Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers. Methods: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles. Results: Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84–567 days). Conclusions: Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose–response has its limitations.

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