Experience with Bilateral Risk-Reducing Mastectomy for an Unaffected BRCA Mutation Carrier

3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replication, resulting in cell death if unrepaired. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation and transcriptional inhibition of HR components. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 27 patients were treated. The MTD and RP2D is sapacitabine 50 mg b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included anorexia, fatigue, abdominal pain, dizziness, nausea, anemia, neutropenia, creatinine elevation, hyperglycemia, hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Two confirmed PRs occurred in patients with pancreatic and breast cancer, both BRCA mutation carriers. SD as best response >/= 12 weeks was observed in 6 additional patients, including one BRCA mutation carrier with ovarian cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types.

Download Full-text

Linkage of a Pedigree Drawing Program and Database to a Program for Determining BRCA Mutation Carrier Probability

Familial Cancer ◽

10.1007/s10689-005-8849-y ◽

2005 ◽

Vol 4 (4) ◽

pp. 313-316 ◽

Cited By ~ 3

Author(s):

Sharon R. Sand ◽

David S. DeRam ◽

Deborah J. MacDonald ◽

Kathleen R. Blazer ◽

Jeffrey N. Weitzel

Keyword(s):

Mutation Carrier ◽

Brca Mutation ◽

Brca Mutation Carrier ◽

Drawing Program ◽

Carrier Probability

Download Full-text

Impact of breast cancer and BRCA mutations on thoughts and feelings of future pregnancies.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.27_suppl.38 ◽

2012 ◽

Vol 30 (27_suppl) ◽

pp. 38-38

Author(s):

Ashley Henriksen Woodson ◽

Kimberly I. Muse ◽

Michelle Jackson ◽

Banu Arun ◽

Jennifer Keating Litton

Keyword(s):

Breast Cancer ◽

Mutation Carrier ◽

Brca Mutation ◽

Brca Mutation Carrier ◽

Brca Mutations ◽

Premenopausal Breast Cancer ◽

Future Child ◽

Future Pregnancy ◽

Answer Choice ◽

The Impact

38 Background: Many women diagnosed with premenopausal breast cancer are concerned with treatment-related infertility. Identifying a BRCA mutation associated with hereditary breast and ovarian cancer may affect attitudes regarding future childbearing. We evaluated attitudes regarding the impact of cancer or potentially being a BRCA mutation carrier on future childbearing. Methods: Women with childbearing potential were invited to participate in an IRB-approved questionnaire study administered prior to genetic counseling and after results disclosure, if applicable. Women were provided a series of 15 statements and asked to rate how often they thought about the impact of cancer or of having a BRCA mutation on the ability to conceive or carry a pregnancy on a 4-point scale ranging from not at all to often. Descriptive statistics were used. Results: We received 148 pre-questionnaires and 114 post-questionnaires. Thirteen women tested positive for a BRCA 1 mutation and 5 with a BRCA 2 mutation. The mean age was 35 (range 20-45) with 71% having breast cancer. The majority (62%) had at least 1 biological child prior to diagnosis and 45% desired a future child. Across 15 statements, 57% of women did not have any thoughts or feelings about the impact of cancer or a BRCA mutation on a future pregnancy at initial visit. Across the same 15 statements, 52% of women who tested positive for a BRCA mutation changed their answer from the pre-questionnaire to post-questionnaire. Of these women, 70% thought about the impact more often than they reported initially. When compared to women who tested negative for a BRCA mutation (n=78), only 40% of women changed their answer choice, with 54% thinking about the impact less often. Conclusions: Women testing positive for a BRCA mutation were more likely to have an increase in thoughts and feelings regarding the impact of cancer or of being a BRCA mutation carrier on the ability to have a future pregnancy, while women who tested negative showed a decrease. Therefore, women with a BRCA mutation may be influenced in their decisions regarding future childbearing.

Download Full-text

Challenging and Complex Decisions in the Management of the BRCA Mutation Carrier

Journal of Women s Health ◽

10.1089/jwh.2013.4407 ◽

2013 ◽

Vol 22 (10) ◽

pp. 825-834 ◽

Cited By ~ 34

Author(s):

Daniela L. Stan ◽

Lynne T. Shuster ◽

Myra J. Wick ◽

Casey L. Swanson ◽

Sandhya Pruthi ◽

...

Keyword(s):

Mutation Carrier ◽

Brca Mutation ◽

Brca Mutation Carrier

Download Full-text

Validation of BRCA mutation-carrier probability model, BRCAPRO, in Japanese.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e12532 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e12532-e12532

Author(s):

Masahiro Ito ◽

Yuri Yasuda ◽

Akihiko Furuta ◽

Noriaki Ohuchi

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Family History ◽

Positive Predictive Value ◽

Mutation Carrier ◽

Predictive Value ◽

Brca Mutation ◽

Brca Mutation Carrier ◽

Mutation Probability ◽

Sensitivity Specificity

e12532 Background: Genetic testing has not been widely performed in Japan. It is not known whether BRCA mutation-carrier model is useful for selecting eligible person of genetic testing. We studied the validation of BRCAPRO in Japanese. Methods: Twenty-six hundred sixty-five people visited to our hospital between 2011 and 2012.They were surveyed family history as a risk factor of inheriting breast cancer according to NCCN guideline. Among them, those who have a number of family history of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer were selected and in addition, genetic counselor constructed family tree. We also calculated BRCA1/2 mutation probability by BRCAPRO.Those who had more than 10% mutation probability and early onset breast cancer, triple negative breast cancer were received genetic counseling and genetic testing for applicants. We also calculated sensitivity, specificity and predictive value at 10% estimated probability. Results: One hundred five people (3.9%) were selected as a risk of inheriting breast cancer, of which sixty-three people (2.3%) were constructed family tree.The number of people who had more than 10% and 30% mutation probability by BRCAPRO was seven (0.26%) and three (0.11%).Nine people performed BRCA1/2 genetic testing (proband : eight, relative: one)Four people carried a deleterious BRCA mutation (BRCA1: three, BRCA2: one).In the cases which had more than 30% mutation probability, all of them carried a deleterious BRCA mutation. Most of their mutation site was L63X which was most frequent in Japan. Using a 10% cut-off, sensitivity was 75%, specificity was 80%,positive predictive value was 75%. When it comes to the cases which had more than 30% mutation probability, Sensitivity, specificity, positive predictive value were all 100%. Conclusions: Our findings suggest BRCAPRO is useful in Japanese, especially those who have more than 30% mutation probability.

Download Full-text