Background: Genetic diseases may display parent-of-origin effects. In such cases, the risk depends on the specific parent or origin allele. Imprinting effect is evident in autosomal dominant hereditary paraganglioma leads to tumors only if inherited from paternal germline. Cancer penetrance in mutations carriers may be determined by the parent origin of BRCA mutation. Methods: From 2007–2010 we analyzed 1889 consecutive (136 ovarian + 1753 breast) breast (BrCa) or ovarian cancer (OvCa) patients presenting for treatment at our outpatient facility. In 130 patients with BRCA 1 or 2 mutations the parent of origin for the mutation was known. Of the 130 patients 2 had both BRCA1 and BRCA2 mutated paternally inherited and were excluded from this analysis. Of the breast cancer patients: 28 patients had paternal and 29 had maternal BRCA1 mutations, 24 had paternal and 21 had maternal BRCA 2 mutations. Of the ovarian cancer patients 6 had paternal and 10 had maternal BRCA1 mutations, 7 had paternal and 3 had maternal BRCA2 mutations. In carriers of BRCA mutations the mean age at diagnosis for ovarian cancer was 51 (range 21–70) and for breast cancer was 43 (range 24–78). Two-sample t-test was used to compare the mean age at diagnosis in patients with BRCA 1 or 2 mutations of paternal or maternal inheritance. For breast cancer maternal allele versus paternal allele 2-sample t-test and p-value were compared for the age at first diagnosis. For breast cancer patients BRCA1 maternal inheritance (mean+SD yrs) 45.73+11.22 versus paternal inheritance 38.04+7.14 2-sample t-test p-value p<0.0020. For breast cancer BRCA2 maternal inheritance (mean+SD yrs) 50.65+10.44 versus paternal inheritance 41.68+6.16, 2-sample t-test p-value p<0.0008. Results: Significantly younger age at breast cancer diagnosis was observed in paternal vs. maternal inheritance of BRCA1 mutation (38 vs 46, respectively, p<0.0020) and BRCA2 mutation (42 vs 51 respectively, p<0.0008). There was no significant difference between paternal and maternal age of ovarian cancer diagnosis of BRCA1 (p<0.1415) or BRCA2 mutation (p<0.3470). Conclusion: The restrospective nature of the study may introduce ascertainment bias. However, the breast and ovarian cancers cases in BRCA1 & 2 carriers with maternal or paternal inheritance mirror the Mendelian autosomal dominant pattern in our unselected consecutive cohort of patients. Maternal and paternal inherited BRCA alleles may not be exchangeable. Women with paternally inherited mutations in BRCA gene mutations develop breast cancer at younger age compared with women who inherit the gene mutations from their mothers. In this small sample, clear differences at age of cancer diagnosis are apparent in paternal inheritance of BRCA gene mutation. If this observation duplicates in larger cohorts results will have important implications for recommendation of surgical risk reduction in BRCA mutation carriers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-13-02.
Background: In premenopausal women with breast cancer any treatment that causes abrupt, premature ovarian failure increases the risk of sexual problems. Randomized-controlled trials in this population reported a worsening in sexual functioning over time irrespective of adjuvant endocrine treatment. We investigated key symptoms related to endocrine therapy, depression and age as predictors of sexual problems in premenopausal women with early breast cancer treated in the IBCSG TEXT/SOFT trials over the first two years of endocrine therapy. Methods: A subset of patients (pts) enrolled by centers with English as primary language to TEXT (1027 of 2672 pts) and SOFT (1260 of 3066 pts) completed a questionnaire consisting of global and symptom-specific quality of life indicators, the CES-Depression (CES-D) and the MOS- Sexual Problems (MOS-SP) measures at baseline, 6, 12 and 24 months. The analysis considered 5 cohorts of pts according to chemotherapy use (yes/no), trial (SOFT/TEXT) and endocrine treatment assignment (tamoxifen alone [T], T or exemestane [E] with ovarian function suppression [OFS]). Mixed modeling was used to test the effect of the following on changes in sexual problems (MOS-SP total score) over two years: changes in treatment-induced symptoms (hot flushes, vaginal dryness, sleep disturbances, bone/joint pain, troubled by weight gain, tiredness, nausea/vomiting) from baseline to 6 months; depression at 6 months; and age at randomization. The model included severity groups of symptoms, depression (all dichotomized by median) and age (< 40 vs ≥40 years), 5 cohorts, time points (6, 12, 24 months), baseline covariates, and interactions of symptoms, timepoints and cohorts. Results: Overall across cohorts, pts with more severe worsening of vaginal dryness and sleep disturbances at 6 months reported a greater increase in sexual problems at all timepoints (p<.0001). The effect of vaginal dryness on sexual problems was most pronounced in the cohort of pts who received T+OFS or E+OFS without chemotherapy; the effect of sleep disturbances was most pronounced in the cohort with prior chemotherapy and T alone. All other symptoms had a smaller impact on differences in changes of sexual problems. Significant effects were only seen in the short-term and varied according to cohort. Severity of depression at six months did not predict sexual problems at the later timepoints in the overall population. In the cohort that received T+OFS or E+OFS without chemotherapy, pts who had more severe depression scores at 6 months reported significantly worse sexual problems at all timepoints (p<.05). No differences were found for younger vs. older pts with respect to sexual problems at any timepoint. Conclusion: Among several key symptoms related to endocrine therapy, only vaginal dryness and sleep disturbances significantly predicted sexual problems during the first two years in pts who received adjuvant endocrine therapy with or without chemotherapy. Depression predicted sexual problems only in the cohort of pts who received combined endocrine treatment without chemotherapy. Early identification of vaginal dryness, sleep disturbances and depression is important for timely and tailored interventions. Citation Format: Ribi K, Luo W, Burstein HJ, Naughton MJ, Chirgwin J, Ansari RH, Walley BA, Salim M, van der Westhuizen A, Abdi E, Francis PA, Budman DR, Kennecke H, Harvey VJ, Giobbie-Hurder A, Fleming GF, Pagani O, Regan MM, Bernhard J. The effects of treatment-induced symptoms, depression and age on sexuality in premenopausal women with early breast cancer receiving adjuvant endocrine therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-09.
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