Abstract only
5078
Background: EOC patients with BRCA mutations have been reported to have better prognosis than non-hereditary (NH) matched cases, an advantage shown especially in the ...Ashkenazi-Jewish (AJ) population. We have analyzed our experience in our ethnically diverse patient cohort from NYC, Israel and Italy. Methods: A retrospective chart review of patients diagnosed with Stage IC-IV EOC between 1995-2008 at the NYU Cancer Institute, Tel Aviv Sourasky MC and Padova Clinical Cancer Centers. Out of >700 patients, 183 were tested for BRCA mutations and evaluated. Results: Median age was 55.5 (range 31–83 years). Out of 183, 86 are carriers of BRCA1/2 mutations and 97 tested negative, 67 and 19 are carriers of BRCA1 and BRCA2 mutation respectively. Carrier frequency in EOC population is 46% (45/97) in AJ's and 48% (41/86) in non-AJ's. AJ patients had the following BRCA1 mutations: 185delAG (29), 5382insC (5), unknown (UK) (2) and BRCA2 mutations: 6174delT (8), UK (1). Non-AJ's were divided by ethnicities into non-AJ, Caucasian, African-American, Hispanic, Middle Eastern or unknown. Non-AJ Jewish patients had BRCA1 mutations in 185delAG (7) and BRCA2 in 6174delT (1), UK (1). Non-Jewish Caucasians exhibited the widest variation of mutation types, with the following BRCA1 sites: 185delAG, K1702X (5223A>T), E1373X, 3829delT, 185delAT, IVS11+1G>A, 5385insC, 5083del19>stop1670, 1720delAF>stop536, 1806C/T>Igu536Ter, del ex1a-2, cod1486ex14:4575delAstop1504, 5563G7A;Trp1815stop, 5181delGTT(Val1688del) and UK and the following BRCA2 sites: 6174delT (2), 5301insA (1), 802delAT (1), cod2960ex22:9106C/t (1), cod68ex3:432delAstop79 (1), 7408A/T;Arg2394stop (1). One African-American patient with BRCA1 at 1294del40, 1 Hispanic BRCA1 at 185delAG. OS was significantly prolonged for BRCA carriers at 93.6 months versus 63.2 months 95% CI: 44.5-91.7 (p=0.0016) for NH. Conclusions: Our data reports a wide variety of BRCA mutations in an ethnically diverse EOC population and confirms that BRCA mutations carriers have a better prognosis with a longer median survival compared to NH population. A larger cohort might manifest prognostic differences between the different types of mutations.
This study reports the efficacy and safety of zoledronic acid (ZOL) in preventing bone loss in postmenopausal patients receiving an aromatase inhibitor (AI) following tamoxifen.
Postmenopausal ...patients with stage I-III hormone receptor-positive breast cancer who received tamoxifen for 2.5-3 years were randomized to receive letrozole (2.5 mg/day) with (n = 47) or without (n = 43) ZOL (4 mg i.v. every 6 months) for 2 years. The primary endpoint was percent change from baseline in lumbar spine (LS) bone mineral density (BMD) up to 60 months.
Ninety patients (86 evaluable) with a median age of 59 years (42.9-83.6), 50/86 of whom had previously been treated with chemotherapy, were followed for a median time of 41.4 months. While the control group showed a significant decrease in LS T-score (p = 0.0005), the ZOL group presented an increase over time (p = 0.0143). Change over time in LS T-score was significantly different between groups, favoring ZOL (p < 0.0001 at 24 and 48 months). No fractures, renal dysfunction or osteonecrosis of the jaw were reported. The toxicity profile was similar to those previously reported for each drug.
The addition of ZOL to letrozole was safe and efficacious in maintaining LS BMD in postmenopausal patients with hormone receptor-positive breast cancer and who were receiving letrozole following 2.5-3 years of tamoxifen.
High rates of psychiatric co-morbidity have been reported in patients with irritable bowel syndrome (IBS) and high rates of post-traumatic stress disorder (PTSD) have been reported in fibromyalgia, a ...disorder also associated with IBS. The primary aim of this study was to assess the frequency of PTSD in IBS patients.
Sixty-four patients who fulfilled the Rome II diagnostic criteria for IBS were asked to complete questionnaires measuring the prevalence and severity of symptoms of PTSD and psychological distress.
Although 86% of IBS patients reported a traumatic life experience, only 7.8% met the diagnostic criteria for PTSD. High rates of somatization, obsessive-compulsive behavior, interpersonal sensitivity, and anxiety symptoms were seen among the IBS patients.
The results show a lower than expected prevalence of PTSD among IBS patients, which is similar to that of the general population. Thus, we did not find that PTSD is over-represented in a sample population of IBS patients.
Introduction: V600E BRAF mutation is an established driver mutation in a variety of tumors. Vemurafenib is a selective inhibitor of the BRAF V600E kinase, known to be highly effective in BRAF ...V600E-positive metastatic melanoma. As a single agent, vemurafenib is relatively ineffective in other V600E-positive malignancies.
Case 1: A 72 year old man with metastatic CRC who failed several previous lines of chemotherapy. Genetic analysis of 315 cancer-related genes (Foundation Medicine, FMI) revealed a BRAF V600E mutation. The patient was treated with vemurafenib resulting in a partial response of 18 months. Genetic analysis following development of resistance revealed a new mutation in KRAS-G12R.
Case 2: V600E mutation was identified in a 59 year old woman with metastatic PTC refractory to radioiodine therapy. The patient was treated with vemurafenib resulting in a partial response lasting 43 months. Genetic analysis following development of resistance revealed a new mutation in NRAS-Q61K.
The presented cases demonstrated the development of rare RAS mutations as a genetic mechanism of acquired BRAF inhibitor resistance. This observation is strongly supported by the analysis of a large database consisting of 712 BRAF V600E-positive melanoma samples showing higher rates of BRAF V600E and RAS mutations co-occurrence in metastatic lesions compared to local tumors (OR = 3.8, p = 0.035). This enrichment is likely a result of the development of RAS mutations following treatment with BRAF inhibitors.
Discussion: We report two cases showing extreme response to vemurafenib, which could not be predicted prior to treatment commencement. Genetic testing demonstrated a resistant mechanism not previously reported in CRC or PTC patients, namely an acquired mutation of RAS. This is supported by an analysis of a large cohort of BRAF V600E-positive melanomas.
Further studies are needed in order to identify predictive markers for response to vemurafenib and to explore novel strategies to overcome RAS-mediated resistance.
PDF
