Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers

<p>Abstract</p> <p>Background</p> <p>Breast cancers (BC) in women carrying mutations in BRCA1 gene are more frequently estrogen receptor negative than the nonhereditary BC. Nevertheless, tamoxifen has been found to have a protective effect in preventing contralateral tumors in BRCA1 mutation carriers. The identification of the second human estrogen receptor, ERβ, raised a question of its role in hereditary breast cancer. The aim of this study was to assess the frequency of ERα, ERβ, PgR (progesterone receptor) and HER-2 expression in breast cancer patients with mutated <it>BRCA1 </it>gene and in the control group.</p> <p>Methods</p> <p>The study group consisted of 48 women with <it>BRCA1 </it>gene mutations confirmed by multiplex PCR assay. The patients were tested for three most common mutations of BRCA1 affecting the Polish population (5382insC, C61G, 4153delA). Immunostaining for ERα, ERβ and PgR (progesterone receptor) was performed using monoclonal antibodies against ERα, PgR (DakoCytomation), and polyclonal antibody against ERβ (Chemicon). The EnVision detection system was applied. The study population comprised a control group of 120 BC operated successively during the years 1998–99.</p> <p>Results</p> <p>The results of our investigation showed that <it>BRCA1 </it>mutation carriers were more likely to have ERα-negative breast cancer than those in the control group. Only 14.5% of <it>BRCA1</it>-related cancers were ERα-positive compared with 57.5% in the control group (<it>P </it>< 0.0001). On the contrary, the expression of ERβ protein was observed in 42% of <it>BRCA1</it>-related tumors and in 55% of the control group. An interesting finding was that most hereditary cancers (75% of the whole group) were triple-negative: ERα(-)/PgR(-)/HER-2(-) but almost half of this group (44.4%) showed the expression of ERβ.</p> <p>Conclusion</p> <p>In the case of <it>BRCA1</it>-associated tumors the expression of ERβ was significantly higher than the expression of ERα. This may explain the effectiveness of tamoxifen in preventing contralateral breast cancer development in <it>BRCA1 </it>mutation carriers.</p

256 Single-agent zalifrelimab (anti-CTLA-4) shows clinical benefit in rare tumors – case report from phase 2 study (NCT03104699)

BackgroundZalifrelimab is a fully human monoclonal antibody against cytotoxic T-lymphocyte -associated protein 4 (CTLA-4). Preliminary data demonstrated clinical benefit and tolerability, as monotherapy, in patients with recurrent solid tumors including rare tumor types. Previously presented Phase I data reported one durable complete response in recurrent cutaneous angiosarcoma (cAS).1 Here we report additional clinical responses from an ongoing Phase 2 study of zalifrelimab monotherapy including clinical benefit in rare solid tumors.MethodsIn an ongoing, phase 2 study (NCT03104699), the safety and efficacy of zalifrelimab, as monotherapy, was evaluated in patients who progressed on prior anti-PD-1/L1 treatment. All patients were treated intravenously (IV) with zalifrelimab at 1 mg/kg every 3 weeks until disease progression or up to 2 years.ResultsOverall, 44 patients were treated and 29 patients were response-evaluable at the time of report. In patients with refractory solid tumors treated with zalifrelimab, we report a disease control rate (CR, PR, and SD) of 51.7%, objective response rate (ORR) of 10.3% (3/29), disease stabilization of 41.3% (12/29). Clinical activity was observed in five solid tumors considered rare, including; cAS (N=1), glucagonoma (N=1), chondrosarcoma (N=1), spindle-cell sarcoma (N=1) and fibroblastic sarcoma (N=1). In these rare tumors, durable partial responses of 45 and 30 weeks were observed in cAS of the scalp with lymph node metastases and glucagonoma, respectively. Both patients remain on zalifrelimab with no evidence of disease progression. Additionally, durable disease stabilization was observed in a patient with spindle-cell sarcoma. Patients with chondrosarcoma and fibroblastic sarcoma progressed on therapy. Zalifrelimab was well tolerated with the most commonly reported treatment-related adverse events including fatigue, nausea, anemia, diarrhea and vomiting, consistent with the drug class. Most events were mild or moderate and resolved with standard treatments.ConclusionsOur data demonstrates the potential for Zalifrelimab to promote meaningful clinical benefit in difficult to treat tumors, including patients that progress on prior PD-1/PD-L1 therapy or chemotherapy. Notably, responses were observed in rare tumor types such as recurrent cutaneous angiosarcoma and glucagonoma. Treatment with zalifrelimab is safe and well tolerated in patients with advanced malignancies.Trial RegistrationNCT03104699.ReferenceVaia Florou, Andrew E Rosenberg, Eric Wieder, Krishna V. Komanduri, Despina Kolonias, Mohamed Uduman, John C Castle, Jennifer S. Buell, Jonathan C. Trent and Breelyn A. Wilky Journal for Immunotherapy of Cancer 2019 7:213

A phase 2 trial of ixabepilone plus cetuximab in first-line treatment of metastatic pancreatic cancer

BACKGROUND: The aim of this phase 2 study was to evaluate the safety and efficacy of ixabepilone plus cetuximab in patients with advanced pancreatic cancer. METHODS: Eligible patients had advanced pancreatic adenocarcinoma that was metastatic or not amenable to resection, a Karnofsky performance status ≥70%, and no prior therapy for advanced disease. Patients received ixabepilone 32 mg/m2 (3-hour IV infusion) every 3 weeks and cetuximab 250 mg/m2 (1-hour IV infusion) weekly. The primary efficacy end point was the 6-month survival rate. Secondary end points included tumor response rate, overall survival, progression- free survival, and tolerability. RESULTS: A total of 54 patients were enrolled on this study. The 6-month survival rate was 57% (31/54:95% CI: 43-71%) with a median overall survival of 7.6 months (95% CI: 5.5-12.2 months). Patients who developed acneiform rash (n = 36) had a median survival of 8.8 months, compared with 2.6 months for those without rash (n = 18). Of 31 patients with measurable disease (defined as response-evaluable), 4 had confirmed partial responses and an additional 24 had stable disease. The combination was generally well-tolerated with the most common grade 3/4 hematological toxicities being leucopenia (39%) and neutropenia (33%). The most common grade 3/4 nonhematologic toxicity was fatigue (17%). CONCLUSIONS: The combination of ixabepilone and cetuximab was active and had acceptable toxicity. The efficacy results are similar to single-agent ixabepilone and gemcitabine-based combination therapies in patients with advanced pancreatic cancer. Exploratory analyses suggest a trend toward improved survival for patients who experienced rash. Gastrointest Cancer Res 5:155-160. © 2012 by International Society of Gastrointestinal Oncology

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

Background The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. Methods M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen. Results Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. Conclusions M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013