No abstract

Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer [1]. It is the most common female cancer and the second most common cause of cancer death in women [2]. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC) [3].HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors [4]. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition [5].In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127]. In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way [8–10]. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1.This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P ¼ 0.007), high-grade tumors (P ¼ 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR ¼ 1.12; 95% confidence intervals, 0.83-1.85; P ¼ 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response.Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336-45. Ó2014 AACR.

No abstract

No abstract

Purpose FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown.MethodsUsing multiplex gene panels we evaluated how the FBXW7 mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed.Results FBXW7 mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested, FBXW7 mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the FBXW7-mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and KRAS was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3–6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months.ConclusionIn patients with advanced cancers, somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.

No abstract

Background: In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and without such a selection rationale.