507 Background: T-based neoadjuvant chemotherapy achieves pCR rates of ~50% in HER2+ BC, enabling frequent conservative surgery. Pre-clinical and clinical data support the synergistic combination of B and T. The ph II AVATAXHER trial (EUDRACT 2009-013410-26) investigated whether adding B to neoadjuvant T+D improved pCR rates in tumors with a low likelihood of attaining pCR (predicted based on relative change in FDG tumoral uptake [ΔSUV] after one cycle of T+D). Methods: Patients were ≥18 yrs old with stage T2/3, N0/1 HER2+ BC. Patients received two 3-weekly cycles of T (8 mg/kg, then 6 mg/kg) and D (100 mg/m2). Those with ≥70% ΔSUV in PET values between cycle 1 and 2 received four more cycles of T+D, one cycle of T, then surgery (standard arm). Those with <70% ΔSUV were randomized 2:1 to four cycles of T+D+B (15 mg/kg; arm a) or T+D (arm b), then one T cycle and surgery. The primary endpoint was pCR rate at surgery. The positive (PPV) and negative predictive value (NPV) of ΔSUV on pCR rate and safety were also investigated. Results: 152 patients were recruited at 26 sites (10 were withdrawn pretreatment; ITT=142). 37/69 (53.6%) patients in the standard arm achieved pCR, 21/48 (43.8%) in arm a and 6/25 (24.0%) in arm b. pCR rates in patients with hormone receptor –ve/+ve disease were: 69.0%/42.5% (standard arm), 57.9%/34.5% (arm a), and 40.0%/13.3% (arm b). Surgery (133 pts) was conservative in 84.8% of patients with surgery in the standard arm, 67.4% in arm a, and 62.5% in arm b. In patients without B, ΔSUV after one cycle predicted pCR with a PPV of 52.9% and a NPV of 75%. Toxicity was mild and included asthenia, myalgia, and increased lacrimation (all pts had ≥1 AE). Grade 3/4 AEs (in 31% of pts) included neutropenia (8.6% pts), febrile neutropenia (3.6%), myalgia (3.6%), asthenia (2.9%), and nail toxicity (2.9%). Conclusions: Adding B to neoadjuvant T+D, in tumors with a low likelihood of pCR predicted by PET ΔSUV, increased the pCR rate from 24.0% to 42.5%. PET ΔSUV, by selecting low responding HER2+ tumors, may be a useful tool for optimizing neoadjuvant therapy for HER2+ BC. Clinical trial information: 2009-013410-26.

BACKGROUND:An effective and well tolerated treatment is needed for patients with early HER2-positive breast cancer who do not achieve a pathological complete response after neoadjuvant therapy. The AVATAXHER trial aimed to predict pathological complete response early with the use of PET and to investigate whether the addition of bevacizumab could improve the proportion of patients achieving a pathological complete response in patients unlikely to respond to treatment. METHODS:AVATAXHER was a randomised, open-label, non-comparative, multicentre phase 2 study that enrolled women (≥18 years of age) with early-stage HER2-positive breast cancer from 26 oncology centres in France. Patients initially received two cycles of neoadjuvant docetaxel (100 mg/m(2) intravenously every 3 weeks) plus trastuzumab (8 mg/kg intravenously every 3 weeks then 6 mg/kg intravenously every 3 weeks for the second course). Before the first and second cycles, [(18)F]-fluorodeoxyglucose (FDG) PET was done and the change in standardised uptake value was used to predict pathological complete response in each patient. Patients who were predicted to be responders on PET continued to receive standard therapy. Predicted non-responders were randomly assigned (2:1) to receive four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) and trastuzumab (6 mg/kg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks; group A) or continue on docetaxel plus trastuzumab alone (group B). Randomisation was open label and was done by an adaptive minimisation method. Although investigators and patients were aware of group assignment, the anatomo-pathologist in charge of centralised review of surgical samples and lymph nodes was masked to treatment assignment. The primary endpoint was centrally assessed pathological complete response according to the Chevallier classification. Efficacy analyses were done in the intention-to-treat population. Safety analyses in this Article were done on all patients who received at least one dose of treatment starting from cycle 3. Survival outcomes are not yet mature. This study is registered with ClinicalTrials.gov (NCT01142778) and EUDRACT (2009-013410-26). FINDINGS:Between May 19, 2010, and Oct 1, 2012, 152 patients were recruited for the study. Ten patients were subsequently excluded, leaving 142 patients in the intention-to-treat population. Of these 142 patients, 69 were predicted by [(18)F]-FDG PET to be treatment responders after two cycles of treatment. The 73 predicted non-responders were randomly assigned to group A (n=48) and group B (n=25). Pathological complete responses were noted in 37 (53·6%, 95% CI 41·2-65·7) of the PET responders, 21 (43·8%, 29·5-58·8) of those in group A, and six (24·0%, 9·4-45·1) of those in group B. Incidences of grade 3-4 adverse events were similar in all three groups. The most common grade 3-4 adverse events were neutropenia (four in PET responders, five in group A, and three in group B), febrile neutropenia (one, three, and one, respectively), and myalgia (four, none, and one, respectively). Overall, 24 serious adverse events were reported in 15 patients (PET responders: nine events in four [6%] of 67 patients; group A: 14 events in ten [21%] of 47 patients; group B: one event in one [4%] of 25 patients). No deaths occurred during the study. INTERPRETATION:In patients with HER2-positive breast cancer, early PET assessment can help to identify non-responders to neoadjuvant docetaxel plus trastuzumab therapy. In these patients, the addition of bevacizumab can increase the proportion of patients achieving a pathological complete response. This potential new role for PET and the activity of bevacizumab in this setting need to be confirmed in larger phase 3 trials. FUNDING:Roche France.

PURPOSE:Few reliable prognostic molecular markers have been characterized for glioblastoma multiforme (GBM), considered the deadliest of human cancers. We hypothesized that genetic polymorphisms in chemokines and their receptors, which together control microglial cell mobilization, may influence survival.METHODS:Distributions of one polymorphism of the chemokine CCL2 (-2518A<G) and two polymorphisms of the chemokine receptor CX3CR1 (termed V249I and T280M) were determined in a prospective series of 230 patients with GBM and correlated with overall survival. The replication study used data from a retrospective series of 106 additional patients with GBM. The extent of microglial cell infiltration was assessed by immunochemistry in 102 tumor specimens.RESULTS:Survival analysis showed that the common CX3CR1-I249 allele was an independent favorable prognostic factor in both groups, prospective and retrospective, with hazard ratios of 0.619 (95% CI, 0.451 to 0.850; P = .0031) and 0.354 (95% CI, 0.217 to 0.580; P < .0001), respectively. This beneficial effect was observed only in patients who underwent surgery. Patients with only this CX3CR1-I249 allele had a substantially longer mean survival (23.5 v 14.1 months; P < .0001). The CCL2-2518G allele was not associated with patient survival. Immunohistochemical analysis of primary tumor biopsies showed that the common CX3CR1 variant allele was associated with reduced microglial cell infiltration.CONCLUSION:The common CX3CR1 allelic variant was associated with increased GBM survival and with reduced tumor infiltration by microglia. The CX3CR1 polymorphism does not seem to be a risk factor for GBM but may prove useful in predicting survival.