Piccart-Gebhart, M.

e12000 Sorafenib is a potent multikinase inhibitor approved by the FDA and EMEA for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. As a single agent, sorafenib has been shown to have activity in pts with BC. Here, we review the TIES program, a compilation of currently ongoing investigator-sponsored phase IIb multinational, randomized, double-blind, placebo-controlled studies that aim to determine the optimal sequencing of pharmacologic agents for the treatment of BC. All studies will combine sorafenib with first- and/or second-line chemotherapy and/or hormonal therapy in pts with HER2-negative metastatic or locally advanced BC, enroll 220 pts, stratify pts by visceral vs nonvisceral disease, allow pts with evaluable and measurable disease, and include pts with treated brain metastases. The primary endpoint of all trials will be progression-free survival. Secondary endpoints will be safety, overall survival, objective response rate, duration of response, and time to progression. Some studies will also assess quality of life, pharmacokinetic sampling, and biomarkers. Additional information on four of the trials is shown below (Table). Patient characteristics and accruals will be reported. [Table: see text] No significant financial relationships to disclose.

Abstract Background Trastuzumab (T) combined with chemotherapy improves survival of women with HER2-positive breast cancer. Dual therapy with T and other HER-2 targeted agents (lapatinib/pertuzumab) has demonstrated improved efficacy compared to T alone in advanced breast cancer, and is in clinical trials in early stage disease. We hypothesize that subgroups of patients with HER2-positive tumors and limited tumor burden (tumor size and no or few positive lymph nodes) have a favorable outcome and would not be candidates for dual therapy. This study will analyze the disease-free survival (DFS)and overall survival (OS) of patients with early stage breast cancer treated with chemotherapy and T in the seminal randomized studies (RCTs). Methods RCTs were identified by a Medline search from 2004-2013. Trial groups from five phase III RCTs agreed to provide data. TrialNumberEligibilityRegimenNSABP B312130T1-3; pN1, pN2a, or pN3a; M0ACx4 then Tx4 VSACx4 then THx4 then Hx40wkNCCTG N98313505T1-3; pN1-2; M0ACx4 then Tx12wk VS ACTx4 then Hx52wk VS ACx4 then Tx12wk then Hx40wkHERA5102T1-3; pN1-2; M0Any (neo)adjuvant regimen, then H q3wk x1yr VS H q3wk x 2yr VS observationFinHER232T1-4; N0-3; M0Vx3 or T*x3 then FECx3 VS Vx3 or T*x3 with Hx9wk then FECx3PACS043010(528 HER2+)T1-3; pN1-2; M0FE(100)Cx6 VSFE(100)Cx6 then Hx1yr VS T*E(75) x6 VS T*E(75) x6 then Hx1yrA, adriamycin; C, cyclophosphamide; T, paclitaxel; T*, docetaxel; H, trastuzumab; P, carboplatin; F, 5-fluorouracil; E, epirubicin; Treatment regimen also included 5 years of hormonal therapy for ER positive patients. The ER+/HER2+ and the ER-/HER2+ cohorts will be analyzed separately. Patients with tumors 3 cm or smaller (T1a, T1b, T1c and >2 cm- 3cm) and 0, 1, 2 and 3 positive lymph nodes will be included. Initially a log rank test will be used to determine if the survival results are different by study. If there is no difference across studies, Kaplan-Meier survival curves with confidence intervals will be estimated. If there is a difference between studies, individual Kaplan-Meier curves will be estimated and the mean of the curves will be estimated along with confidence intervals using the adjusted standard deviation. Estimates at 3, 5 and 8 years will be presented as well as estimates of the event rates within each subpopulation defined by tumor size, number of positive lymph nodes, and ER status. Survival endpoints of DFS, and OS as defined in the original studies will be analyzed. Results and Conclusion Data from the five trials will be analyzed and an abstract provided prior to the meeting. Subgroups of patients with a very favorable outcome when treated with adjuvant chemotherapy and T will be identified. Our survival estimates might serve as benchmarks for future trials evaluating therapy reduction. Our results will complement those of the Dana Farber single arm multicenter trial in patients with “low risk” HER2-positive disease (APT trial; NCT00542451), being submitted to SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-03.

Abstract In the Breast International Group (BIG) and North Central Cancer Treatment Group (NCCTG) co-led phase III adjuvant breast cancer trial, ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), two central laboratories, the European Institute of Oncology (IEO; Milan, Italy) and Mayo Clinic (Rochester, MN), are responsible for confirming the human epidermal growth factor receptor-2 (HER2), estrogen receptor α(ER), and progesterone receptor status of the primary breast tumors for the Rest of World (excluding China, which conducts a separate central review) and North American patients, respectively, prior to patient study entry. As of December 2009, discordance in HER2 and ER testing between local and central laboratories was observed by both central laboratories. For IEO, 14.5% of 8,037 HER2 cases locally positive [by either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH)] were not able to be confirmed as centrally positive; whereas for Mayo, 5.8% of 412 HER2 cases locally positive were not able to be confirmed as centrally positive (Table 1). Central and local IHC ER discordance was 12.1% and 11.7% for 9,021 IEO screened cases and 419 Mayo screened cases, respectively (Table 2). In particular, IEO observed more false-positive (locally positive/centrally negative) HER2 findings than Mayo and Mayo observed more false-positive ER findings than IEO. Purpose: Motivated by the above findings, we launched a ring study to assess whether the central lab results of a subset of local/central discordant ALTTO cases could be confirmed in the other central lab. Methods: IEO and Mayo exchanged and retested a subset of FFPE breast tumors collected in ALTTO. IEO sent 20 HER2 false-positive, 5 ER false-positive, and 5 ER false-negative (locally negative/centrally positive) ALTTO breast tumors to Mayo. Mayo sent 5 HER2 false-positive, 20 ER false-positive, and 5 ER false-negative ALTTO breast tumors to IEO. IEO and Mayo performed IHC for ER according to their own methodology: DAKO cocktail of ER 1D5 and 2.123 monoclonal antibodies and monoclonal ER 1D5 antibody, respectively. The two laboratories performed IHC for HER2 according to the HercepTest® manufacturers’ instructions (Dako, Carpenteria, CA) and FISH for HER2 using the PathVysion HER2 DNA probe kit and the HER2/centromere 17 probe mixture (Abbott Molecular, Des Plaines, IL). Results: IEO and Mayo confirmed the central HER2-negative result in 100% of 25 cases. Analyses of ER are ongoing and ER results will be presented. Conclusions: In this subset of patients, enrollment ineligibility did not change when HER2 testing was performed by either IEO or Mayo Clinic central laboratories. Table 1. HER2 Local/Central Lab Results Table 2. ER Local/Central Lab Results Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-36.