Citations

Purpose We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)– amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy. Patients and Methods Women with stages II to III HER2-positive breast cancers were eligible. They received trastuzumab once per week (4 mg/kg loading, then 2 mg/kg) and lapatinib 1000 mg once per day for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone–releasing hormone [LHRH] agonist if premenopausal). Pathologic response was assessed by ER status. Biopsies were obtained at baseline, weeks 2 and 8, and time of surgery. Results Sixty-six patients were enrolled, and 64 were eligible and evaluable for response. Median tumor size was 6 cm (range, 1.5 to 30 cm). Adverse events were mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 metabolic, GI, and liver (18%; 12 patients) and grade 4 liver toxicities (one patient) were also observed. Overall, in-breast pathologic complete response (pCR; yp T 0 - is ) was 27% (ER positive, 21%; ER negative, 36%). The rate of low-volume residual disease ( yp T 1a-b ) was 22% (ER positive, 33%; ER negative, 4%). Conclusion In patients with locally advanced HER2-positive breast cancer, our approach of targeted therapy only resulted in a high pCR rate without chemotherapy. Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study.

PurposeOn initial publication of GI Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 [A Phase III Randomized Study of 5-Fluorouracil (5-FU), Mitomycin, and Radiotherapy Versus 5-Fluorouracil, Cisplatin and Radiotherapy in Carcinoma of the Anal Canal], concurrent chemoradiation (CCR) with fluorouracil (FU) plus mitomycin (MMC) decreased colostomy failure (CF) when compared with induction plus concurrent FU plus cisplatin (CDDP), but did not significantly impact disease-free survival (DFS) or overall survival (OS) for anal canal carcinoma. The intent of the updated analysis was to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free survival [CFS]), CF, and relapse (locoregional failure [LRF], distant metastasis) in this patient group.Patients and MethodsStratification factors included sex, clinical node status, and primary size. DFS and OS were estimated univariately by the Kaplan-Meier method, and treatment arms were compared by log-rank test. Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Gray's test. Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors.ResultsOf 682 patients accrued, 649 were analyzable for outcomes. DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for CFS (P = .05), LRF (P = .087), and CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS.ConclusionCCR with FU/MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP, and it has borderline significance for CFS, CF, and LRF. Therefore, RT + FU/MMC remains the preferred standard of care.

PurposeThe ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity.Patients and MethodsBetween 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS).ResultsA total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P = .77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P = .44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS.ConclusionFor women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome.

Abstract Purpose: PACS 01 trial demonstrated that the sequential adjuvant chemotherapy with FEC100 followed by docetaxel (D) significantly improves disease-free and overall survival in node-positive(N+) early breast cancer (BC). However, Triple negative (TN) and ER+/ PR-/HER2− subgroups are significantly associated to a worse prognosis even after adjunction of D. As Ixabepilone (Ixa) has notable preclinical and clinical activity in these subgroups, the PACS 08 trial aims to compare standard FEC100-D regimen to 3 cycles of FEC100 followed by 3 cycles of Ixa. We report the preliminary results of the toxicity profile. Patients and methods: Patients (pts) had localized resectable unilateral ER-/PR-/HER2− or ER+/PR-/HER2− BC. Main inclusion criteria were: age<70 years, normal cardiac, hepatic, haematological and renal functions. Arm A: pts received 3 cycles of FEC100 (F and C, each at 500 mg/m2, E 100 mg/m2, every 3 weeks) followed by 3 cycles of D (100 mg/m2 every 3 weeks); Arm B, Ixa 40 mg/m2 replaced D. Radiotherapy was mandatory after conservative surgery and endocrine therapy was given to ER+ pts. A 5% absolute difference in disease-free survival at 5 years is the main statistical end-point. Results: Between October 2007 and September 2010, 762 pts with TNBC or ER+/PR-/HER2− BC were enrolled. Recruitment was interrupted due to BMS decision to stop Ixa development in adjuvant setting. Main pts characteristics were well balanced between the 2 arms: median age 53 years, postmenopausal 57.8%, conservative surgery 68.4%, node positive 59.5%. A total of 755 pts were evaluable for safety. Treatment was completed for 93.4% and 86.1% of pts in arms A and B, respectively. During FEC100 sequence, toxicities were well balanced between the two arms. From cycle 4, whereas Gr3/4 sensory neurotoxicity (12pts; 3.5%) and thrombopenia (7pts; 2%) were reported in Ixa arm, none of these toxicities was reported in the D arm (p0.001). There were significantly more Gr3/4 neutropenia on day 21 in Ixa arm (13pts, 6.6% vs 4pts, 1.9%; p<10.005). No significant difference was observed for febrile neutropenia. Fewer cutaneous toxicities were observed in Ixa arm (2pts, 0.6% vs 10pts, 2.6%; p<0.05). No significant difference was observed neither for motor neurotoxicity or hepatic function between two arms. More pts discontinued treatment in Ixa arm compared to D arm (49pts (13%) vs 26pts (7%), p<0.05). Main reasons were Gr3/4 haematological adverse events (AE) and Gr3/4 neurotoxicities for Ixa arm and due to GR3/4 haematological AE for D arm. One non expected Gr4 bullous dermatitis was reported during the first Ixa cycle. 2 deaths due to septic shock occured in Ixa arm (both at cycle 4 for a 56- and a 66-year-old woman). However, according to the IDMC no obvious precipitating factor questioning the Ixa arm was identified. Conclusion: Our results indicate that D arm is more often associated to significant haematological toxicities, whereas both neurotoxicities and haematological toxicities are reported in the Ixa arm. Although significantly more pts discontinued treatment due to adverse events in Ixa arm compared to D arm, Ixa may still represent a promising therapeutic option for pts in the adjuvant setting especially for poor prognosis BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-04.