BackgroundTo define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy.MethodsThis open-label, phase II study randomized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab, lapatinib, or both, 2 weeks prior to and during chemotherapy with FEC75 for 4 courses; then paclitaxel 80 mg/m2 weekly for 12 courses, then surgery. Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy. Data were correlated with pCR, defined as absence of invasive tumor in breast and lymph nodes.ResultsOf 100 enrolled patients, the analysis population included those who had surgery and received ≥75% chemotherapy (78% [n = 78]). pCRs by arm are: trastuzumab (n = 26), 54% [n = 14]; lapatinib (n = 29), 45% [n = 13]; trastuzumab plus lapatinib (n = 23), 74% [n = 17]). Paired biopsy specimens were available for 49 patients (63%). Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO, phosphorylated Stat5, and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3K and autophagy proteins compared with no pCR.ConclusionIn this exploratory study, pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells. These data may provide candidate biomarkers to stratify initial treatment and potential combination therapies for future study. Tissue preservation technology introduced here makes this procedure widely feasible.Trial registrationClinicalTrials.gov: NCT00524303

Purpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T).Experimental Design: Treatment comprised eight cycles of AC!T (T dose: 100 mg/m 2 on day 1) or AC!XT (X dose: 825 mg/m 2 twice daily, days 1-14; T dose: 75 mg/m 2 on day 1). The primary endpoint was 5-year disease-free survival (DFS).Results: Of 2,611 women, 1,304 were randomly assigned to receive AC!T and 1,307 to receive AC!XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67-1.05; P ¼ 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC!XT versus AC!T (HR, 0.68; 95% CI, 0.51-0.92; P ¼ 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)-positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of <10% or <20%, respectively, and only 17 (2%) and 53 (6%) DFS events, respectively, occurred in these groups at 7 years.Conclusions: The very low event rate in patients with ERpositive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients.

Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by paclitaxel is a safe and effective adjuvant chemotherapy regimen. Every-3-week nab-paclitaxel is safe and more effective at 50% higher dose than every-3-week paclitaxel in metastatic breast cancer (BC). This study evaluated the safety of adjuvant dose-dense AC followed by dose-dense nab-paclitaxel for early-stage BC. Women with operable, histologically confirmed BC received four cycles of dose-dense A 60 mg/m(2) plus C 600 mg/m(2) with pegfilgrastim, followed by dose-dense 260 mg/m(2) nab-paclitaxel (with pegfilgrastim given as needed). Endpoints were adverse events (AEs), including myelosuppression. Patients with neuropathy were followed until symptom improvement to grade ≤ 1. Thirty women received four cycles of dose-dense AC with no unanticipated AEs, one withdrew after AC therapy. Of 29 women who began nab-paclitaxel therapy, 27 received all the four doses (mean cumulative dose, 959 mg/m(2)); one discontinued nab-paclitaxel after two doses due to unacceptable AEs. Four patients had a grade 3 nab-paclitaxel-related neuropathy (no grade 4 event). Of 29 patients, 34% received pegfilgrastim during nab-paclitaxel therapy and 31% had a nab-paclitaxel treatment delay, mainly due to hematologic toxicity. Based on the Kaplan-Meier probability estimates, the percentage of patients having ≤ 1 grade neuropathy at the end of treatment, 2, and 8 months after treatment were 59, 79, and 97%. Administering adjuvant dose-dense AC followed by 260 mg/m(2) dose-dense nab-paclitaxel was feasible in women with early-stage BC, with manageable AEs. Most patients had ≤ 1 grade neuropathy 2 months after treatment completion.

Ramucirumab combined with eribulin did not significantly improve PFS in advanced MBC.

Background: Combination regimens incorporating anthracyclines and taxanes are among the most effective for EBC and are particularly suitable for pts with high-risk disease. Significant efficacy benefit has been shown in phase III trials integrating capecitabine (X) into anthracycline/taxane-containing (neo)adjuvant regimens (Joensuu H, et al. Lancet Oncol 2009; Steger G, et al. ASCO 2010). We present first efficacy results of a large, randomized, multicenter phase III study comparing adjuvant doxorubicin plus cyclophosphamide (AC) followed by docetaxel (T) with or without X in high-risk early stage BC. Methods: Pts aged 18-70 years, with high-risk, histologically-confirmed BC were eligible. High risk was defined as ≥1 positive lymph node, T1-3, and M0; or node negative with tumors &gt;2 cm and M0; or node negative with tumors &gt;1 cm, both ER and PgR negative, and M0. Treatment comprised four 3-weekly cycles of AC (A: 60mg/m2, C: 600mg/m2, both day 1) followed by four 3-weekly cycles of T (100mg/m2 day 1) or XT (X: 825mg/m2 b.i.d., days 1-14; T: 75mg/m2 day 1). Pts with hormone receptor-positive disease received tamoxifen or aromatase inhibitor for 5 years, and after 2005, pts with HER2-positive disease were offered 1-yr of concurrent or post-study trastuzumab. Primary endpoint: DFS (518 events were expected at 5 years); secondary endpoints: OS; safety; delivered dose intensity. Results: Between Aug 2002 and Feb 2006, 2,611 pts were randomized to AC→T (n=1,304) or AC→XT (n=1,307). The treatment arms were well balanced at baseline: median age was 51 yrs (range 26–72) and most pts had ECOG PS 0 (91%). The study failed to meet its primary endpoint of DFS (HR 0.84, 95% CI: 0.67-1.05; p=0.125) after a median follow-up of 5 years, with 304 events. However, a statistically significant improvement in OS was seen in pts receiving AC→XT vs AC→T (HR 0.68, 95% CI: 0.51-0.92; p=0.011), with 183 events. Subgroup analyses of DFS and OS appeared to favor the AC→XT arm over the AC→T arm, with few exceptions. The frequency of AEs was similar in both arms: 99.8% AC→T (n=1,305) vs 100% AC→XT (n=1,283), as was the incidence of serious AEs: 20.2% vs 15.6%, respectively. Differences were noted between the AC→T and AC→XT arms, respectively, in terms of the incidence of grade 3 hand-foot syndrome (3.8% vs 18.1%), and grade 3/4 stomatitis (4.5% vs 9.1%), diarrhea (2.9% vs 5.1%) and febrile neutropenia (13.1% vs 9.4%). Median dose intensity of T was 0.97 (range: 0.08-1.41) in the AC→T arm and 0.96 (range: 0.03-1.45) in the AC→XT arm; the corresponding value for X was 0.67 (range: 0.00-1.20), which is lower than reported with XT in MBC. Conclusions: Although this pivotal study failed to meet its primary endpoint of DFS, improvements in OS were seen with the addition of X to a standard anthracycline/taxane-containing adjuvant regimen. These results must be interpreted with caution due to the lower than expected event rate at 5 years. No new safety signals were detected, but the incidence of grade 3/4 stomatitis in the AC→XT arm was higher than previously reported with XT in the metastatic setting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-2.