Purpose: Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens. Patients and Methods: Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS). Results: One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02). Conclusions: The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.
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 >2 cm and M0; or node negative with tumors >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.
Triple-negative breast cancer (TNBC) is classically defined by estrogen receptor (ER) and progesterone receptor (PR) immunohistochemistry expression <1% and absence of HER2 amplification/overexpression. HER2-negative breast cancer with low ER/PR expression (1–10%) has a gene expression profile similar to TNBC; however, real-world treatment patterns, chemotherapy response, endocrine therapy benefit, and survival outcomes for the Low-ER group are not well known. 516 patients with stage I-III HER2-negative breast cancer and ER/PR expression ≤10% who were enrolled in a multisite prospective registry between 2011 and 2019 were categorized on the basis of ER/PR expression. TNBC (ER and PR < 1%) and Low-ER (ER and/or PR 1–10%) groups comprised 87.4% (n = 451) and 12.6% (n = 65) of patients, respectively. Demographic, clinical, and treatment characteristics, including prevalence of germline BRCA1/2 mutation, racial and ethnic distribution, and chemotherapy use were not different between TNBC and Low-ER groups. No difference was observed in recurrence-free survival (RFS) and overall survival (OS) between TNBC and Low-ER groups (3-year RFS 82.5% versus 82.4%, respectively, p = 0.728; 3-year OS 88.0% versus 83.4%, respectively, p = 0.632). Among 358 patients receiving neoadjuvant chemotherapy, rates of pathologic complete response were similar for TNBC and Low-ER groups (49.2% vs 51.3%, respectively, p = 0.808). The HER2-negative Low-ER group is often excluded from TNBC clinical trials assessing novel treatments (immunotherapy and antibody-drug conjugates), thus limiting efficacy data for newer effective therapies in this group. Given that HER2-negative Low-ER disease displays clinical characteristics and outcomes similar to TNBC, inclusion of this group in TNBC clinical trials is encouraged.
This regimen is tolerable palliative option for patients with metastatic esophageal cancer.
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