Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance)

Abstract

Background: CALGB (Alliance) 40603 measured the effects of adding carboplatin (Cb) and/or bevacizumab (Bev) to standard neoadjuvant chemotherapy (weekly paclitaxel x 12 then doxorubicin/cyclophosphamide every 2 weeks x 4) on pathologic complete response (pCR) rates in stage II-III triple-negative breast cancer (TNBC). As previously reported (Sikov et al, JCO 2015), pCR breast (ypT0/is) and pCR breast/axilla (pCR Br/Ax) (ypT0/isN0) rates increased from 46% to 60% and 41% to 54%, respectively, with Cb and from 48% to 59% and 44% to 52%, respectively, with Bev. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Methods: EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause and OS from study entry to death from any cause in all patients (pts) who started study treatment. Pts without an event were censored as of their last clinical assessment. Hazard ratios (HR) were calculated for pts who achieved pCR vs. not and for pts assigned to receive drug (Cb or Bev) vs. not. All p-values are 2-sided. Results: 443 pts started study treatment. Median follow-up was 39 months (range 28-66). 110 EFS events and 77 deaths have been reported. At 3 yrs, overall EFS was 74.1% and OS 83.2%. Pts who achieved pCR breast had 3-yr EFS of 84.8% vs. 61.8% for those who did not. Table 1 shows the association between pCR and pCR or minimal residual invasive disease (Residual Cancer Burden Class I (RCB I), Symmans et al, JCO 2007) and outcomes; p-values for all comparisons <0.0001: Table 1 pCR BreastpCR Br/AxpCR Br/Ax or RCB IYes/No N (%)231 (52%)/212 (48%)207 (47%)/236 (53%)266 (60%)/177 (40%)EFS-HR0.33 (0.22-0.50)0.30 (0.19-0.46)0.29 (0.20-0.43)OS-HR0.28 (0.17-0.46)0.20 (0.11-0.36)0.21 (0.13-0.34) Pts assigned to Cb vs. not had 3-yr EFS 76.5% vs. 71.6% and OS 81.9% vs. 84.6%. Pts assigned to Bev vs. not had 3-yr EFS 75.5% vs. 72.9% and OS 85.5% vs. 80.9%. Table 2 shows HRs by assigned treatment: Table 2 CbBevN (Yes/No)225/218222/221EFS - HR0.84 (0.58-1.22) p=0.360.80 (0.55-1.17) p=0.25OS - HR1.15 (0.74-1.79) p=0.530.76 (0.49-1.19) p=0.23 Conclusions: Pts with TNBC who achieved pCR with study treatment had significantly better EFS and OS than pts who did not, consistent with findings from a published meta-analysis (Cortazar et al, Lancet 2014); the addition of RCB I did not weaken this association. Our study was not powered to assess the impact of Cb or Bev on these endpoints. While our findings are consistent with predictions from the meta-analysis as to the impact of raising the pCR rate on EFS (Berry-Hudis, JAMA Oncology 2015), the wide confidence intervals illustrate the challenge of conclusively demonstrating a correlation between pCR increment and EFS benefit, especially as the control pCR rate rises. While the addition of Bev has failed to improve long-term outcomes in TNBC in large randomized adjuvant trials, our results support ongoing and planned neoadjuvant and adjuvant studies designed to further assess the value of Cb-containing regimens in stage II-III TNBC. Support: U10s - CA180821, CA180882, CA180820, CA076001, CA025224, CA180868, CA180888. Citation Format: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Somlo G, Port ER, Qamar R, Sturtz K, Mamounas E, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-05.

Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer

“…One patient with HER2+ breast cancer received 4 cycles of ddAC followed by THL chemotherapy. Finally, one patient with TNBC was co-enrolled in CALGB study 40603 as described in Materials and Methods [24]. …”

Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts

“…In GeparSixto a 44% improvement in 3-year Event free survival (EFS) was noted with the addition of concurrent carboplatin to anthracycline plus taxane plus bevacizumab chemotherapy backbone. On the other hand, in CALGB 40603 addition of carboplatin to taxane followed by sequential doxorubicin/cyclophosphamide did improve pCR rate but, improvement in 3 year EFS or overall survival (OS) was not noted (46, 47). It is important to point out that, neither of these two trials were powered sufficiently for EFS and OS end points and thus cannot be considered definitive studies to answer the question of clinical utility of platinum agents for early stage TNBC.…”

Neoadjuvant Dose-Dense and Dose-Intensified Chemotherapy in Breast Cancer - Review of the Literature

“…After a median follow-up of 35 months, the addition of carboplatin improved DFS in patients with TNBC (HR 0.56, p = 0.035) but showed no effect in patients with HER2-positive disease (HR 1.33, p = 0.372, test for interaction p = 0.046) [24]. The impact of the addition of carboplatin and bevacizumab to a dose-dense regimen consisting of paclitaxel weekly (80 mg/m 2 ) followed by EC (90 /600 mg/m 2 ) given every 2 weeks was investigated by Sikov et al [25], demonstrating a better DFS and OS for patients having a pCR after a median follow-up of 39 months. The addition of carboplatin or bevacizumab did not have a significant impact on the DFS or OS.…”