Abstract S4-05: Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Allianc
Authors: Sikov William M , Barry William T , Hoadley Katherine A , Pitcher Brandelyn N , Singh Baljit , Tolaney Sara M , Kuzma Charles S , Pluard Timothy J , Somlo George , Port Elisa R , Golshan Mehra , Berry Donald A , Hahn Olwen M , Carey Lisa A , Perou Charles M , Hudis Clifford A , Winer Eric P 
Published: May 2015

Abstract
Background: Adding either Cb or Bev to standard NACT significantly increases pCR rates in TNBC (Sikov et al, SABCS 2013). Genomic analysis may help us to identify determinants of response within this clinical phenotype.
Methods: Patients (pts) with clinical stage II-III TNBC received weekly paclitaxel x 12 followed by ddAC x 4 +/- Cb and/or Bev. Pre-treatment biopsies were collected in formalin, RNAlater and OCT; residual disease at surgery was biopsied when possible. Illumina mRNA sequencing (RNAseq) was performed. Gene expression values were normalized to a TCGA subset of clinically TNBC samples prior to downstream analysis. pCR was defined as the absence of residual invasive cancer in the breast (ypT0/is). For each molecular signature, prognostic (effect on pCR in the overall study population) and predictive (effect of the addition of Cb or Bev, separately, on pCR) relationships were explored with logistic regression models.
Results: PAM50 subtype analysis was performed on 367 pre-treatment samples (of 443 pts who started NACT); pCR results were available for 360, comprising the analysis subset. 87% of these displayed a basal-like gene expression pattern, 2% claudin-low, 4% HER2-enriched, &lt;1% luminal A and 7% normal-like. In pts with basal-like tumors, pCRs rose from 47% to 61% with the addition of Cb (p=0.014), an increment which did not differ significantly from the overall study population (adding in the small number of non-basal-like tumors) (interaction p=0.93). In contrast, the addition of Bev increased pCRs in basal-like tumors from 45% to 64% (p=0.0009), while reducing pCRs in non-basal-likes from 60% to 43% (interaction p=0.024); thus, a basal-like gene expression pattern was predictive of benefit from Bev. Expression of a variety of immune signatures (B cell, T cell, IgG) was positively associated with pCR, but not predictive of increased benefit from either Cb or Bev. High expression of the HER2 amplicon signature was uncommon and not prognostic for pCR overall but was associated with reduced benefit from Cb (interaction p = 0.025). High proliferation, high p53 mutation and low IE (estrogen signaling) signatures were prognostic for higher pCR rates and predictive of benefit from Bev (interaction p=0.031, 0.0017, 0.0002, respectively). In basal-like pts with residual disease, surgical samples often (52%) displayed a normal-like PAM50 pattern, though this might be due to ‘contamination’ in low volume residual disease.
Conclusions: Selection criteria led to accrual of a high % of pts with basal-like tumors, limiting our ability to assess prognostic or predictive impact of intrinsic subtype on pCR. Given that limitation, the magnitude of pCR benefit with Cb was consistent across subtypes, while a basal-like pattern was predictive of greater pCR increment with Bev. Ongoing studies will test a large number of other gene signatures and biomarkers, including the Lehmann et al subtypes. Recognition of clinically relevant subpopulations within TNBC may distinguish pts likely to achieve a pCR from those for whom an investigational approach might be considered.
Citation Format: William M Sikov, William T Barry, Katherine A Hoadley, Brandelyn N Pitcher, Baljit Singh, Sara M Tolaney, Charles S Kuzma, Timothy J Pluard, George Somlo, Elisa R Port, Mehra Golshan, Donald A Berry, Olwen M Hahn, Lisa A Carey, Charles M Perou, Clifford A Hudis, Eric P Winer. Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Allianc [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S4-05.