Abstract P1-07-05: Integrated transcriptional analysis of the triple negative 'proliferation paradox': High proliferation, chemosensitivity, and poor prognosis
Authors: Stover DG , Selfors LM , Winer EP , Partridge AH , Barry WT 
Published: March 2017

Abstract
Background: In triple-negative breast cancers (TNBC), high proliferation is associated with greater chemosensitivity but, paradoxically, also associated with poor prognosis. We hypothesized that this subset of TNBC has distinct transcriptional features that contribute to poor prognosis.
Approach: To evaluate transcriptional signatures associated with this 'proliferation paradox,' we identified 17 study cohorts of TNBC treated with neoadjuvant chemotherapy (NAC) that reported receptor status, pathologic response, and had expression data from biopsies obtained prior to NAC (n=446). In 6 studies, distant metastasis-free survival (DMFS) data was available for 235 patients with a median follow-up of 31.2 months. We calculated scores for 135 published gene expression signatures for each tumor and evaluated the association with response to chemotherapy and DMFS.
Results: Using recursive partitioning to develop a model of response using a training set (n=340), six of the 135 expression signatures stratify primary tumors into four groups based on signatures of proliferation, BRCA1 mutation, immune, luminal, Ras, and PI3K phenotypes (Table 1.). Response to NAC ranged from 11% to 61% pCR/RCB-I and results were highly concordant when applied to a validation set (n = 106, p = 0.006). The group that was highly proliferative but chemoresistant ('resistant' group) had a distinct transcriptional profile, including lower 'BRCA-ness' and DNA damage expression signatures with higher Ras and stem cell signatures. The 'resistant' group had the poorest DMFS (HR 2.48 [1.52-4.06]; log-rank p=0.002) and this poor survival was validated among chemotherapy-treated TNBCs in a separate dataset, METABRIC. Analyses of only patients with residual disease after NAC demonstrated that the 'resistant' group remained poorest prognosis, with median DMFS of only 31 months from diagnosis.
Conclusions: Using a novel approach to categorize primary TNBC tumors based on six signatures, we can effectively distinguish subgroups with higher versus lower pCR rates. One specific group demonstrated high proliferation but low response to chemotherapy and particularly poor survival. This group demonstrates expression signatures implicating DNA damage repair, stemness, and Ras pathway activity as potential mediators of the phenotype. We identify specific molecular characteristics for investigation in patients within a poor prognosis subgroup of TNBC.
Table 1. Proportion Pathologic Complete Response or RCB-I and Survival Low ProlifHigh Prolif / ResistantHigh Prolif / SensitiveHigh ImmuneSignature StratificationLow GGI + High LuminalHigh GGI + Low BRCA1mut or High RasHigh GGI + High PI3K or Low RasHigh TNBC ImmunepCR/RCB-I rate: Training Set11/105 (10.5%)26/127 (20.5%)42/81 (51.9%)16/27 (59.3%)pCR/RCB-I rate: Validation Set3/23 (13.0%)11/45 (24.4%)13/29 (44.8%)6/9 (66.7%)pCR/RCB-I rate: TOTAL14/128 (10.9%)37/172 (21.5%)55/110 (50.0%)22/36 (61.1%)Overall Survival (n=235)Hazard Ratio (95% CI)1.62 (0.99-2.64)2.48 (1.52-4.06)(ref.)0.47 (0.29-0.77)Signatures GGI (Sotiriou, JNCI 2006); Luminal (Lim, Nat Med 2009); BRCA1 mutation (van't Veer, Nature 2002); Ras (Pratilas, PNAS 2009); PI3K (Gatza, PNAS 2010), TNBC Immune (Lehmann, JCI 2011)
Citation Format: Stover DG, Selfors LM, Winer EP, Partridge AH, Barry WT. Integrated transcriptional analysis of the triple negative 'proliferation paradox': High proliferation, chemosensitivity, and poor prognosis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-05.