Abstract 3607: Quantitative dimensions of the PAM50 in breast tumors are prognostic and predict paclitaxel response
Authors: Camp Nicola J. , Madsen Michael J. , Valera Jesus H. , Carrasco Eva , Caballero Rosalia , Martin Miguel , Bernard Philip S. 
Published: August 2018

Abstract
Standard of care for women with locally advanced breast cancer is aggressive chemotherapy with a combined anthracycline-taxane regimen. Multiple randomized clinical trials have shown survival benefit to adding a taxane, e.g., paclitaxel; however, this can cause serious toxicities such as peripheral neuropathy. Identifying patients who benefit from taxane would improve survival outcomes, reduce toxicities and allow future randomization to more effective agents. So far, gene expression signatures have proven prognostic in the adjuvant chemotherapy setting but not predictive to particular regimens. We recently described 5 breast tumor dimensions using principal components (PC1-5): orthogonal quantitative tumor traits capturing the majority of expression variance in the PAM50 genes. Here we evaluate these dimensions and disease-free survival (DFS) in 819 patients in the Grupo Español para la Investigación del Cáncer de Mama (GEICAM) trial 9906, which evaluated fluorouracil, epirubicin and cyclophosphamide (FEC) vs. FEC followed by weekly paclitaxel (FEC-P). To investigate prognosis, we first ignored trial arm. PC1 was significantly associated with DFS in a Cox regression analysis (p=6.7x10-7), outperforming other predictors including nodal status, tumor size, grade, ER/PR/HER2/ki67 status, age at diagnosis and intrinsic subtype. PC1 remained significant in multivariate Cox regression adjusted for nodal status, tumor size and grade (p=8.7 x 10-4). Modeled as quintiles in a Kaplan-Meier (KM) analysis, PC1 was not only significant (p=3.7 x 10-6) but quantitatively prognostic, with the proportion surviving to 4 years decreasing for each quintile: 91%, 88%, 79%, 71%, 66% for low to high PC1 quintiles, respectively. To investigate response we examined interactions between dimensions and trial arm. Interactions were seen for PC3* arm (p=0.05) and PC4* arm (p=0.05). KM curves showed women with low-PC3 tumors responded to the addition of paclitaxel (p=0.006, 85% survival on FEC-P vs 72% FEC at 4 years), but women with high-PC3 tumors did not (p=0.94, 81% FEC-P, 82% FEC). Survival rates suggest that cases with high-PC3 were FEC super-responders, gaining no benefit from paclitaxel. Response to paclitaxel was seen for low-PC4 tumors (p=0.003, 89% FEC-P, 75% FEC), but not high-PC4 tumors (p=0.92, 70% FEC-P, 71% FEC); cases with high-PC4 tumors were poor responders to either treatment. Combining orthogonal traits PC3 and PC4 defined 44% of women (high-PC3 or high-PC4) with no benefit from paclitaxel (both arms 76% at 4 years), and 56% with lower PC3/PC4 tumors and substantial survival gain (p=0.002, 90% FEC-P, 73% FEC). In conclusion, breast tumor dimension PC1 shows great promise for quantitative prognostics. Dimensions PC3 and PC4 predict paclitaxel response, in particular identifying a large proportion of women (44%) who may be overtreated with paclitaxel, a drug class currently part of standard of care.
Citation Format: Nicola J. Camp, Michael J. Madsen, Jesus H. Valera, Eva Carrasco, Rosalia Caballero, Miguel Martin, Philip S. Bernard. Quantitative dimensions of the PAM50 in breast tumors are prognostic and predict paclitaxel response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3607.