Abstract P1-15-07: Phase II trial of neoadjuvant carboplatin and nab-paclitaxel in patients with locally advanced triple negative breast cancer
Authors: Yuan Y , Frankel P , Li M , Kruper L , Jones V , Treece T , Waisman J , Yim J , Tumyan L , Schmolze D , Hurria A , Yeon C , Mortimer J , Somlo G 
Published: May 2019

Background: Response to neoadjuvant therapy (NT) predicts progression-free and overall survival in triple negative breast cancer (TNBC). Carboplatin has shown efficacy in patients with TNBC. The current phase II prospective neoadjuvant trial was designed to decrease toxicities and improve efficacy.

Methods: Patients with TNBC received carboplatin (carb) and nab-paclitaxel (nab). Pre-NT biopsies were procured to evaluate for biological predictors of pathological complete response (pCR). Newly diagnosed stage II-III patients with TNBC were treated with 4 cycles of carb (AUC 6, day 1 of 28 day cycle) and weekly nab 100 mg/m2 x 16. Targeted accrual goal is 70. RNA extracted from formalin fixed paraffin embedded (FFPE) biopsies pre-NT was tested for MammaPrint/BluePrint and custom Agilent full genome microarrays for gene expression (GE, by Agendia Inc). The raw gMeanSignal was log2 transformed and normalized to the 75thpercentile for GE analysis. Association between MammaPrint/ BluePrint results and pCR was tested by Fisher exact test. The linear model from R limma package was applied. Ingenuity Pathway Analysis (IPA) was applied to assess functional pathways associated with pCR. Cellular distribution by CIBERSORT analysis was carried out to estimate the abundance of 22 different cell types in each patient sample, and test whether the distribution of cell types is different between pCR and non-responders.

Results: A total of 64 patients were enrolled. Two patients were deemed ineligible (Her2+), and three were too early, resulting in 59 patients evaluable for pathological response. The pCR rate was 47% (RCB0, 28/59). Eight patients had RCB I. RCB0 plus RCBI reached 61%. Sufficient quality RNA and DNA were available from the first 43 of 55 pts with TNBC. 44/59 (75%) required dose modifications (mostly hematologic), 5 patients had grade 3 peripheral neuropathy (PN), 3 had grade 2 PN, and 3 patients had grade 2 LFTs. In the 53 pts with GE assessment, pCR was inversely associated with luminal BluePrint type (p=0.04). With fold change &gt;1.5 and p-value &lt; 0.05, 36 genes were differentially expressed (DE) in TNBC. CIBERSORT analysis suggested that T-cell regulatory cells (TREGS) were associated with pCR in TNBC, and 5 cell types (plasma cells, TREGS, macrophage, dendritic cells and neutrophils) presented differently between all pCR and non-pCRs with P-value &lt;0.05. TDP analysis to assess correlation with pCR is ongoing.

Conclusions: The combination of carboplatin and nab-paclitaxel given in the neoadjuvant setting reached a promising pCR rate of 47%. The MammaPrint non-luminal BluePrint subtype was predictive of pCR in TNBC. Preliminary analysis suggested that a 36-gene signature for TNBC was associated with pCR. CIBERSORT analysis revealed 5 cell types with different abundance between the pCR and non-responders, suggesting the need to target the tumor microenvironment.

Citation Format: Yuan Y, Frankel P, Li M, Kruper L, Jones V, Treece T, Waisman J, Yim J, Tumyan L, Schmolze D, Hurria A, Yeon C, Mortimer J, Somlo G. Phase II trial of neoadjuvant carboplatin and nab-paclitaxel in patients with locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-07.