Abstract P1-08-10: Integration of next generation sequencing (NGS) and patient derived xenografts (PDX) to identify novel markers of paclitaxel (T) response in the breast cancer genome guided therapy study (BEAUTY)
Authors: Goetz MP , Boughey JC , Kalari KR , Eckel-Passow J , Suman VJ , Sicotte H , Hart SN , Moyer AM , Visscher DW , Yu J , Gao B , Sinnwell JP , Mahoney DW , Barman P , Vedell P , Tang X , Thompson K , Dockter TJ , Jones KN , Conners AL , McLaughlin SA , Moreno-Aspitia A , Northfelt DW , Gray RJ , Wieben ED , Farrugia G , Schultz C , Ingle JN , Wang L , Weinshilboum RW 
Published: August 2014

Background:

Based upon the association between pathologic response and disease free survival, the neoadjuvant setting is increasingly being used for drug development. NGS has identified unique and recurrent genetic alterations in breast cancer (BC) that are potentially targetable; however, the clinical implications are mostly unknown. We developed a prospective neoadjuvant study (BEAUTY) in high risk BC patients (pts) using weekly T followed by anthracycline-based chemo wherein percutaneous tumor biopsies (PTB) are obtained before/during/after chemo for NGS and PDX. Our goal is to identify novel biomarkers/pathways and develop PDX to test new therapeutic approaches.

Methods: Pts underwent PTB at baseline and after 12 wks of T. Response to T was defined based upon 12 week Ki-67: responder (&lt;15%) vs non-responder (≥15%). Pts with histologic response and absence of invasive BC at 12 wks were classified as responders. NGS was performed using PTB/blood DNA (exome) and PTB (RNA seq). MRI response was classified using RECIST criteria. NGS data were used to identify somatic copy number variants (cnvs) and expressed single nucleotide variants (eSNVs). Non-SCID mice (estrogen supplemented) were implanted ≤ 30 minutes with PTB samples.

Results: Of the first 78 pts, 44 have completed T. Here we focus on 18 pts with either triple negative or luminal B BC. Clinical characteristics according to Ki-67 response are shown in Table 1. Comparison of genomic alterations in BEAUTY pts with TCGA identified a greater overlap with copy number gains (73%) compared to deletions (40%), along with similar observations of mutations in TP53, PTEN, RYR2, and AKT1 genes. Association analysis of CNVs and eSNVs between responders/non-responders identified 33 genes (predominantly located in chromosomes 1, 8, 13) and 580 eSNVs (corresponding to 497 genes) with a p &lt; 0.05. Differential gene expression (DGE) analysis of responders/non-responders identified 198 genes with a p-value &lt; 0.05. Integrated analysis of 539 genes (CNVs, eSNVs and DGE) identified pathways such as TGF-beta, Jak-Stat, WNT and NOTCH signalling. PDX take rate was 44% [triple negative (6/10); Luminal B (2/8)]. PDX growth rate was significantly associated with clinical baseline Ki-67 (p = 0.00014).

Conclusion: This is the first prospective study to demonstrate the feasibility of using PTB to obtain both NGS data and PDX in the neoadjuvant setting. PDX take rate is associated with BC subtype and baseline Ki-67. Studies are ongoing to 1) validate genes/pathways associated with treatment response in subsequent BEAUTY pts; 2) genomically characterize and assess PDX in vivo response to T and 3) Use NGS data to prioritize new drugs/drug combinations in PDX.

Funded by Mayo Clinic Center for Individualized Medicine and MC Cancer Center.

Clinical CharacteristicsOverallResponders: 12 week Ki-67 &lt; 15% (n = 9)Non-Responders: 12 week Ki-67 ≥ 15% (n = 9)Median Age495345T stage T2/T314 (78%)7 (78%)7 (78%)Node Positive8 (44%)4 (44%)4 (44%)Triple negative10 (56%)6 (67%)4 (44%)Luminal B8 (44%)3 (33%)5 (56%)Ki-67 after 12 Weeks of T Median 5% (0-11%)Median 35% (17-60%)Complete/Partial MRI Response after T 6 (67%)2 (22%)

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-10.