Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial

Abstract

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344-54. ©2017 AACR.

Trial registration: ClinicalTrials.gov NCT02750657.

Figure 1

COMPASS Consort Diagram.

Figure 2

Summary of WGS and RNASeq results. Oncoprint showing sequencing results from 62 tumors as columns, with summary plots on the right. The top section shows the mutation and copy number status of six PDAC driver genes. Next, the somatic SNV, indel, and SV load and type distribution are displayed. CNVs are shown for each chromosome, followed by neo-antigen load and ploidy status. Finally, Waddell, Moffitt, Collisson, and Bailey classifications are presented for each sample.

Figure 3

A, RNA subtypes and chemotherapy response. The best percent change in size of tumor target lesions from baseline (before starting chemotherapy) measured by RECIST 1.1 for 49 chemotherapy response evaluable patients (48 PDAC + 1 acinar cell carcinoma) with RNASeq data are shown. Patients marked with * were treated with gemcitabine/nab-paclitaxel (GP)-based therapy, and the rest were treated with modified FOLFIRINOX (m-FOLFIRINOX). The cases numbered in red were locally advanced disease, the rest had metastatic disease. Four patients highlighted by red arrows had progressive disease by RECIST 1.1 due to unequivocal progression in nontarget lesions despite <20% growth in target lesions measured. The cases highlighted with blue arrows were COMP-0019 and COMP-0043 with duplication signature, COMP-0037 with BRCA2 germline mutation with somatic LOH, and COMP-0047 with unstable Waddell subtype and a BRAF mutation. These patients all had classical subtype tumors and responded (3 PR + 1 SD) to m-FOLFIRINOX chemotherapy. COMP-0021, highlighted with a green arrow, who achieved partial response to m-FOLFIRINOX, had basal-like RNA subtype and high neo-antigen load. COMP-0057, highlighted with yellow arrow, harbored BRCA2 germline mutation with no second hit (somatic LOH or mutation). COMP-0055 (black arrow) had acinar cell carcinoma. B, Duration of treatment on first-line therapy for COMPASS patients with RNASeq data who had at least one cycle of chemotherapy (N = 55). The median duration of treatment on first-line therapy in basal-like cases was 1.5 months (range, 1–6 months) and that in classical cases was 4 months (range, 0.5–18 months). The arrow indicates that patient was still on first-line chemotherapy.

Figure 4

Detection of GATA6 by RNA in situ hybridization assay (RNAScope) in metastatic PDAC (×400). Most tumor cells depicted in A (COMPASS 0042) and B (COMPASS 0046) display numerous red punctate signals, scores 3 and 2, respectively. In C (COMPASS 0026), many tumor cells contain only one to two dot-like signals each (score 1). Very few dots in rare tumor cells (score 0) are shown in D (COMPASS 0039). Scores 2 and 3 were typically seen in tumors with classical subtype Moffitt signature, whereas scores 1 and 0 were uniformly present in the basal-like subtype tumors.

Figure 5

PFS and OS. Hazard ratios (HR) are shown with 95% confidence intervals and P values. A, PFS of patients with advanced PDAC with Moffitt tumor classical and basal-like RNA subtypes (N = 59). B, Overall survival of patients with advanced PDAC with classical and basal-like subtypes (N = 59). C, PFS of patients with metastatic PDAC with classical and basal-like subtypes who had at least one cycle of chemotherapy (N = 49). D, OS of patients with metastatic PDAC with classical and basal-like subtypes who had at least one cycle of chemotherapy (N = 49).