Abstract P4-04-02: Identifying ERBB-2 activating mutations (mts) in HER2 negative tumors for clinical trials – Impact of institute-wide genomic testing and trial matching on trial enrollment in clinical practice
Authors: Exman P , Garrido-Castro A , Hughes ME , Freedman RA , Ma C , Bose R , Cerami E , Wagle N , Barroso-Sousa R , Fitz CD , Lindeman NI , MacConaill L , Bychkovsky BL , Lloyd MR , Mackichan CR , Kumari P , Tolaney SM , Krop IE , Winer EP , Dillon DA , Lin NU 
Published: May 2019

Abstract
Introduction
Tailored treatment trials with biomarker-driven hypotheses are becoming an important strategy in drug development. Umbrella, basket and enrichment trials with eligibility predicated upon results of tumor sequencing are increasingly common. Several institutional and commercial genomic assays have been developed. However, the value of broad-based testing in recruiting patients (pts) to molecular-based clinical trials designed for small subgroups has not been fully evaluated and has been challenging to assess in a real-world setting. We evaluated the likelihood of trial enrollment based upon an institute-wide genomic test.
Methods
Since 2013, all pts with metastatic breast cancer (MBC) seen at least once at Dana-Farber Cancer Institute have been offered the option of tumor sequencing using multiplexed copy number variation (CNV) and mts detection across the full coding regions of a total of 447 cancer genes and 191 regions across 60 genes for rearrangement detection (Oncopanel; OP). For our primary analysis, we selected the ongoing multi-center phase II trial (NCT01670877) activated at our site on Sep 30, 2013, evaluating neratinib in ERBB-2 mutated pts, as the study provided a clear delineation of eligible mts, and timing of slot availability was retrievable retrospectively over an extended time frame. Our primary aim was to describe the proportion of pts with a qualifying ERBB-2 mt detected by OP who enrolled on the selected trial. Secondary objectives included median time from OP result to trial registration and description of ERBB-2 mts spectrum within each subtype. Associations were calculated by Fisher's test.
Results
We identified a total of 1,046 pts with HER-2 negative MBC and who had OP results between Sep 1, 2013 and Jun 1, 2017. A total of 43 pts (4.1%) were found to have ERBB-2 mts. Of these, 20 (1.9%) had activating eligible mts. The proportion of these pts who enrolled in the trial was 30% (6/20). Of the remaining 14 pts, 5 screen-failed and 2 were enrolled with known ERBB-2 mt through other testing modalities. Seven of 20 (35%) molecularly eligible pts were not approached (3 pts lost to follow-up, 3 enrolled in other clinical trials and 1 pt chose standard treatment). The median time from OP result to trial enrollment was 85 days (34-554). A significantly higher frequency of ERBB2 activating mts was found in ER+ compared to ER- primary tumors (2.5% vs. 0.3%, p =0.036), and in lobular tumors compared with ductal (5.5% vs. 1.25%, p=0.003). Frequency of eligible mts in primary tumors were similar to metastatic site (1.9% and 1.8%, respectively p=1.0)
Discussion
In this cohort, activating ERBB-2 mts were present in 20 of 1046 (1.9%) pts tested. Although over half of pts with eligible mts on OP testing were approached for NCT01670877, only 0.5% of the total tested population were enrolled (6/1046). Our data illustrate the substantial challenges in screening and enrolling to trials of rare subsets, even within a large academic institution, and point to the need for creative and novel approaches to leverage pts and community- and academic-based providers to more effectively support the success of such studies.
Citation Format: Exman P, Garrido-Castro A, Hughes ME, Freedman RA, Ma C, Bose R, Cerami E, Wagle N, Barroso-Sousa R, Fitz CD, Lindeman NI, MacConaill L, Bychkovsky BL, Lloyd MR, Mackichan CR, Kumari P, Tolaney SM, Krop IE, Winer EP, Dillon DA, Lin NU. Identifying ERBB-2 activating mutations (mts) in HER2 negative tumors for clinical trials – Impact of institute-wide genomic testing and trial matching on trial enrollment in clinical practice [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 P4-04-02.