Abstract PD6-07: Genomic sequencing in metastatic breast cancer patients to inform clinical practice at the University of North Carolina at Chapel Hill
Authors: Grilley-Olsen J , Keith KC , Hayward M , Dees EC , Deal A , Ivanova A , Benbow JM , Parker J , Patel NM , Eberhard D , Mieczkowski P , Weck KE , Hayes DN , Muss H , Jolly T , Reeder-Hayes K , Earp HS , Sharpless N , Carey L , Anders CK 
Published: May 2016

Background: An increasing number of molecularly-targeted therapies for metastatic breast cancer (MBC) are clinically-available (approved and investigational). These anti-cancer agents target specific molecular abnormalities such as mutated, amplified, deleted, or rearranged genes. Reporting of unique tumor genetic alterations is not included in routine clinical/diagnostic panels. In MBC, knowledge of mutational status may foster efficient transitions in clinical care and trial enrollment at disease progression. We describe the development and implementation of a clinically-integrated genomic sequencing program and report how information regarding targetable genomic aberrations in MBC patients (pts) is used to improve clinical practice in an academic setting.

Methods: Genomic sequencing of investigative biomarkers was prospectively offered to pts with MBC. DNA libraries were prepared separately from a retrieved archival FFPE tumor sample and a matched normal sample from each pt. Relevant targets were enriched by custom Agilent SureSelect hybrid capture baits using standard protocols. Samples were sequenced on Illumina HiSeq 2000/2500 platforms. Mutational findings were reviewed by a molecular tumor board (MTB); variants identified to be potentially actionable underwent confirmatory testing in a CLIA-approved laboratory. Confirmed findings were inserted into the pt's EMR accessible by both the pt and the treating oncologist.

Results: Of the 725 MBC pts seen at UNC since 1/1/2012, 194 (27%) contributed samples for genomic sequencing. Of those whose tumors were sequenced, average age at MBC diagnosis was 54 (25 - 91); 73% were Caucasian, 16% African American. De novo MBC accounted for 39 (20%) sequenced pts. Of sequenced patients, sites of metastatic disease included bone only (7%), visceral only (46%), and both bone and visceral (47%). Approximately 1/3 of pts were consented for sequencing at time of initial MBC diagnosis, 1/4 after 1st line therapy for MBC, and the remaining at or beyond their 2nd line. In total, 131 (68%) pts have sequencing results available of which 43% of pts had reportable mutations deemed actionable by the MTB. Specific mutations and observed frequency by subtype are shown below. Pts (19%) whose tumors were sequenced were more commonly enrolled in a therapeutic clinical trial for MBC, a higher rate than seen in the non-sequenced group (7%) (p&lt;0.001). To date, 27% of pts' tumors harbored an alteration that is an eligibility requirement for a molecularly-targeted therapeutic trial accruing pts at UNC.

Observed Mutation by Clinical Subype Genes Total # (56 pts)HR+/HER2- (25 pts)HER2+ (13 pts)TNBC (18pts)PIK3CA15933TP5315456CCND19531NF-14103FGFR13300PTEN3012KRAS2011MDM22110PIK3R12002ROS12011TSC12011Other*14518TOTAL73281728*Mutations observed only once

Conclusion: Preemptive genomic sequencing can be integrated into the clinical and operational practice of a comprehensive cancer center. Currently this research tool and program provides valuable information that has the potential to foster both clinical trial eligibility and/or enrollment. With longer follow-up, we hope such an approach ultimately will improve patient outcomes.

Citation Format: Grilley-Olsen J, Keith KC, Hayward M, Dees EC, Deal A, Ivanova A, Benbow JM, Parker J, Patel NM, Eberhard D, Mieczkowski P, Weck KE, Hayes DN, Muss H, Jolly T, Reeder-Hayes K, Earp HS, Sharpless N, Carey L, Anders CK. Genomic sequencing in metastatic breast cancer patients to inform clinical practice at the University of North Carolina at Chapel Hill. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD6-07.