Expanding the Clinical Trial Z1031 for Breast Cancer Tumor Sequencing (CIP)

Previously, we sequenced 50 tumor/normal pairs from the ACOSOG Z1031 breast cancer trial. We propose to sequence additional breast cancer patients to include a more complete spectrum of clinically important estrogen receptor positive breast cancer subtypes.

Expanding the Clinical Trial Z1031 for Breast Cancer Tumor Sequencing (CIP) Details

Center Initiated Projects (CIPs) are proposed by the McDonnell Genome Institute to help fulfill the mission and strategic vision of the NHGRI and NIH. All CIP data will be released in a timely manner via appropriate databases in accordance with NHGRI and NIH guidelines.

Project Summary: We were approved in 2009 to use NHGRI Center funds, with our institutional funds, to sequence 50 tumor/normal pairs from ACOSOG Z1031. Our plans were to study paired genomes from 25 aromatase inhibitor-resistant (AI-resistant) and 25 aromatase inhibitor-responsive (AI-responsive) samples and their matched blood normals, using Illumina-based whole genome sequencing and our analysis pipeline that discovers the genome-wide positions of single point mutations, focused insertion and deletion events, and large structural variations. In particular, we are requesting funds to sequence and analyze additional patients that fall into other subtypes of estrogen receptor-positive breast cancer, including the Luminal A and ER+ HER2+ (Luminal B) subtypes. Specifically, we propose to sequence an additional 10 luminal A subtype patients with very low baseline proliferation index and 10 ER+ HER2+ patients and matched normals. This would equal 40 additional whole genomes for the first requested extension of Z1031 sequencing. Effectively, this additional sequencing effort expands the database to include a more complete spectrum of clinically important estrogen receptor positive subtypes. The second interesting question that remains to be answered by sequencing of Z1031 specimens is to examine the impact of aromatase inhibitor (estrogen deprivation) therapy on the genomes of both resistant and responsive disease. We hypothesize that after four months of treatment estrogen deprivation therapy will result in the enrichment of a subset of mutations associated with therapeutic resistance. Conceptually this proposal builds on our recent report in Nature, which suggested that analysis of serial samples during the clinical course of the disease will assist in the differentiation between passenger and driver mutations. To address this postulate, we therefore are requesting support to sequence an additional 20 genomes of tumor biopsies resulting from surgical resection following the 4 months of AI treatment, where response versus resistance is gauged by Ki67 proliferation index. Here, we propose to stratify samples according to the Ki67 index, and to try to include samples whose subtype changed from the subtype determined prior to AI treatment. These samples also will be characterized by RNA-based subtyping using the Agilent gene expression array, for comparison to their subtype designation prior to the AI therapy course. Our total request for this sequencing equals 20 additional whole genomes and accompanying analysis. Status of Samples: 20 tumor:normal pairs plus 20 post-treatment samples originally projected. 33 tumor:normal pairs plus 26 post-treatment samples in house. Whole genome sequencing on hold. Follow-up work to include validation and extension sequencing. Collaborators: Dr. Matthew Ellis. IRB Status: Compliant, but WGS holding on dbGaP certification.