Journal Article

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance)

Davies, Sherri R, Citron, Marc L, Carey, Lisa A, Friedman, Paula N, Gradishar, William J, Snider, Jacqueline E, Norton, Larry, Barry, William T, Bernard, Philip S, Perou, Charles M, Reed, Jerry P, Nielsen, Torsten O, Pitcher, Brandelyn N, Singh, Baljit, Martino, Silvana, Hudis, Clifford A, DeSchryver, Katherine, Mardis, Elaine R, Liu, Minetta C, Perez, Edith A, Winer, Eric P, Vickery, Tammi L, Ellis, Matthew J

2016

Overview

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha=0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio=1.20; 95% confidence interval=0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS ( P <0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P =0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P <0.0001), but no association with treatment benefit was seen ( P =0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence. Genomic testing: Predictive power of multigene activity Testing the activity of a set of 50 genes predicts breast cancer outcomes, but requires further validation as a tool to guide treatment. Minetta Liu of the Mayo Clinic in Minnesota, United States, together with US and Canadian colleagues, assessed the predictive power of the PAM50 genomic test for breast cancer. They analyzed tumor samples taken from 1,471 patients more than 12 years ago, comparing their results with knowledge of subsequent clinical outcomes and relapse. The team found that while specific PAM50 gene activity signatures were highly predictive of disease outcome and the incidence of relapse, PAM50 test results did not indicate the likelihood of improved outcomes with 2-weekly dose dense anthracycline and taxane-based chemotherapy. Predicting the benefit of different therapeutic strategies therefore remains a challenge. Future studies should investigate the potential of PAM50 testing for guiding chemotherapy choices.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1347 / 631/67/1857 / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Biology / Human Genetics / Oncology