P3-14-04: Assessment of Genomic Prognostic Signatures as Predictors of Response to Neoadjuvant Chemotherapy in Patients with Early Stage Breast Cancer.
Authors: Culakova E , Poniewierski MS , Huang M , Kuderer NM , Ginsburg GS , Barry W , Marcom PK , Ready N , Abernethy A , Lyman GH 
Published: June 2012

Abstract
Background: Based on results from randomized clinical trials, adjuvant and neoadjuvant chemotherapy (NCT) strategies in early stage breast cancer patients (ESBC) achieve comparable long term results. Recently, a number of genomic signatures have been reported, distinguishing patients with low versus high risk of recurrence. While developed primarily as prognostic assays, these classifiers have also been proposed to be predictive of benefit from systemic chemotherapy. Neoadjuvant studies provide an opportunity to evaluate their predictive value for response to NCT.
Methods: A systematic review of gene expression profile studies in ESBC patients receiving chemotherapy was conducted. Medline search of original research articles of human studies published between January 2000 and February 2011 was based on key words and MeSH heading terms. Publications presenting outcomes for chemotherapy treated patients in groups stratified by multi-gene array signatures and utilizing a new independent cohort of patients compared to the original development cohort were selected. Information from eligible studies was extracted by dual abstraction. Reported results were synthesized into combined diagnostic odds ratio (DOR) using method of Mantel-Haenszel. This analysis is restricted to neoadjuvant studies investigating the association of genomic signature prognostic categories with objective tumor response to chemotherapy. Results: A total of 42 articles were eligible for data abstraction. Out of these, 6 publications evaluated response to NCT in good (low risk of recurrence) versus poor prognosis groups based on genomic prediction. Since two of the studies analyzed the same signature on a cohort with large overlap, only 5 studies were included in the final analysis, accounting for n=918 patients. Response consisted of pathologic complete response (pCR) in 3 studies, pCR or minimal residual disease (1 study), and clinical complete response (1 study). Prognostic genomic assays included Oncotype DX (1), MammaPrint (1), Genomic Grade Index (2) and PAM50 Risk of Relapse Score (1). Eight different chemotherapy regimens were utilized. The most common drugs were cyclophosphamide, anthracyclines, taxanes, and 5-fluorouracil. Across all genomic signatures, good prognosis patients, as defined by gene expression data, demonstrated consistently low rates of response to chemotherapy (median 3%, range 0–12%) compared to patients with less favorable prognosis (median 32%, range 19–43%). Odds ratio for response in poor versus good prognosis patients ranged from 3.9 to 21.7 with combined DOR= 6.6 (95% CI 3.9−11.3, P&lt;0.0001). No heterogeneity was determined across studies (P=0.4). The C-statistic estimating assay discriminatory ability was reported in 3 studies ranged from 0.72 to 0.78.
Conclusions: Across all genomic prognostic signatures reported, only a very small proportion of patients with signature predicted good prognosis achieved complete response to NCT. This suggests low sensitivity to chemotherapy among good prognosis patients, as determined by the prognostic genomic signatures. This further confirms the association between poor prognosis tumors and higher responsiveness to chemotherapy.
Funding: NCI: UC2CA14041-01
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-04.