Combined with MammaPrint high1/(ultra)high 2 status, several mechanism-of-action-based biomarkers predict high-risk HER2-negative breast cancer response to combination therapy with veliparib and carboplatin (VC), according to findings from the phase 2 I-SPY2 trial (ClinicalTrials.gov Identifier: NCT01042379), presented at the 2016 San Antonio Breast Cancer Symposium.
“By prespecified analyses, PARPi-7, ‘BRCAness,’ and MP1/2 specifically predict VC response,” reported Denise Wolf, PhD, of the University of California, San Francisco. “Our sample size is small; we need to validate findings in bigger trials, and in carboplatin as a single treatment.”
I-SPY2 is an adaptively-randomized study platform for testing neoadjuvant treatments. It employs a single controlled arm of patients who receive standard chemotherapy, and up to 4 simultaneous investigational arms. Patients are matched to therapies for which their cancer subtype is proving most responsive, using hormone receptor (HR) and HER2 status and MammaPrint 70-gene signature status. The study’s primary endpoint is pathological complete responses (pCR), defined by the absence of residual cancer tissue in breast or lymph tissue.
The trial platform also evaluates biomarkers associated with tested drugs’ mechanisms of action. From the candidate biomarkers the authors evaluated, 3 were predictive of pCR in patients treated with VC: PAPRi-7 (a gene-expression signature of DNA damage repair deficiency), BRCAness (a 77-gene BRCA1/2 deficiency signature), and MammaPrint (MP) 1/2 class. There was moderate concordance (50% to 67%) between the VC sensitivity biomarkers, meaning they were not redundant or identifying exactly the same patients, noted Dr Wolf.
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Patients who are also MP2 and PARPi7-high were “more sensitive to VC than patients with fewer markers in the ‘sensitive’ state, with a prevalence of 40% in triple-negative breast cancer and 9% of HR+/HER2-negative,” Dr Wolf said.
- Wolf DM, Yau C, Sanil A, et al. DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.