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.


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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.

Reference

  1. 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.