Abstract
Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2− patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2− patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the ‘predicted sensitive’ group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2− patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care.
Highlights
Poly(ADP-ribose) polymerase (PARP) inhibitors belong to an emerging class of drugs that operate on the principle known as ‘synthetic lethality’.1, 2 PARP is involved in single strand break (SSB) DNA repair; and upon PARP inhibition, some SSBs are converted into double strand breaks (DSBs) at replication forks
We evaluated the PARPi-7, BRCA1ness and MP1/2 signatures in relation to the graduating triple negative (TN) signature, by adding biomarkerpositive HR+/HER2− patients to the TN group and evaluating whether the treatment effect of Veliparib combined with carboplatin (VC) remains significant in this expanded population of ‘predicted sensitive’ patients
Our results demonstrate that ‘double biomarkerpositive’ in both TN and HR+HER2− patients may be more sensitive to VC than patients with fewer markers in the ‘sensitive’ state, the prevalence of MP2/PARPi7-high patients in the TN subset is relatively high (42%; Fig. 4i), whereas HR+/HER2− patients with these markers are relatively rare (11%; Fig. 5h)
Summary
Poly(ADP-ribose) polymerase (PARP) inhibitors belong to an emerging class of drugs that operate on the principle known as ‘synthetic lethality’.1, 2 PARP is involved in single strand break (SSB) DNA repair; and upon PARP inhibition, some SSBs are converted into double strand breaks (DSBs) at replication forks. The PARP inhibitor, olaparib, was recently FDA approved for BRCA1/2 mutation positive patients with advanced ovarian cancer. Women with HER2+ disease receive trastuzumab or other HER2-targeted therapy This trial is adaptive, in that a patient randomized to receive experimental treatment is assigned preferentially to the arm where her cancer subtype is repair deficiency expression signature (PARPi-7) that predicts breast cancer cell line sensitivity to the PARP inhibitor olaparib; 34 (3) a 77-gene BRCA1ness expression signature;[40, 41] (4) the CIN70 chromosomal instability expression signature;[42, 43] and (5) PARP1 most likely to respond. I-SPY 2 is to identify (graduate) regimens with >85% predicted probability of succeeding in a 1:1 randomized 300-patient phase 3 trial where pCR is the endpoint, in the signatures defined by HR, HER2, and MP where the drug is most effective (graduates). VC successfully graduated in the TN signature;[23] but not all TN
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