TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Abstract

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users.

ATTAIN: Phase III Study of Etirinotecan Pegol Versus Treatment of Physician’s Choice in Patients with Metastatic Breast Cancer and Brain Metastases

“…In this open-label study, 18 patients (with a median of three prior therapies) were diagnosed with glioblastoma multiforme; three of the 18 (17%) had a partial response to single-agent EP, with two responses lasting for ≥18 months. Additionally, a Phase II trial for patients with BCBM testing iniparib and irinotecan yielded a response rate of 12%, primarily attributed to irinotecan [57]. These data further support the preclinical evidence for the activity of irinotecan-based drugs within the brain.…”

The role of BRCA status on prognosis in patients with triple-negative breast cancer

“…TNBC patients with BRCA1 mutations or promoter methylation may be more sensitive to chemotherapy, and thus may benefit from adjuvant chemotherapy [ 4 , 39 , 40 ]. Furthermore, multiple clinical trials on the efficacy of chemotherapy with PARP inhibitors in metastatic TNBC patients have shown positive results [ 41 , 42 ]. Thus, it is vital to understand the role of BRCA1/2 dysfunction in TNBC.…”

Global Analysis of miRNA–mRNA Interaction Network in Breast Cancer with Brain Metastasis

“…Nearly half the patients with advanced triple-negative breast cancer develop brain metastases (19). The expression levels of the above selected 11 miRNAs were compared between triple-negative and non-triple negative breast cancer.…”