Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer.

Baylor Charles A. Sammons Cancer Center, Dallas, TX 75246, USA.
New England Journal of Medicine (Impact Factor: 54.42). 01/2011; 364(3):205-14. DOI: 10.1056/NEJMoa1011418
Source: PubMed

ABSTRACT Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition.
We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8--with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11--every 21 days. Primary end points were the rate of clinical benefit (i.e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival.
The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P=0.01) and the rate of overall response from 32% to 52% (P=0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P=0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; P=0.01). The most frequent grade 3 or 4 adverse events in either treatment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events.
The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Funded by BiPar Sciences [now owned by Sanofi-Aventis]; number, NCT00540358.).


Available from: Cynthia Osborne, Jun 20, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: As the testing criteria for BRCA expand, we are identifying a greater number of young women at significant risk for breast and ovarian cancer. Fortunately, there is strong evidence to support risk reduction from mastectomy and oophorectomy. However, these surgeries come with significant psychological and physical health consequences. For breast cancer, screening with mammogram and magnetic resonance imaging may be a reasonable approach for a woman who does not desire surgery. However, there is no evidence to suggest any efficacy in screening for ovarian cancer, and women electing to not undergo surgery must have a detailed discussion with their physician regarding the risks and benefits of different management strategies. As more women are electing to undergo surgical risk reduction, providers must also be able to counsel and care for these women who will face unique health challenges after surgical menopause at a young age. A review of the current evidence behind management of the BRCA woman follows, with a focus on areas of controversy and current research.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Poly (ADP-ribose) polymerase (PARP) inhibitors are particularly efficient against tumors with defects in the homologous recombination repair pathway. Nonetheless poly(ADP-ribosylation) (PARylation) modulates prometastasic activities and adaptation of tumor to a hostile microenvironment. Modulation of metastasis-promoting traits is possible through the alteration of key transcription factors involved in the regulation of the hypoxic response, the recruitment of new vessels (or angiogenesis), and the stimulation of epithelial to mesenchymal transition (EMT). In this review, we summarized some of the findings that focalize on PARP-1's action on tumor aggressiveness, suggesting new therapeutic opportunities against an assembly of tumors not necessarily bearing DNA repair defects. Metastasis accounts for the vast majority of mortality derived from solid cancer. PARP-1 is an active player in tumor adaptation to metastasis and PARP inhibitors, recognized as promising therapeutic agents against homologous recombination deficient tumors, has novel properties responsible for the antimetastatic actions in different tumor settings. © 2015 Wiley Periodicals, Inc.
    Medicinal Research Reviews 01/2015; DOI:10.1002/med.21339 · 8.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.
    OncoTargets and Therapy 01/2015; 8:177–193. DOI:10.2147/OTT.S67673 · 1.34 Impact Factor