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: 55.87). 01/2011; 364(3):205-14. DOI: 10.1056/NEJMoa1011418
Source: PubMed


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.).

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Available from: Cynthia Osborne, Jun 20, 2014
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    • "Breast cancer is the second leading cause of cancer related deaths in women [1]. While several targeted chemotherapeutics have been developed, the use of these drugs is limited to those patients who exhibit the proper cellular profile, such as triple negative or HER2 positive [2] [3] [4] [5] [6] [7]. In lieu of these targeted therapies, a more nonspecific treatment must be utilized. "
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    ABSTRACT: As part of a larger study synthesizing a more directed form of chemotherapy, we have begun to assess the efficacy of different potential toxins that could be delivered locally rather than systemically. In doing so, we hope to reduce the systemic side effects commonly observed, while maintaining a high level of toxicity and eliminating the need for metabolic alterations. In a search for this more efficient method for killing cancerous cells, we have begun studying cantharidin, a toxin used in traditional Chinese medicine, as a potential chemotherapeutic. Using an MTT cell viability assay, the toxicity of cantharidin was compared to both cyclophosphamide and paclitaxel in three different breast cancer cell lines: MCF-7, MDA-MB-231, and SK-BR-3. Increasing the concentration of chemotherapy drugs did decrease cell viability in all cell lines when cantharidin and cyclophosphamide were applied; however differences for paclitaxel were cell-specific. Additionally, cantharidin exhibited the highest decrease in cell viability regardless of cell type, indicating it may be a much more potent and less specific chemotherapeutic. These results will help us move forward in developing a potentially more potent treatment for breast cancer that might eliminate the need for subtype-specific treatments.
    09/2014; 2014:423059. DOI:10.1155/2014/423059
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    • "In fact, the data obtained for the triple-negative population was positive in terms of PFS for all agents, except for lapatinib, which may even be detrimental, sunitinib and sorafenib. Unfortunately , iniparib activity, which in a phase II study seemed very promising, was not confirmed in the phase III study [31] [41]. TNBC patients do not have the option of using antiHER2 drugs or hormonal agents, so for this population, other BAs are urgently required. "
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    ABSTRACT: Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis is poor, and there is no specific target therapy but biological agents combined with chemotherapy may be effective. To assess the role of biological agents in metastatic triple-negative breast cancer we performed a systematic review of phase III randomized controlled trials published from January 2006 to February 2013 and presentations at ESMO, ASCO, and SABCS congresses in 2010–2012. We consulted PubMed and Only studies comparing biological agents and chemotherapy versus chemotherapy alone were considered. Relevant statistical variables were log of the hazard ratio and relative variance for progression-free survival (PFS) and overall survival (OS). Of 353 PubMed publications and 229 studies registered on, ten trials were selected and 5,293 patients were analyzed: 1,546 had mTNBC. Biological agents considered were bevacizumab, sunitinib, sorafenib, lapatinib, iniparib and cetuximab. In addition, a meta analysis of the 4 studies containing bevacizumab was performed and it showed a PFS improvement with a relative risk reduction of 35% (95% CI: 25%-43%). No effect on OS was observed. No PFS and OS benefit was detected with the other agents. No improvement of OS was detected in patients treated with biological agents plus chemotherapy, while a significant PFS improvement was observed only for bevacizumab and cetuximab. The overall impact of these agents on patient survival was not as great as expected, probably because the molecular basis of this illness needs to be better understood so that treatment can be more appropriately tailored.
    Cancer Treatment Reviews 06/2014; 40(5). DOI:10.1016/j.ctrv.2014.01.003 · 7.59 Impact Factor
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    • "Targeted therapy with poly(ADP ribose) polymerase inhibitors (PARPi), which are novel agents selective for cancers with dysfunctional homologous recombination DNA repair (HRR) (Bryant et al, 2005; Farmer et al, 2005), depends on the identification of HRR dysfunction. PARPi have promising anticancer activity with minimal toxicity in clinical trials in patients carrying mutations in BRCA1/2, which encode key proteins in the HRR pathway (Fong et al, 2009; O'Shaughnessy et al, 2011; De Bono et al, 2013; Kaufman et al, 2013; Ledermann et al, 2013; Michie et al, 2013). However, HRR is a multifactorial process, and screening for BRCA mutations alone is likely to underestimate the proportion of cancers with HRR defects that could potentially benefit from PARPi therapy (McCabe et al, 2006). "
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    ABSTRACT: Background: Patients with malignant pleural effusions (MPEs) generally have advanced disease with poor survival and few therapeutic options. Cells within MPEs may be used to stratify patients for targeted therapy. Targeted therapy with poly(ADP ribose) polymerase inhibitors (PARPi) depends on identifying homologous recombination DNA repair (HRR)-defective cancer cells. We aimed to determine the feasibility of assaying HRR status in MPE cells. Methods: A total of 15 MPE samples were collected from consenting patients with non-small-cell lung cancer (NSCLC), mesothelioma and ovarian and breast cancer. Primary cultures were confirmed as epithelial by pancytokeratin, and HRR status was determined by the detection of γH2AX and RAD51 foci following a 24-h exposure to rucaparib, by immunofluorescence microscopy. Massively parallel next-generation sequencing of DNA repair genes was performed on cultured MPE cells. Results: From 15 MPE samples, 13 cultures were successfully established, with HRR function successfully determined in 12 cultures. Four samples – three NSCLC and one mesothelioma – were HRR defective and eight samples – one NSCLC, one mesothelioma, one sarcomatoid, one breast and four ovarian cancers – were HRR functional. No mutations in DNA repair genes were associated with HRR status, but there was probable loss of heterozygosity of FANCG, RPA1 and PARP1. Conclusions: HRR function can be successfully detected in MPE cells demonstrating the potential to stratify patients for targeted therapy with PARPi.
    British Journal of Cancer 05/2014; 111(1). DOI:10.1038/bjc.2014.261 · 4.84 Impact Factor
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