Iniparib plus chemotherapy in metastatic triple-negative breast cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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]; ClinicalTrials.gov number, NCT00540358.).

Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types.

Poly (ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair and is implicated in pathways of tumorigenesis. PARP inhibitors have gained recent attention as rationally designed therapeutics for the treatment of several malignancies, particularly those associated with dysfunctional DNA repair pathways, including triple-negative breast cancer (TNBC). We investigated the PARP1 gene expression profile in surgical samples from more than 8,000 primary malignant and normal human tissues. PARP1 expression was found to be significantly increased in several malignant tissues, including those isolated from patients with breast, uterine, lung, ovarian, and skin cancers, and non-Hodgkin's lymphoma. Within breast infiltrating ductal carcinoma (IDC) samples tested, mean PARP1 expression was significantly higher relative to normal breast tissue, with over 30% of IDC samples demonstrating upregulation of PARP1, compared with 2.9% of normal tissues. Because of known DNA repair defects, including BRCA1 dysfunction, associated with TNBC, exploration of PARP1 expression in breast cancers related to expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) led to the observation that negative expression of any of the 3 receptors was associated with upregulation of PARP1 expression, compared with receptor-positive tissues. To validate these observations, an independent set of breast adenocarcinomas was evaluated and demonstrated >2-fold upregulation of PARP1 in approximately 70% of primary breast adenocarcinomas, including TNBC, compared with syngeneic nonmalignant breast tissues. Immunohistochemistry (IHC) showed that upregulation of the PARP1 gene was consistent with increased protein expression in TNBC. These analyses suggest a potential biological role for PARP1 in several distinct malignancies, including TNBC. Further investigation of PARP1 as a biomarker for the therapeutic activity of PARP inhibitor-based therapy is warranted.

Oral poly(ADP-ribose) polymerase-1 inhibitor BSI-401 has antitumor activity and synergizes with oxaliplatin against pancreatic cancer, preventing acute neurotoxicity.

PURPOSE: Development of novel agents and drug combinations are urgently needed for treatment of pancreatic cancer. Oxaliplatin belongs to an important class of DNA-damaging organoplatinum agents, useful in pancreatic cancer therapy. However, increased ability of cancer cells to recognize and repair DNA damage enables resistance to these agents. Poly (ADP ribose) polymerase-1 is a sensor of DNA damage with key roles in DNA repair. Here, we report the therapeutic activity of the poly (ADP ribose) polymerase-1 inhibitor BSI-401, as a single agent and in combination with oxaliplatin in orthotopic nude mouse models of pancreatic cancer, and its effect on oxaliplatin-induced acute neurotoxicity. EXPERIMENTAL DESIGN: We determined in vitro the effect of BSI-401 and its synergism with oxaliplatin on the growth of pancreatic cancer cells. Activity of different dosages of parenteral and oral BSI-401, alone and in combination with oxaliplatin, was evaluated in orthotopic nude mouse models with luciferase-expressing pancreatic cancer cells. The effect of BSI-401 in preventing oxaliplatin-induced acute cold allodynia was measured in rats using a temperature-controlled plate. RESULTS: BSI-401 alone and in synergism with oxaliplatin significantly inhibited the growth of pancreatic cancer cells in vitro. In nude mice, i.p. [200 mg/kg once a week (QW) x 4] and oral [400 mg/kg days 1-5 of each week (QD5 + R2) x 4] administration of BSI-401 significantly reduced tumor burden and prolonged survival (46 versus 144 days, P = 0.0018; 73 versus 194 days, P = 0.0017) compared with no treatment. BSI-401 combined with oxaliplatin had potent synergistic antitumor activity (46 versus 132 days, P = 0.0063), and significantly (P = 0.0148) prevented acute oxaliplatin-induced neurotoxicity. CONCLUSIONS: BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer.

The Impact of Biotechnology on Surgery in the 1990s.

Medical practice is generally divided into medical and surgical sub-groups based on therapeutic approaches. Physicians in medically oriented specialities, such as internal medicine and paediatrics, traditionally rely largely on drugs to influence the course of disease while general and speciality surgeons usually have some type of surgical procedure at the core of their discipline. (Obviously, these are gross generalisations; surgeons have long been at the forefront of the use of antibiotics and nutritional support.) But these distinctions are becoming increasingly blurred as cardiologists guide catheters into ever smaller vessels and gastroenterologists send fibreoptic scopes into yet other ducts and snare would-be cancers from ever more remote parts of the gut. The recent explosion in scientific knowledge will continue to fuel this trend. Greater understanding of the fundamental mechanisms of disease inevitably leads to a simpler approach to diagnosis and therapy.