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Clinical Cancer Research : An Official... Aug 2016BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three...
PURPOSE
BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).
EXPERIMENTAL DESIGN
We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy.
RESULTS
In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials.
CONCLUSIONS
HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.
Topics: Allelic Imbalance; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Female; Genes, BRCA1; Genes, BRCA2; Homologous Recombination; Humans; Loss of Heterozygosity; Mutation; Neoplasm Staging; Odds Ratio; Platinum; Prognosis; Telomere; Treatment Outcome; Triple Negative Breast Neoplasms
PubMed: 26957554
DOI: 10.1158/1078-0432.CCR-15-2477 -
Pharmacological Research Jun 2018In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop... (Review)
Review
In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2 BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.
Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Drug Delivery Systems; Humans
PubMed: 29604436
DOI: 10.1016/j.phrs.2018.03.021 -
The Oncologist Mar 2023Iniparib (BSI-201), a novel anticancer agent thought to have poly(ADP-ribose) polymerase (PARP) inhibitory activity and synergy with both gemcitabine and carboplatin...
BACKGROUND
Iniparib (BSI-201), a novel anticancer agent thought to have poly(ADP-ribose) polymerase (PARP) inhibitory activity and synergy with both gemcitabine and carboplatin (GC) was evaluated in 2 cohorts with GC.
METHODS
Parallel multicenter, single-arm, phase II studies using a Simon two-stage design. Eligible patients had a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-sensitive (≥6 months [mo]) or -resistant disease (relapse 2-6 mo post-platinum). Carboplatin (AUC 4 IV day 1), gemcitabine (1000 mg/m2 IV days 1 and 8), and iniparib (5.6 mg/kg IV days 1, 4, 8, and 11) were given on a 21-day cycle.
RESULTS
The overall response rate (ORR RECIST 1.0) in platinum sensitive disease was 66% (95% CI, 49-80) with a higher response rate in the 15 pts with germline BRCA mutations (gBRCAmut) (73%). Median PFS was 9.9 (95% CI, 8.2-11.3) months. In the platinum resistant population the ORR was 26% (95% CI, 14-42), however in the 11 pts for whom BRCA mutation was present, the best overall response was PR in 5 (46%). Median PFS was 6.8 months (range, 5.7-7.7 months). Notably, among the 17 CA-125-response-evaluable patients who did not achieve tumor response, 7 (41.2%) patients had a CA125 response, and 93% has clinical benefit (CR + PR + SD). The GCI combination was generally well tolerated despite a high incidence of thrombocytopenia and neutropenia, with no new toxicities.
CONCLUSIONS
Given the subsequent lack of efficacy demonstrated for iniparib in breast cancer, these are studies of GC and demonstrate a higher than traditionally appreciated activity in patients with platinum-sensitive and -resistant recurrent ovarian cancer, especially in patients that harbor a BRCA mutation, resetting the benchmark for efficacy in phase II trials. (ClinicalTrials.gov Identifiers: NCT01033292 & NCT01033123).
Topics: Humans; Female; Gemcitabine; Carboplatin; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Treatment Outcome; Disease-Free Survival; Neutropenia; Neoplasm Recurrence, Local; Recurrence; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36718018
DOI: 10.1093/oncolo/oyac275 -
Clinical Cancer Research : An Official... Jan 2019Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard...
PURPOSE
Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM).
PATIENTS AND METHODS
Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib ( = 5) was followed by an efficacy study ( = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide).
RESULTS
The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17-24] and the HR was 0.44 (95% CI, 0.35-0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia.
CONCLUSIONS
Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.
Topics: Benzamides; Brain Neoplasms; Chemoradiotherapy; Combined Modality Therapy; Female; Glioblastoma; Humans; Male; Middle Aged; Temozolomide; Treatment Outcome
PubMed: 30131387
DOI: 10.1158/1078-0432.CCR-18-0110 -
PloS One 2016Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their... (Clinical Trial)
Clinical Trial Comparative Study
Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV). Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT) and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD) of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within the comparative oncology approach are evident from this successfully executed comparative clinical trial and exemplify the value of such studies in drug development.
Topics: Animals; Antineoplastic Agents; Benzamides; Breast Neoplasms; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Male; Maximum Tolerated Dose; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms
PubMed: 26866698
DOI: 10.1371/journal.pone.0149194 -
Journal of the National Cancer Institute Dec 2011As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control... (Review)
Review
As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control arm to "crossover" and receive the experimental therapy after disease progression. Although some researchers worry that allowing such crossover may abolish gains in progression-free survival in the experimental arm, the possibility that crossover might inadvertently benefit the experimental arm has not been addressed. In clinical trials in which the experimental agent has little or no intrinsic activity and is used to modulate an active combination, such crossover might negatively affect the overall survival of the control arm. Because resistance to the active combination--manifested as disease progression--has occurred, the likelihood of benefit from adding the experimental drug is reduced. Consequently, patients who were randomly assigned to the control arm continue to receive the now inactive combination after crossover, whereas patients in the experimental arm who discontinue study participation may seek out potentially effective salvage regimens. This difference in subsequent therapies may confer an advantage to the experimental arm that is manifested as gains beyond those achieved in progression-free survival, gains that occur not because the experimental therapy induced a change in tumor biology that persists beyond treatment discontinuation but because the control arm suffers by continuing to receive a therapy on which their tumor is progressing. Such an outcome may explain the recently reported trial results for iniparib in triple-negative breast cancer. Given that allowing patients in the control arm to receive the experimental agent may confound interpretation of overall survival, such crossover should not be used indiscriminately, especially if the experimental agent has little or no intrinsic activity.
Topics: Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Breast Neoplasms; Confounding Factors, Epidemiologic; Cross-Over Studies; Disease Progression; Disease-Free Survival; Female; Humans; Indoles; Interferon-gamma; Neoplasms; Patient Selection; Pyrroles; Randomized Controlled Trials as Topic; Research Design; Sunitinib; Treatment Outcome
PubMed: 22045362
DOI: 10.1093/jnci/djr386 -
Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis.Core Evidence 2014To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in... (Review)
Review
OBJECTIVE
To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in patients with metastatic triple-negative breast cancer (TNBC).
METHODS
Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS). We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR) or risk ratio, with their corresponding 95% confidence intervals (95% CIs).
RESULTS
The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib). PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51-0.75; P<0.00001). Also, PFS was higher in one study that tested Bev plus CT combination in previously treated patients (HR 0.49, 95% CI 0.33-0.74; P=0.0006). Sor plus CT was also tested as first-line and second-line treatments. The pooled data of PFS favored the combination CT plus Sor (fixed effect, HR 0.69, 95% CI 0.49-0.98; P=0.04). Comparisons of iniparib plus CT also had a better PFS than CT alone (fixed effect, HR 0.75, 95% CI 0.62-0.90; P=0.002).
CONCLUSION
Targeted therapy, when associated with conventional CT, demonstrated gains in the PFS of patients with TNBC.
PubMed: 24476748
DOI: 10.2147/CE.S52197 -
The New England Journal of Medicine Jan 2011Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose)... (Randomized Controlled Trial)
Randomized Controlled Trial
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.).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast Neoplasms; Carboplatin; Cross-Over Studies; Deoxycytidine; Female; Humans; Kaplan-Meier Estimate; Neoplasm Metastasis; Poly(ADP-ribose) Polymerase Inhibitors; Survival Analysis; Gemcitabine
PubMed: 21208101
DOI: 10.1056/NEJMoa1011418 -
Medicine Nov 2017Triple-negative breast cancer (TNBC) lacks the expression of the estrogen receptor, progesterone receptor, and receptor tyrosine-protein kinase erbB-2 (HER2/neu),... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Triple-negative breast cancer (TNBC) lacks the expression of the estrogen receptor, progesterone receptor, and receptor tyrosine-protein kinase erbB-2 (HER2/neu), which renders hormone-related endocrine and targeted therapy essentially futile.
OBJECTIVE
We performed a meta-analysis to assess the effects of antitumor regimens in the treatment of TNBC patients.
METHODS
We searched electronic databases, including PubMed, Embase, and the Cochrane Library, through January 2017 using the following keywords: "triple negative breast cancer," "TNBC," and "random*" without language restrictions. The major outcome in the present analysis was the overall response rate (ORR), and the secondary outcomes were progression-free survival (PFS) and overall survival (OS). A network meta-analysis and multilevel mixed-effects logistic regression were used to compare antitumor regimens.
RESULTS
We included 35 articles assessing a total of 8476 TNBC patients in our systematic review. The regimen of Bevacizumab, Carboplatin, and Paclitaxel (78.2%) was the most likely to improve the ORR in TNBC patients, followed by EndoTAG-1 and Paclitaxel (69.7%), Carboplatin and Paclitaxel (65.0%), and Bevacizumab and Paclitaxel (61.8%). In the patients without metastasis, the regimen of Bevacizumab, Carboplatin, and Paclitaxel (74.9%) remained the most likely to improve the ORR. We could not analyze the results for patients with metastasis or outcomes of PFS and OS because no >4 regimens formed a network. In the regression analysis, Bevacizumab (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.43-2.05; P < .001) and Carboplatin (OR, 2.07; 95% CI, 1.62-2.64; P < .001) correlated with superior ORR outcome, and Iniparib (OR, 1.51; 95% CI, 1.11-2.07; P = .009) correlated with superior OS outcome.
CONCLUSION
The regimen including Bevacizumab, Carboplatin, and Paclitaxel was the most likely to improve the ORR in TNBC patients and in advanced metastatic TNBC patients. The administration of Bevacizumab and Carboplatin provided greater benefit toward improved patient ORR.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bevacizumab; Carboplatin; Female; Humans; Paclitaxel; Randomized Controlled Trials as Topic; Survival Analysis; Triple Negative Breast Neoplasms
PubMed: 29137021
DOI: 10.1097/MD.0000000000008389 -
Breast (Edinburgh, Scotland) Oct 2011Epithelial carcinomas in general arise as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone within the tissues of the... (Review)
Review
Epithelial carcinomas in general arise as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone within the tissues of the primary organ of origin. In the last two decades genome caretakers, which function in key areas of DNA damage response, have been recognized as important tumour suppressor genes. Inactivating mutations in these genes occur both as germline and/or somatic mutations with increasing evidence of epigenetic silencing as an additional cause of loss of function. In any event, loss of function in a tumour cell pre-cursor clone leads to accelerated mutation acquisition and underpins the aetiology of the tumour. With increasing understanding of the complex network that is the DNA damage response, signaling pathways already recognized to be central to the establishment of the cancer phenotype are gaining additional roles as controllers of DNA repair. This has relevance to identification of wider populations of patients with tumours susceptible to approaches that target DNA repair deficiency. These have classically been with DNA damaging chemotherapy but the recently developed small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target tumour deficiencies in DNA repair as well sensitizing to DNA damaging therapeutics such as radiation and chemotherapy. Early phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, olaparib, veliparib, iniparib and MK4827. The results of the first phase II trials exploring monotherapy PARP inhibitor strategies, which are based on revisiting the concept of synthetic lethality, have emerged and are reviewed herein. The clinical trials that have or are exploring combinations with DNA damaging therapy in these contexts are discussed with particular reference to breast cancer, as are biomarkers that have been proposed and are being investigated to develop optimal drug schedule and patient selection criteria for these DNA repair targeting approaches.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; DNA Repair; DNA Repair Enzymes; Disease-Free Survival; Early Diagnosis; Female; Humans; Molecular Targeted Therapy; Neoplasm Staging; Patient Safety; Patient Selection; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Prognosis; Risk Assessment; Survival Analysis; Treatment Outcome
PubMed: 22015278
DOI: 10.1016/S0960-9776(11)70288-0