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Proceedings (Baylor University. Medical Center) 04/2011; 24(2):86-8.
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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]; ClinicalTrials.gov number, NCT00540358.).
New England Journal of Medicine 01/2011; 364(3):205-14. · 53.30 Impact Factor
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ABSTRACT: An independent Adjuvant Cardiac Review and Evaluation Committee (ACREC) systematically reviewed cases of symptomatic heart failure events to uniformly define the cardiac event rate across two large trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31 and North Central Cancer Treatment Group [NCCTG] N9831) that assessed the addition of trastuzumab to standard adjuvant chemotherapy.
The committee was composed of six independent oncologists and cardiologists. A retrospective review of patients with a cardiac event was performed by the primary investigators of the trials. The ACREC prospectively established criteria for determining a symptomatic heart failure event. Recovery status was determined from documented resolution of signs and symptoms. Potential risk factors were also assessed.
Medical records for a total of 173 patients were reviewed: 40 in the chemotherapy-alone arm and 133 in the trastuzumab arm. Trastuzumab-treated patients had a 2.0% incidence of symptomatic heart failure events compared with 0.45% in the chemotherapy-alone arm. Complete or partial recovery was observed in 86.1% of trastuzumab-treated patients with symptomatic heart failure events. Of five patients who died, only one patient had received trastuzumab. Independent predictors for cardiac events were age older than 50 years, a low ejection fraction at the start of paclitaxel treatment, and trastuzumab treatment.
The incidence of symptomatic heart failure events is 2.0% in patients treated with adjuvant trastuzumab, and the majority of these patients recover with appropriate treatment.
Journal of Clinical Oncology 07/2010; 28(21):3416-21. · 18.37 Impact Factor
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Stephen Jones,
Frankie Ann Holmes,
Joyce O'Shaughnessy,
Joanne L Blum,
Svetislava J Vukelja,
Kristi J McIntyre, John E Pippen,
James H Bordelon,
Robert L Kirby,
John Sandbach,
William J Hyman,
Donald A Richards,
Robert G Mennel,
Kristi A Boehm,
Wally G Meyer,
Lina Asmar,
Daniel Mackey,
Stefan Riedel,
Hyman Muss,
Michael A Savin
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ABSTRACT: We previously reported that four cycles of docetaxel/cyclophosphamide (TC) produced superior disease-free survival (DFS) compared with four cycles of doxorubicin/cyclophosphamide (AC) in early breast cancer. Older women are under-represented in adjuvant chemotherapy trials. In our trial 16% of patients were > or = 65 years. We now report 7-year results for DFS and overall survival (OS) as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity.
Patients were randomly assigned to receive either four cycles of standard-dose AC (60/600 mg/m(2); n = 510), or TC (75/600 mg/m(2); n = 506), administered by intravenous infusion every 3 weeks.
The median age in women younger than 65, was 50 years (range, 27 to 64) and for women > or = 65 was 69 years (range, 65 to 77). Baseline characteristics in the two age subgroups were generally well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in DFS between TC and AC was significant (81% TC v 75% AC; P = .033; hazard ratio [HR], 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P = .032; HR, 0.69; 95% CI, 0.50 to 0.97). TC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER-2 status and treatment. Older women experienced more febrile neutropenia with TC and more anemia with AC.
With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in both older and younger patients.
Journal of Clinical Oncology 03/2009; 27(8):1177-83. · 18.37 Impact Factor
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ABSTRACT: Nanoparticle albumin-bound paclitaxel, a solvent-free, albumin-bound paclitaxel, demonstrated antitumor activity in patients with taxane-naive metastatic breast cancer (MBC). We examined albumin-bound paclitaxel (100 mg/m2 or 125 mg/m2 administered weekly) to determine the antitumor activity in patients with MBC whose disease progressed despite conventional taxane therapy.
Women with MBC that was previously treated with taxanes were eligible for participation. Taxane failure was defined as metastatic disease progression during taxane therapy or relapse within 12 months of adjuvant taxane therapy. Primary objectives were response rates (RRs) and the safety/tolerability of albumin-bound paclitaxel.
Women were treated with albumin-bound paclitaxel 100 mg/m2 (n = 106) or 125 mg/m2 (n = 75) on days 1, 8, and 15 of a 28-day cycle. Response rates were 14% and 16% for the 100-mg/m2 and 125-mg/m2 cohorts, respectively; an additional 12% and 21% of patients, respectively, had stable disease (SD) > or = 16 weeks. Median progression-free survival times were 3 months at 100 mg/m2 and 3.5 months at 125 mg/m2; median survival times were 9.2 months and 9.1 months, respectively. Survival was similar for responding patients and those with SD. No severe hypersensitivity reactions were reported. Patients who developed treatment-limiting peripheral neuropathy typically could be restarted on a reduced dose of albumin-bound paclitaxel after a 1-2-week delay. Grade 4 neutropenia occurred in < 5% of patients.
Albumin-bound paclitaxel 100 mg/m2 given weekly demonstrated the same antitumor activity as albumin-bound paclitaxel 125 mg/m2 weekly and a more favorable safety profile in patients with MBC that had progressed with previous taxane therapy. Survival of patients with SD > or = 16 weeks was similar to that of responders.
Clinical Breast Cancer 12/2007; 7(11):850-6. · 2.38 Impact Factor
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Yun Gong,
Kai Yan,
Feng Lin,
Keith Anderson,
Christos Sotiriou,
Fabrice Andre,
Frankie A Holmes,
Vicente Valero,
Daniel Booser, John E Pippen,
Svetislava Vukelja,
Henry Gomez,
Jaime Mejia,
Luis J Barajas,
Kenneth R Hess,
Nour Sneige,
Gabriel N Hortobagyi,
Lajos Pusztai,
W Fraser Symmans
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ABSTRACT: Gene expression microarrays are being used to develop new prognostic and predictive tests for breast cancer, and might be used at the same time to confirm oestrogen-receptor status and ERBB2 status. Our goal was to establish a new method to assign oestrogen receptor and ERBB2-receptor status to breast carcinoma based on mRNA expression measured using Affymetrix U133A gene-expression profiling.
We used gene expression data of 495 breast cancer samples to assess the correlation between oestrogen receptor (ESR1) and ERBB2 mRNA and clinical status of these genes (as established by immunohistochemical [IHC] or fluorescence in-situ hybridisation [FISH], or both). Data from 195 fine-needle aspiration (FNA) samples were used to define mRNA cutoff values that assign receptor status. We assessed the accuracy of these cutoffs in two independent datasets: 123 FNA samples and 177 tissue samples (ie, resected or core-needle biopsied tissues). Profiling was done at two institutions by use of the same platform (Affymetrix U133A GeneChip). All data were uniformly normalised with dCHIP software.
ESR1 and ERBB2 mRNA levels correlated closely with routine measurements for receptor status in all three datasets. Spearman's correlation coefficients ranged from 0.62 to 0.77. An ESR1 mRNA cutoff value of 500 identified oestrogen-receptor-positive status with an overall accuracy of 90% (training set), 88% (first validation set), and 96% (second validation set). An ERBB2 mRNA threshold of 1150 identified ERBB2-positive status with the overall accuracy of 93% (training set), 89% (first validation set), and 90% (second validation set). Reproducibility of mRNA measurements in 34 replicate experiments was high (correlation coefficient 0.975 for ESR1, 0.984 for ERBB2).
Amounts of ESR1 and ERBB2 mRNA as measured by the Affymetrix GeneChip reliably and reproducibly establish oestrogen-receptor status and ERBB2 status, respectively.
The Lancet Oncology 04/2007; 8(3):203-11. · 22.59 Impact Factor
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Stephen E Jones,
Michael A Savin,
Frankie Ann Holmes,
Joyce A O'Shaughnessy,
Joanne L Blum,
Svetislava Vukelja,
Kristi J McIntyre, John E Pippen,
James H Bordelon,
Robert Kirby,
John Sandbach,
William J Hyman,
Pankaj Khandelwal,
Angel G Negron,
Donald A Richards,
Stephen P Anthony,
Robert G Mennel,
Kristi A Boehm,
Walter G Meyer,
Lina Asmar
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ABSTRACT: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS).
Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and December 1999, 1,016 patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively; n = 510) or TC (75 and 600 mg/m2, respectively; n = 506), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy.
Both treatment groups (TC and AC) were well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was significantly superior for TC compared with AC (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = .015). Overall survival rates for TC and AC were 90% and 87%, respectively (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the TC arm; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure.
At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.
Journal of Clinical Oncology 01/2007; 24(34):5381-7. · 18.37 Impact Factor
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ABSTRACT: We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy.
Clinical Breast Cancer 07/2004; 5(2):142-7. · 2.38 Impact Factor
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ABSTRACT: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR).
This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity.
Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study.
Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.
Journal of Clinical Oncology 03/2003; 21(6):1007-14. · 18.37 Impact Factor
