Showing papers by "Eastern Cooperative Oncology Group published in 2009"

Adjuvant Chemotherapy in Older Women with Early-Stage Breast Cancer

Abstract: Background Older women with breast cancer are underrepresented in clinical trials, and data on the effects of adjuvant chemotherapy in such patients are scant. We tested for the noninferiority of capecitabine as compared with standard chemotherapy in women with breast cancer who were 65 years of age or older. Methods We randomly assigned patients with stage I, II, IIIA, or IIIB breast cancer to standard chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide plus doxorubicin) or capecitabine. Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor–positive tumors. A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients. The primary end point was relapse-free survival. Results When the 600th patient was enrolled, the probability that, with longer follow-up, capecitabine therapy was highly likely to be inferior to standard chemotherapy met a prescribed level, and enrollment was discontinued. After an additi...

Bortezomib in Relapsed or Refractory Waldenström's Macroglobulinemia

Abstract: Bortezomib is a proteasome inhibitor that induces apoptosis in primary Waldenstrom's macroglobulinemia (WM) cells and WM cell lines. To date, 3 clinical trials of single-agent bortezomib in WM have been published. Of the 64 patients pooled from these studies (most with relapsed/refractory disease), a 25% or greater reduction of IgM was achieved in 78%-85%. Responses were rapid in onset, suggesting a role for bortezomib in the management of hyperviscosity or other settings where rapid IgM reduction is indicated. Neuropathy appears more severe and frequent in WM than in myeloma or other indolent lymphomas treated with bortezomib. Bortezomib-based combination therapies, with consideration for attenuated or intermittent dosing of bortezomib to minimize neuropathy, are under investigation.

Relationship between Topoisomerase 2A RNA Expression and Recurrence after Adjuvant Chemotherapy for Breast Cancer

Abstract: PURPOSE: To perform an exploratory analysis of the relationship between gene expression and recurrence in operable hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-normal breast cancer patients treated with adjuvant doxorubicin-containing chemotherapy. EXPERIMENTAL DESIGN: RNA was extracted from archived tumor samples derived from 378 patients with stage I to III HR-positive, HER2-normal breast cancer and analyzed by reverse transcription-PCR for a panel of 374 genes, including the 21-gene recurrence score (RS). Patients were randomized to receive adjuvant doxorubicin plus cyclophosphamide or docetaxel in trial E2197, with no difference in recurrence seen in the treatment arms. All available recurrent cases were selected plus a nonrecurrent cohort. Cox proportional hazard models were used to identify relationships between gene expression and recurrence. RESULTS: TOP2A expression exhibited the strongest association with increased recurrence risk (P = 0.01), and was significantly associated with recurrence (P = 0.008) in a multivariate analysis adjusted for clinicopathologic features. Elevated TOP2A expression above the median was associated with a 2.6-fold increase (95% confidence interval, 1.3-5.2; P = 0.008) in risk of recurrence if the RS was <18, and a 2.0-fold increase (95% confidence interval, 1.2-3.2, P = 0.003) if there was an intermediate RS of 18 to 30. CONCLUSIONS: In patients with HR-positive, HER2-normal breast cancer, a population known to have a low incidence of TOP2A gene alterations thought to be predictive of anthracycline benefit, there is a range of TOP2A RNA expression that is strongly associated with recurrence after adjuvant anthracyclines, which provides information complementary to RS, indicating that it merits further evaluation as a prognostic and predictive marker. (Clin Cancer Res 2009;15(24):7693-700).

Recombinant interferon-α2b added to oral cyclophosphamide either as induction or maintenance in treatment-naive follicular lymphoma: final analysis of CALGB 8691

Abstract: Recombinant interferon alpha-2b (IFN-alpha2) has direct and indirect antiproliferative effects in lymphoma, and may augment cytotoxicity when combined with chemotherapy. CALGB 8691 is a randomized study of daily oral cyclophosphamide (CPA) at 100 mg/m2 with or without IFN-alpha2 at 2 x 106 IU/m2 three times per week, followed by a second randomization between IFN-alpha2 maintenance (2 x 106 IU/m2 three times weekly) versus observation in treatment-naive patients with follicular lymphoma (FL). Five hundred eighty-one patients were randomized to either CPA (n = 293) or CPA plus IFN-alpha2 (n = 288). One hundred five responding patients were randomized to observation and 99 to maintenance IFN-alpha2. With a median follow-up of 11.5 years, the median event-free and overall survival (OS) for CPA induction alone were 2.5 years (95% CI 2.2, 3.0) and 9 years (95% CI 7.7, 10.2), compared to 2.4 years (95% CI 2.1, 3.1) and 8.4 years (95% CI 7.5, 11.1) for the combination arm (p = NS). Patients with a partial response (PR) and randomized to observation had the worst outcome (event-free survival (EFS) 1.8 years versus 3.9 years; p = 0.002). Patients with a PR randomized to IFN-alpha2 had a similar EFS to compared to patients with complete response (CR), but this did not translate into a survival advantage. Myelosuppression was increased in IFN-alpha2-containing arms. Despite the small benefit in EFS in patients with PR randomized to IFN-alpha2 maintenance, we conclude that the addition of low dose IFN-alpha2 did not significantly improve the response rate, duration of response, event-free, or OS obtained with single-agent daily oral CPA in patients with previously untreated FL.

Black Race Is Associated with a Worse Outcome in Patients with Hormone Receptor Positive, HER2-Normal Breast Cancer Treated with Adjuvant Chemohormonal Therapy.

Abstract: Background: Black race has been associated with worse outcome in operable breast cancer, which has been attributed to a higher incidence of “triple negative” (TN) disease, disparities in care, and comorbidities. We evaluated the effect of black race on outcomes by hormone receptor (HR) and HER2 expression in patients treated with standard adjuvant therapy in trial E1199 (N Eng J Med 2008; 358: 1663)Methods: This study included 4950 eligible women with axillary lymph node positive or high-risk node-negative breast cancer, all of whom received doxorubicin and taxane-containing chemotherapy, plus standard endocrine therapy if HR-positive (but not trastuzumab if HER2-positive). Endocrine therapy included tamoxifen alone (38%) or followed by an AI (57%), or an AI alone (5%). The effect of black race was evaluated using Cox9s proportional hazards model method (1) as a single variable, (2) in a model that included race, phenotype (TN vs. HER2-pos vs. HR-pos, HER2-neg/unknown [HR+]) and their interaction, and (3) in a multivariate model considering age, tumor size, number of positive lymph nodes, body mass index (BMI), and treatment arm. The stepwise method was used for model selection. The endpoints evaluated included disease free survival (DFS) and overall survival (OS). Results are expressed as hazard ratios (HR), with a HR > 1 indicating a worse outcome for black race. All p-values are two sided.Results: Of 4950 eligible patients, 416 (8.4%) were black. Black race was associated with significantly higher rates of TN disease (34% vs. 19%; p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 37.

GRB7-dependent pathways are potential therapeutic targets in triple-negative breast cancer.

Abstract: CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #25 Background: Breast cancer lacking expression of the estrogen and progesterone receptor and overexpression of HER2/ neu (ie, "triple-negative” disease) accounts for about 10-15% of all breast cancer and is characterized by a higher risk of recurrence, early recurrence, resistance to cytotoxic therapy, and lack of any specific targeted therapy. Methods: We extracted RNA from primary tumor samples of 246 patients with stage I-III triple-negative breast cancer (confirmed in a central lab) treated with 4 cycles of adjuvant doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) or docetaxel (60 mg/m2) who were enrolled on trial E2197, and correlated RNA expression (by quantitative RT-PCR using a panel of 371 rationally selected genes) with recurrence. There was no difference in recurrence between the two treatment arms in the entire study population, nor in the 246 patients in this analysis (of whom 59 recurred) after a median followup of 76 months. Results: Higher expression of GRB7 was the only gene significantly associated with an increased risk of recurrence (nominal p value 0.0000853, Korn's adjusted p value controlling false discovery at 10% (KP10) p=0.0359), but did not correlate with any clinicopathologic features except age (low expression associated with age > 65 years, p=0.03). In a Cox proportional hazards model adjusted for age, nodal status, tumor size, and grade, higher GRB7 expression was associated with an increased risk of recurrence when evaluated as a continuous variable (hazard ratio 3.41; p = 0.001) or as a dichotomous variable (hazard ratio 2.24 above vs. below median; p=0.006). The 5-year recurrence rates were 10.5% (95% C.I.7.8%, 14.1%) in the low and 20.4% (95% C.I. 16.5%, 25.0%) in the high GRB7 groups. There were only six genes whose expression correlated with GRB7 (r> 0.4), including ERBB2 (r=0.70), DDR1 (discoidin domain receptor tyrosine kinase 1; r=0.53), KRT19 (keratin 19; r=0.49), ERBB3 (r=0.48), GPR56 (G protein-coupled receptor 56; r=0.48) and PHB (prohibitin; r=0.42). Conclusions: GRB7 is a calmodulin-binding protein which has an SH2 (Src homology 2) domain that binds to phosphorylated tyrosine residues and other specific protein targets, and which plays a critical role in signaling (EGFR, HER2), motility (eprhins), migration (focal adhesion kinase), and cell-matrix/cell-cell interactions (integrins). Higher GRB7 RNA expression is associated with a significantly higher risk of recurrence in triple-negative breast cancer, indicating that GRB7 or GRB7 -dependent pathways are potential therapeutic targets in triple-negative disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 25.

Gene Expression Profiling of Phenotypically-Defined Hormone-Receptor Positive Breast Cancer: Evidence for Increased Transcriptional Activity of the Insulin Growth Factor Receptor Pathway and Other Pathways.

Abstract: Background: Approximately 70% of all breast cancers are hormone receptor (HR)-positive tumors that are sensitive to endocrine therapy, but some patients have recurrence despite adjuvant endocrine therapy. We performed an exploratory analysis of gene expression in HR-pos operable breast cancer in order to identify potential novel therapeutic targets and biomarkers associated with recurrence. Methods: RNA was extracted from primary tumor samples obtained from 776 patients with stage I-III breast cancer treated with adjuvant chemohormonal therapy in trial E2197 (JCO 2008; 26: 4092-4099), of whom 458 had HR-pos disease (defined in a central lab; JCO 2008; 26: 2473). We evaluated RNA expression patterns (by quantitative RT-PCR using a panel of 371 rationally selected genes) in HR-pos cases compared with the HR-neg cases using weighted T statistics, and determined which genes in the HR-pos, HER2-neg group were associated with recurrence (using Cox proportional hazards model score test, Korn9s adjusted P value Results: The top 10 genes exhibiting significantly higher expression in the HR-pos group (p≤ 6.17e-160) included ESR1 plus 5 estrogen regulated genes, confirming our approach of evaluating gene expression in phenotypically-defined subsets. Other pathways that exhibited higher expression in the HR-pos group (among the 40 top genes with higher expression, p IRS1, IGFR1, IGFB2 ), Ras ( RhoB, RhoC, RAB27B, GGPS1 ), and HER pathways ( ERBB2, ERBB3, ERBB4 ), and other genes involved in apoptosis ( BCL2, BCL2L1, BAG1, NME6, BBC3 ), signaling ( MAPK3, SEMA3F, RXRA ), mismatch repair ( MSH3 ), cell cycle regulation ( CCND1 ), stress response ( HSPB1 ), and tumor suppressor genes ( TP53BP1, APC ). These patterns were similar in HER2-pos cases. Pathway analysis (Ingenuity) revealed substantial interconnectivity among these genes, especially between IGFR1 , ERB2/3/4 , MAPK3 , BCL2 , and CCND1 , but not RhoB/RhoC . Genes for which increased expression was associated with increased recurrence included those associated with proliferation ( TOP2A, AURKB, PLK1 ) and apoptosis ( BIRC5 - survivin). Conclusions: This exploratory analysis reveals several pathways that exhibit higher transcriptional expression in HR-pos disease, some of which are also associated with a higher risk of recurrence, suggesting that they may be potential therapeutic targets. This provides rationale for testing agents currently available in the clinic that inhibit the IGF and other pathways. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5165.