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Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer.

ABSTRACT: We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial.Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status.With a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17).pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel.

SUBMITTER: Yang SX

PROVIDER: S-EPMC2903333 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer.

Yang Sherry X SX Costantino Joseph P JP Kim Chungyeul C Mamounas Eleftherios P EP Nguyen Dat D Jeong Jong-Hyeon JH Wolmark Norman N Kidwell Kelley K Paik Soonmyung S Swain Sandra M SM

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100517 18

<h4>Purpose</h4>We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial.<h4>Patients and methods</h4>Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned ...[more]

PMID: 20479407

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Project description:BackgroundThe recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.MethodsIn a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival.ResultsA total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.ConclusionsAmong premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

Project description:BackgroundContemporary treatment of node-positive (N+) colon cancer consists of adjuvant chemotherapy; however, randomized data supporting this practice were derived from lesions T2 or greater. Minimal data exist regarding the use and need for adjuvant chemotherapy in T1N+ disease.ObjectiveThe aim of this study was to determine treatment trends and the effects of adjuvant chemotherapy on T1N+ colon cancers by using the National Cancer Database.DesignThis was a retrospective study. Baseline demographics, tumor, and cancer treatment characteristics were compared. Groups were matched on the propensity to receive chemotherapy. Adjusted long-term survival stratified by chemotherapy use was compared by using the Kaplan-Meier method with the log-rank test. Predictors of not receiving chemotherapy were identified by using a multivariable logistic regression model.SettingsData were collected from the National Cancer Database, which collects cancer data from over 1500 cancer centers.PatientsWe identified patients from 1998 to 2006 with T1N+ disease, excluding those with metastatic disease or previous cancer. Patients were stratified based on whether or not they received chemotherapy.Main outcome measuresThe primary outcome measure of this study was long-term survival.ResultsThree thousand one hundred thirty-seven patients had T1N+ disease; 70.6% (n = 2216) received chemotherapy, and utilization significantly increased from 1998 to 2011 (p < 0.001). Unadjusted analysis revealed that patients treated with chemotherapy were statistically younger and healthier, and had shorter postoperative lengths of stay (all p < 0.001). Unadjusted 5-year survival was higher in patients receiving chemotherapy (87.9% vs 63.0% in patients with no chemotherapy; p < 0.001) and this persisted after propensity matching with (83.4% and 63.0% in patients with or without chemotherapy; p < 0.001). Only age (OR, 0.29; p < 0.001) predicted not receiving chemotherapy.LimitationsLimitations include potential selection bias as well as the inability to compare disease-free survival/recurrence.ConclusionsAdjuvant chemotherapy appears to significantly improve long-term survival in patients receiving chemotherapy in T1N+ disease. Thus, the use of chemotherapy in T1N+ disease is justified and provides a highly significant survival benefit.

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Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer.

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Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer.

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