American Society of Clinical Oncology (ASCO)
0732-183X
1527-7755
Cơ quản chủ quản: LIPPINCOTT WILLIAMS & WILKINS , Lippincott Williams and Wilkins Ltd.
Lĩnh vực:
Medicine (miscellaneous)Cancer ResearchOncology
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Retrospective Analysis of Time to Recurrence in the ATAC Trial According to Hormone Receptor Status: An Hypothesis-Generating Study Purpose Arimidex, tamoxifen alone, or in combination (ATAC) trial of anastrozole (Arimidex) versus tamoxifen or a combination of the two in 9,366 postmenopausal patients with primary breast cancer found a significant improvement in disease-free survival and time to recurrence (TTR) for anastrozole compared with tamoxifen, that was restricted to patients with hormone receptor-positive (ie, estrogen receptor–positive [ER+] and/or progesterone receptor-positive [PgR+]) disease, the target population for these therapies. We retrospectively tested the hypothesis that this benefit might differ according to PgR status. Patients and Methods TTR was compared between the three treatment groups for subgroups defined by ER and PgR status using Cox's proportional hazards model, with and without adjustment for baseline variables. Results The unadjusted hazard ratio (HR) for anastrozole versus tamoxifen for TTR was 0.74 (95% CI, 0.64 to 0.87) for women with either ER+ or PgR+ tumors. In the ER+/PgR+ subgroup (n = 3,834) the HR was 0.84 (95% CI, 0.69 to 1.02) compared with 0.43 (95% CI, 0.31 to 0.61) in the ER+/PgR-negative (PgR–) subgroup (n = 880). In the adjusted model the HRs were 0.83 and 0.45, respectively. Conclusion Time to recurrence was longer for anastrozole- than tamoxifen-treated patients in both ER+/PgR+ and ER+/PgR– subgroups, but the benefit was substantially greater in the PgR– subgroup. As this was an “exploratory” analysis, this effect should be considered as hypothesis generating and assessed prospectively in other trials comparing the adjuvant use of an aromatase inhibitor with tamoxifen.
Tập 23 Số 30 - Trang 7512-7517 - 2005
Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/or ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial PURPOSE: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively. PATIENTS AND METHODS: Postmenopausal patients with estrogen– and/or progesterone receptor–positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria. RESULTS: For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P = .004), and fewer patients underwent breast conservation (36%, P = .036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P = .0004). CONCLUSION: ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.
Tập 19 Số 18 - Trang 3808-3816 - 2001
Neoadjuvant Treatment of Postmenopausal Breast Cancer With Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) Multicenter Double-Blind Randomized Trial Purpose The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) trial was designed to test the hypothesis that the clinical and/or biologic effects of neoadjuvant tamoxifen compared with anastrozole and with the combination of tamoxifen and anastrozole before surgery in postmenopausal women with estrogen receptor (ER) –positive, invasive, nonmetastatic breast cancer might predict for outcome in the Arimidex, Tamoxifen Alone or in Combination (ATAC) adjuvant therapy trial. Patients and Methods Postmenopausal women with ER-positive, invasive, nonmetastatic, and operable or locally advanced potentially operable breast cancer were randomly assigned to neoadjuvant tamoxifen (20 mg daily), anastrozole (1 mg daily), or a combination of tamoxifen and anastrozole for 3 months. The tumor objective response (OR) was assessed by both caliper and ultrasound. Comparisons were also made of clinical response with ultrasound response, actual and feasible surgery with feasible surgery at baseline, OR in human epidermal growth factor receptor 2 (HER2) –positive cancers, and tolerability. Results There were no significant differences in OR in the intent-to-treat population between patients receiving tamoxifen, anastrozole, or the combination. In patients who were assessed as requiring mastectomy at baseline (n = 124), 44% of patients received breast-conserving surgery (BCS) after anastrozole compared with 31% of patients after tamoxifen (P = .23); this difference became significant for patients who were deemed feasible for BCS by their surgeon (46% v 22%, respectively; P = .03). The OR for patients with HER2-positive cancer (n = 34) was 58% for anastrozole compared with 22% for tamoxifen (P = .18). All treatments were well tolerated. Conclusion Neoadjuvant anastrozole is as effective and well tolerated as tamoxifen in ER-positive operable breast cancer in postmenopausal women, but the hypothesis that clinical outcome might predict for long-term outcome in adjuvant therapy was not fulfilled.
Tập 23 Số 22 - Trang 5108-5116 - 2005
Estrogen-Independent Proliferation Is Present in Estrogen-Receptor<i>HER2</i>-Positive Primary Breast Cancer After Neoadjuvant Letrozole Purpose To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) –positive (ER ≥ 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials. Patients and Methods FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67. Results HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors. Conclusion Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.
Tập 24 Số 19 - Trang 3019-3025 - 2006
Superior Efficacy of Letrozole Versus Tamoxifen as First-Line Therapy for Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Study of the International Letrozole Breast Cancer Group PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor– and/or progesterone receptor–positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P = .0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P = .0006), as was the rate of clinical benefit (49% v 38%; P = .001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Tập 19 Số 10 - Trang 2596-2606 - 2001
First mature analysis of the Intergroup Exemestane Study LBA527 Background: We have previously shown that switching to exemestane (E) after 2–3 years tamoxifen (T) improves disease free survival (DFS) in postmenopausal (PM) women with early breast cancer (BC). We report results with 95% of patients (pts) having ≥3 years follow-up. Methods: 4724 PM pts (2352 E vs 2372 T) with ER +ve/unknown unilateral BC, disease-free after 2–3 years T, were randomized to continue T or switch to E to complete a total of 5 years adjuvant endocrine therapy. 122 pts (56 E vs 66 T) originally reported as ER unknown were later found to be ER −ve. In addition to intention to treat (ITT), we repeated analyses excluding ER −ve pts. Adverse events (pre relapse) by treatment received were analysed on treatment (TRT) and also including follow-up (TRTFU). In safety analyses P < 0.01 was taken as significant due to multiple testing. Results: With median follow up of 58 months there were 808 first events (disease relapse, contralateral breast cancer (CLBC), intercurrent death) and 483 deaths. See table for unadjusted hazard ratios (HR). In ER +ve/unknown pts, adjusting for pre-specified prognostic factors of nodal status, chemo use, HRT use, gave HR for DFS of 0.74 (0.64, 0.85); p < 0.0001 and for overall survival (OS) of 0.83 (0.69, 0.99); P = 0.04. There were 145 intercurrent deaths (65 E vs 80 T), including deaths from cardiac (14 E vs 13 T), vascular (17 E vs 11 T) and other cancers (20 E vs 35 T). No statistically significant differences in myocardial infarctions, angina, or cerebrovascular accidents were observed. In T pts there were more thromboembolic (TRT p = 0.006, TRTFU p = NS) and serious gynaecologic events (TRT p < 0.001, TRTFU p < 0.001) and less fractures (TRT p = NS, TRTFU p = 0.003). Conclusions: Switching to E following 2–3 years of T significantly improves DFS, reducing chance of first event, CLBC and distant recurrence. In ER +ve/unknown pts, the switching strategy with E significantly reduces the risk of dying. [Table: see text] [Table: see text]
Tập 24 Số 18_suppl - Trang LBA527-LBA527 - 2006
Biological and clinical outcomes from a phase II placebo-controlled neoadjuvant study of anastrozole alone or with gefitinib in postmenopausal women with ER/PgR+ breast cancer (Study 223) 515 Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, reduces breast cancer cell growth and potentiates endocrine therapy in model systems. This double-blind multicentre study compared anastrozole 1 mg/day alone with anastrozole + gefitinib 250 mg/day as neoadjuvant therapy for breast cancer in a novel design aiming to assess additional benefit from gefitinib in individual patients. Methods: Postmenopausal women with stage I-IIIB breast cancer and ER and/or PgR+ tumours received anastrozole for 16 wks and were randomised (2:5:5 ratio) to: combination with gefitinib for 16 wks (AG); placebo for 2 wks then gefitinib for 14 wks (A:AG, to test for additional Ki67 suppression); placebo for 16 wks (A alone). Biopsies were taken at baseline, 2 and 16 wks. Primary comparison was change in Ki67 by 16 wks. Secondary comparison was objective tumour response rate (ORR) using UICC/WHO criteria at 16 wks. Results: 206 patients (pts) were randomised: (31 AG, 90 A:AG, 85 A alone); demography was well balanced between the groups. 109 pts were evaluable for Ki67: 59 AG + A:AG; 50 A alone. Change in Ki67 levels at 16 wks was not significantly different in those pts who received gefitinib + anastrozole versus anastrozole alone (p=0.257). The addition of gefitinib after 2 weeks of anastrozole did not further suppress Ki67 levels (p=0.164). 188 pts were evaluable for ORR (109 AG + A:AG; 79 A alone). The ORR was 48% in pts who received gefitinib + anastrozole and 61% in pts treated with anastrozole alone (p=0.067). Conclusions: Neither the biological nor the clinical activity of anastrozole was enhanced by the addition of gefitinib; although non-significant, both endpoints unexpectedly suggested a trend against the combination in this patient population. Molecular investigations of signal transduction pathways are underway to understand the significance of these findings. [Table: see text] [Table: see text]
Tập 24 Số 18_suppl - Trang 515-515 - 2006
Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer—A Study from the IMPACT Trialists Purpose To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy. Patients and Methods The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment. Results A decrease in the proliferation marker Ki67 occurred in the majority of patients: 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks. Conclusion These results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.
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