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Regan M.M.,Dana-Farber Cancer Institute | Regan M.M.,Harvard University | Neven P.,Catholic University of Leuven | Giobbie-Hurder A.,Dana-Farber Cancer Institute | And 17 more authors.
The Lancet Oncology | Year: 2011

Background: Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. Methods: BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.gov NCT00004205. Findings: 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. Interpretation: For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. Funding: Novartis, United States National Cancer Institute, International Breast Cancer Study Group. © 2011 Elsevier Ltd.

Munzone E.,Italian National Cancer Institute | Giobbie-Hurder A.,Dana-Farber Cancer Institute | Gusterson B.A.,University of Glasgow | Mallon E.,Southern General Hospital | And 14 more authors.
Annals of Oncology | Year: 2015

Background: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial. Patients and methods: The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years. Results: Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94-11.7; P = 0.06]. Conclusions: Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease. © 2015 Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Bigaard J.,Ringsted Hospital | Stahlberg C.,University of Southern Denmark | Jensen M.-B.,Danish Breast Cancer Cooperative Group DBCG | Ewertz M.,University of Southern Denmark | Kroman N.,University of Southern Denmark
Breast Cancer Research and Treatment | Year: 2012

During the past 50 years, breast cancer incidence has increased by 2-3 % annually. Despite many years of testing for estrogen receptors (ER), evidence is scarce on breast cancer incidence by ER status. The aim of this paper was to investigate the increase in breast cancer incidence by ERstatus.Datawere obtained fromthe clinical database of the Danish Breast Cancer Cooperative Group which holds nationwide data on diagnosis, including pathology, treatment, and follow-up on primary breast cancers since 1977. All Danish women <80 years diagnosed with primary breast cancer 1996-2007 were identified in this prospective register based study. ER status was evaluated using immunohistochemical staining by standardized laboratory methods in the Danish Pathology Departments and reported to the database. From 1996 to 2007, breast cancer incidence increased overall with a tendency to level off after 2002. In all women a significant decreasewas found inERunknown tumors.However, in both pre- and postmenopausalwomen, significant increases were seen in incidence of ER+ tumors; though the increase levelled off for premenopausal women after 2002. In postmenopausal women, the incidence of ER- breast cancer decreased significantly throughout the period. In women \35 years, we found a minor non-significant increase in both ER? and ER- tumors. ER unknown decreased in all women andwas themost distinct in premenopausalwomen aged 35+. We found a significant increase in ER+ breast cancer incidence in postmenopausal women whereas the incidence in premenopausal women (aged 35+) levelled off after 2002. © Springer Science+Business Media New York 2012.

Eckhoff L.,University of Southern Denmark | Nielsen M.,University of Southern Denmark | Moeller S.,Danish Breast Cancer Cooperative Group DBCG | Knoop A.,University of Southern Denmark
Acta Oncologica | Year: 2011

Background. In 2007 docetaxel was introduced as part of the adjuvant setting offered to high risk breast cancer patients in Denmark. Meta-analyses had shown that taxane-containing chemotherapy reduced the relative risk of relapse and death by 2030%, apparently with moderate side effects. The treatment was given as three cycles of cyclophosphamide (600 mg/m 2) and epirubicin (90 mg/m 2) followed by three cycles of docetaxel (100 mg/m 2). Because of an apparent high incidence of side effects, especially febrile neutropenia (FN) and non-hematologic side effects, the DBCG (The Danish Breast Cancer Cooperative Group) initiated a retrospective study of adverse reactions to the newly introduced regime and all patients were offered primary prophylaxis with growth factors (G-CSF) pr 1/1-2008. Material and methods. Two medical doctors examined available journals and nurse charts from the 13 oncology departments in Denmark, and graded all side effects according to NCI CTC version 2.0. To be enrolled, the patients should have received three cycles of EC and at least one cycle of docetaxel. The side effects were investigated before and after routine use of G-CSF. Results. One thousand one hundred and forty-three patients entered the study. In 2007 (before G-CSF) the incidence of FN was 25% and 90.6% of the patients completed the planned treatment. In 2008 (after the introduction of G-CSF) the incidence of FN was 10% and 94.5% completed the treatment. The incidence of non-hematological adverse events, in 2007 and 2008 combined, was for neuropathy 35%, mucositis 75%, muscle and joint pain 53%, skin rash 25% and fatigue 43% (all grades). Conclusion. The introduction of G-CSF was justified because of the high incidence of FN. However, it could not have been predicted after reviewing the published literature. The incidence of non-hematological adverse events had been reported in some, but not all adjuvant taxanes studies. In the future, focus should be more on the side effects, especially when introducing new toxic systemic regimes. © 2011 Informa Healthcare.

Chirgwin J.,Australian New Zealand Breast Cancer Trials Group | Chirgwin J.,Monash University | Sun Z.,Dana-Farber Cancer Institute | Smith I.,Institute of Cancer Research | And 9 more authors.
Breast Cancer Research and Treatment | Year: 2012

Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients. © 2011 Springer Science+Business Media, LLC.

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