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Lugano, Switzerland

Baselga J.,Harvard University | Baselga J.,SOLTI Breast Cancer Research Group | Bradbury I.,Frontier Science Scotland | Bradbury I.,Queens University of Belfast | And 28 more authors.
The Lancet | Year: 2012

Background: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. Methods: In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/m 2, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m 2) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. Findings: 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3; 95 CI 43·1-59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5; 22·4-37·5]; difference 21·1, 9·1-34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7, 18·1-32·3]) and the trastuzumab (difference -4·8, -17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4]) and lapatinib plus trastuzumab (32 [21·1]) than with trastuzumab (three [2·0]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5]) and lapatinib plus trastuzumab (15 [9·9]) than with trastuzumab (11 [7·4]). Interpretation: Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. Funding: GlaxoSmithKline. © 2012 Elsevier Ltd.

Metzger-Filho O.,Dana-Farber Cancer Institute | de Azambuja E.,Free University of Colombia | Procter M.,Frontier Science Scotland Ltd | Krieguer M.,Free University of Colombia | And 11 more authors.
Breast Cancer Research and Treatment | Year: 2016

This retrospective analysis conducted using data from patients enrolled onto the Herceptin Adjuvant has two objectives: The first is to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI) upon overall survival (OS). The second is to describe the duration of trastuzumab-based regimens in the metastatic setting for patients previously treated with adjuvant trastuzumab. The first objective included 187 patients treated with adjuvant trastuzumab and diagnosed with distant recurrence at 4-year median follow-up. The second objective included data from questionnaires sent to investigators retreating patients with trastuzumab upon distant recurrence: 144 of 156 questionnaires were returned (93 %), and 90 patients were selected based on available clinical information and consent for subsequent studies. There was no statistically significant relationship between TDRI following 1 year of adjuvant trastuzumab and OS from distant recurrence: hazard ratio 0.991, p = 0.46. The median OS from distant recurrence was numerically longer among patients with a TDRI of ≥12 months (n = 103) than <12 months (n = 84) but not statistically significant (23.7 vs. 17.8 months, p = 0.47). The median duration of first-line trastuzumab-based regimens for patients previously treated with adjuvant trastuzumab and diagnosed with distant disease recurrence was 8.8 months (n = 88). This retrospective, exploratory study suggests that TDRI did not impact on OS measured from distant recurrence. We argue that prospective collection of treatment information beyond disease progression should be included in future clinical studies. © 2015, Springer Science+Business Media New York.

Huober J.,Breast Center | Huober J.,Swiss Group for Clinical Cancer Research SAKK | Gelber S.,Dana-Farber Cancer Institute | Gelber S.,Frontier Science and Technology Research Foundation | And 13 more authors.
Annals of Oncology | Year: 2012

Background: To evaluate whether medullary breast cancer has a better prognosis compared with invasive ductal tumors. Methods: Among 12 409 patients, 127 were recorded as invasive medullary tumors and 8096 invasive ductal tumors. Medullary and ductal invasive tumors were compared with regard to stage, age at diagnosis, grade, hormone receptor status, peritumoral vascular invasion, and local and systemic treatment. Pattern of relapse, distant recurrence-free interval (DRFI), and overall survival (OS) were determined for both histological groups. Two cohorts were investigated: a full cohort including the pathologist-determined medullary histology without regard to any other tumor features and a cohort restricted to patients with ER-negative grade 3 tumors. Results: Fourteen-year DRFI and OS percents for medullary tumors (n = 127) and invasive ductal tumors (n = 8096) of the full cohort were 76% and 64% [hazard ratio (HR) 0.52, P = 0.0005] and 66% and 57% (HR = 0.75, P = 0.03), respectively. For the restricted cohort, 14-year DRFI and OS percents for the medullary (n = 47) and invasive ductal tumors (n = 1407) were 89% and 63% (HR 0.24, P = 0.002) and 74% and 54% (HR = 0.55, P = 0.01), respectively. Competing risk analysis for DRFI favored medullary tumors (HR medullary/ductal = 0.32; 95% confidence interval = 0.13-0.78, P = 0.01). Conclusion: Medullary tumors have a favorable prognosis compared with invasive ductal tumors. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Ribi K.,Coordinating Center | Aldridge J.,Dana-Farber Cancer Institute | Phillips K.-A.,University of Melbourne | Thompson A.,University of Dundee | And 18 more authors.
British Journal of Cancer | Year: 2012

Background: In the BIG 1-98 trial objective cognitive function improved in postmenopausal women 1 year after cessation of adjuvant endocrine therapy for breast cancer. This report evaluates changes in subjective cognitive function (SCF). Methods: One hundred postmenopausal women, randomised to receive 5 years of adjuvant tamoxifen, letrozole, or a sequence of the two, completed self-reported measures on SCF, psychological distress, fatigue, and quality of life during the fifth year of trial treatment (year 5) and 1 year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. Subjective cognitive function and its correlates were explored. Results: Subjective cognitive function and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement for hot flushes (P=0.0005). No difference in changes was found between women taking tamoxifen or letrozole. Subjective cognitive function was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman's R0.80). Correlations between SCF and the other patient-reported outcomes were generally low. Conclusion: Improved objective cognitive function but not SCF occur following cessation of adjuvant endocrine therapy in the BIG 1-98 trial. The substantial correlation of SCF scores over time may represent a stable attribute. © 2012 Cancer Research UK. All rights reserved.

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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