Long-term Follow-up Data from Pivotal Studies of Adjuvant Trastuzumab in Early Breast Cancer.
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ABSTRACT:
SUBMITTER: Kristeleit H
PROVIDER: S-EPMC5054055 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
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Long-term Follow-up Data from Pivotal Studies of Adjuvant Trastuzumab in Early Breast Cancer.
Kristeleit Hartmut H Parton Marina M Beresford Mark M Macpherson Iain R IR Sharma Rajan R Lazarus Loren L Kelleher Muireann M
Targeted oncology 20161001 5
The addition of adjuvant trastuzumab therapy for 1 year to standard chemotherapy significantly improved disease-free survival and overall survival versus chemotherapy alone in a number of pivotal early breast cancer studies. Here we review long-term follow-up data on the efficacy, cardiac safety, and general safety of trastuzumab in these pivotal studies. We also evaluate ongoing phase II/III adjuvant trials with newer HER2-targeted agents and the efficacy and safety of the recently developed su ...[more]
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Project description:BackgroundClinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.MethodsHERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032).FindingsOf the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group.Interpretation1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.FundingF Hoffmann-La Roche (Roche).
| S-EPMC5465633 | biostudies-literature
Project description:In follow-up studies, interactions are often assessed by including a cross-product term in a (multiplicative) Cox model. However, epidemiologists/clinicians often misinterpret a significant multiplicative interaction as a genuine mechanistic interaction. Though indices specific to mechanistic interactions have been proposed, including the 'relative excess risk due to interaction' (RERI) and the 'peril ratio index of synergy based on multiplicativity' (PRISM), these indices assume no loss to follow up and no competing death in a study. In this paper, the authors propose a novel 'mechanistic interaction test' (MIT) for censored data. Monte-Carlo simulation shows that when the hazard curves are proportional to, non-proportional to, or even crossing over one another, the proposed MIT can maintain reasonably accurate type I error rates for censored data. It has far greater powers than the modified RERI and PRISM tests (modified for censored data scenarios). To test mechanistic interactions in censored data, we recommend using MIT in light of its desirable statistical properties.
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Project description:Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS.[Media: see text].
| S-EPMC10419413 | biostudies-literature
Project description:BackgroundPertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.MethodsWe randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.ResultsIn the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).ConclusionsPertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .).
| S-EPMC5538020 | biostudies-literature
Project description:Large randomized trials assessing the benefit of adjuvant trastuzumab in early-stage breast cancer positive for the human epidermal growth factor receptor 2 (her2) have demonstrated a significant improvement in survival. The objective of the present study was to describe the outcomes of women who received adjuvant trastuzumab for her2-positive breast cancer in British Columbia since publicly funded population-based use was initiated in July 2005.Women from British Columbia, newly diagnosed with stage i-iii breast cancer between July 2004 and December 2006, who were positive for her2 overexpression by immunohistochemistry (3+) or amplification by fluorescence in situ hybridization (ratio ? 2.0) were included in the study. Data were collected from the prospectively assembled BC Cancer Agency Outcomes Unit, with cases linked to the provincial pharmacy data repository to determine the proportion of women who received adjuvant trastuzumab.Our retrospective study identified 703 her2-positive patients, of whom 480 (68%) received trastuzumab. In patients receiving trastuzumab, the 2-year relapse-free survival was 96.1% [95% confidence interval (CI): 93.6% to 97.7%] and the overall survival was 99.3% (95% CI: 97.9% to 99.8%). Among node-negative and -positive patients, the 2-year relapse-free survival was 97.8% and 94.8% respectively (p = 0.09) for the trastuzumab-treated group and 90.9% and 77.3% (p = 0.01) for the group not receiving trastuzumab (n = 223). Site of first distant metastasis was the central nervous system in 19.5% of the entire cohort and in 37.5% of patients treated with trastuzumab.This population-based analysis of adjuvant trastuzumab use among Canadian women demonstrates highly favorable outcomes at the 2-year follow-up.
| S-EPMC3410828 | biostudies-literature
Project description:PurposeSignificant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted.MethodsNCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models.ResultsThe 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C.ConclusionThe cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.
| S-EPMC4980566 | biostudies-literature
Project description:Adjuvant systemic therapy along with screening has been key to the observed improvements in disease-free and overall survival (DFS/OS) in breast cancer. Improvements in overall survival already take into account therapy related toxicities that can result in death. However, this measure alone does not adequately capture the impact on health-related quality of life. Therefore, it is important to examine the prevalence, frequency and short/long-term impact of therapy-related toxicities, identify patients who might be at greatest risk. Ultimately decisions regarding expected therapy benefits (relative and absolute percentage improvements in DFS/OS) must be made against a background of known potential harms. For many patients with early breast cancer (EBC), their risk of recurrence is not zero but is small. At the same time, for many therapies for early stage breast cancer, the risk of serious side effects is small but is not zero. As we better understand the long-term side effects of adjuvant chemotherapy and targeted therapy, it becomes critical to integrate our growing understanding of breast cancer biology with standard high-quality histopathologic measures to better identify the patients most likely to benefit from the various options for combined multimodality therapy. Hence, we must strive against the notion of recommending adjuvant systemic chemotherapy "just in case." This article focuses on the long-term side effects of adjuvant chemotherapy in patients with EBC.
| S-EPMC4743500 | biostudies-literature
Project description:BackgroundSystematic reviews have found that luteinizing hormone-releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer.MethodsWe conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen.ResultsFifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant.ConclusionsTwo years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.
| S-EPMC2650713 | biostudies-literature
Project description:Coxa valga (with or withour excessive femoral anteversion) combined with acetabular dysplasia is a well-known cause of early osteoarthritis. Many authors have stated that the best result of an osteotomy can be achieved at an early stage of these osteoarthritic changes. In this study, we present 26 patients with a symmetrical hip deformity for which we performed a therapeutic osteotomy on the symptomatic hip. The contralateral hip had the same anatomical predisposition to develop an OA, but there were only minor to no complaints. We advised and performed an early osteotomy on these hips. On radiological evaluation, an average Sharp angle of 42.2 degrees and an average CCD of 142 degrees was present. During an average follow-up period of 19.9 years (range 15.0-25.9), 14 hips were converted to THR after the primary osteotomy, whereas there were only 6 after the early osteotomy (chi-square P<0.05). Using a Pearson correlation analysis, the age, preoperative grade of OA, preoperative Merle d'Aubigne score and excessive femoral anteversion were significantly correlated with the outcome. Our results show that the effect of an early, more prophylactic varus osteotomy in patients with a coxa valga with excessive femoral anteversion and acetabular dysplasia can be superior to the results achieved when surgery is postponed until the complaints and arthrosis have become more severe.
| S-EPMC2267573 | biostudies-other
Project description:ContextDespite tremendous interest in hypoparathyroidism, large cohort studies describing typical treatment patterns, laboratory parameters, and rates of complications are lacking.ObjectiveOur objective was to characterize the course of disease in a large cohort of hypoparathyroid patients.Design and settingWe conducted a chart review of patients with permanent hypoparathyroidism identified via a clinical patient data registry. Patients were seen at a Boston tertiary-care hospital system between 1988 and 2009.PatientsWe identified 120 patients. Diagnosis was confirmed by documented hypocalcemia with a simultaneous low or inappropriately normal PTH level for at least 1 yr. Mean age at the end of the observation period was 52 ± 19 (range 2-87) yr, and the cohort was 73% female.Main outcome measureWe evaluated serum and urine laboratory results and renal and brain imaging.ResultsWe calculated time-weighted average serum calcium measurements for all patients. The time-weighted average for calcium was between 7.5 and 9.5 mg/dl for the majority (88%) of patients. Using linear interpolation, we estimated the proportion of time within the target calcium range for each patient with a median of 86% (interquartile range 67-98%). Of those with a 24-h urine collection for calcium (n = 53), 38% had at least one measurement over 300 mg/d. Of those with renal imaging (n = 54), 31% had renal calcifications, and 52% of those with head imaging (n = 31) had basal ganglia calcifications. Rates of chronic kidney disease stage 3 or higher were 2- to 17-fold greater than age-appropriate norms.ConclusionsHypoparathyroidism and its treatment carry a large burden of disease. Renal abnormalities are particularly common.
| S-EPMC3513540 | biostudies-literature