Summary Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early ...breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0–56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio HR 0·76; 95% CI 0·66–0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3% vs 87·7%, respectively; HR 0·85; 95% CI 0·70–1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5–52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51–0·90; p=0·0077). Higher incidences of grade 3–4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. Funding F Hoffmann-La Roche, Michelangelo Foundation.
Summary Background Clinical 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. Methods HERA (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 ). Findings Of 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. Interpretation 1 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. Funding F Hoffmann-La Roche (Roche).
Summary Background Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant ...trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. Methods We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Results Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 2% of 1703 patients) and the observation group (32 2% of 1698; p=0·55 Gray's test). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 57% of 227) than in the group given trastuzumab for 1 year (88 47% of 186; p=0·06 Gray's test). Most CNS relapses were symptomatic (189 87% of 217). Conclusion Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. Funding None.
Summary Background Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved ...rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. Methods We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m2 ). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 ) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov , number NCT00553358. Findings 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50–4·22), 3-year event-free survival was 78% (95% CI 70–84) in the lapatinib group, 76% (68–82) in the trastuzumab group, and 84% (77–89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66–1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47–1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60–4·24), and 3-year overall survival was 93% (95% CI 87–96) for lapatinib, 90% (84–94) for trastuzumab, and 95% (90–98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45–1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30–1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22–0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15–0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. Interpretation Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. Funding GlaxoSmithKline.
Summary Background Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but ...the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0–10) is also reported. This study is registered with ClinicalTrials.gov , number NCT00045032. Findings We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio HR 0·99, 95% CI 0·85–1·14, p=0·86). Grade 3–4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 20·4% vs 275 16·3% grade 3–4 adverse events, and 120 7·2% vs 69 4·1% decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67–0·86, p<0·0001) for disease-free survival and 0·76 (0·65–0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. Interpretation 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. Funding F Hoffmann-La Roche (Roche).
Summary 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/m2 , 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/m2 ) 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.
SummaryBackgroundEndocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the ...phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses. MethodsIn this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I–III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02273973, and is closed to accrual. FindingsBetween Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7–5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 39% of 168 patients in the placebo group vs 83 50% of 166 in the taselisib group; odds ratio OR 1·55, 95% CI 1·00–2·38; p=0·049) and in the PIK3CA-mutant subset (30 38% of 79 vs 41 56% of 73; OR 2·03, 95% CI 1·06–3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three 2% of 166 in the taselisib group vs one 1% of 168 in the placebo group; OR 3·07 95% CI 0·32–29·85, p=0·37) or in the PIK3CA-mutant cohort (one patient 1%) vs none 0%; OR not estimable, p=0·48). The most common grade 3–4 adverse events in the taselisib group were gastrointestinal (13 8% of 167 patients), infections (eight 5%), and skin–subcutaneous tissue disorders (eight 5%). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight 5% patients with infections and seven 4% with gastrointestinal effects) than in the placebo group (one 1% patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related. InterpretationThe increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer. FundingGenentech and F Hoffmann-La Roche.
Summary Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean ...countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.
Trastuzumab (herceptin) for early-stage breast cancer Ismael, Gustavo; Rosa, Daniela Dornelles; de Azambuja, Evandro ...
Hematology/oncology clinics of North America,
04/2007, Volume:
21, Issue:
2
Journal Article
Peer reviewed
Breast cancer patients who have HER2 gene amplification and, consequently, protein overexpression, generally show an aggressive course with short disease-free and overall survivals. Trastuzumab, a ...humanized monoclonal antibody against the extracellular domain of HER2 protein, has been shown to benefit patients who have HER2-positive metastatic breast cancer, and recently, the results of five adjuvant trials involving more than 13,000 women have been released. Here, the authors summarize the main results and outline the differences among these trials, which have demonstrated an important role of trastuzumab in the treatment of women who have HER2-overexpressing/amplified early breast cancer.
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