Duration of adjuvant trastuzumab: might less be more?
Authors: O. Metzger Filho, H.J. Burstein
Journal: Annals of Oncology (2018)

The pivotal trials of adjuvant trastuzumab—NSABP B-31, NCCTG N9831, HERA, and BCIRG 006—which transformed our management of early stage, HER2+ breast cancer, all deployed 1 year of adjuvant trastuzumab. Investigators developing these trials knew that the observed synergy between chemotherapy and trastuzumab argued for several months of overlap between the two classes of agents. Beyond that, it was not known when these trials were being developed whether 'maintenance' trastuzumab would be valuable, nor what a suitable duration might be. In the end, study sponsors and investigators settled on a total of 1 year of adjuvant therapy. It proved an inspired, if arbitrary, decision. Among the seminal studies that led to the approval of adjuvant trastuzumab, the Herceptin Adjuvant (HERA) trial was the only study that also evaluated different durations of adjuvant trastuzumab. Results from the HERA trial confirmed that a second year of adjuvant trastuzumab was not superior to the standard 1-year regimen [1.Goldhirsch A. Gelber R.D. Piccart-Gebhart M.J. et al.2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.Lancet. 2013; 382: 1021-1028Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar]. During the same period, results from the Finland Herceptin (FinHER) trial, which included a small subset of HER2+ breast cancer patients, pointed to a significant benefit with a mere 9 weeks of adjuvant trastuzumab, implying that the shorter trastuzumab duration might be a useful option. Multiple randomized studies were designed to test whether shorter treatment durations would be equally effective as the standard 12-month duration of adjuvant trastuzumab among women with HER2+, early stage breast cancer. The PHARE, Hellenic Oncology Research Group (HORG), and PERSEPHONE clinical trials compared 6 versus 12 months of adjuvant trastuzumab (see Table 1) [2.Pivot X. Romieu G. Debled M. et al.6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 741-748Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 3.Mavroudis D. Saloustros E. Malamos N. et al.Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG.Ann Oncol. 2015; 26: 1333-1340Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 4.Earl H.M. Hiller L. Vallier A.-L. et al.PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.J Clin Oncol. 2018; 36 (506): 506Crossref Google Scholar]. The SOLD and Short-HER compared 9 weeks versus 12 months duration (see Table 1) [5.Joensuu H. Fraser J. Wildiers H. et al.Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial.JAMA Oncol. 2018; 4: 1199-1206Crossref PubMed Scopus (103) Google Scholar, 6.Conte P. Frassoldati A. Bisagni G. et al.Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.Ann Oncol. 2018; Abstract Full Text Full Text PDF Scopus (95) Google Scholar]. Each of these trials carried a noninferiority design; in essence, the studies were powered to show that a shorter duration of treatment would not be inferior to the 12-month standard arm. Investigators conducting noninferiority studies face considerable challenges inherent to the design of these trials. From a methodological standpoint, the null hypothesis in noninferiority studies holds that the investigational arm is inferior to the comparator arm. To reject the null hypothesis with a clinically acceptable inferiority margin, usually within a narrow band of percentage points to the 'standard' arm, these studies require larger sample sizes than classical superiority studies. Such sample size considerations make noninferiority studies less appealing to industry sponsors, and also carry the risk that a statistically 'noninferior' result might still appear numerically inferior, making clinicians and patients squeamish about the noninferior arm.Table 1Noninferiority studies designed comparing 12 months to shorter durations of adjuvant trastuzumabStudyNRandomization of 12-month trastuzumab versusΔ absolute rate of cardiac toxicityaStudies differed with respect to definitions for cardiotoxicity. % with longer durationΔ DFS absolute benefit % for longer durationHRNoninferior (NI)?PHARE [2.Pivot X. Romieu G. Debled M. et al.6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 741-748Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar]33846 months3.8%2.6%1.28Not NIHORG [3.Mavroudis D. Saloustros E. Malamos N. et al.Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG.Ann Oncol. 2015; 26: 1333-1340Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]4816 months0.0%2.4%1.57Not NIPERSEPHONE [4.Earl H.M. Hiller L. Vallier A.-L. et al.PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.J Clin Oncol. 2018; 36 (506): 506Crossref Google Scholar]40886 months4.0%0.4%1.07NISOLD [5.Joensuu H. Fraser J. Wildiers H. et al.Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial.JAMA Oncol. 2018; 4: 1199-1206Crossref PubMed Scopus (103) Google Scholar]21749 weeks0.9%2.5%1.39Not NIShort-HER [6.Conte P. Frassoldati A. Bisagni G. et al.Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.Ann Oncol. 2018; Abstract Full Text Full Text PDF Scopus (95) Google Scholar]12549 weeks8.8%3.0%1.13Not NIa Studies differed with respect to definitions for cardiotoxicity. Open table in a new tab The Short-HER clinical trial in this issue of the Annals of Oncology randomized 1253 women with HER2+ breast cancer to a short 9-week treatment of trastuzumab given concurrently with chemotherapy, or to the standard 12-month duration [6.Conte P. Frassoldati A. Bisagni G. et al.Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.Ann Oncol. 2018; Abstract Full Text Full Text PDF Scopus (95) Google Scholar]. In the short-duration arm, trastuzumab was given weekly for 9 weeks concomitantly with three cycles of docetaxel. This regimen was followed by three cycles of FEC (5-fluourouracil, epirubicin, and cyclophosphamide). In the control arm of the study, patients were treated with four cycles of AC (doxorubicin, cyclophosphamide) or EC followed by four cycles of either paclitaxel or docetaxel. Trastuzumab was administered every 3 weeks for 18 doses, starting with the first taxane dose. The study primary end point was disease-free survival (DFS) with cardiac safety as an important secondary end point. Cardiac events were defined as a decrease in the left ventricular ejection fraction (LVEF) >15% points from baseline or >10% points drop with absolute value below 50%, or symptomatic congestive heart failure, or any other grade 2 or 3 cardiac events. In order to demonstrate the noninferiority at pre-specified boundary at 1.29 and with 80% power, the study was planned with a sample size of 2332 patients but due to lower than expected enrollment, the sample size was reduced to 1252 patients. Fifty-four percent of the study population was node negative and 68% hormone receptor positive. The 5-year DFS rate in 626 patients who received 1 year of treatment was 88%, besting the 85% DFS rate among 627 patients who received 9 weeks of treatment, yielding a hazard ratio of 1.13 (90% CI 0.89–1.42), with the upper limit of the 90% CI crossing the noninferiority margin set at 1.29. In short, Short-HER could not prove noninferiority for shorter courses of adjuvant trastuzumab. However, the shorter trastuzumab treatment was also associated with a lower risk of cardiac events (4.3%) compared with 13.1% in the longer treatment regimen. Thus, the Short-HER study suggests tradeoffs between reducing the risk of cancer recurrence and incurring the risk of cardiotoxicity with a full year of trastuzumab. The PHARE, HORG, and SOLD studies also failed to demonstrate noninferiority. To date, only one of the five trials of shorter versus longer durations of adjuvant trastuzumab—the PERSEPHONE study of 6 versus 12 months—has demonstrated noninferiority for a shorter regimen (Table 1). All the others showed a measurable 2%–3% reduction in recurrence risk with the longer duration of trastuzumab therapy. Notably in the PERSEPHONE trial, the subset of patients who received optimal, contemporary patterns of adjuvant treatment including taxane-based chemotherapy and concurrent chemotherapy with trastuzumab actually had a lower risk of recurrence when given the longer, 12-month trastuzumab treatment. At the same time, these trials all show—to varying degrees—higher risks of cardiac events with longer durations of treatment. Fortunately, clinical experience suggests that the risk of trastuzumab-associated cardiac injury is lower with nonanthracycline regimens, and that the vast majority of these instances of cardiotoxicity are asymptomatic changes in LVEF, which lack important clinical sequelae. A patient with early stage, HER2+ breast cancer wants 'the best' treatment to prevent cancer recurrence while preserving quality of life and avoiding serious, long-term consequences of therapy. That treatment undeniably includes trastuzumab, given concurrently with taxane-based chemotherapy. The 'gains' of longer trastuzumab therapy are quite modest, amounting to single-digit reductions in recurrence rates for women with average risk, HER2+ tumors. For patients who developed cardiac toxicity or otherwise do not tolerate trastuzumab, or in situations where only shorter durations of trastuzumab are available, it seems clear that the 'lion's share' of benefit is achievable with 6 months of treatment. But based on the data in Short-HER2 and four other trials of treatment duration, we believe that 12 months of trastuzumab, including 3 months of concurrent administration with taxane-based chemotherapy, remains the standard of care and the optimal duration of therapy. Lesser durations of trastuzumab maintenance treatment appear associated with a greater risk of disease recurrence. Finally, in cases of higher risk, HER2+ breast cancer, current treatment standards may include additional anti-HER2 therapies such as pertuzumab or neratinib. We note that there are simply no data that these interventions benefit women who received less than 12 months of trastuzumab. One year is a long time, especially when getting treatment of breast cancer. But for most women with HER2+ tumors, that looks like time well spent. None declared.