De-escalation attempts for adjuvant trastuzumab: longer beats shorter
Authors: G. Curigliano, A. Goldhirsch
Journal: Annals of Oncology (2015)

Patients with HER2-positive early breast cancer given adjuvant trastuzumab had a significant improvement in disease-free (DFS) and overall survival (OS) compared with those not given trastuzumab [1.Piccart-Gebhart M.J. Procter M. Leyland-Jones B. et al.Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.N Engl J Med. 2005; 353: 1659-1672Crossref PubMed Scopus (4168) Google Scholar, 2.Romond E.H. Perez E.A. Bryant J. et al.Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.N Engl J Med. 2005; 353: 1673-1684Crossref PubMed Scopus (4495) Google Scholar, 3.Slamon D. Eiermann W. Robert N. et al.Adjuvant trastuzumab in HER2-positive breast cancer.N Engl J Med. 2011; 365: 1273-1283Crossref PubMed Scopus (1896) Google Scholar, 4.Gianni L. Dafni U. Gelber R.D. et al.Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.Lancet Oncol. 2011; 12: 236-244Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar, 5.Perez E.A. Romond E.H. Suman V.J. et al.Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31.J Clin Oncol. 2011; 29: 3366-3373Crossref PubMed Scopus (586) Google Scholar]. The HERA trial also tested whether continuation of trastuzumab treatment of 2 years would be superior to 1 year [6.Goldhirsch A. Gelber R.D. Piccart-Gebhart M.J. et al.for the Herceptin Adjuvant (HERA) Trial Study Team. 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 (403) Google Scholar]. The final results of the HERA trial showed no significant benefit for the former, leading to an unfavourable benefit–risk ratio for the longer duration of adjuvant trastuzumab. This finding supports a standard duration of 12 months of adjuvant trastuzumab. In the current issue of Annals of Oncology, Mavroudis et al. report results from the multicentre randomized study by the Hellenic Oncology Research Group (HORG) comparing 6 versus 12 months of adjuvant trastuzumab combined, for a limited time period, with dose dense, filgrastim-supported docetaxel [7.Mavroudis D. Saloustros E. Malamos N. et al.Six versus twelve 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 (120) Google Scholar]. All patients also received upfront dose dense, filgrastim-supported 5-fluorouracil 700mg/sm, epirubicin 75mg/sm, cyclophosphamide 700mg/sm. The primary end point was the 3-year DFS. A total of 481 patients were randomized to receive 12 months (n = 241) or 6 months (n = 240) of adjuvant trastuzumab. After a median follow-up of 47 and 51 months, 17 (7.1%) and 28 (11.7%) patients had experienced disease recurrence (P = 0.08), while 10 (4.1%) and 8 (3.3%) patients had died (P = 0.6) in the 12- and 6-month groups, respectively. The 3-year DFS was 95.7% versus 93.3% in favour of the 12-month treatment group [hazard ratio (HR) = 1.57; 95% confidence interval (CI) 0.86–2.10; P = 0.137]. The HORG trial has methodological and treatment-related potential limitations: (i) the trial failed to demonstrate non-inferiority for the 6 versus 12 months administration, thus being inconclusive for the primary end point; (ii) the number of patients enrolled was relatively small; (iii) the 8% non-inferiority margin set by the statistical hypothesis was quite large; (iv) there was a limited number of events; (v) there was limited evidence on the rational allowing the administration of i.v. trastuzumab every 2 weeks (in contrast with the standard schedule of weekly or q 3-weeks). Despite all these comments, the question on whether there is a patient group for which shorter duration of adjuvant trastuzumab might suffice is still open. Together with the PERSEPHONE (NCT00712140) (planned accrual 4000 patients, 6 versus 12 months), SHORT-HER (NCT00629278) (planned accrual 1250 patients, 3 versus 12 months) and SOLD (NCT00593697) (planned accrual 3000 patients, 9 versus 12 months), the HORG trial is one of the studies assessing a shorter duration of trastuzumab therapy in women with HER2-positive breast cancer. A direct randomized comparison of 6 versus 12 months of trastuzumab was also undertaken by the PHARE investigators, and the results for 3380 patients at 42.5 months of median follow-up has been reported [8.Pivot X. Romieu G. Deblet 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 (269) Google Scholar]. The results of the PHARE trial showed that 6 months of trastuzumab were non-inferior to 12 months (HR 1.28, 95% CI 1.05–1.56, P = 0.29 for a non-inferiority HR of 1.15). In the PHARE trial, patients with oestrogen receptor (ER)-negative tumours treated with 6 months of sequential trastuzumab chemotherapy had significantly shorter DFS than did patients with ER-negative tumours treated with 12 months of sequential trastuzumab chemotherapy (HR 1.57, 95% CI 1.08–2.28). In patients with ER-negative tumours who received concurrent chemotherapy and trastuzumab in the PHARE trial, the estimate of 6 versus 12 months of trastuzumab was the most compatible with the non-inferiority hypothesis (HR 1.10, 95% CI 0.73–1.65). In the HORG trial, the benefit of longer trastuzumab administration almost reached statistical significance (HR = 2.20, 95% CI 0.91–5.31) for patients with ER-positive tumours. Hormone receptor (HR) status identifies and represents a substantially different underlying biology and ability to respond to trastuzumab. Therefore, in the group of ER-negative/HER2-positive tumours, most of the adjuvant effects might occur early during therapy, possibly during the concurrent administration of chemotherapy and trastuzumab. Indeed, 3–6 months of chemotherapy and HER2-targeting agents (including dual targeting) administered in the neoadjuvant setting yielded the highest rates of pathological complete response respect to HR-positive/HER2+ breast cancer, a well-recognized surrogate of long-term clinical benefit [9.Gianni L. Pienkowski T. Im Y.H. Roman L. et al.Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.Lancet Oncol. 2012; 13: 25-32Abstract Full Text Full Text PDF PubMed Scopus (1589) Google Scholar]. Pre-defined subgroup analyses by HR status in the HERA trial have intriguing results. Within the cohort of patients with HR-positive disease, the second year of treatment can be taken as a comparison between endocrine treatment plus trastuzumab versus endocrine therapy alone [6.Goldhirsch A. Gelber R.D. Piccart-Gebhart M.J. et al.for the Herceptin Adjuvant (HERA) Trial Study Team. 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 (403) Google Scholar]. In contrast, for the HR-negative cohort treatments during the second year included either trastuzumab alone or no further adjuvant treatment. The temporary and not statistically significant separation of the curves in favour of 2 years of trastuzumab in the HR-negative cohort is indicative of an increased short-term risk of relapse in the patients of the control group, who did not receive any adjuvant therapy during that time. In contrast, the pattern of relapse in the HR-negative cohort receiving a second year of trastuzumab closely resembles that observed also in patients with HR-positive disease [6.Goldhirsch A. Gelber R.D. Piccart-Gebhart M.J. et al.for the Herceptin Adjuvant (HERA) Trial Study Team. 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 (403) Google Scholar]. In order to pursue similar subgroup analyses, the magnitude of benefit of trastuzumab therapy was evaluated in patient sub-populations of the PHARE trial, defining a prognostic score by steroid HRs, nodal involvement, tumour size, histological grade, the presence of inflammatory disease and age [10.Kramar A. Bachelot T. Madrange N. et al.Trastuzumab duration effects within patient prognostic subgroups in the PHARE trial.Ann Oncol. 2014; 25: 1563-1570Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. The 6-month trastuzumab arm was used as a validation set in order to test for heterogeneity. In the very low-risk group, only 23 events were observed, for an estimated overall 3-year cumulative incidence for metastases of only 1.7%. In the high-risk group, representing 10% of patients, 78 metastatic events were observed, for an estimated overall 3-year cumulative incidence for metastases of 23.6%. During the validation step in the 6-month treatment arm, HR status added information to the score: it was related to metastasis-free survival (MFS) in the very low-risk group (HR = 0.07; 95% CI 0.01–0.55, P = 0.001). In the very low-risk category, there were 4.3% events (9/212) in the HR-negative group versus 0.3% events (1/340) in the HR-positive group. On the other hand, there was no impact on MFS in the 12-month arm for the very low-risk group: 2.5% (5/202) versus 2.3% (8/350) in HR-negative and -positive subgroups, respectively. Thus, in this very low-risk group, the potential absolute benefit of standard duration of trastuzumab was small enough to indicate that optimal standard treatment might be clinically questionable. No single standard treatment exists for patients with small, node-negative, HER2-positive breast cancers. In a recent trial among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of ∼2% [11.Tolaney S.M. Barry W.T. Dang C.T. et al.Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.N Engl J Med. 2015; 372: 134-141Crossref PubMed Scopus (479) Google Scholar]. The study population in this trial had a higher proportion of HR-positive tumours (67%). Are combinations of endocrine agents and HER2-targeting agents can be currently considered in the adjuvant setting for this sub-population of patients? What are the possible future developments of this therapeutic approach? Is it possible to combine trastuzumab to endocrine therapy and other targeted agents (mTOR inhibitor or PIK3CA inhibitors)? Is it possible to consider a chemo-free regimen with dual anti-HER2-targeting and endocrine therapy? This hypothesis was explored in three trials conducted in patients with locally advanced and/or metastatic breast cancer [12.Kaufman B. Mackey J.R. Clemens M.R. et al.Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.J Clin Oncol. 2009; 27: 5529-5537Crossref PubMed Scopus (681) Google Scholar, 13.Johnston S. Pippen Jr, J. Pivot X. et al.Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.J Clin Oncol. 2009; 27: 5538-5546Crossref PubMed Scopus (870) Google Scholar, 14.Huober J. Fasching P.A. Barsoum M. et al.Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer—results of the eLEcTRA trial.Breast. 2012; 21: 27-33Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. While the ‘Trastuzumab and Anastrozole Directed Against ER-Positive HER2-Positive Mammary Carcinoma’ (TanDEM) and the ‘Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer’ (eLEcTRA) studies were phase III randomized trials conducted in HER2-positive/ER-positive breast cancer patients, the ‘EGF30008’ study was conducted in 1286 women with HR-positive breast cancer patients not selected on the basis of their HER2 status [13.Johnston S. Pippen Jr, J. Pivot X. et al.Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.J Clin Oncol. 2009; 27: 5538-5546Crossref PubMed Scopus (870) Google Scholar]. The three trials provided consistent results, indicating that the combination of an anti-HER2 agent and an AI significantly improved response rates, clinical benefit rate and PFS, compared with endocrine therapy alone. A randomized phase II study comparing pertuzumab in combination with trastuzumab plus an aromatase inhibitor or trastuzumab alone plus an aromatase inhibitor in patients with HR-positive, HER2-positive metastatic breast cancer (PERTAIN) completed the accrual. It is not appropriate to extrapolate data from the metastatic into the adjuvant setting but it is reasonable to presume that, for patients with low-risk HER2-positive breast cancer (stage I, high expression or ER and progestinic receptor), the optimum duration of adjuvant trastuzumab remains unknown and, perhaps, a shorter duration may be explored in clinical trials. The results of PERSEPHONE, SHORT-HER and SOLD trials will provide information on shorter durations of adjuvant trastuzumab. Furthermore, studies investigating dual HER2 blockade will probably lead to further improvement of treatment outcome of adjuvant treatment of HER2-positive breast cancer. The authors have declared no conflicts of interest.