ER+/HER2+ breast cancer: are we really de-escalating?
Authors: E. de Azambuja, M. Piccart-Gebhart
Journal: Annals of Oncology (2019)

The outcome of women with early breast cancer (BC) has gradually improved in the last 15 years following the introduction of trastuzumab and subsequently dual blockade (trastuzumab-pertuzumab or trastuzumab followed by neratinib) [1.von Minckwitz G. Procter M. de Azambuja E. et al.Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.N Engl J Med. 2017; 377: 122-131Crossref PubMed Scopus (833) Google Scholar, 2.Martin M. Holmes F.A. Ejlertsen B. et al.Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1688-1700Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar]. In the latest pivotal adjuvant trial, Aphinity, in which 60% of patients had node-positive disease, the rate of invasive disease-free survival (iDFS) in the control arm (chemotherapy + trastuzumab) was over 90% at a median follow-up of 45 months [1.von Minckwitz G. Procter M. de Azambuja E. et al.Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.N Engl J Med. 2017; 377: 122-131Crossref PubMed Scopus (833) Google Scholar]. Medical oncologists are now starting to worry about potential patient overtreatment and the last few years have witnessed a growing number of trials investigating ‘de-escalation’ in terms of chemotherapy (e.g. omitting anthracyclines or replacing chemotherapy by endocrine therapy in case of hormone-receptor positive disease) or in terms of anti-human epidermal growth factor receptor 2 (HER2) duration (9 weeks or 3 or 6 months instead of the standard 12-month duration) [3.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, 4.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; 29: 2328-2333Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 5.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, 6.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, 7.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]. The first successful de-escalation attempt is the APT trial which consisted in a single-arm adjuvant approach based on 12 weeks of paclitaxel with 12 months of trastuzumab tested in a carefully selected ‘low-risk’ population [based on disease burden, namely small tumours (mostly T1) with node-negative disease] [8.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 (495) Google Scholar, 9.Tolaney S.M. Guo H. Pernas S. et al.Seven-year follow-up of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer.J Clin Oncol. 2019 Apr 2Crossref Scopus (164) Google Scholar]. The excellent 7-year iDFS rate of 93.3% (95% confidence interval: 90.4–96.2) has led to the endorsement of this regimen by most guidelines for women with stage I HER2-positive early BC. The neoadjuvant approach is the obvious next step on the path towards de-escalation of drug treatment. Indeed, its intermediate surrogate end point of pathological complete response (pCR) allows oncologists to identify patients who are likely to do very well from those with a much worse prognosis [10.Cortazar P. Zhang L. Untch M. et al.Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.Lancet. 2014; 384: 164-172Abstract Full Text Full Text PDF PubMed Scopus (2613) Google Scholar]. While the former group is the logical target for de-escalation, the latter needs further trials. The recently reported Katherine trial is practice changing, as it unequivocally shows that T-DM1 is the ‘salvage’ drug for these patients, improving their 3-year iDFS by 11.3% compared with the continuation of trastuzumab [11.von Minckwitz G. Huang C.-S. Mano M.S. et al.Trastuzumab emtansine for residual invasive HER2-positive breast cancer.N Engl J Med. 2019; 380: 617-628Crossref PubMed Scopus (1114) Google Scholar]. Of note, the pre-surgical treatment in Katherine was chemotherapy-based and included trastuzumab with or without pertuzumab. Could patients with HER2+/ER+ disease be ‘de-escalated’ through the use of endocrine therapy with the adjunction of dual HER2 blockade instead of chemotherapy? In this issue of Annals of Oncology, two trials attempt to study this approach: PerELISa and TBCRC006. In the article by Guarneri et al. [12.Guarneri V. Dieci M.V. Bisagni G. et al.De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study.Ann Oncol. 2019; 30: 921-926Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar], authors selected an approach of identifying molecular responders and non-responders based on a 2-week assessment of Ki67 relative reduction >20% from baseline after treatment with letrozole. Molecular responders (44 out 64) continued with letrozole and trastuzumab-pertuzumab for five cycles until surgery whereas molecular non-responders received 13 weeks of paclitaxel and trastuzumab-pertuzumab. pCR rate was 20.5% and 81.3% for molecular responders and non-responders, respectively (pCR of 45.5% in molecular responders and HER2-enriched subtype). The authors concluded that Ki67 reduction after short letrozole exposure can identify patients to whom a meaningful pCR rate can be obtained without chemotherapy. In the second article by Veeraraghavan et al. [13.Veeraraghavan J. De Angelis C. Mao R. et al.A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.Ann Oncol. 2019; 30: 927-933Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar], baseline tumours from patients with ER+/HER2+ early BC treated with neoadjuvant endocrine therapy, lapatinib-trastuzumab for 12 weeks, were tested for HER2 amplification (FISH), HER2 copy number (CN) and FISH ratio and PI3KCA pathways status defined by PI3KCA mutation or PTEN loss. pCR was achieved in 23% of patients (13 of 56): 0 of 11 patients achieved pCR in case of a low HER2 ratio and/or CN whereas 29% pCR rate (13 of 45) was observed in patients with higher HER2 ratio and/or CN. Higher pCR rates were observed in patients whose tumours expressed high PTEN or PI3KCA WT and in patients with high HER2 ratio and intact PI3KCA pathway (39% and 44%, respectively). The authors concluded that a combination of HER2 FISH ratio and PI3KCA pathway status may help to identify patients who may be treated with anti-HER2-targeted therapy without chemotherapy. The merit of these two trials is to use biomarkers, and not disease burden, as a potential way to identify subpopulations adequately served by a chemotherapy-free regimen. In PerElisa, the Ki67 drop after 2 weeks of letrozole was used to eliminate patients unlikely to be very endocrine-sensitive (these patients received paclitaxel and dual anti-HER2 blockade and showed a high pCR rate), while maintaining the other patients in the de-escalation approach. The pCR rate of these molecular responders was, however, only 20.5%. In TBCRC006, a different combination of anti-HER2 drugs, namely trastuzumab and lapatinib combined with endocrine therapy, found a pCR rate in excess of 39% only in tumours with a high HER2 expression and no PI3K pathway alterations in retrospective biomarker analysis. The PAMELA trial tested a chemotherapy-free regimen containing lapatinib-trastuzumab and letrozole or tamoxifen for a total duration of 18 weeks. Patients with HER2-enriched tumours had a pCR rate of 41% compared with only 10% in other subtypes (P = 0.0004) [14.Llombart-Cussac A. Cortés J. Paré L. et al.HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial.Lancet Oncol. 2017; 18: 545-554Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar]. There are at least two serious limitations in these trials, which are shared by many other neoadjuvant approaches towards de-escalation [including the West German Study Group (WSG) trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) trial of T-DM1 ± endocrine therapy and the NA-PHER2 (Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer) trial of fulvestrant + palbociclib + trastuzumab-pertuzumab] [15.Nitz U.A. Gluz O. Christgen M. et al.De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel.Ann Oncol. 2017; 28: 2768-2772Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 16.Gianni L. Bisagni G. Colleoni M. et al.Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study.Lancet Oncol. 2018; 19: 249-256Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. First, they are not powered for event-free survival (EFS) which is the relevant end point for patients; second, post-surgical treatment in case of pCR was left at physician’s discretion and very often consisted of the addition of chemotherapy (this information, unfortunately, is often missing). Why is there reluctance to stop drug therapy in patients with pCR? One reason is the 10%–15% relapse rate of these patients reported in all neoadjuvant trials conducted for early HER2-positive BC [17.de Azambuja E. Holmes A.P. Piccart-Gebhart M. et al.Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response.Lancet Oncol. 2014; 15: 1137-1146Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 18.Gianni L. Pienkowski T. Im Y.-H. et al.5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.Lancet Oncol. 2016; 17: 791-800Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar, 19.Krop I.E. Hillman D. Polley M.-Y. et al.Abstract GS3-02: invasive disease-free survival and gene expression signatures in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab.Cancer Res. 2018; 78: GS3-G02Google Scholar, 20.Swain S.M. Tang G. Lucas P.C. et al.Intrinsic subtypes of HER2-positive breast cancer and their associations with pathologic complete response (pCR) and outcomes: findings from NSABP B-41, a randomized neoadjuvant trial.J Clin Oncol. 2018; 36: 580Crossref Google Scholar]. An ongoing meta-analysis of all neoadjuvant trials conducted for the BC subtype will try to identify risk factors for this relapse, but one can already hypothesize that ‘bulky disease’ upfront will be one of them. For all these reasons, new indications for drug treatment de-escalation in HER2-positive BC are not at the ‘door-step’. While we have better knowledge of the molecular subsets for de-escalation, we will need more ambitious ‘de-escalation’ neoadjuvant trials powered for EFS and requiring no chemotherapy administration in case of pCR. One innovative ongoing trial that satisfies some of the above criteria is the PHERGAIN study, in which patients will start with anti-HER2 drugs and endocrine therapy for two cycles. Those patients with PET response after two cycles will continue on trastuzumab-pertuzumab and endocrine therapy for six additional cycles. If pCR is found at surgery, patients will continue on the same treatment for 10 additional cycles. Long-term outcomes (3-year iDFS) will be assessed to ensure safety of the de-escalating approach (NCT03161353). In conclusion, we do believe that it is the right time to follow the example of our colleagues in the field of haematologic and pediatric cancers [21.Prince H.M. Kim Y.H. Horwitz S.M. et al.Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.Lancet. 2017; 390: 555-566Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 22.Mossé Y.P. Voss S.D. Lim M.S. et al.Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children’s Oncology Group Study.J Clin Oncol. 2017; 35: 3215-3221Crossref PubMed Scopus (249) Google Scholar] and explore de-escalation strategies for early HER2-positive BC patients. This exploration should ideally (i) be done separately for HER2+/ER+ and HER2+/ER- subsets; (ii) consist in trials adequately powered for EFS where post-surgical therapy is clearly defined; (iii) enrol patients who are clinically node negative; (iv) formulate biological hypothesis for hierarchical testing, where the primary statistical test is formulated for a biomarker-enriched population; (v) incorporate ‘on-treatment’ (imaging) biomarkers which may lead in the future to shorter exposure of patients to drugs unlikely to generate a pCR. None declared.