Original Research| Volume 181, P92-101, March 2023

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Ten-year survival of neoadjuvant dual HER2 blockade in patients with HER2-positive breast cancer

Published:January 09, 2023DOI:


      • Neoadjuvant lapatinib and/or trastuzumab treatment optimisation is the longest-lasting neoadjuvant study in human epidermal growth factor receptor-2 (HER2)-positive breast cancer.
      • Patients with pathological complete response (pCR) show better survival than those without pCR.
      • This gain is especially seen in hormone-receptor-negative or dual anti-HER2 subgroups.
      • pCR benefit is durable as hazard risk is low (er) even after 5–10 years from surgery.



      Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR.


      Neoadjuvant lapatinib and/or trastuzumab treatment optimisation (NCT00553358) is an international, randomised, open-label, phase III study investigating the addition of lapatinib to chemotherapy plus trastuzumab in HER2-positive early BC. Ten-year event-free survival (EFS), overall survival (OS) and safety were assessed on intention-to-treat population. The association between pCR and EFS or OS was investigated in landmark population.


      A total of 455 patients were randomised to receive lapatinib (154), trastuzumab (149) or the combination (152). Ten-year EFS estimates were 63% (95% confidence interval [CI], 54%–71%) in the lapatinib group, 64% (95% CI, 55%–72%) in the trastuzumab group and 67% (95% CI, 58%–74%) in the combination group. Ten-year OS rates were 76% (95% CI, 67%–83%), 75% (95% CI, 66%–82%) and 80% (95% CI, 73%–86%) in the lapatinib, trastuzumab and combination groups, respectively. Women who achieved a pCR had improved EFS (hazard ratio 0.48, 95% CI, 0.31–0.73) and OS (hazard ratio 0.37, 95% CI, 0.20–0.63) compared with those who did not. The numerical difference in survival according to pCR status was greater in women treated with the combination and those with hormone-receptor-negative tumours. There were no new or long-term safety concerns.


      Patients with HER2-positive BC showed a durable survival benefit of neoadjuvant anti-HER2, irrespective of treatment arm. Patients who achieve pCR have significantly better outcomes than patients without pCR.


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        • Baselga J.
        • Bradbury I.
        • Eidtmann H.
        • et al.
        Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
        Lancet. 2012; 379: 633-640
        • Gianni L.
        • Pienkowski T.
        • Im Y.H.
        • 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: 25-32
        • Robidoux A.
        • Tang G.
        • Rastogi P.
        • et al.
        Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial.
        Lancet Oncol. 2013; 14: 1183-1192
        • Guarneri V.
        • Dieci M.v.
        • Griguolo G.
        • et al.
        Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: survival analyses of the CHER-Lob trial.
        Eur J Cancer. 2021; 153: 133-141
        • 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: 1137-1146
        • Huober J.
        • Holmes E.
        • Baselga J.
        • et al.
        Survival outcomes of the NeoALTTO study (BIG 1–06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer.
        Eur J Cancer. 2019; 118: 169-177
        • Anderson J.R.
        • Cain K.C.
        • Gelber R.D.
        Analysis of survival by tumor response and other comparisons of time-to-event by outcome variables.
        J Clin Oncol. 2008; 26: 3913-3915
        • Chumsri S.
        • Li Z.
        • Serie D.J.
        • et al.
        Incidence of late relapses in patients with HER2-positive breast cancer receiving adjuvant trastuzumab: combined analysis of NCCTG N9831 (alliance) and NRG Oncology/NSABP B-31.
        J Clin Oncol. 2019; 37: 3425-3435
        • 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: 164-172
        • Broglio K.R.
        • Quintana M.
        • Foster M.
        • et al.
        Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes.
        JAMA Oncol. 2016; 2: 751
        • Spring L.M.
        • Fell G.
        • Arfe A.
        • et al.
        Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis.
        Clin Cancer Res. 2020; 26: 2838-2848
        • Schettini F.
        • Pascual T.
        • Conte B.
        • et al.
        HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: a systematic review and meta-analysis.
        Cancer Treat Rev. 2020; 84101965
        • Scaltriti M.
        • Nuciforo P.
        • Bradbury I.
        • et al.
        High HER2 expression correlates with response to the combination of lapatinib and trastuzumab.
        Clin Cancer Res. 2015; 21: 569-576
        • Carey L.A.
        • Berry D.A.
        • Cirrincione C.T.
        • et al.
        Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib.
        J Clin Oncol. 2016; 34: 542-549
        • Fumagalli D.
        • Venet D.
        • Ignatiadis M.
        • et al.
        RNA sequencing to predict response to neoadjuvant anti-HER2 therapy.
        JAMA Oncol. 2017; 3: 227
        • Salgado R.
        • Denkert C.
        • Campbell C.
        • et al.
        Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab.
        JAMA Oncol. 2015; 1: 448
        • Denkert C.
        • von Minckwitz G.
        • Darb-Esfahani S.
        • et al.
        Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy.
        Lancet Oncol. 2018; 19: 40-50
        • Guarneri V.
        • Frassoldati A.
        • Bottini A.
        • et al.
        Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2–positive operable breast cancer: results of the randomized phase II CHER-LOB study.
        J Clin Oncol. 2012; 30: 1989-1995
        • Fernandez-Martinez A.
        • Krop I.E.
        • Hillman D.W.
        • et al.
        Survival, pathologic response, and genomics in CALGB 40601 (alliance), a neoadjuvant phase III trial of paclitaxel-trastuzumab with or without lapatinib in HER2-positive breast cancer.
        J Clin Oncol. 2020; 38: 4184-4193
        • Piccart-Gebhart M.
        • Holmes E.
        • Baselga J.
        • et al.
        Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2–positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
        J Clin Oncol. 2016; 34: 1034-1042