Final analysis of the ATEMPT study confirms the outstanding efficacy of trastuzumab emtansine (T-DM1) at preventing recurrences of stage I HER2-positive breast cancer, with a 5-year recurrence-free interval (RFI) of 98.3%. Based on the excellent long-term outcomes and favourable tolerability, one year of adjuvant T-DM1 represents an alternative treatment option to 12 weeks of adjuvant paclitaxel combined with one year of trastuzumab for patients with stage I HER2-positive breast cancer.
A comprehensive assessment of the tumour biology with the HER2DX tool showed that a pre-established risk score threshold was able to discriminate a small proportion of patients (6.4%) with significantly higher risk of recurrence in the ATEMPT study. This finding and the results from the APT study underscore the promise of HER2DX in tailoring treatments for patients with early-stage HER2-positive tumours, warranting prospective validation according to Dr. Sara M. Tolaney of the Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center, Harvard Medical School in Boston, MA, US and colleagues from the Translational Breast Cancer Research Consortium (TBCRC), who published the findings on 27 June 2024 in the JCO.
Patients with stage I HER2–positive breast cancer have recurrence rates ranging between 5% and 30%, supporting the administration of adjuvant systemic therapy. The APT study found that 12 weeks of adjuvant paclitaxel, combined with one year of trastuzumab, was associated with a 10-year invasive disease-free survival (iDFS) of 91.3% for patients with small node-negative HER2-positive tumours. Although adjuvant paclitaxel combined with trastuzumab is less toxic than trastuzumab combined with poly-chemotherapy regimens, it is still associated with adverse events that can affect quality-of-life including fatigue, neutropenia, peripheral neuropathy, and alopecia. Optimising adjuvant treatment remains an area of active interest in this setting.
The authors wrote in the background that T-DM1 is currently approved for the adjuvant treatment of patients with HER2-positive breast cancer with residual invasive disease after neoadjuvant treatment or with metastatic disease, and in the metastatic setting, it has shown similar efficacy with lower toxicity compared with trastuzumab plus taxane. The randomised phase II ATEMPT study was designed to evaluate the activity of one year of adjuvant T-DM1 and to compare the rate of clinically relevant toxicities with that of adjuvant regimen of paclitaxel combined with trastuzumab in patients with stage I centrally confirmed HER2-positive breast cancer.
Patients were randomly assigned 3:1 to adjuvant T-DM1 for one year or paclitaxel combined with trastuzumab. Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive iDFS with T-DM1 In the initial analysis, T-DM1 resulted in 3-year iDFS of 97.8% (95% confidence interval [CI] 96.3 to 99.3), which rejected the null hypothesis for efficacy (p < 0.001). The rate of clinically relevant toxicities was 46% for patients on T-DM1 and 47% for patients on adjuvant paclitaxel combined with trastuzumab (p = 0.83).
In this final preplanned analysis, the investigators report the 5-year survival outcomes for patients enrolled in ATEMPT and conduct a multidimensional assessment of HER2 heterogeneity, evaluated through machine learning algorithms, single-cell fluorescence in situ hybridisation (FISH), spatial proteomics, and the HER2DX genomic assay. They also investigated genomic correlates of thrombocytopenia or bleeding with T-DM1 through germline whole-genome sequencing (WGS).
After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI 95.2 to 98.7). At 5 years, the RFI was 98.3% (95% CI 97.0 to 99.7), the overall survival 97.8% (95% CI 96.3 to 99.3), and the breast cancer-specific survival 99.4% (95% CI 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumour size, hormone receptor status, centrally determined HER2 immunohistochemical (IHC) score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this endpoint, the 5-year iDFS was 91.1% in the arm of adjuvant paclitaxel combined with trastuzumab.
Among 187 patients with sufficient tissue for HER2DX testing, 5-year outcomes significantly differed according to HER2DX risk score, with better RFI, 98.1% versus 81.8% (hazard ratio [HR] 0.10; p = 0.01) and iDFS, 96.3% versus 81.8% (HR 0.20; p = 0.047) among patients with HER2DX low-risk versus high-risk tumours.
Despite favourable long-term outcomes observed with deescalated regimens, a small number of recurrences were still observed in APT and ATEMPT, irrespective of the tumour size, HER2 IHC score, and hormone receptor status of the disease. How standard clinicopathologic features alone were not able to identify higher-risk tumours, the ATEMPT investigators conducted multiomic analyses to evaluate innovative prognostic and predictive biomarkers in this setting. The presence of HER2 heterogeneity has been previously associated with the lack of response to T-DM1, so they focused on this feature, evaluated through comprehensive genomic and proteomic analyses and through novel machine learning-based algorithms.
Single-cell FISH analysis confirmed that HER2 heterogenous tumours account for a minority of HER2-positive tumours, representing approximately 8% in ATEMPT. However, this feature had no significant impact on survival outcomes. Even when assessed through machine learning-based algorithms and using spatial proteomic analyses, HER2 heterogeneity did not show a clear relationship with survival although the small number of recurrences provided limited power for these analyses.
In addition to looking at HER2 heterogeneity andHER2DX, the study team used spatial proteomic analyses to identify biomarkers associated with a higher risk of recurrence. NF1 and CTLA4 were found to be overexpressed in primary tumours of patients experiencing ipsilateral or contralateral events, whereas most proteins found to be upregulated in controls are associated either with the activation of the apoptotic pathway (Cleaved Caspase 9) or with immune activation (CD25, ICOS, GITR, and GZMB), suggesting that an active antitumour immune response, inducing a higher degree of apoptosis among cancer cells, may signal a better prognosis.
No germline genomic variants predictive of thrombocytopenia and bleeding with T-DM1 could be identified in the study, possibly because of little statistical power or the complex, multifactorial mechanism of T-DM1–induced thrombocytopenia.
To further improve treatment tolerability, a randomised phase II ATEMPT 2.0 study is testing a shorter course of six cycles of adjuvant T-DM1 for stage I HER2-positive breast cancer. In addition, the phase II ADEPT study is testing the chemotherapy-free regimen of endocrine treatment plus subcutaneous trastuzumab plus pertuzumab for stage I, hormone receptor-positive/HER2-positive breast cancer.
The study findings were previously presented on 9 December 2022 at the San Antonio Breast Cancer Symposium in San Antonio, TX, US.
The study was supported by Genentech and the Gloria Spivak Faculty Advancement Fund. The authors acknowledged the funding support to the TBCRC from The Breast Cancer Research Foundation and Susan G. Komen for translational analyses from MLSC Women's Health Collaboration.
Reference
Tarantino P, Tayob N, Villacampa G, et al. on behalf of the Consortium of the TBCRC Translational Investigators. Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT. JCO; Published online 27 June 2024. DOI: https://doi.org/10.1200/JCO.23.02170