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

Abstract

Purpose: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.

Methods: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia.

Results: 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 recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively.

Conclusion: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Trial registration: ClinicalTrials.gov NCT01853748.

FIG 1.

CONSORT diagram. T-DM1, trastuzumab emtansine; TH, paclitaxel plus trastuzumab.

FIG 2.

Survival outcomes in the T-DM1 arm in terms of (A) iDFS, (B) RFI, (C) OS, and (D) BCSS. Outstanding long-term outcomes were observed among patients with stage I HER2-positive breast cancer receiving adjuvant T-DM1, with a 5-year iDFS of 97.0%, and only three distant recurrences were observed among 383 patients treated in the study arm. BCSS, breast cancer–specific survival; HER2, human epidermal growth factor receptor 2; iDFS, invasive disease-free survival; RFI, recurrence-free interval; T-DM1, trastuzumab emtansine.

FIG 3.

Survival outcomes in the T-DM1 arm by tumor size ((A) iDFS), hormone receptor status ((B) iDFS), HER2 IHC score ((C) iDFS, (D) RFI), and exposure of T-DM1 for more or <26 weeks ((E) iDFS, (F) RFI). Comparable survival outcomes were observed among patients with stage I HER2-positive breast cancer receiving adjuvant T-DM1 irrespective of the baseline tumor size, hormone receptor status, HER2 IHC score, and exposure to more or less than 26 weeks of T-DM1. HER2, human epidermal growth factor receptor 2; iDFS, invasive disease-free survival; RFI, recurrence-free interval.

FIG 4.

The HER2DX risk score predicts the risk of recurrence in ATEMPT. (A) Distribution of the HER2DX risk score, pCR score, and main biologic features captured by HER2DX, including the expression of HER2 mRNA, the luminal signature, the proliferation signature, and the IgG signature. (B) HER2DX risk score ranking and association with iDFS events and RFI events. Five-year (C) iDFS and (D) 5-year RFI, stratified by HER2DX risk group. Compared with patients having HER2DX high-risk disease (n = 12, 6.4%), those with HER2DX low-risk disease (n = 175, 93.6%) had significantly better 5-year RFI (98.1% v 81.8%, HR, 0.10 [95% CI, 0.02 to 0.57], P = .01) and 5-year iDFS (96.3% v 81.8%, HR, 0.20 [95% CI, 0.04 to 0.98], P = .047). HER2, human epidermal growth factor receptor 2; HR, hazard ratio; iDFS, invasive disease-free survival; IgG, immunoglobulin G; pCR, pathologic complete response; ref., reference; RFI, recurrence-free interval.

FIG 5.

Machine learning–assisted analysis of HER2 expression patterns. (A and B) Machine learning–derived HER2 stain intensity variability in the (A) overall population and (B) by study arm. (C and D) Percentage of tumor cells exhibiting intense and complete HER2 staining or weak and incomplete HER2 staining depending on (C) ER expression and (D) PR expression. (E) Distribution of tumor cells with different HER2 staining intensities among patients experiencing RFI events in each study arm. (F) Examples of tumors exhibiting high entropy (left panel, entropy = 1.55, ie, high HER2 heterogeneity) and low entropy (right panel, entropy = 0.39, ie, low HER2 heterogeneity). The colors of the dots in each cell represent different staining intensities and completeness, as defined in Figure 2A. Entropy distribution (ie, level of HER2 heterogeneity) according to (G) the ER expression and (H) PR expression of the tumor, (I) according to the recurrence status overall, and (J) depending on the study arm. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; RFI, recurrence-free interval; T-DM1, trastuzumab emtansine; TH, paclitaxel plus trastuzumab.

FIG 6.

Characterization of HER2 genetic heterogeneity through single-cell FISH. (A and B) Rates of recurrence by the presence or absence of HER2 genetic heterogeneity in (A) the overall case-control study population and (B) only among patients receiving adjuvant T-DM1. (C) Example of HER2 heterogenous cases with dissection in populations of cells (in terms of absolute numbers and percentage) having different HER2 ratios and copy numbers. (D) Example of HER2 nonheterogenous case with dissection in populations of cells (in terms of absolute numbers and percentage) having different HER2 ratios and copy numbers. H, copy number; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; Perc., percentage; R, ratio; T-DM1, trastuzumab emtansine.