HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Abstract

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.

Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.

Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).

Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.

Figure 1.

ERBB2 vs intrinsic subtypes in the combined neoadjuvant HER2-positive dataset (n = 265). A) Distribution of the intrinsic subtypes in all patients and based on hormone receptor status. B) Distribution of tumor samples based on ERBB2 mRNA levels. C) Distribution of HER2-E subtype within ERBB2-high and ERBB2-low groups. HER2-E= HER2-enriched; HR + hormone receptor.

Figure 2.

HER2-E/ERBB2-high biomarker in the EGF104900 trial of advanced HER2-positive breast cancer. A) Progression-free survival (PFS). B) Overall survival (OS). C) PFS according to treatment arm. D) OS according to treatment arm. Estimates of PFS and OS were from Kaplan–Meier curves and tests of differences by two-sided log-rank test. HER2-E = HER2-enriched; HER2-E/ERBB2-high = HER2-enriched and ERBB2-high group; T = trastuzumab; L = lapatinib.

Figure 3.

HER2-E/ERBB2-high biomarker in patients with HER2-positive breast cancer. A) Proportion of patients according to intrinsic subtype and ERBB2 levels. B) Schematic view of the four potential cell signaling scenarios (HER2 and its downstream signaling activation, such as the RAS/MAPK pathway) identified within HER2-positive breast cancer based on ERBB2 mRNA levels and intrinsic subtype (HER2-E vs non-HER2-E). In HER2-E/ERBB2-low disease, it is plausible that another transmembrane growth factor receptor with kinase activity such as FGFR4 is driving the HER2-E phenotype either alone or in combination with HER2. HER2-E = HER2-enriched; HER2-E/ERBB2 = HER2-E and ERBB2 group; HR + hormone receptor; MAPK = mitogen-activated protein kinase.