HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade
Menée à partir de l'analyse d'échantillons tumoraux prélevés sur 422 patientes atteintes d'un cancer du sein HER2+ de stade précoce et ayant reçu un traitement néo-adjuvant par lapatinib ou pertuzumab en combinaison avec le trastuzumab, cette étude évalue la possibilité d'utiliser un test déterminant à la fois le sous-type tumoral HER2-enrichi et le niveau d'expression de l'ARN messager du gène ERBB2 pour identifier les tumeurs hautement sensibles aux thérapies ciblant le récepteur HER2
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 5 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 : 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/ERBB2-high group showed a higher pCR rate compared to the rest (44.5% [95% CI = 35.4-53.9%] vs. 11.6% [95% CI = 6.9-18.0%]; adjusted odds ratio [OR]=6.05 [95%CI=3.10-11.80]; P<0.001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high [95% CI = 22.3-95.7%] vs. 14.7% in others [95% CI = 4.9-31.1%]; OR = 11.60, [95% CI 1.66-81.10]; p = 0.01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio=0.52 [95% CI = 0.35-0.79]; p < 0.001), higher ORR (16.3% [95% CI = 8.9-26.2%] vs. 3.7%; [95% CI = 0.8-10.3%]; p = 0.02) and longer OS (hazard ratio=0.66 [95% CI = 0.44-0.97]; p = 0.01).
Conclusions : Combining HER2-E subtype and ERBB2 mRNA into single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in ∼40% of patients with HER2-positive breast cancer.
Journal of the National Cancer Institute , résumé, 2018