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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.

SUBMITTER: Prat A 

PROVIDER: S-EPMC7850037 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Prat Aleix A   Pascual Tomás T   De Angelis Carmine C   Gutierrez Carolina C   Llombart-Cussac Antonio A   Wang Tao T   Cortés Javier J   Rexer Brent B   Paré Laia L   Forero Andres A   Wolff Antonio C AC   Morales Serafín S   Adamo Barbara B   Brasó-Maristany Fara F   Vidal Maria M   Veeraraghavan Jamunarani J   Krop Ian I   Galván Patricia P   Pavlick Anne C AC   Bermejo Begoña B   Izquierdo Miguel M   Rodrik-Outmezguine Vanessa V   Rodrik-Outmezguine Vanessa V   Reis-Filho Jorge S JS   Hilsenbeck Susan G SG   Oliveira Mafalda M   Dieci Maria Vittoria MV   Griguolo Gaia G   Fasani Roberta R   Nuciforo Paolo P   Parker Joel S JS   Conte PierFranco P   Schiff Rachel R   Guarneri Valentina V   Osborne C Kent CK   Rimawi Mothaffar F MF  

Journal of the National Cancer Institute 20200101 1


<h4>Background</h4>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.<h4>Methods</h4>A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA  ...[more]

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