HER2 heterogeneity and treatment response–associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial
Zheqi Li, Otto Metzger Filho, Giuseppe Viale, Patrizia dell’Orto, Leila Russo, Marie-Anne Goyette, Avni Kamat, Denise A. Yardley, Vandana Gupta Abramson, Carlos L. Arteaga, Laura M. Spring, Kami Chiotti, Carol Halsey, Adrienne G. Waks, Tari A. King, Susan C. Lester, Jennifer R. Bellon, Eric P. Winer, Paul T. Spellman, Ian E. Krop, Kornelia Polyak
Zheqi Li, Otto Metzger Filho, Giuseppe Viale, Patrizia dell’Orto, Leila Russo, Marie-Anne Goyette, Avni Kamat, Denise A. Yardley, Vandana Gupta Abramson, Carlos L. Arteaga, Laura M. Spring, Kami Chiotti, Carol Halsey, Adrienne G. Waks, Tari A. King, Susan C. Lester, Jennifer R. Bellon, Eric P. Winer, Paul T. Spellman, Ian E. Krop, Kornelia Polyak
View: Text | PDF
Clinical Research and Public Health Oncology

HER2 heterogeneity and treatment response–associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial

Abstract

BACKGROUND HER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODS To investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTS Pretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSION Resistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATION ClinicalTrials.gov NCT02326974.FUNDING This study was funded by Roche and the National Cancer Institute.

Authors

Zheqi Li, Otto Metzger Filho, Giuseppe Viale, Patrizia dell’Orto, Leila Russo, Marie-Anne Goyette, Avni Kamat, Denise A. Yardley, Vandana Gupta Abramson, Carlos L. Arteaga, Laura M. Spring, Kami Chiotti, Carol Halsey, Adrienne G. Waks, Tari A. King, Susan C. Lester, Jennifer R. Bellon, Eric P. Winer, Paul T. Spellman, Ian E. Krop, Kornelia Polyak

×

Figure 1

Transcriptional differences based on HER2 heterogeneity and response to treatment.

Options: View larger image (or click on image) Download as PowerPoint
Transcriptional differences based on HER2 heterogeneity and response to ...
(A) Schematic outline of the clinical trial and sample collection. (B) PCA plot depicting transcriptome variation of 242 pretreatment samples colored on the basis of HER2 heterogeneity and pCR status. (C) Box plots depicting ERBB2 mRNA expression in the indicated groups at patient level using the mean expression of 2 biopsies from the same patient. (D) Scatterplot showing the correlation of RCB score and ERBB2 expression in tumors assessed at patient level. (E) Volcano plots illustrating differentially expressed genes (DEGs) between pretreatment samples from the indicated comparisons. Top DEGs are indicated. (F) Box plots showing enrichment scores of 4 different ERBB/PI3K pathway signatures in HER2 non-HET/pCR, non-HET/no pCR, and HET/no pCR patients. Mean scores of 2 pretreatment biopsies from the same patient were used. (G) Heatmap depicting relative expression of KEGG ERBB signaling signature genes in HER2-HET and non-HET samples without pCR normalized to pCR samples. Genes are ordered from commonly different in the 2 groups compared with pCR cases to uniquely different in the HET and non-HET groups. P values were calculated based on 2-tailed Mann-Whitney U test (C and F) and Pearson’s correlation (D).