Molecular Pathway Activation Markers Are Associated with Efficacy of Trastuzumab Therapy in Metastatic HER2-Positive Breast Cancer Better than Individual Gene Expression Levels

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M. Sorokin^1,2,3, K. Ignatev⁴, V. Barbara⁴, U. Vladimirova^1,3, A. Muraveva³, M. Suntsova¹, N. Gaifullin⁵, I. Vorotnikov⁶, D. Kamashev^1,3, A. Bondarenko⁷, M. Baranova^7,8, E. Poddubskaya^3,7, and A. Buzdin^1,2,3,9,a*

¹Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

²OmicsWay Corp., Walnut, 91789 CA, USA

³Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia

⁴Republican Oncological Dispensary, 185002 Petrozavodsk, Karelia Republic, Russia

⁵Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia

⁶Blokhin Russian Cancer Research Center, 115478 Moscow, Russia

⁷Vitamed Oncological Clinics, Moscow, Russia

⁸Petrovsky Russian Research Center of Surgery, 119991 Moscow, Russia

⁹Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia

^* To whom correspondence should be addressed.

Received March 31, 2020; Revised May 29, 2020; Accepted May 31, 2020

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Increased expression or amplification of HER2 receptor tyrosine kinase gene ERBB2 is well-known and widely used as a prognostic biomarker of breast cancer (BC) response to the targeted treatment with trastuzumab and its analogs. Considering that part of the BC patients overexpressing HER2 does not respond to trastuzumab, clinical trial NCT03521245 was initiated to identify additional gene expression and molecular pathway activation response biomarkers to trastuzumab treatment in HER2-positive BC. Using RNA sequencing gene expression in 23 formalin-fixed, paraffin embedded HER2 positive BC tissue blocks from patients who either responded or not responded to trastuzumab treatment was profiled. Differentially regulated genes and molecular pathways were identified in the groups of trastuzumab responders and non-responders. These results were next compared with the 42 previously published BC trastuzumab responder and non-responder RNA sequencing profiles from the clinical trials NCT00513292 and NCT00353483. No correlation was observed between the response status and the expression levels of ERBB2 gene in the HER2 positive BC samples. Analysis of the differentially expressed genes and molecular pathways in the combined dataset revealed 15/27 commonly up/down regulated genes and 15/25 pathways, respectively. However, only the intersection of molecular pathways upregulated in trastuzumab responders vs non-responders was statistically significantly enriched compared to the random expectation model. A classifier built using the most significantly upregulated molecular pathway – cAMP Pathway Protein Retention – demonstrated the best performance for prediction of the HER2 positive BC response to trastuzumab for both our experimental and previously reported data. This pathway also predicted time to recurrence in the combined dataset with Log-rank p-value 0.041.

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KEY WORDS: breast cancer, HER2, ERBB2, transcriptomics, RNA sequencing, trastuzumab, targeted therapy, personalized medicine, NCT03521245

DOI: 10.1134/S0006297920070044

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