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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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Abstract

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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Abbreviations

AUC:

area under ROC-curve

BC:

breast cancer

ER:

estrogen receptor

PAL:

pathway activation level

PR:

progesterone receptor

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This study was financially supported by the OmicsWay research program in oncology and by the Russian Science Foundation (project No. 18-15-00061, M. Su., M. So., U. V., and A. B.).

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Authors and Affiliations

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

    M. Sorokin, U. Vladimirova, M. Suntsova, D. Kamashev & A. Buzdin

  2. OmicsWay Corp., 91789, Walnut, CA, USA

    M. Sorokin & A. Buzdin

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

    M. Sorokin, U. Vladimirova, A. Muraveva, D. Kamashev, E. Poddubskaya & A. Buzdin

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

    K. Ignatev & V. Barbara

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

    N. Gaifullin

  6. Blokhin Russian Cancer Research Center, 115478, Moscow, Russia

    I. Vorotnikov

  7. Vitamed Oncological Clinics, 121309, Moscow, Russia

    A. Bondarenko, M. Baranova & E. Poddubskaya

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

    M. Baranova

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

    A. Buzdin

Authors
  1. M. Sorokin
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  2. K. Ignatev
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  3. V. Barbara
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  4. U. Vladimirova
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  5. A. Muraveva
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  6. M. Suntsova
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  7. N. Gaifullin
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  8. I. Vorotnikov
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  9. D. Kamashev
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  10. A. Bondarenko
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  11. M. Baranova
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  12. E. Poddubskaya
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  13. A. Buzdin
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Corresponding author

Correspondence to A. Buzdin.

Ethics declarations

For all the biosamples, informed written consents were collected from the patients to participate in the clinical trial NCT03521245 “Molecular pathway activation markers predicting efficacy of trastuzumab therapy for HER2-positive breast cancer” and to communicate the results in this report. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Karelia Republic Oncological Hospital, Petrozavodsk, and the Vitamed Oncological Clinical Center, Moscow.

The authors M. Sorokin and A. Buzdin were employed by the company OmicsWay Corp. The authors declare that this study received funding from OmicsWay Corp. The funder had the following involvement in the study: data analysis and interpretation as well as the writing of this manuscript. The funder was not involved in the study design, collection of data, decision to submit this article for publication. The remaining authors declare no conflict of interest in financial or any other sphere.

Electronic supplementary material

Fig. S1.

Expression of ERBB2 gene in the cohorts of responders and non-responders. DESeq2 normalized gene counts for ERBB2 are shown on X-axis, number of samples is shown on Y-axis.

Table S1.

Clinical and molecular annotations of HER2+ BC experimental biosamples

Table S2.

Clinical and molecular annotations of HER2+ BC literature biosamples

Table S3.

List of molecular pathways investigated in this study

Table S4.

Differential gene expression between the trastuzumab responders and non-responders in the experimental dataset (NCT03521245) and in the literature dataset dbGAP phs001291.v1.p1

Table S5.

Differentially activated molecular pathways between the trastuzumab responders and non-responders in the experimental dataset (NCT03521245) and in the literature dataset dbGAP phs001291.v1.p1

Table S6.

Number of differential genes involved in biomarker pathways

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Sorokin, M., Ignatev, K., Barbara, V. et al. Molecular Pathway Activation Markers Are Associated with Efficacy of Trastuzumab Therapy in Metastatic HER2-Positive Breast Cancer Better than Individual Gene Expression Levels. Biochemistry Moscow 85, 758–772 (2020). https://doi.org/10.1134/S0006297920070044

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  • DOI: https://doi.org/10.1134/S0006297920070044

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