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Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy

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Abstract

In a prior substudy of the CAN-NCIC-MA.22 clinical trial (ClinicalTrials.gov identifier NCT00066443), we observed that neoadjuvant chemotherapy reduced tumor RNA integrity in breast cancer patients, a phenomenon we term “RNA disruption.” The purpose of the current study was to assess in the full patient cohort the relationship between mid-treatment tumor RNA disruption and both pCR post-treatment and, subsequently, disease-free survival (DFS) up to 108 months post-treatment. To meet these objectives, we developed the RNA disruption assay (RDA) to quantify RNA disruption and stratify it into 3 response zones of clinical importance. Zone 1 is a level of RNA disruption inadequate for pathologic complete response (pCR); Zone 2 is an intermediate level, while Zone 3 has high RNA disruption. The same RNA disruption cut points developed for pCR response were then utilized for DFS. Tumor RDA identified >fourfold more chemotherapy non-responders than did clinical response by calipers. pCR responders were clustered in RDA Zone 3, irrespective of tumor subtype. DFS was about 2-fold greater for patients with tumors in Zone 3 compared to Zone 1 patients. Kaplan–Meier survival curves corroborated these findings that high tumor RNA disruption was associated with increased DFS. DFS values for patients in zone 3 that did not achieve a pCR were similar to that of pCR recipients across tumor subtypes, including patients with hormone receptor positive tumors that seldom achieve a pCR. RDA appears superior to pCR as a chemotherapy response biomarker, supporting the prospect of its use in response-guided chemotherapy.

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Abbreviations

RNA:

Ribonucleic acid

RDA:

RNA disruption assay

RDI:

RNA disruption index

pCR:

Pathologic complete response

DFS:

Disease-free survival

LABC:

Locally advanced breast cancer advanced

FDG:

Fluoro-deoxyglucose

TNBC:

Triple-negative breast cancer

PET:

Positron emission tomography

RIN:

RNA integrity number

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor 2

HR+:

Hormone receptor positive

WSR:

Wilcoxon Signed-Rank test

MWW:

Mann–Whitney Wilcoxon

MC:

Mantel Cox Test

K-M:

Kaplan–Meier

WT:

Wald Test

rRNA:

Ribosomal RNA

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Acknowledgments

This work was supported by funding from Sanofi-Aventis Pharmaceuticals and the Cancer Research Fund of the Ontario Institute for Cancer Research (Grant Number 02-MAY-0159) to A.M.P. Funding is also acknowledged from the Canadian Cancer Society that supports the NCIC Clinical Trials Group, and from RNA Diagnostics, Inc. We are extremely grateful to the patients who participated in this study.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd., Sudbury, ON, P3E 2C6, Canada

    Amadeo M. Parissenti

  2. Advanced Medical Research Institute of Canada, Laurentian University and Northeast Cancer Centre, 41 Ramsey Lake Rd., Sudbury, ON, P3E 5J1, Canada

    Amadeo M. Parissenti & Baoqing Guo

  3. RNA Diagnostics, Inc., 100 College St., Suite 252, Toronto, ON, M5G 1L5, Canada

    Amadeo M. Parissenti, Baoqing Guo, Laura B. Pritzker, Kenneth P. H. Pritzker & Xiaohui Wang

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Kenneth P. H. Pritzker

  5. Department of Statistics and Actuarial Science, University of Waterloo, 200 University Av. W, Waterloo, ON, N2L 3G1, Canada

    Mu Zhu

  6. NCIC Clinical Trials Group, Queens University, 10 Stuart St., Kingston, ON, K7L 3N6, Canada

    Lois E. Shepherd

  7. Sunnybrook Health Sciences Centre, 2075 Bayview Av., Toronto, ON, M4N 3N5, Canada

    Maureen E. Trudeau

  8. Department of Medicine, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Maureen E. Trudeau

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  1. Amadeo M. Parissenti
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  2. Baoqing Guo
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  4. Kenneth P. H. Pritzker
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  5. Xiaohui Wang
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  6. Mu Zhu
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  7. Lois E. Shepherd
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  8. Maureen E. Trudeau
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Corresponding author

Correspondence to Amadeo M. Parissenti.

Ethics declarations

Ethical approval

All patients involved in this study provided written consent for participation in the trial and for the provision of the tumor core biopsies. Approvals were also obtained from the research ethics board of all cancer treatment centers involved in this study. Approval for the biomarker study was also obtained from the Research Ethics Board of Health Sciences North, at which the biomarker study was conducted. We declare the clinical trial and associated biomarker study comply with the current laws governing clinical research studies in Canada.

Conflict of interest

The authors disclose financial competing interests. Drs. Parissenti and Guo are inventors of a patent owned by Laurentian University entitled “Method of using tumor RNA integrity to measure response to chemotherapy in cancer patients,” the subject of this study. The patent was based, in part, on data from patients in the MA.22 clinical trial described in this study. Dr. Maureen Trudeau was the principal investigator of the trial, and Dr. Lois Shepherd was the physician coordinator of the trial, administered by the NCIC Clinical Trials Group. Drs. Parissenti and Guo have received royalties from commercialization activities associated with this activity. This includes the creation of RNA Diagnostics, Inc., which developed the RNA disruption assay described in this study. Drs. Parissenti and Pritzker are shareholders in RNA Diagnostics, Inc. Dr. Maureen Trudeau is the Chair of the Clinical Advisory Board for RNA Diagnostics, Inc. and has received financial compensation and shares for her roles/activities in the company. Some of the analyses described in this manuscript were performed by employees of RNA Diagnostics, Inc. (Dr. L. Pritzker and Ms. Xiaohui Wang). It should be noted that Drs. Parissenti and Guo submitted tumor RNA quality data to the NCIC Clinical Trials Group in a blinded fashion. They did not have access to the clinical response data or tumor pathology data of the patients prior to this submission. This was revealed to them and to RNA Diagnostics, Inc. only upon conclusion of the trial.

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10549_2015_3498_MOESM1_ESM.docx

Supplemental Table 1: Multivariate discriminant analysis revealing the ability of multiple variables (total epirubicin dose, total docetaxel dose, and the dose schedule) to significantly affect disease-free survival, when used in combination (Wald test). In single factor analysis, patients with tumor RDI values >50 had significantly greater DFS than patients with RDI ≤ 50 (Wald test). Supplementary material 1 (DOCX 14 kb)

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Parissenti, A.M., Guo, B., Pritzker, L.B. et al. Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy. Breast Cancer Res Treat 153, 135–144 (2015). https://doi.org/10.1007/s10549-015-3498-9

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