title: Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd., Sudbury, ON, P3E 2C6, Canada, aparissenti@hsnsudbury.ca.
authors.forename: Amadeo M
authors.initials: AM
authors.lastname: Parissenti
authors.forename: Baoqing
authors.initials: B
authors.lastname: Guo
authors.forename: Laura B
authors.initials: LB
authors.lastname: Pritzker
authors.forename: Kenneth P H
authors.initials: KP
authors.lastname: Pritzker
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Mu
authors.initials: M
authors.lastname: Zhu
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Trudeau
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D012334:RNA, Neoplasm; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012334:RNA, Neoplasm