title: A phase I/II trial of epirubicin and docetaxel in locally advanced breast cancer (LABC) on 2-weekly or 3-weekly schedules: NCIC CTG MA.22.
abstract: This phase I/II neoadjuvant trial (ClinicalTrials.gov identifier NCT00066443) determined maximally-tolerated doses (MTD), dose-limiting toxicities, response-to-therapy, and explored the role of novel response biomarkers. MA.22 accrued T3N0, any N2 or N3, and T4 breast cancer patients. Treatment was 6 cycles of 3-weekly (Schedule A; N = 47) or 8 cycles of 2-weekly (Schedule B; N = 46) epirubicin/docetaxel chemotherapy in sequential phase I/II studies, with growth factor support. In phase I of each schedule, MTDs were based on DLT. In phase II, clinical responses (CR/PR) and pathologic complete responses (pCR) were assessed. Tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 for pathologic assessment; 3 for microarray studies. DLT for Schedule A was febrile neutropenia at 105 mg/m(2) epirubicin and 75 mg/m(2) docetaxel; for schedule B, it was fatigue at 75 mg/m(2) for both agents. Phase II doses were 90 mg/m(2) epirubicin/75 mg/m(2) docetaxel for Schedule A and 60 mg/m(2) (both agents) for Schedule B. Schedule A CR/PR and pCR rates were 90 and 10 %, with large reductions in tumor RNA content and integrity following treatment; Schedule B results were 93 and 0 %, with smaller reductions in RNA quality. Pre-treatment expression of several genes was associated with clinical response, including those within a likely amplicon at 17q12 (ERBB2, TCAP, GSDMB, and PNMT). The combination regimens had acceptable toxicity, good clinical response, induction of changes in tumor RNA content and integrity. Pre-treatment expression of particular genes was associated with clinical responses, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness.
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada.
authors.forename: Maureen Elizabeth
authors.initials: ME
authors.lastname: Trudeau
authors.affiliation: NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada.
authors.forename: Judith-Anne W
authors.initials: JA
authors.lastname: Chapman
authors.affiliation: Advanced Medical Research Institute of Canada (AMRIC), 41 Ramsey Lake Road, Sudbury, ON P3E 5J1 Canada.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Guo
authors.affiliation: The Ottawa Hospital Cancer Centre, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Clemons
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Dent
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada.
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Jong
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada.
authors.forename: Harriette J
authors.initials: HJ
authors.lastname: Kahn
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada.
authors.forename: Patti
authors.initials: P
authors.lastname: O'Brien
authors.affiliation: NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.affiliation: Advanced Medical Research Institute of Canada (AMRIC), 41 Ramsey Lake Road, Sudbury, ON P3E 5J1 Canada.
authors.forename: Amadeo M
authors.initials: AM
authors.lastname: Parissenti
keywords: Docetaxel; Epirubicin; LABC; Microarray; Phase I/II; Response biomarkers