| Autor: |
Trudeau ME; Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada., Chapman JA; NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada., Guo B; Advanced Medical Research Institute of Canada (AMRIC), 41 Ramsey Lake Road, Sudbury, ON P3E 5J1 Canada., Clemons MJ; The Ottawa Hospital Cancer Centre, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada., Dent RA; Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada., Jong RA; Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada., Kahn HJ; Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada., Pritchard KI; Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada., Han L; NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada., O'Brien P; NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada., Shepherd LE; NCIC Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, ON K7L 3N6 Canada., Parissenti AM; Advanced Medical Research Institute of Canada (AMRIC), 41 Ramsey Lake Road, Sudbury, ON P3E 5J1 Canada. |
| Abstrakt: |
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. |
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