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/m2 epirubicin and 75 mg/m2 docetaxel; for schedule B, it was fatigue at 75 mg/m2 for both agents. Phase II doses were 90 mg/m2 epirubicin/75 mg/m2 docetaxel for Schedule A and 60 mg/m2 (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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1392-x) contains supplementary material, which is available to authorized users.
Highlights
LABC is traditionally defined as stage IIB (T3N0) and Stage IIIA/B/C from the TMN classification (Chia et al 2008; Hortobagyi et al 1995)
We examined the efficacies and toxicities associated with epirubicin/docetaxel combination chemotherapy at various doses and schedules for women with LABC
The phase I maximally-tolerated doses (MTD) for the three weekly regimen (Schedule A) was 120 mg/m2 epirubicin and 75 mg/m2 docetaxel, with the phase II portion conducted at 105 and 75 mg/m2, respectively
Summary
LABC is traditionally defined as stage IIB (T3N0) and Stage IIIA/B/C from the TMN classification (Chia et al 2008; Hortobagyi et al 1995). Preferably before systemic therapy, would significantly enhance patient care (Carey et al 2007; Esserman et al 2012; Carey and Winer 2014; Cortazar et al 2014; Houssami et al 2012). A number of commonly used anthracycline and taxane containing regimens have been studied in combination (TAC) or in sequence [dd(AC-P), AC-weekly P, FECD, AC-D] (Aigner et al 2011; Gandhi et al 2015; Raza et al 2009). Optimal doses and schedules for anthracycline/taxane combination regimens have not been established for epirubicin and docetaxel. We examined the efficacies and toxicities associated with epirubicin/docetaxel combination chemotherapy at various doses and schedules for women with LABC. We conducted exploratory tumor genome profiling studies for prospective biomarkers of response to the regimens
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