Abstract OT1-1-02: A phase II randomized trial evaluating the effect of trastuzumab on disease free survival in early stage HER2-negative breast cancer patients with ERBB2-expressing bone marrow disseminated tumor cells
Authors: Aft R , Mudalagiriyappa C , Watson M , Pillai S , Fleming T , Trinkaus K , Pluard T 
Published: August 2014

Abstract
Background: Adjuvant trastuzumab administered concurrently with chemotherapy improves survival in women with Her2-positive breast cancers (BC). A subset of patients with Her2-negative tumors benefit from trastuzumab treatment. We and others have reported discordance in Her2 expression between primary tumors, circulating tumor cells, disseminated tumor cells (DTCs), and metastases. Our data indicate that patients with Her2-negative tumors and Her2-positive DTCs have a greater hazard of recurrence than patients with Her2-negative tumors and Her2-negative DTCs or Her2-positive DTCs treated with trastuzumab. We hypothesize that the subgroup of patients with Her2-negative primary tumors and Her2-positive DTCs will benefit from trastuzumab therapy.
Trial Design: We are conducting a randomized phase II trial in early stage Her2-negative BC patients with Her2-positive DTCs in their bone marrow (BM) at the time of diagnosis who are candidates for chemotherapy. Chemotherapy is doxorubicin/cyclophosphamide q2 weeks for 4 cycles followed by weekly paclitaxel for 12 weeks. Patients randomized to the trastuzumab arm will receive IV trastuzumab concomitant with taxane treatment and then q3 weeks for a total of 52 weeks.
Specific Aims: The primary endpoints are two year recurrence and death rates. Additional endpoints include: elimination of Her2-positive DTCs at completion of therapy, PAM50 analysis of the primary tumor, and association of DTC specific gene expression with outcome.
Eligibility: Patients with newly diagnosed Her2-negative, stage I-III invasive BC who are eligible for chemotherapy and have Her2-positive BM DTCs, as defined by a molecular based assay performed in a CLIA-licensed facility are eligible.
Statistical Methods: Based on our preliminary data, we estimate that 25% of stage II/III Her2-negative breast cancer patients will harbor Her2-positive DTCs in their BM. 200 patients will have their BM screened for Her2-positive DTCs to enroll 50 patients into the trial. Based on the literature and preliminary data, the expected 2-year recurrence rate is 75% in the placebo arm and 40% in the trastuzumab arm. A sample of 46 patients, 23 per arm, will provide power = 0.8 to detect this difference at a 0.05 significance level. The expected proportion of patients who eliminate Her2-positive DTCs from BM is &lt; 10% in the placebo arm and 80% in the trastuzumab arm. The proposed sample will provide power &gt; 0.9 to distinguish Her2-positive DTC elimination rates of 10% vs. 80% and at least 80% power to distinguish a difference of 50% in the elimination rates (e.g. 29% vs. 70%). One interim analysis will be conducted after the first 15 patients have completed 2 years of follow-up and 2 year recurrence rates have been determined. Conditional study power will be used to evaluate the estimates on which study power has been calculated, and the sample size will be adjusted, if necessary. Analysis of the primary endpoints will be at a significance level of 0.0052 for the interim analysis and 0.048 for the final analysis in order to preserve an overall significance level of 0.05.
Accrual: Accrual is anticipated to open August 2013. Target = 25 per arm. NCT01779050.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-02.