OT1-02-05: A Phase III Clinical Trial Comparing Trastuzumab Given Concurrently with Radiation Therapy to Radiation Therapy (RT) Alone for Women with HER2−Positive DCIS Resected by Lumpectomy: NSABP B-43.
Authors: Julian TB , Anderson SJ , Cobleigh MA , Siziopikou KP , Arthur DW , Zheng P , Mamounas EP , Pajon ER , Behrens RJ , Chu L , Leasure NC , Atkins JN , Polikoff J , Seay TE , McCaskill-Stevens W , Rabinovitch R , Wolmark N 
Published: June 2012

Abstract
Background
Because a substantial portion of DCIS is ER negative and overexpresses HER2, therapy targeting this protein is a promising strategy for HER2−overexpressing DCIS.
Preclinical studies have shown that trastuzumab (T) boosts the effectiveness of RT in xenograft models and in cell lines with no detrimental effect on irradiated HER2−normal cells. Studies correlating clinical response with molecular markers in T-treated patients show that apoptosis occurs within 1 wk of starting singleagent T, with little effect on proliferation. Shorter duration treatments with this agent require investigation. Adjuvant trials using T during breast irradiation have already provided ample safety evidence. Will T administered during WBI improve lumpectomy + WBI results in women with HER2−positive DCIS? This trial will allow us to better understand the biology of breast cancer and its prevention and will extend the benefits of breast-conserving surgery for women with DCIS.
Trial Design: Post lumpectomy for DCIS without evidence of an invasive component, a central review of each patient's pure DCIS lesion is carried out for HER2 by IHC analysis. If the HER2 is 2+, FISH analysis is done, and patients whose tumors are HER2 3+ or FISH positive can be randomly assigned to receive 2 doses of T 3 wk apart during WBI or to receive WBI alone.
Eligibility criteria: Women 18 years or older with an ECOG status of 0 or 1 who have undergone a margin-clear lumpectomy for DCIS and whose tumors are clinically or pathologically node negative are eligible. DCIS must be HER2 positive by central testing. ER and/or PR status must be known before random assignment.
Specific aims: The primary aim is to determine if T given concurrently with WBI is more beneficial in preventing IBC recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS compared with WBI alone for HER2−positive DCIS resected by lumpectomy. Secondary aims are to compare the possible benefit of T given during WBI to that of WBI alone in preventing regional or distant recurrence and contralateral invasive or DCIS breast cancer. B-43 will determine if invasive or DCIS DFS, recurrence-free interval, and OS can be improved with the addition of T to WBI. The effects of T on ovarian function in premenopausal women will also be assessed.
Statistical methods and accrual: Our design calls for accrual of 2000 patients during a 7.9-year period. As of May 31, 2011, 578 patients have been entered. A definitive analysis of primary endpoints will be performed when 163 ipsilateral breast cancer events occur (7.5 and 8 years after protocol initiation). This number of events affords 80% power to detect a hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 100 patient-years to 1.11 events per 100 patient-years. The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate.
Supported by PHS grants NCI-U10-CA-69651, NCI-U10-CA-12027, and NCI P30-CA-14599 from the US NCI and Genentech, Inc.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-05.