Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS

Irene L. Wapnir ) James J. Dignam Bernard Fisher Eleftherios P. Mamounas Stewart J. Anderson Thomas B. Julian Stephanie R. Land Richard G. Margolese Sandra M. Swain Joseph P. Costantino Norman Wolmark Background Methods Results Conclusions The prevalence of clinically occult ductal carcinoma in situ (DCIS) has increased dramatically over the last two decades largely as a result of detection by the increased use of mammographic screening, accounting for approximately 25% of all new breast cancers today (1,2). The implementation of clinical trials to study breast-conserving techniques in this type of breast cancer was temporally preceded by trials comparing mastectomy to lumpectomy for invasive breast cancer (3,4). By the mid-1980s, singleinstitution nonrandomized studies of DCIS treated by breast-conserving surgery began to emerge (59). Satisfactory local control and similar survival after lumpectomy as compared with mastectomy were reported (8,10,11). However, concerns over the risk of subsequent ipsilateral breast tumor recurrences (IBTRs) with lumpectomy, particularly the occurrence of invasive IBTR (I-IBTR) persisted (9). In 1985, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a groundbreaking prospective randomized trial (NSABP B-17) comparing IBTR after lumpectomy only (LO) to lumpectomy followed by radiation therapy (LRT) in patients with localized DCIS (9). Five-year outcomes were first reported for the B-17 trial in 1993 (12). Women treated by LRT had a 60% lower risk of IBTR compared with those treated by LO. Subsequent updates continue to demonstrate a large benefit for LRT compared with LO (12,13). A second prospective randomized trial (NSABP B-24) investigated the addition of tamoxifen (TAM) to LRT (LRT + TAM) (14). Updated findings of this trial showed that women treated with LRT + TAM experienced a 31% reduction in risk of IBTR compared with those treated by LRT, as well as a 53% reduction in risk of contralateral breast tumors (15). All invasive breast cancers have an associated risk of metastasis. Therefore, it is important to investigate the impact of I-IBTR on the long-term prognosis of patients receiving breast-conserving treatments for DCIS (16,17). The B-17 and B-24 trials were closed to further follow-up, providing the impetus for an update on the incidence of I-IBTRs and its effect on mortality. Participants and Methods Trial Characteristics Previous publications have provided detailed descriptions of study designs, patient eligibility, and treatments in NSABP B-17 and B-24 trials (1214). Trials were approved by institutional review boards of participating institutions, and patients were required to sign informed consent to participate. The NSABP B-17 trial enrolled 818 patients with DCIS treated by lumpectomy that achieved tumor-free margins between October 1, 1985, and December 31, 1990 (the trial also included a registry of patients diagnosed with lobular carcinoma in situ) (18). Participants were randomly assigned to receive either radiation to the affected breast (LRT) or no further therapy (LO). A subsequent trial, NSABP B-24, enrolled 1804 patients between May 9, 1991, and April 13, 1994. Patients in the B-24 trial underwent LRT and were randomly assigned (double blind) to receive either 5 years of tamoxifen (AstraZeneca, Wilmington, DE), or placebo, shown in a CONSORT trial flow diagram (Figure 1). In contrast to B-17, B-24 allowed entry of women whose tumor margins were involved with DCIS and women whose mammograms contained foci of calcifications that were not excised, as long as their radiological appearance was not suggestive of invasive cancer (14). With respect to margin status, patients for whom margin status was Prior knowledge Lumpectomy performed to treat ductal carcinoma in situ (DCIS) is associated with the risk of ipsilateral breast tumor recurrence (IBTR), particularly with invasive IBTR (I-IBTR). Study design Two prospective randomized trials by the National Surgical Adjuvant Breast and Bowel Project (NSABP) compared the risk of IBTR in patients with localized DCIS who were treated by lumpectomy only (LO) or lumpectomy followed by radiation therapy (LRT) in the B-17 trial, and with 5 years of placebo (LRT + placebo) or tamoxifen (LRT + TAM) added to LRT in the B-24 trial. The longterm findings of these trials showing the most risk reduction in LRT + TAM group are published. In the current update of the B-17 and B-24 trials, the 15-year cumulative incidence of the primary failure event I-IBTR and its impact on survival have been investigated in LO, LRT, LRT + placebo, and LRT + TAM groups, along with recurrence of DCIS and other failure events. Contribution Results showed that after 15 years I-IBTR developed in 19.4% of patients who received LO for treatment of DCIS compared with 8.5% of patients who received LRT + TAM. I-IBTR was associated with an increase in mortality risk, but recurrence of DCIS was not. Overall mortality was low in patients who underwent lumpectomy. Implications Although I-IBTR increases the risk of breast cancerrelated death, adjuvant therapies like radiation and tamoxifen remain highly effective in treatment of DCIS after lumpectomy. Limitations The trials were designed over 20 years ago when breast imaging technologies were inferior. There was no evaluation of hormone receptor and HER2 status in these trials, as their role in DCIS was not known. From the Editors reported as uncertain or was unknown were considered to be margin positive. Initially, axillary dissections were required in B-17, but the requirement was dropped in 1987, and excluded altogether in B-24. Radiation Treatment In both B-17 and B-24, radiation to the whole breast began within 8 weeks of definitive surgery. The treatment occurred over 5 weeks to a dose of 50 Gy given at 10 Gy/wk. In B-24, investigators were permitted to modify the radiation technique by adding a boost of 10 Gy (range 0.120 Gy) to the lumpectomy cavity (19). Follow-up and Event Determination Follow-up clinical examinations were conducted semiannually, and mammography was performed annually. An IBTR was defined as recurrent DCIS (DCIS-IBTR) or invasive carcinoma (I-IBTR) occurring after lumpectomy in either the skin or parenchyma of the ipsilateral breast. Tumor in the non-breast skin of the ipsilateral chest wall was defined as other local failure. Recurrences in the ipsilateral internal mammary, supraclavicular, infraclavicular, and axillary nodes were classified as regional recurrences. Local or regional failures were verified by tissue biopsy or fine needle aspiration cytology. Distant metastases were confirmed by clinical, radiographic, or pathological findings. Second primary cancers and deaths without evidence of recurrence or second primary cancer were also verified by NSABP central medical review. These findings reflect information reported to the NSABP Biostatistical Center through June 30, 2007, following c (...truncated)