Review - Haymarket Media Group

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<strong>Review</strong> ma and/or peau d’orange, and biopsy-confirmed invasive carcinoma with or without evidence of dermal lymphatic invasion. Tumors were classified as HER2 positive if they exhibited 3+ staining by immunohistochemistry (IHC) and/or gene amplification by fluorescence in situ hybridization (FISH) technique. Tumors were classified as HER2 negative if they exhibited 1+ or negative staining by HER2 is amplified in approximately 30% of breast tumors. IHC and/or no gene amplification by FISH. All patients received adjuvant anthracycline-based chemotherapy regimens followed by a mastectomy, comprehensive radiation therapy to chest wall and axilla, and adjuvant hormonal therapy when appropriate. Patients with HER2-positive tumors did not receive adjuvant trastuzumab as the monoclonal antibody had not received approval for use in the Unadjusted estimates* 18 The American Journal of Hematology/Oncology adjuvant setting at the time of diagnosis. Upon recurrence, patients with HER2-positive tumors were allowed to have received trastuzumab. Recurrence-free survival (RFS), defined from the date of diagnosis to the date of local or distant recurrence or last follow-up, and overall survival (OS), defined from the date of diagnosis to death from any cause or last follow-up, was computed. The Kaplan-Meier product limit method was used to determine 5-year survival estimates, which were compared across groups using log-rank statistics. Cox proportional hazards models were then fitted to determine the association of HER2 status to survival outcomes after adjusting for patient and tumor characteristics. Of the 179 patients, 111 (62%) had HER2-negative disease and 68 (38%) had HER2-positive disease. <strong>Media</strong>n age for the cohort was 51 years (range, 28-78 years), and median follow-up among all patients still alive at last follow-up was 41 months (range, 3-198 months). At the time of the analysis a total of 104 patients had recurred; 62 of 111 (55.9%) with HER2negative disease and 42 of 68 (61.8%) with HER2positive disease. Of the 42 patients with HER2-positive disease who recurred, 31 (73.8%) received trastuzumab in the metastatic setting. The Table summarizes the unadjusted and adjusted RFS and OS estimates. Overall Kaplan-Meier estimates for 5year RFS was 37.8% (95% CI, 29.9%-45.7%), and 5- Table Unadjusted and Adjusted 5-Year Recurrence-Free and Overall Survival Estimates Recurrence- Overall Free Survival P Value Survival P Value HER2 negative 38.8% 49.8% (28.7%-48.8%) (38.0%-60.6%) HER2 positive 36.5% 0.750 57.8% 0.245 (24.0%-49.0%) (43.4%-69.8%) Adjusted estimates † HER2 0.75 0.241 0.56 0.024 (positive vs negative) (0.46-1.22) (0.34-0.93) *These are Kaplan-Meier estimates that have been compared across groups using log-rank statistics. † These are adjusted hazard ratios. The models were adjusted for age (continuous), estrogen receptor status (positive vs negative), progesterone receptor status (positive vs negative), lymphovascular invasion (yes vs no), grade of tumor (3 vs 1 and 2), lymph node status (positive vs negative), and pathological complete response (yes vs no).
year OS was 53.1% (95% CI, 44.0%-61.3%). In the univariate analysis, no significant differences were observed in both survival end points when stratified by HER2 status, although a nonsignificant trend that favored patients with HER2-positive disease compared to those with HER2-negative disease was noted for OS. After adjusting for age, grade, hormone receptor status, pathological complete response, lymph node status, and lymphovascular invasion, HER2 status was not observed to significantly affect RFS. In the multivariate model for OS, patients with HER2-positive disease had a 44% decreased risk of death that was statistically significant (HR=0.56; 95% CI, 0.34-0.93; P=0.024) compared with patients with HER2-negative disease. Discussion The study we conducted is unique for a number of reasons. First, most studies have been hampered by nonspecific clinical diagnostic criteria used to identify patients with IBC, making interpretation and comparisons difficult. Using standard institutional criteria for IBC, which conform to the American Joint Committee on Cancer definition of IBC, allowed us to clearly identify patients with IBC and separate them from women with locally advanced non-IBC tumors. Second, our sample size was relatively large compared with previously published studies involving patients with IBC. Third, by using a cohort that did not receive trastuzumab in the adjuvant setting but was allowed to use the agent upon recurrence, we were uniquely able to study both the prognostic impact of HER2 status as well as the efficacy of trastuzumab in patients with IBC. The results of our study indicate that HER2 status did not impact RFS, even after controlling for patient and tumor characteristics in the multivariate model. This is in sharp contrast to the initial observations made by Slamon and colleagues, 4 who reported HER2 amplification not only as being associated with worse RFS and OS outcomes compared with women whose tumors did not exhibit HER2 amplification but also as being of superior prognostic significance to other well-established factors such as hormone receptor status and the presence of lymph node involvement. As such, we hypothesize that prognostic factors typically used for non-IBC tumors may not confer the same information in IBC tumors. Studies have shown that factors such as increased expression of the epidermal growth factor receptor and p53 and loss of p27 may be indicative of poor HER2 status and inflammatory breast cancer prognosis in the IBC cohort, although larger studies are required to confirm this. 14,15 When assessing overall survival, results from our multivariate model indicated that women with HER2-positive tumors had a 44% decreased risk of death that was statistically significant (HR=0.56; 95% CI, 0.34-0.93; P=0.024) compared with women with The results of our study indicate that HER2 status did not impact relapse-free survival. HER2-negative tumors. The improved survival observed is attributed to the fact that the majority of women with HER2-positive disease who relapsed received trastuzumab. This observation indicates that trastuzumab is indeed efficacious when administered to women with IBC tumors. It also provides evidence of the fact that when trastuzumab is administered to patients with HER2-positive IBC, they attain superior outcomes compared to patients with HER2-negative tumors. Conclusion The results of this study are important and applicable to the clinical management of women with IBC. Randomized clinical trials that have assessed the efficacy of trastuzumab have been unable to determine its efficacy in women with IBC tumors. The results of this study provide evidence of the efficacy of this agent in this cohort despite the lack of prognostic difference observed between women with HER2-positive and HER2-negative tumors in the absence of trastuzumab administration. It is well known that the natural history of this aggressive subtype of breast cancer is different compared with other types of breast cancer, making it important for future research to focus on conducting clinical trials specifically aimed at this cohort. Until such initiatives are undertaken, results from studies such as ours will be an important component in guiding physician management of women with IBC. F (continued on page 22) November 2008 • Vol 7 • Supplement 5 19
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