Abstract P3-07-55: Predictive value of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation in triple-negative breast cancer patients receiving carboplatin
Authors: Fontanella C , Gehlhaar C , Denkert C , Schneeweiss A , Heppner B-I , Koch I , Blohmer J-U , Jackisch C , Lederer B , Fasching PA , Müller V , Untch M , Aprile G , Puglisi F , Nekljudova V , Heppner F , von Minckwitz G , Loibl S 
Published: May 2016

Background: The epigenetic profile of triple-negative breast cancer (TNBC) showed a wide prevalence of MGMT promoter methylation.Aberrant methylation of MGMT seems to be an independent predictor of poor survival in patients with basal-like breast cancer. Moreover, patients with MGMT-negative basal-like tumors who received cyclophosphamide had asignificantly improved DFS and OS compared with MGMT-positive tumors.However, the impact of MGMT methylation in the context of modern therapy concepts is not clear.

Methods: We retrospectively evaluated 174 TNBC tumors of patients enrolled into the neoadjuvantGeparSixtotrial from 08/2011 to 12/2012. Patients were randomized to receive 18 weeks of neoadjuvant treatment with paclitaxel (80mg/m2/week) and non-pegylated liposomal doxorubicin (20mg/m2/week) with or without addition of carboplatin (AUC 2.0-1.5/week).Hormone-receptor status, HER2status, and Ki67 were centrally confirmed prior to randomization. We defined pathological complete response (pCR)as ypT0/is ypN0. MGMT promoter methylation status was determined by PCR using EZ DNA Methylation Kit™ (Zymo Research); TNBCtumors were considered to be methylated if they had an average methylation ≥10%, some tumors were considered borderline due to high heterogeneity among GpC islands.We investigated the effect of MGMT methylation on pCR and its correlation with baseline characteristics.

Results: A total of210 tumors from the TNBC cohort of the GeparSixtotrial(n=315) were available with a tumor content &gt;20%. In 174 tumors the methylation assay was performed successfully. The number of tumorswith methylated MGMT was similar in carboplatin vs. non-carboplatin treated cohorts. In the carboplatin group 19.3% (17/88) of TNBC were methylated, 65.5% (58/88)unmethylated, and 14.8% (13/88) borderline.In the non-carboplatin group 20.9% (18/86) of TNBC were methylated, 62.8% (54/86)unmethylated, and 16.3% (14/86) borderline.In the entire cohort,there was no association between MGMT methylation status and pCR (p=0.522).Non-carboplatin cohort: 33.3% (6/18) of patients with methylated MGMT achieved pCR vs. 51.9% (28/54) of unmethylatedand 21.4% (3/14) of borderline (p=0.079).Carboplatin cohort: 52.9% (9/17) of patients with methylated MGMT achieved pCR vs. 55.2% (32/58) of unmethylatedand 76.9% (10/13) of borderline (p=0.320). In TNBC patients with methylated MGMT, the addition of carboplatin resulted in a 20% increased pCR rate (p=0.241).

Conclusion: In this study no statistically significant association between MGMT methylation andpCR was found.Patients with MGMT methylation seemed to have a lower possibility to achieve a pCR and the addition of carboplatin seemed to reverse this effect. However, a clear classification of the borderline MGMT samples and further studies in larger series of TNBC are warranted.

Citation Format: Fontanella C, Gehlhaar C, Denkert C, Schneeweiss A, Heppner B-I, Koch I, Blohmer J-U, Jackisch C, Lederer B, Fasching PA, Müller V, Untch M, Aprile G, Puglisi F, Nekljudova V, Heppner F, von Minckwitz G, Loibl S. Predictive value of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation in triple-negative breast cancer patients receiving carboplatin. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-55.