Abstract
The O6-methylguanine-DNA methyltransferase (MGMT) protein protects cells from alkylating agents by removing alkyl groups from the O6-position of guanine. However, its effect on DNA damage induced by cyclophosphamide (CPM) is unclear. The present study investigated whether MGMT expression was correlated with prognosis in patients with breast cancer that was managed according to a common therapeutic protocol or treated with CPM-based chemotherapy. The intrinsic subtypes and MGMT protein expression levels were assessed in 635 consecutive patients with breast cancer using immunohistochemistry. In total, 425 (67%) luminal A, 95 (15%) luminal B, 47 (7%) human epidermal growth factor receptor-2+/estrogen receptor− (HER2+/ER−) and 48 (8%) basal-like subtypes were identified. Of these, MGMT positivity was identified in 398 (63%) of 635 breast cancers; 68% of luminal A, 67% of luminal B, 30% of HER2+/ER− and 46% of basal-like subtypes were positive. The overall survival (OS) and disease-free survival (DFS) rates did not significantly differ according to the MGMT status among patients with luminal A, luminal B or HER2+/ER− subtypes, and patients with MGMT-negative basal-like cancers tended to have a longer DFS, but not a significantly longer OS time. CPM-containing chemotherapy was administered to 26%, 40%, 47% and 31% of patients with luminal A, luminal B, HER2+/ER− and basal-like tumors, respectively. Although the MGMT status and clinical outcomes of patients with the luminal A, luminal B or HER2+/ER− subtypes treated with CPM were not significantly correlated, the patients with MGMT-negative basal-like tumors who received CPM exhibited significantly improved DFS and OS compared with the CPM-treated patients with MGMT-positive tumors. MGMT may be a useful prognostic and predictive marker for CPM-containing chemotherapy in basal-like breast cancer.
Highlights
Alkylating agents comprise a large class of chemotherapeutic drugs used to treat several types of cancers
The 635 cases of invasive carcinoma were classified into 5 clinical subtypes using immunohistochemical markers as follows: Luminal A (ER+ and/or progesterone receptor (PgR)+ and human epidermal growth factor receptor‐2 (HER2)‐), luminal B (ER+ and/or PgR+ and HER2+), HER2+/estrogen receptor (ER)‐ (ER, PgR‐ and HER+), basal‐like (ER, PgR, HER2, CK 5/6+ and/or HER1+) and unclassified [24]
MGMT status was assessed in patients with breast cancer by analyzing MGMT protein expression using an immunohistochemical method, which can be performed without specific equipment, even on archived formalin‐fixed, paraffin‐embedded specimens, together with other immunohistochemical studies for tumor diagnosis
Summary
Alkylating agents comprise a large class of chemotherapeutic drugs used to treat several types of cancers. Various human tumor cell lines and xenografts have been used to demonstrate the association between the activity of MGMT and the ability to withstand methylating agents and alkylating nitrosoureas [1]. In the patients with breast cancer that was treated with neoadjuvant chemotherapy, including CPM, no correlation was observed between MGMT expression and the response to CPM [7]. ISONO et al: MGMT AS A PREDICTIVE MARKER FOR CPM-TREATED BASAL-LIKE BREAST CANCER a recent study demonstrated the predictive value of MGMT protein expression in breast tumor biopsies obtained prior to CPM‐containing neoadjuvant chemotherapy [8]
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