Prevalence and clinicopathologic correlates of O⁶-methylguanine-DNA methyltransferase methylation status in patients with triple-negative breast cancer treated preoperatively by alkylating drugs.
BACKGROUND
Predictive factors of benefit from specific chemotherapy regimens are not currently available in triple-negative breast cancer (TNBC). MGMT (O(6)-methylguanine-DNA methyltransferase) controls DNA repair pathways, and its epigenetic silencing is used for predicting the response to the alkylating drug temozolomide in patients with glioma.


METHODS
The study population was composed of 84 patients with TNBC treated with alkylating agents and evaluated for clinicopathologic parameters (tumor shrinkage and pathologic complete response [pCR]). MGMT methylation status was assessed in formalin-fixed, paraffin-embedded tumor specimens by pyrosequencing. The samples were categorized as methylated (mean methylation value > 5%), indeterminate (4%-5%), and unmethylated (≤ 3%).


RESULTS
MGMT methylation status was successfully evaluated in all the cases: 58.3% were methylated; 27.4%, unmethylated; and 14.3%, indeterminate. MGMT methylation was observed in 80%, 62%, and 29% of patients showing a 100%, 99% to 30%, and < 30% tumor reduction, respectively, a trend not achieving statistical significance (P = .23). There was no association between MGMT methylation status and pCR.


CONCLUSIONS
The present study provided evidence that pyrosequencing performs well for the evaluation of MGMT methylation even in small bioptic samples, suggesting that it could be reliably used in translational studies of preoperative clinical trials. Although there was an association trend between high methylation levels and clinical response to therapy, no statistically significant association with the pCR was found. Further studies in larger series of patients are warranted for ascertaining the putative clinical role of MGMT in patients with TNBC.
Division of Pathology, European Institute of Oncology, Milan, Italy.
Caterina
C
Fumagalli
Division of Medical Senology, European Institute of Oncology, Milan, Italy.
Silvia
S
Della Pasqua
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
Vincenzo
V
Bagnardi
Division of Medical Senology, European Institute of Oncology, Milan, Italy.
Anna
A
Cardillo
Division of Medical Senology, European Institute of Oncology, Milan, Italy.
Andrea
A
Sporchia
Division of Medical Senology, European Institute of Oncology, Milan, Italy.
Marco
M
Colleoni
Division of Pathology, European Institute of Oncology, Milan, Italy; University of Milan School of Medicine; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.
Giuseppe
G
Viale
Division of Pathology, European Institute of Oncology, Milan, Italy.
Massimo
M
Barberis
Division of Pathology, European Institute of Oncology, Milan, Italy; University of Milan School of Medicine; Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy. Electronic address: giancarlo.pruneri@ieo.it.
Giancarlo
G
Pruneri
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015331:Cohort Studies; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
DNA repair; Epigenetic alterations; Mammary tumors; Neoadjuvant therapy; Prognosis