Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers.
OBJECTIVE
Loss of function or expression of the mismatch repair gene MLH1 has been implicated in experimentally acquired resistance to cisplatin (CDDP) and other anticancer agents. The clinical significance of MLH1 expression was evaluated in advanced thoracic squamous cell carcinoma of the esophagus (ESCC) treated by neoadjuvant chemotherapy.


METHODS
We investigated MLH1 and P53 expression by immunohistochemistry in the surgical specimens of 107 patients who had undergone preoperative chemotherapy using CDDP along with 5-FU and ADM. These findings were correlated with the clinical outcome for this treatment. Biopsy samples before chemotherapy in 20 of these patients, and another 43 surgical specimens without chemotherapy, were also examined as control samples.


RESULTS
In surgical specimens of ESCC, low MLH1 expression was not frequent without chemotherapy, whereas it was commonly observed after chemotherapy (14 versus 37%, P = 0.0057). Comparison between samples before and after chemotherapy revealed that MLH1 expression was unchanged during chemotherapy in 12 of 20 patients (60%) but was from high to low in 8 of 20 patients (40%). In the surgical specimen after neoadjuvant chemotherapy, MLH1 expression was not correlated with any clinicopathological factors, including the response to chemotherapy. However, low MLH1 showed poorer prognosis than high MLH1 (5-year survival 40.6 versus 19.3%, P = 0.0393), and in multivariate analysis, MLH1 was an independent prognostic factor for this multimodal treatment, following lymph node metastasis and clinical response to chemotherapy. Positive p53 expression, which was not affected by chemotherapy, was weakly associated with a poor response and clinical outcome, although this trend was not significant.


CONCLUSIONS
In advanced ESCC, expression of MLH1 is reduced during CDDP-based chemotherapy, and this may partly account for poor postoperative survival.
Kishi
Kentaro
K
Department of Surgery and Clinical Oncology Graduate School of Medicine Osaka University, Osaka 565-0871, Japan.
Doki
Yuichiro
Y
Yano
Masahiko
M
Yasuda
Takushi
T
Fujiwara
Yoshiyuki
Y
Takiguchi
Syuji
S
Kim
Sontae
S
Higuchi
Ichiro
I
Monden
Morito
M
D048868:Adaptor Proteins, Signal Transducing; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D020137:Base Pair Mismatch; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000601:surgery; D002352:Carrier Proteins; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D011184:Postoperative Period; D011300:Preoperative Care; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000070957:MutL Protein Homolog 1; D002945:Cisplatin; D005472:Fluorouracil