Reduced MLH1 expression in breast tumors after primary chemotherapy predicts disease-free survival.
OBJECTIVE
Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival.


METHODS
Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively.


RESULTS
Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P =.010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P =.0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors.


CONCLUSIONS
Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.
Mackay
H J
HJ
CRC Department of Medical Oncology, Cancer Research Campaign, Beatson Laboratories, Glasgow University, United Kingdom.
Cameron
D
D
Rahilly
M
M
Mackean
M J
MJ
Paul
J
J
Kaye
S B
SB
Brown
R
R
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D020137:Base Pair Mismatch; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D002352:Carrier Proteins; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016013:Likelihood Functions; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins; D011379:Prognosis; D012044:Regression Analysis; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000070957:MutL Protein Homolog 1