p53 Mutation status predicts pathological response to chemoradiotherapy in locally advanced esophageal cancer.
OBJECTIVE
The p53 gene promotes cell-cycle arrest and apoptosis upon DNA damage and is associated with chemo- and radiosensitivity of cancer cells. However, its clinical significance has not been confirmed, especially in squamous cell carcinoma of the esophagus (ESCC). We investigated the correlation between p53 disorders (gene mutation and protein accumulation) and the effects of chemoradiotherapy (CRT).


METHODS
Biopsy specimens obtained before CRT (40-60 Gy; low-dose 5-fluorouracil plus cisplatin) from 64 patients with locally advanced (T2-T4) ESCC were examined for p53 gene mutations (MT) of exons 4-9 by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and protein accumulation by immunohistochemistry (IHC). These were correlated with the pathological effects of CRT and cause-specific survival.


RESULTS
Pathological complete response (pCR) was observed in 21.9% (14/64) patients, who showed better survival than non-pCR patients (2-year survival 78.6% versus 40.5%, P = 0.007). p53 mutation (MT)+ and p53 IHC+ were observed in 31.3% (20/64) and 65.6% (42/64) patients, respectively, and each was significantly associated with non-pCR (P = 0.004 and 0.042, respectively). Combined evaluation of p53 MT and p53 IHC correlated well with pCR frequency, showing 0% (0/12) for MT+/IHC+, 0% (0/8) for MT+/IHC-, 20% (6/30) for MT-/IHC+ and 57.1% (8/14) for MT-/IHC-. These results indicate that presence of p53 mutations was associated with non-pCR regardless of IHC status, and that p53 immunoreactivity was helpful in predicting non-pCR among p53 mutation-negative patients.


CONCLUSIONS
Analysis of ESCC biopsy specimens for p53 gene mutation can identify patients who will not achieve pCR by CRT. The results should be confirmed by large cohort prospective studies.
Makino
Tomoki
T
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. tmakino@gesurg.med.osaka-u.ac.jp
Yamasaki
Makoto
M
Miyata
Hiroshi
H
Yoshioka
Setsuko
S
Takiguchi
Shuji
S
Fujiwara
Yoshiyuki
Y
Nakajima
Kiyokazu
K
Nishida
Toshirou
T
Mori
Masaki
M
Doki
Yuichiro
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; D005472:Fluorouracil