Tumor response to neoadjuvant chemoradiation therapy for rectal adenocarcinoma is mediated by p53-dependent and caspase 8-dependent apoptotic pathways.
BACKGROUND
We tested the hypothesis that rectal tumors are most responsive to neoadjuvant therapy if they possess p53 and/or caspase 8 activity.


METHODS
Fifty patients diagnosed with biopsy-proven rectal cancer underwent neoadjuvant chemoradiation therapy consisting of 5-fluorouracil (300 mg/m(2) daily) and radiation (4,500 cGy). Endorectal ultrasonography was performed before and after neoadjuvant therapy along with digital rectal examination and/or sigmoidoscopy for staging purposes and to evaluate response to therapy. All patients underwent resection with specimens submitted for gross and microscopic review. Pretreatment biopsy specimens were subjected to immunohistochemical staining for mutated p53 and caspase 8 bioactivity.


RESULTS
The study population consisted of 32 men and 18 women. There were 17 complete responses (CRs; 34%), 17 partial responses (PRs; 34%), and 16 cases of no response (NR; 32%). There were 10 stage I tumors (20%), 22 stage II tumors (44%), and 18 stage III tumors (36%) in the cohort at the time of initial diagnosis. p53 protein staining (ie, mutated p53) was positive in 31 tumors (62%; CR, n = 8; PR, n = 11; NR, n = 12); caspase 8 positivity was apparent in 30 specimens (60%; CR, n = 13; PR, n = 13; NR, n = 4). In terms of pretreatment predictions, we scored 3 separate levels of response (CR, 3; PR, 2; NR, 1) and compared them with the expected responses (ie, p53 positivity and caspase 8 negativity should yield NR, whereas all other combinations should yield responses). Wilcoxon 2-sample tests yielded a 1-sided P value of 0.007.


CONCLUSIONS
The present study highlights a possible mechanism for tumor response to neoadjuvant manipulation, namely that dual mechanisms for apoptotic cell death are working in concert to cause tumor regression; one is p53 transcription-dependent, and the other is p53 transcription-independent.
Kelley
Scott T
ST
H. Lee Moffitt Cancer Center and Department of Surgery , Tampa, FL, USA.
Coppola
Domenico
D
Yeatman
Timothy
T
Marcet
Jorge
J
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis; D015415:Biomarkers; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011237:Predictive Value of Tests; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000473:pathology / Q000628:therapy*; D012189:Retrospective Studies; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D016159:Tumor Suppressor Protein p53; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D005472:Fluorouracil