title: Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer.
abstract: OBJECTIVE
  Preoperative chemoradiation (CRT) for locally advanced rectal adenocarcinoma achieves pathologic complete response (pCR) in 8-20% of patients. Mutations in critical cancer genes may contribute to lack of pCR. We retrospectively evaluated our institutional experience to determine potential mutational and clinical predictors of pCR in patients treated with CRT.
  
  
  METHODS
  Patients with locally advanced rectal adenocarcinoma treated with preoperative CRT (n = 79) were identified. A clinical cancer genotyping assay evaluated 140 hotspot mutation sites across 15 cancer genes in 47 patients with sufficient tissue. Mutational profiles were compared in pre- and post-CRT specimens and with pCR rate. Clinical variables were evaluated using logistic regression.
  
  
  RESULTS
  Genotyping identified mutations in KRAS (43%), APC (17%), BRAF (4%), NRAS (4%), PIK3CA (4%), and TP53 (11%). In the entire cohort, 21.5% had a pCR. No patients with BRAF, NRAS, APC, or TP53 achieved a pCR. pCR rate was 23.5% (4/17) in wild-type tumors versus 3.3% (1/30) in those with a mutation. There was no difference in the mutation rates in pre- versus post-CRT specimens. On univariate analysis, clinical predictors of pCR included post-RT carcinoembriogenic antigen level of ≤2.5 and smaller tumor size. No patients with a pCR developed recurrence.
  
  
  CONCLUSIONS
  Patients without mutations in commonly mutated cancer genes may be associated with a higher likelihood of having a pCR after preoperative CRT. This should be confirmed in a prospective study.
authors.affiliation: Harvard Radiation Oncology Program, Boston, MA, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Russo
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Wo
authors.forename: Jackie
authors.initials: J
authors.lastname: Szymonifka
authors.forename: Wen-Yih
authors.initials: WY
authors.lastname: Liang
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Jill N
authors.initials: JN
authors.lastname: Allen
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: David L
authors.initials: DL
authors.lastname: Berger
authors.forename: James C
authors.initials: JC
authors.lastname: Cusack
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Mamon
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Hong
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics*; D000069287:Capecitabine; D059248:Chemoradiotherapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012189:Retrospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D005472:Fluorouracil