title: KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy.
abstract: The response of rectal cancers to neoadjuvant chemoradiation (CRT) is variable, but tools to predict response remain lacking. We evaluated whether KRAS and TP53 mutations are associated with pathologic complete response (pCR) and lymph node metastasis after adjusting for neoadjuvant regimen.
  
  
  
  Retrospective analysis of 229 pretreatment biopsies from patients with stage II/III rectal cancer was performed. All patients received CRT. Patients received 0-8 cycles of FOLFOX either before or after CRT, but prior to surgical excision. A subset was analyzed to assess concordance between mutation calls by Sanger Sequencing and a next-generation assay.
  
  
  
  A total of 96 tumors (42 %) had KRAS mutation, 150 had TP53 mutation (66 %), and 59 (26 %) had both. Following neoadjuvant therapy, 59 patients (26 %) achieved pCR. Of 133 KRAS wild-type tumors, 45 (34 %) had pCR, compared with 14 of 96 (15 %) KRAS mutant tumors (p = .001). KRAS mutation remained independently associated with a lower pCR rate on multivariable analysis after adjusting for clinical stage, CRT-to-surgery interval and cycles of FOLFOX (OR 0.34; 95 % CI 0.17-0.66, p < .01). Of 29 patients with KRAS G12V or G13D, only 2 (7 %) achieved pCR. Tumors with both KRAS and TP53 mutation were associated with lymph node metastasis. The concordance between platforms was high for KRAS (40 of 43, 93 %).
  
  
  
  KRAS mutation is independently associated with a lower pCR rate in locally advanced rectal cancer after adjusting for variations in neoadjuvant regimen. Genomic data can potentially be used to select patients for "watch and wait" strategies.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Chow
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kuk
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Metin
authors.initials: M
authors.lastname: Keskin
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: J Joshua
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Niedzica
authors.initials: N
authors.lastname: Camacho
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Pelossof
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Chin-Tung
authors.initials: CT
authors.lastname: Chen
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Zhenbin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Avila
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Bergsland
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA. garciaaj@mskcc.org.
authors.forename: Julio
authors.initials: J
authors.lastname: Garcia-Aguilar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D059248:Chemoradiotherapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D011379:Prognosis; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras) / 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: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)