KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy
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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.
KeywordsRectal Cancer Sanger Sequencing KRAS Mutation TP53 Mutation Timing Trial
This study was supported by the National Institutes of Health (NIH), National Cancer Institute (NCI) R01 Grant CA090559 (JGA) and the MSK Core Grant P30 CA008748.
Additional thanks for the contributions of Garrett Nash, Larissa Temple, José Guillem, Philip Paty (Surgical faculty members from the Colorectal Service of Memorial Sloan Kettering Cancer Center) and members of the Timing of Rectal Cancer Response to Chemoradiation Consortium: David Smith, Jorge Marcet, Peter Cataldo, Madhulika Varma, Anjali Kumar, Samuel Oommen, Theodore Coutsoftides, Steven Hunt, Michael Stamos, Charles Ternent, Daniel Herzig, Alessandro Fichera, Blase Polite, David Dietz.
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