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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.

SUBMITTER: Chow OS

PROVIDER: S-EPMC5047012 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy.

Chow Oliver S OS Kuk Deborah D Keskin Metin M Smith J Joshua JJ Camacho Niedzica N Pelossof Raphael R Chen Chin-Tung CT Chen Zhenbin Z Avila Karin K Weiser Martin R MR Berger Michael F MF Patil Sujata S Bergsland Emily E Garcia-Aguilar Julio J

Annals of surgical oncology 20160328 8

<h4>Background</h4>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.<h4>Methods</h4>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 F ...[more]

PMID: 27020587

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Project description:ImportanceTreatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases.ObjectiveTo compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC.Design, setting, and participantsA retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified.ExposuresOf the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT).Main outcomes and measuresTreatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK.ResultsOf the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort.Conclusions and relevanceOur findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

Dataset Information

KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy.

Publications

KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy.

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