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01-08-2016 | Colorectal Cancer

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

Authors: Oliver S. Chow, MD, Deborah Kuk, ScM, Metin Keskin, MD, J. Joshua Smith, MD, PhD, Niedzica Camacho, PhD, Raphael Pelossof, PhD, Chin-Tung Chen, MS, Zhenbin Chen, PhD, Karin Avila, MS, Martin R. Weiser, MD, Michael F. Berger, PhD, Sujata Patil, PhD, Emily Bergsland, MD, Julio Garcia-Aguilar, MD, PhD

Published in: Annals of Surgical Oncology | Issue 8/2016

Abstract

Background

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.

Methods

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.

Results

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 %).

Conclusions

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.

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Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240:711–7; discussion 717–8.

Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg. 2012;256:965–72. doi:10.1097/SLA.0b013e3182759f1c.CrossRefPubMed

Guillem JG, Chessin DB, Shia J, et al. Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate end point. J Clin Oncol. 2005;23:3475–9. doi:10.1200/JCO.2005.06.114.CrossRefPubMed

Radovanovic Z, Breberina M, Petrovic T, Golubovic A, Radovanovic D. Accuracy of endorectal ultrasonography in staging locally advanced rectal cancer after preoperative chemoradiation. Surg Endosc. 2008;22:2412–5. doi:10.1007/s00464-008-0037-3.CrossRefPubMed

Huh JW, Park YA, Jung EJ, Lee KY, Sohn S-K. Accuracy of endorectal ultrasonography and computed tomography for restaging rectal cancer after preoperative chemoradiation. J Am Coll Surg. 2008;207:7–12. doi:10.1016/j.jamcollsurg.2008.01.002.CrossRefPubMed

Leibold T, Akhurst TJ, Chessin DB, et al. Evaluation of ¹⁸F-FDG-PET for early detection of suboptimal response of rectal cancer to preoperative chemoradiotherapy: a prospective analysis. Ann Surg Oncol. 2011;18:2783–9. doi:10.1245/s10434-011-1634-2.CrossRefPubMed

Memon S, Lynch AC, Bressel M, Wise AG, Heriot AG. Systematic review and meta-analysis of the accuracy of MRI and ERUS in the restaging and response assessment of rectal cancer following neoadjuvant therapy. Colorectal Dis. 2015;17:748–61. doi:10.1111/codi.12976.CrossRefPubMed

Garcia-Aguilar J, Chen Z, Smith DD, et al. Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg. 2011;254:486–92; discussion 492–3. doi:10.1097/SLA.0b013e31822b8cfa.

Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015;16:957–66. doi:10.1016/S1470-2045(15)00004-2.CrossRefPubMed

10.

Kalady MF, de Campos-Lobato LF, Stocchi L, Geisler DP, Dietz D, Lavery IC, Fazio VW. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009;250:582–9. doi:10.1097/SLA.0b013e3181b91e63.PubMed

11.

Wolthuis AM, Penninckx F, Haustermans K, De Hertogh G, Fieuws S, Van Cutsem E, D’Hoore A. Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome. Ann Surg Oncol. 2012;19:2833–41. doi:10.1245/s10434-012-2327-1.CrossRefPubMed

12.

Zeng W-G, Zhou Z-X, Liang J-W, et al. Impact of interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer on surgical and oncologic outcome. J Surg Oncol. 2014;110:463–7. doi:10.1002/jso.23665.CrossRefPubMed

13.

Calvo FA, Morillo V, Santos M, et al. Interval between neoadjuvant treatment and definitive surgery in locally advanced rectal cancer: impact on response and oncologic outcomes. J Cancer Res Clin Oncol. 2014;140:1651–60. doi:10.1007/s00432-014-1718-z.CrossRefPubMed

14.

Cercek A, Goodman KA, Hajj C, et al. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Canc Netw. 2014;12:513–9. http://www.ncbi.nlm.nih.gov/pubmed/24717570. Accessed Dec 15, 2014.

15.

Gao Y-H, Lin J-Z, An X, et al. Neoadjuvant sandwich treatment with oxaliplatin and capecitabine administered prior to, concurrently with, and following radiation therapy in locally advanced rectal cancer: a prospective phase 2 trial. Int J Radiat Oncol Biol Phys. 2014;90:1153–60. doi:10.1016/j.ijrobp.2014.07.021.CrossRefPubMed

16.

Cheng DT, Mitchell T, Zehir A, et al. MSK-IMPACT: a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64. doi:10.1016/j.jmoldx.2014.12.006.CrossRefPubMed

17.

Hyman DM, Solit DB, Arcila ME, et al. Precision medicine at Memorial Sloan Kettering Cancer Center: clinical next-generation sequencing enabling next-generation targeted therapy trials. Drug Discov Today. 2015;20:1422–8. doi:10.1016/j.drudis.2015.08.005.CrossRefPubMed

18.

Duldulao MP, Lee W, Nelson RA, Li W, Chen Z, Kim J, Garcia-Aguilar J. Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. Ann Surg Oncol. 2013;20:2166–71. doi:10.1245/s10434-013-2910-0.CrossRefPubMed

19.

Lièvre A, Bachet J-B, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5. doi:10.1158/0008-5472.CAN-06-0191.CrossRefPubMed

20.

Michelassi F, Erroi F, Roncella M, Block GE. Ras oncogene and the acquisition of metastasizing properties by rectal adenocarcinoma. Dis Colon Rectum. 1989;32:665–8. http://www.ncbi.nlm.nih.gov/pubmed/2666052. Accessed June 8, 2015.

21.

Segelov E, Chan D, Shapiro J, Price TJ, Karapetis CS, Tebbutt NC, Pavlakis N. The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials. Br J Cancer. 2014;111:1122–31. doi:10.1038/bjc.2014.404.CrossRefPubMedPubMedCentral

22.

Lee D-W, Kim KJ, Han S-W, et al. KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX. Ann Surg Oncol. 2015;22:187–94. doi:10.1245/s10434-014-3826-z.CrossRefPubMed

23.

Yoon HH, Tougeron D, Shi Q, et al. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res. 2014;20:3033–43. doi:10.1158/1078-0432.CCR-13-3140.CrossRefPubMedPubMedCentral

24.

Clancy C, Burke JP, Coffey JC. KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Surg Oncol. 2013;22:105–11. doi:10.1016/j.suronc.2013.02.001.CrossRefPubMed

25.

Gaedcke J, Grade M, Jung K, et al. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy. Radiother Oncol. 2010;94:76–81. doi:10.1016/j.radonc.2009.10.001.CrossRefPubMed

Title: KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy
Authors: Oliver S. Chow, MD
Deborah Kuk, ScM
Metin Keskin, MD
J. Joshua Smith, MD, PhD
Niedzica Camacho, PhD
Raphael Pelossof, PhD
Chin-Tung Chen, MS
Zhenbin Chen, PhD
Karin Avila, MS
Martin R. Weiser, MD
Michael F. Berger, PhD
Sujata Patil, PhD
Emily Bergsland, MD
Julio Garcia-Aguilar, MD, PhD
Publication date: 01-08-2016
Publisher: Springer International Publishing
Published in: Annals of Surgical Oncology / Issue 8/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-016-5205-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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