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Value of KRAS, BRAF, and PIK3CA Mutations and Survival Benefit from Systemic Chemotherapy in Colorectal Peritoneal Carcinomatosis

  • Sasaki, Yusuke (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Hamaguchi, Tetsuya (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Yamada, Yasuhide (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Takahashi, Naoki (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Shoji, Hirokazu (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Honma, Yoshitaka (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Iwasa, Satoru (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Okita, Natsuko (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Takashima, Atsuo (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Kato, Ken (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Nagai, Yushi (Exploratory Oncology Research & Clinical Trial Center, National Cancer Center) ;
  • Taniguchi, Hirokazu (Pathology and Clinical Laboratory Division, National Cancer Center Hospital) ;
  • Boku, Narikazu (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital) ;
  • Ushijima, Toshikazu (Division of Epigenomics, National Cancer Center Research Institute) ;
  • Shimada, Yasuhiro (Gastrointestinal Medical Oncology Division, National Cancer Center Hospital)
  • Published : 2016.03.07

Abstract

Background: It is well known that peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is associated with a poor prognosis. However, data on the prognostic significance of modern chemotherapy containing bevacizumab, cetuximab or panitumumab are not available. Materials and Methods: This retrospective review concerned 526 patients with metastatic CRC who were classified into two groups according to the presence or absence of PC, and were treated with systemic chemotherapy, with or without bevacizumab or anti-EGFR antibodies. The genetic background, in particular KRAS, BRAF, and PIK3CA gene mutations, and overall survival (OS) were compared between the two groups. Results: The median OS values were 23.3 and 29.1 months for PC and non-PC patients, respectively (hazard ratio [HR]=1.20; p=0.17). Among all patients, tumor location, number of metastatic sites and BRAF mutation status were significant prognostic factors, whereas the presence of PC was not. In the PC group, chemotherapy with bevacizumab resulted in a significantly longer OS than forchemotherapy without bevacizumab (HR=0.38, p<0.01), but this was not the case in the non-PC group (HR=0.80, p=0.10). Furthermore, the incidence of the BRAF V600E mutation was significantly higher in PC than in non-PC patients (27.7% versus 7.3%, p<0.01). BRAF mutations displayed a strong correlation with shorter OS in non-PC (HR=2.26), but not PC patients (HR=1.04). Conclusions: Systemic chemotherapy, especially when combined with bevacizumab, improved survival in patients with PC from CRC as well as non-PC patients. While BRAF mutation demonstrated a high frequency in PC patients, but it was not associated with prognosis.

Keywords

BRAF;colorectal cancer;KRAS;peritoneal carcinomatosis;PIK3CA

References

  1. De Roock W, Claes B, Bernasconi D, et al (2010). Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol, 11, 753-62. https://doi.org/10.1016/S1470-2045(10)70130-3
  2. Douillard JY, Oliner KS, Siena S, et al (2013). Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 369, 1023-34. https://doi.org/10.1056/NEJMoa1305275
  3. Eklöf V, Wikberg ML, Edin S, et al (2013). The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer. Br J Cancer, 108, 2153-63. https://doi.org/10.1038/bjc.2013.212
  4. Franko J, Shi Q, Goldman CD, et al (2012). Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol, 30, 263-7. https://doi.org/10.1200/JCO.2011.37.1039
  5. Garrido-Laguna I, Hong DS, Janku F, et al (2012). KRASness and PIK3CAness in patients with advanced colorectal cancer:outcome after treatment with early-phase trials with targeted pathway inhibitors. PLoS One, 7, 38033. https://doi.org/10.1371/journal.pone.0038033
  6. Gonsalves W, Mahoney MR, Sargent DJ, et al (2014). Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. J Natl Cancer Inst, 106, published online.
  7. Jayne DG, Fook S, Loi C, et al (2002). Peritoneal carcinomatosis from colorectal cancer. Br J Surg, 89, 1545-50. https://doi.org/10.1046/j.1365-2168.2002.02274.x
  8. Koppe MJ, Boerman OC, Oyen WJ, et al (2006). Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg, 243, 212-22. https://doi.org/10.1097/01.sla.0000197702.46394.16
  9. Kraft A, Weindel K, Ochs A, et al (1999). Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer, 85, 178-87. https://doi.org/10.1002/(SICI)1097-0142(19990101)85:1<178::AID-CNCR25>3.0.CO;2-7
  10. Mao C, Yang ZY, Hu XF, et al (2012). PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol, 23, 1518-25. https://doi.org/10.1093/annonc/mdr464
  11. Neumann J, Zeindl-Eberhart E, Kirchner T, et al (2009). Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract, 205, 858-62. https://doi.org/10.1016/j.prp.2009.07.010
  12. Pichler M, Balic M, Stadelmeyer E, et al (2009). Evaluation of high-resolution melting analysis as a diagnostic tool to detect the BRAF V600E mutation in colorectal tumors. J Mol Diagn, 11, 140-7. https://doi.org/10.2353/jmoldx.2009.080100
  13. Richman SD, Seymour MT, Chambers P, et al (2009). KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol, 27, 5931-7. https://doi.org/10.1200/JCO.2009.22.4295
  14. Sadeghi B, Arvieux C, Glehen O, et al (2000). Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer, 88, 358-63. https://doi.org/10.1002/(SICI)1097-0142(20000115)88:2<358::AID-CNCR16>3.0.CO;2-O
  15. Sanger F, Nicklen S, Coulson AR (1977). DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A, 74, 5463-7. https://doi.org/10.1073/pnas.74.12.5463
  16. Tran B, Kopetz S, Tie J, et al (2011). Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer, 117, 4623-32. https://doi.org/10.1002/cncr.26086
  17. Van Cutsem E, Kohne CH, Lang I, et al (2011). Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol, 29, 2011-9. https://doi.org/10.1200/JCO.2010.33.5091
  18. Verwaal VJ, van Ruth S, de Bree E, et al (2003). Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol, 21, 3737-43. https://doi.org/10.1200/JCO.2003.04.187

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