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International Conference on Software Engineering and Formal Methods

SEFM 2014: Software Engineering and Formal Methods pp 243–258Cite as

A Mathematical Model for Assessing KRAS Mutation Effect on Monoclonal Antibody Treatment of Colorectal Cancer

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Part of the book series: Lecture Notes in Computer Science ((LNPSE,volume 8938))

Abstract

The most challenging task in colorectal cancer research nowadays is to understand the development of acquired resistance to anti-EGFR drugs. The key reason for this problem is the KRAS mutations produced after the treatment with monoclonal antibodies (mAb). KRAS screening tests done before the start of the treatment are not very sensitive to identify minute quantity of the mutated cells, which can produce resistance to the therapy after the beginning of the treatment. Here we present a mathematical model for the analysis of KRAS mutations behavior in colorectal cancer with respect to mAb treatments. To evaluate the drug performance we have developed equations for two types of tumors cells, i.e. KRAS mutated and KRAS wildtype. Both tumor cell populations were treated with a combination of mAb and chemotherapy drugs. It was observed that even the minimal initial concentration of KRAS mutation before the treatment has the ability to make the tumor refractory to the treatment. Patient’s immune responses are specifically taken into considerations and it is found that, in case of KRAS mutations, the immune strength does not affect medication efficacy. Finally, Cetuximab (mAb) and Irinotecan (chemotherapy) drugs are analyzed as first-line treatment of colorectal cancer with few KRAS mutated cells. Results show that this combined treatment is only effective for patients with high immune strengths and it should not be recommended as first-line therapy for patients with moderate immune strengths or weak immune systems because of a potential risk of relapse, with KRAS mutant cells acquired resistance involved with them.

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References

  1. WHO/Europe—Colorectal cancer. http://www.euro.who.int/en/health-topics/noncommunicable-diseases/cancer/news/news/2012/2/early-detection-of-common-cancers/colorectal-cancer

  2. Deschoolmeester, V., Baay, M., Specenier, P., Lardon, F., Vermorken, J.B.: A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 15, 699–731 (2010)

    Article  Google Scholar 

  3. Repetto, L., Gianni, W., Aglianò, A.M., Gazzaniga, P.: Impact of EGFR expression on colorectal cancer patient prognosis and survival: a response. Ann. Oncol. 16, 1557 (2005)

    Article  Google Scholar 

  4. Gschwind, A., Fischer, O.M., Ullrich, A.: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer. 4, 361–370 (2004)

    Article  Google Scholar 

  5. Van Cutsem, E., Peeters, M., Siena, S., Humblet, Y., Hendlisz, A., Neyns, B., Canon, J.L., Van Laethem, J.L., Maurel, J., Richardson, G., Wolf, M., Amado, R.G.: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007)

    Article  Google Scholar 

  6. Martinelli, E., De Palma, R., Orditura, M., De Vita, F., Ciardiello, F.: Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin. Exp. Immunol. 158, 1–9 (2009)

    Article  Google Scholar 

  7. Parsons, B.L., Meng, F.: K-RAS mutation in the screening, prognosis and treatment of cancer. Biomark Med. 3, 757–769 (2009)

    Article  Google Scholar 

  8. Bando, H., Yoshino, T., Tsuchihara, K., Ogasawara, N., Fuse, N., Kojima, T., Tahara, M., Kojima, M., Kaneko, K., Doi, T., Ochiai, A., Esumi, H., Ohtsu, A.: KRAS mutations detected by the amplification refractory mutation system-scorpion assays strongly correlate with therapeutic effect of cetuximab. Br. J. Cancer 105, 403–406 (2011)

    Article  Google Scholar 

  9. Karapetis, C.S., Khambata-Ford, S., Jonker, D.J., O’Callaghan, C.J., Tu, D., Tebbutt, N.C., Simes, R.J., Chalchal, H., Shapiro, J.D., Robitaille, S., Price, T.J., Shepherd, L., Au, H.J., Langer, C., Moore, M.J., Zalcberg, J.R.: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008)

    Article  Google Scholar 

  10. Amado, R.G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D.J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., Patterson, S.D., Chang, D.D.: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008)

    Article  Google Scholar 

  11. Van Cutsem, E., Köhne, C.H., Hitre, E., Zaluski, J., Chang Chien, C.R., Makhson, A., D’Haens, G., Pintér, T., Lim, R., Bodoky, G., Roh, J.K., Folprecht, G., Ruff, P., Stroh, C., Tejpar, S., Schlichting, M., Nippgen, J., Rougier, P.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009)

    Article  Google Scholar 

  12. Fakih, M.M.: KRAS mutation screening in colorectal cancer: from paper to practice. Clin. Colorectal Cancer 9, 22–30 (2010)

    Article  Google Scholar 

  13. De Roock, W., Piessevaux, H., De Schutter, J., Janssens, M., De Hertogh, G., Personeni, N., Biesmans, B., Van Laethem, J.L., Peeters, M., Humblet, Y., Van Cutsem, E., Tejpar, S.: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol. 19, 508–515 (2008)

    Article  Google Scholar 

  14. Parsons, B.L., Myers, M.B.: KRAS mutant tumor subpopulations can subvert durable responses to personalized cancer treatments. Pers. Med. 10, 191–199 (2013)

    Article  Google Scholar 

  15. Tougeron, D., Lecomte, T., Pagés, J.C., Villalva, C., Collin, C., Ferru, A., Tourani, J.M., Silvain, C., Levillain, P., Karayan-Tapon, L.: Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer. Ann. Oncol. 24, 1267–1273 (2013)

    Article  Google Scholar 

  16. Ballesta, A., Clairambault, J.: Physiologically based mathematical models to optimize therapies against metastatic colorectal cancer: a mini-review. Curr. Pharm. Des. 20, 37–48 (2014)

    Article  Google Scholar 

  17. Johnston, M.D., Edwards, C.M., Bodmer, W.F., Maini, P.K., Chapman, S.J.: Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer. Proc. Natl. Acad. Sci. U.S.A. 104, 4008–4013 (2007)

    Article  Google Scholar 

  18. van Leeuwen, I.M., Byrne, H.M., Jensen, O.E., King, J.R.: Crypt dynamics and colorectal cancer: advances in mathematical modelling. Cell Prolif. 39, 157–181 (2006)

    Article  Google Scholar 

  19. Fletcher, A.G., Breward, C.J.W., Chapman, S.J.: Mathematical modeling of monoclonal conversion in the colonic crypt. J. Theor. Biol. 300, 118–133 (2012)

    Article  MathSciNet  Google Scholar 

  20. Murray, P.J., Walter, A., Fletcher, A.G., Edwards, C.M., Tindall, M.J., Maini, P.K.: Comparing a discrete and continuum model of the intestinal crypt. Phys. Biol. 8, 1478–3975 (2011)

    Article  Google Scholar 

  21. Johnston, M.D., Edwards, C.M., Bodmer, W.F., Maini, P.K., Chapman, S.J.: Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer. Proc. Natl. Acad. Sci. U.S.A. 104(10), 4008–4013 (2007)

    Article  Google Scholar 

  22. Monro, H.C., Gaffney, E.A.: Modelling chemotherapy resistance in palliation and failed cure. J. Theor. Biol. 257, 292–302 (2009)

    Article  Google Scholar 

  23. Boston, E.A.J., Gaffney, E.A.: The influence of toxicity constraints in models of chemotherapeutic protocol escalation. Math. Med. Biol. 28, 357–384 (2011)

    Article  MATH  MathSciNet  Google Scholar 

  24. Diaz, L.A., Williams, R.T., Wu, J., Kinde, I., Hecht, J.R., Berlin, J., Allen, B., Bozic, I., Reiter, J.G., Nowak, M.A., Kinzler, K.W., Oliner, K.S., Vogelstein, B.: The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012)

    Google Scholar 

  25. Stites, E.C.: Differences in sensitivity to EGFR inhibitors could be explained by described biochemical differences between oncogenic Ras mutants. bioRxiv (2014). http://dx.doi.org/10.1101/005397

  26. de Pillis, L.G., Savage, H., Radunskaya, A.E.: Mathematical model of colorectal cancer with monoclonal antibody treatments. Brit. J. of Med. and Medical Res. 4(16), 3101–3131 (2014)

    Article  Google Scholar 

  27. GNU Octave 3.8.1. http://www.gnu.org/software/octave/

  28. Eaton, J.W., Bateman, D., Hauberg, S.: GNU Octave version 3.0.1 manual: a high-level interactive language for numerical computations, CreateSpace Independent Publishing Platform. ISBN: 1441413006 (2009). http://www.gnu.org/software/octave/doc/interpreter

  29. Arnold, D., Seufferlein, T.: Targeted treatments in colorectal cancer: state of the art and future perspectives. Gut 59, 838–858 (2010)

    Article  Google Scholar 

  30. Prewett, M.C., Hooper, A.T., Bassi, R., Ellis, L.M., Waksal, H.W., Hicklin, D.J.: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin. Cancer Res. 8, 994–1003 (2002)

    Google Scholar 

  31. Jonker, D.J., O’Callaghan, C.J., Karapetis, C.S., Zalcberg, J.R., Tu, D., Au, H.J., Berry, S.R., Krahn, M., Price, T., Simes, R.J., Tebbutt, N.C., van Hazel, G., Wierzbicki, R., Langer, C., Moore, M.J.: Cetuximab for the treatment of colorectal cancer. N. Engl. J. Med. 357, 2040–2048 (2007)

    Article  Google Scholar 

  32. Wu, L., Adams, M., Carter, T., Chen, R., Muller, G., Stirling, D., Schafer, P., Bartlett, J.B.: lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin. Cancer Res. 14, 4650–4657 (2008)

    Article  Google Scholar 

  33. Vilar, E., Tabernero, J.: Cancer: pinprick diagnostics. Nature 486, 482–483 (2012)

    Article  Google Scholar 

  34. Baldus, S.E., Schaefer, K.L., Engers, R., Hartleb, D., Stoecklein, N.H., Gabbert, H.E.: Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin. Cancer Res. 16, 790–799 (2010)

    Article  Google Scholar 

  35. Hasovits, C., Pavlakis, N., Howell, V., Gill, A., Clarke, S.: Resistance to EGFR targeted antibodies - expansion of clones present from the start of treatment. The more things change, the more they stay the same (Plus ca change, plus ca ne change pas!. Transl. Gastrointest. Cancer 2, 44–46 (2013)

    Google Scholar 

  36. Smakman, N., Veenendaal, L.M., van Diest, P., Bos, R., Offringa, R., Borel Rinkes, I.H., Kranenburg, O.: Dual effect of Kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy. Oncogene 24, 8338–8342 (2005)

    Article  Google Scholar 

  37. Folprecht, G., Lutz, M.P., Schöffski, P., Seufferlein, T., Nolting, A., Pollert, P., Köhne, C.H.: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann. Oncol. 17, 450–456 (2006)

    Article  Google Scholar 

  38. Pfeiffer, P., Nielsen, D., Bjerregaard, J., Qvortrup, C., Yilmaz, M., Jensen, B.: Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Ann. Oncol. 19, 1141–1145 (2008)

    Article  Google Scholar 

  39. Vincenzi, B., Santini, D., Rabitti, C., Coppola, R., Beomonte Zobel, B., Trodella, L., Tonini, G.: Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br. J. Cancer. 94, 792–797 (2006)

    Article  Google Scholar 

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Authors and Affiliations

  1. Dipartimento di Informatica, Università di Pisa, Pisa, Italy

    Sheema Sameen, Roberto Barbuti, Paolo Milazzo & Antonio Cerone

Authors
  1. Sheema Sameen
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  2. Roberto Barbuti
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  3. Paolo Milazzo
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  4. Antonio Cerone
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Corresponding author

Correspondence to Paolo Milazzo .

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Editors and Affiliations

  1. University of Malaga, Malaga, Spain

    Carlos Canal

  2. LIG Lab, Saint Martin d'Hères Cedex, France

    Akram Idani

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© 2015 Springer International Publishing Switzerland

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Sameen, S., Barbuti, R., Milazzo, P., Cerone, A. (2015). A Mathematical Model for Assessing KRAS Mutation Effect on Monoclonal Antibody Treatment of Colorectal Cancer. In: Canal, C., Idani, A. (eds) Software Engineering and Formal Methods. SEFM 2014. Lecture Notes in Computer Science(), vol 8938. Springer, Cham. https://doi.org/10.1007/978-3-319-15201-1_16

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  • DOI: https://doi.org/10.1007/978-3-319-15201-1_16

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-15200-4

  • Online ISBN: 978-3-319-15201-1

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