Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer

Christophe Bounaix Morand du Puch, Michelle Nouaille, Stéphanie Giraud, Anaïs Labrunie, Sandrine Luce, Pierre-Marie Preux, François Labrousse, Alain Gainant, Nicole Tubiana-Mathieu, Valérie Le Brun-Ly, Denis Valleix, Angélique Guillaudeau, Laura Mesturoux, Béma Coulibaly, Christophe Lautrette, Muriel Mathonnet, Christophe Bounaix Morand du Puch, Michelle Nouaille, Stéphanie Giraud, Anaïs Labrunie, Sandrine Luce, Pierre-Marie Preux, François Labrousse, Alain Gainant, Nicole Tubiana-Mathieu, Valérie Le Brun-Ly, Denis Valleix, Angélique Guillaudeau, Laura Mesturoux, Béma Coulibaly, Christophe Lautrette, Muriel Mathonnet

Abstract

Background: Colorectal cancer (CRC) remains a major public concern. While conventional chemotherapeutic regimens have proved useful against advanced/metastatic diseases, progresses are to be made to effectively cure the large portion of patients not benefiting from these treatments. One direction to improve response rates is to develop chemosensitivity and resistance assays (CSRAs) efficiently assisting clinicians in treatment selection process, an already long preoccupation of oncologists and researchers. Several methods have been described to this day, none achieving yet sufficient reliability for recommended use in the clinical routine.

Methods: We led a pilot study on 19 metastatic CRC patients evaluating capacity of the Oncogramme, a standardized process using tumor ex vivo models, to provide chemosensitivity profiles and predict clinical outcome of patients receiving standard CRC chemotherapeutics. Oncogramme responses were categorized according to the method of percentiles to assess sensitivity, specificity and concordance.

Results: We report from a primary analysis a success rate of 97.4 %, a very good sensitivity (84.6 %), a below-average specificity (33.3 %), along with a global agreement of 63.6 % and a concordance between Oncogramme results and patients' responses (Kappa coefficient) of 0.193. A supplementary analysis, focusing on CRC patients with no treatment switch over a longer time course, demonstrated improvement in specificity and concordance.

Conclusions: Results establish feasibility and usefulness of the Oncogramme, prelude to a larger-scale trial. Advantages and drawbacks of the procedure are discussed, as well as the place of CSRAs within the future arsenal of methods available to clinicians to individualize treatments and improve patient prognosis.

Trial registration: ClinicalTrials.gov database, registration number: NCT02305368.

Figures

Fig. 1
Fig. 1
a Overview of patient selection process in the pilot trial, from initial recruitment to final inclusion. From the 64 individuals originally recruited, exclusion and inclusion criteria allowed to finally select 19 patients with stage-IV CRC, pre- + post- or post-surgery treatment, RECIST 1.1-measurable lesions and consistent clinical follow-up. b Overview of the Oncogramme experimental procedure, from surgery to readout. Viable samples were recovered and processed to obtain primary cultures that were subsequently utilized for realization of the Oncogramme by exposure to chemotherapeutic drugs and cell death analysis. Whole time course was inferior to 2 weeks

References

    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107.
    1. Boyle P, Leon ME. Epidemiology of colorectal cancer. Br Med Bull. 2002;64:1–25. doi: 10.1093/bmb/64.1.1.
    1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–1502. doi: 10.1016/S0140-6736(13)61649-9.
    1. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:2059–2069. doi: 10.1200/JCO.2003.11.126.
    1. Fornaro L, Masi G, Loupakis F, Vasile E, Falcone A. Palliative treatment of unresectable metastatic colorectal cancer. Expert Opin Pharmacother. 2010;11:63–77. doi: 10.1517/14656560903427997.
    1. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104–117. doi: 10.3322/caac.21220.
    1. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010;375:1030–1047. doi: 10.1016/S0140-6736(10)60353-4.
    1. Moorcraft SY, Smyth EC, Cunningham D. The role of personalized medicine in metastatic colorectal cancer: an evolving landscape. Ther. Adv. Gastroenterol. 2013;6:381–395. doi: 10.1177/1756283X13491797.
    1. Ó Céilleachair AJ, Hanly P, Skally M, O’Neill C, Fitzpatrick P, Kapur K, et al. Cost comparisons and methodological heterogeneity in cost-of-illness studies: the example of colorectal cancer. Med Care. 2013;51:339–350. doi: 10.1097/MLR.0b013e3182726c13.
    1. Ross JS, Torres-Mora J, Wagle N, Jennings TA, Jones DM. Biomarker-based prediction of response to therapy for colorectal cancer: current perspective. Am J Clin Pathol. 2010;134:478–490. doi: 10.1309/AJCP2Y8KTDPOAORH.
    1. Bellamy WT. Prediction of response to drug therapy of cancer. A review of in vitro assays. Drugs. 1992;44:690–708. doi: 10.2165/00003495-199244050-00002.
    1. Hamburger AW, Salmon SE. Primary bioassay of human tumor stem cells. Science. 1977;197:461–463. doi: 10.1126/science.560061.
    1. Kern DH, Drogemuller CR, Kennedy MC, Hildebrand-Zanki SU, Tanigawa N, Sondak VK. Development of a miniaturized, improved nucleic acid precursor incorporation assay for chemosensitivity testing of human solid tumors. Cancer Res. 1985;45:5436–5441.
    1. Weisenthal LM, Marsden JA, Dill PL, Macaluso CK. A novel dye exclusion method for testing in vitro chemosensitivity of human tumors. Cancer Res. 1983;43:749–757.
    1. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 1987;47:936–942.
    1. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990;82:1107–1112. doi: 10.1093/jnci/82.13.1107.
    1. Kangas L, Grönroos M, Nieminen AL. Bioluminescence of cellular ATP: a new method for evaluating cytotoxic agents in vitro. Med. Biol. 1984;62:338–343.
    1. Kobayashi H, Tanisaka K, Doi O, Kodama K, Higashiyama M, Nakagawa H, et al. An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures. Int J Oncol. 1997;11:449–455.
    1. Kravtsov VD, Greer JP, Whitlock JA, Koury MJ. Use of the microculture kinetic assay of apoptosis to determine chemosensitivities of leukemias. Blood. 1998;92:968–980.
    1. Nagourney RA. Ex vivo programmed cell death and the prediction of response to chemotherapy. Curr Treat Options Oncol. 2006;7:103–110. doi: 10.1007/s11864-006-0045-2.
    1. Burstein HJ, Mangu PB, Somerfield MR, Schrag D, Samson D, Holt L, et al. American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29:3328–3330. doi: 10.1200/JCO.2011.36.0354.
    1. Nagourney RA, Blitzer JB, Shuman RL, Asciuto TJ, Deo EA, Paulsen M, et al. Functional profiling to select chemotherapy in untreated, advanced or metastatic non-small cell lung cancer. Anticancer Res. 2012;32:4453–4460.
    1. Weisenthal LM. Differential staining cytotoxicity assay: a review. Methods Mol Biol Clifton NJ. 2011;731:259–283. doi: 10.1007/978-1-61779-080-5_22.
    1. Grendys EC, Fiorica JV, Orr JW, Holloway R, Wang D, Tian C, et al. Overview of a chemoresponse assay in ovarian cancer. Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. 2014;16:761–769.
    1. Kubota T, Weisenthal L. Chemotherapy sensitivity and resistance testing: to be “standard” or to be individualized, that is the question. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2006;9:82–87.
    1. Bosanquet AG, Richards SM, Wade R, Else M, Matutes E, Dyer MJS, et al. Drug cross-resistance and therapy-induced resistance in chronic lymphocytic leukaemia by an enhanced method of individualised tumour response testing. Br J Haematol. 2009;146:384–395. doi: 10.1111/j.1365-2141.2009.07741.x.
    1. Loum E, Giraud S, Bessette B, Battu S, Mathonnet M, Lautrette C. Oncogramme, a new individualized tumor response testing method: application to colon cancer. Cytotechnology. 2010;62:381–388. doi: 10.1007/s10616-010-9298-5.
    1. Giraud S, Loum E, Bessette B, Fermeaux V, Lautrette C. Oncogramme, a new promising method for individualized breast tumour response testing for cancer treatment. Anticancer Res. 2011;31:139–145.
    1. Giraud S, Croce S, Bessette B, Stoeckle E, Guyon F, Mac Grogan G, et al. Oncogramme, an adapted method for individualized tumour response testing of ovary cancer treatments. J Cancer Res Ther Oncol. 2014;2:1–9. doi: 10.14312/2052-4994.2014-1.
    1. Mélin C, Perraud A, Bounaix Morand du Puch C, Loum E, Giraud S, Cardot P, et al. Sedimentation field flow fractionation monitoring of in vitro enrichment in cancer stem cells by specific serum-free culture medium. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;963:40–46. doi: 10.1016/j.jchromb.2014.05.039.
    1. Giraud S, Bounaix Morand du Puch C, Fermeaux V, Guillaudeau A, Lautrette C. Oncogramme responses of breast tumour cells treated with herceptin correlate with HER2/C-ERB B2 pathological status. Anticancer Res. 2012;32:1323–1325.
    1. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7. New York: Springer-Verlag; 2011.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer Oxf Engl 1990. 2009;45:228–247.
    1. Krivak TC, Lele S, Richard S, Secord AA, Leath CA, Brower SL, et al. A chemoresponse assay for prediction of platinum resistance in primary ovarian cancer. Am J Obstet Gynecol. 2014;211(68):e1–e8.
    1. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–174. doi: 10.2307/2529310.
    1. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:1539–1544. doi: 10.1200/JCO.2006.09.6305.
    1. Tanigawa N, Kern DH, Hikasa Y, Morton DL. Rapid assay for evaluating the chemosensitivity of human tumors in soft agar culture. Cancer Res. 1982;42:2159–2164.
    1. Furukawa T, Kubota T, Hoffman RM. Clinical applications of the histoculture drug response assay. Clin Cancer Res Off J Am Assoc Cancer Res. 1995;1:305–311.
    1. Cho YB, Lee WY, Song SY, Choi SH, Shin HJ, Ahn K-D, et al. In vitro chemosensitivity based on depth of invasion in advanced colorectal cancer using ATP-based chemotherapy response assay (ATP-CRA) Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 2009;35:951–956.
    1. Huh JW, Park YA, Lee KY, Sohn SK. Heterogeneity of adenosine triphosphate-based chemotherapy response assay in colorectal cancer–secondary publication. Yonsei Med J. 2009;50:697–703. doi: 10.3349/ymj.2009.50.5.697.
    1. Brouquet A, Taleb P, Lot AS, Beauchet A, Julie C, Prevost G, et al. A model of primary culture of colorectal cancer and liver metastasis to predict chemosensitivity. J Surg Res. 2011;166:247–254. doi: 10.1016/j.jss.2009.04.039.
    1. Arienti C, Tesei A, Verdecchia GM, Framarini M, Virzì S, Grassi A, et al. Role of conventional chemosensitivity test and tissue biomarker expression in predicting response to treatment of peritoneal carcinomatosis from colon cancer. Clin Colorectal Cancer. 2013;12:122–127. doi: 10.1016/j.clcc.2012.11.006.
    1. Zeig-Owens R, Gershman ST, Knowlton R, Jacobson JS. Survival and time interval from surgery to start of chemotherapy among colon cancer patients. J Regist Manag. 2009;36:30–41.
    1. Pavlik EJ, Flanigan RC, van Nagell JR, Hanson MB, Donaldson ES, Keaton K, et al. Esterase activity, exclusion of propidium iodide, and proliferation in tumor cells exposed to anticancer agents: phenomena relevant to chemosensitivity determinations. Cancer Invest. 1985;3:413–426. doi: 10.3109/07357908509039802.
    1. Pfeiffer P, Qvortrup C, Bjerregaard JK. Current status of treatment of metastatic colorectal cancer with special reference to cetuximab and elderly patients. OncoTargets Ther. 2009;2:17–27.
    1. Cortazar P, Johnson BE. Review of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer. J Clin Oncol Off J Am Soc Clin Oncol. 1999;17:1625–1631.
    1. Zheng Y, Zhou J, Tong Y. Gene signatures of drug resistance predict patient survival in colorectal cancer. Pharmacogn J. 2015;15:135–143. doi: 10.1038/tpj.2014.45.
    1. Fanali C, Lucchetti D, Farina M, Corbi M, Cufino V, Cittadini A, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol WJG. 2014;20:923–942. doi: 10.3748/wjg.v20.i4.923.
    1. Gillet J-P, Varma S, Gottesman MM. The clinical relevance of cancer cell lines. J Natl Cancer Inst. 2013;105:452–458. doi: 10.1093/jnci/djt007.
    1. Takebayashi K, Mekata E, Sonoda H, Shimizu T, Shiomi H, Naka S, et al. Differences in chemosensitivity between primary and metastatic tumors in colorectal cancer. PLoS One. 2013;8:e73215. doi: 10.1371/journal.pone.0073215.
    1. Unger FT, Witte I, David KA. Prediction of individual response to anticancer therapy: historical and future perspectives. Cell Mol Life Sci CMLS. 2015;72:729–757. doi: 10.1007/s00018-014-1772-3.
    1. Arienti C, Tesei A, Verdecchia GM, Framarini M, Virzì S, Grassi A, et al. Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy. J Transl Med. 2011;9:94. doi: 10.1186/1479-5876-9-94.
    1. Bosserman LD, Rajurkar SP, Rogers K, Davidson DC, Chernick M, Hallquist A, et al. Correlation of drug-induced apoptosis assay results with oncologist treatment decisions and patient response and survival. Cancer. 2012;118:4877–4883. doi: 10.1002/cncr.27444.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever