The Journal of the Korea Contents Association (한국콘텐츠학회논문지)

The Korea Contents Association (한국콘텐츠학회)
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Application of Molecular Diagnostics Technology in the Development of a Companion Diagnostics for Malignant Solid Tumors

악성 고형암의 항암제 동반진단 기술에서 분자진단기술의 적용

  • 김진희 (청주대학교 보건의료대학 임상병리학과)
  • Received : 2019.01.23
  • Accepted : 2019.02.27
  • Published : 2019.03.28
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Abstract

Unlike benign tumors, malignant tumors are capable of metastasis, easy to relapse, poor survival, and low quality of life. In Korea, here is a tendency to treat the tumors collectively according to the General Principles of Cancer Chemotherapy(GPCC) of the Health Insurance Review & Assessment Service (HIRA). But recently, companion diagnostics(CDx) is recommended rather than unilateral medication because biomarker-based molecular diagnostics is possible to predict the drug response of patients before drug treatment. Not only domestic but also overseas Food and Drug Administratio (FDA) recommends the development of the CDx system at the stage of drug development to ensure the responsiveness and safety of medicines. In this study, I focused on the necessity of CDx development direction as well as CDx development status through literature review. Furthermore I also discussed CDx types according to the molecular diagnostic technology such as immunohistochemistry (IHC), polymerase chain reaction (PCR), in situ hybridization (ISH), and next-generation sequencing (NGS) not only in the approved CDx but also in the developing one by US FDA. And I suggested the technology issue of CDx development process such as a selection of molecular diagnostics at the time of release, a clear understanding of the CDx mechanism, and a convergence of drug with CDx development. The necessity of social insurance system also was proposed for CDx development.

악성종양은 양성종양과 달리 전이가 가능하고 재발이 쉬울 뿐 아니라 생존율 및 삶의 질이 떨어지는 질환이다. 국내의 경우 악성종양 치료 시 건강보험심사평가원이 제시한 항암화학요법 일반원칙에 따라 일괄적으로 치료하는 경향이 있다. 하지만 근래에는 일방적인 약물치료보다는 동반진단제를 사용을 권고하는데 이는 바이오마커를 이용한 분자진단기법으로 동반진단하여 치료 전에 환자의 약물 반응을 예측할 수 있기 때문이며, 국내외 식품의약품안전처에서는 의약품의 반응성 및 안전성을 확보하기 위하여 신약개발단계에서 동반진단제를 함께 개발하기를 권고한다. 본 종설에서는 악성 고형암을 중심으로 동반진단제의 개발방향 및 개발현황을 문헌고찰을 통해 분석하였고, 동반진단제로 사용되는 다양한 분자진단기법, 예컨대 면역조직화학염색법, 중합효소연쇄반응법, 제자리부합법, 차세대염기서열분석법 등에 따른 동반진단제 개발현황 및 미국 식품의약품안전청의 승인사례를 조사하여 최신 동반진단 개발동향을 함께 살폈다. 그리고 동반진단제 개발과정에서 기술적 사항으로 허가시점에 맞춘 분자진단기술을 선택과 진단제에 대한 명확한 기전이해와 더불어 치료와 동반진단제의 융합을 제언하였고, 사회적으로 동반진단제에 대한 공공보험의 급여책정이 필요함을 제언하였다.

Keywords

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그림 1. 신약개발 과정 중 동반진단제 동시 개발 전략

표 1. 양성종양과 악성종양의 특성 비교

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표 2. 기전에 따른 세포독성 항암제의 분류

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표 3. 분자진단기술의 체외진단시장

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표 4. FDA에 승인된 IHC 기법을 이용한 동반진단제 현황

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표 5. FDA에 승인된 PCR 기법을 이용한 동반진단제 현황

CCTHCV_2019_v19n3_365_t0005.png 이미지

표 6. FDA에 승인된 ISH 기법을 이용한 동반진단제 현황

CCTHCV_2019_v19n3_365_t0006.png 이미지

References

  1. P. Rubin and G. Casarett, "Microcirculation of tumors. I. Anatomy, function, and necrosis," Clin Radiol, Vol.17, pp.220-229, 1966. https://doi.org/10.1016/S0009-9260(66)80027-2
  2. R. K. Jain, "Determinants of tumor blood flow: a review," Cancer Res, Vol.48, pp.2641-2658, 1988.
  3. W. H. Clark, "Tumour progression and the nature of cancer," Br. J. Cancer, Vol.64, No.4, pp.631-644, 1991. https://doi.org/10.1038/bjc.1991.375
  4. B. A. Chabner and T. G. Roberts, "Timeline: Chemotherapy and the war on cancer," Nature reviews cancer, Vol.5, No.1, pp.65-72, 2005. https://doi.org/10.1038/nrc1529
  5. P. Bumming, J. Andersson, J. M. Meis-Kindblom, H. Klingenstierna, K. Engstrom, U. Stierner, B. Wangberg, S. Jansson, H. Ahlman, L. G. Kindblom, and B. Nilsson, "Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: a centre-based study of 17 patients," British journal of cancer, Vol.89, No.3, pp.460-464, 2003. https://doi.org/10.1038/sj.bjc.6600965
  6. A. G. Hall and M. J. Tilby "Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies," Blood review, Vol.6, No.3, pp.163-173, 1992. https://doi.org/10.1016/0268-960X(92)90028-O
  7. J. Bardy, N. J. Slevin, K. L. Mais, and A. Molassiotis, "A systematic review of honey uses and its potential value within oncology care," Journal of Clinical Nursing, Vol.17, No.9, pp.2661-2664, 2008. https://doi.org/10.1111/j.1365-2702.2008.02473.x
  8. T. A. Baudino, "Targeted Cancer Therapy: The Next Generation of Cancer Treatment. Current drug discovery technologies," Current drug discovery technologies, Vol.12, No.1, pp.3-20, 2001. https://doi.org/10.2174/1570163812666150602144310
  9. M. Jamal-Hanjani, A. Hackshaw, Y. Ngai, J. Shaw, C. Dive, and S. Quezada, "Tracking genomic cancer evolution for precision medicine: the lung TRACERx study," PLoS Biol, Vol.12, p.e1001906, 2014. https://doi.org/10.1371/journal.pbio.1001906
  10. M. Goozner, "Drug approvals 2011: focus on companion diagnostics," Journal of the National Cancer Institute, Vol.104, No.2, pp.84-86, 2012. https://doi.org/10.1093/jnci/djr552
  11. National Evidence-based healthcare Collaborating Agency, Development of Guidelines for New Health Technology Assessment, 2014.
  12. National Institute of Food and Drug Safety Evaluation, Review guidelines for Market Authorization (IVD Companion Diagnostics). Cheongju: National Institute of Food and Drug Safety Evaluation, 2015.
  13. C. S. Karapetis, S. Khambata-Ford, D. J. Jonker, C. J. O'Callaghan, D. Tu, N. C. Tebbutt, R. J. Simes, H. Chalchal, J. D. Shapiro, S. Robitaille, T. J. Price, L. Shepherd, H. J. Au, C. Langer, M. J. Moore, and J. R. Zalcberg, "K-ras mutations and benefit from cetuximab in advanced colorectal cancer," N Engl J Med, Vol.359, No.17, pp.1757-1765, 2008. https://doi.org/10.1056/NEJMoa0804385
  14. B. J. Solomon, T. Mok, D. W. Kim, Y. L. Wu, K. Nakagawa, T. Mekhail, E. Felip, F. Cappuzzo, J. Paolini, T. Usari, S. Iyer, A. Reisman, K. D. Wilner, J. Tursi, and F. Blackhall, "First-line crizotinib versus chemotherapy in ALK-positive lung cancer," N Engl J Med, Vol.371, No.23, pp.2167-2177, 2014. https://doi.org/10.1056/NEJMoa1408440
  15. T. W. Jacobs, A. M. Gown, H. Yaziji, M. J. Barnes, and S. J. Schnitt, "Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system," J Clin Oncol, Vol.7, No.7, pp.1983-1987, 1999.
  16. A. Agarwal, D. Ressler, and G. Snyder, "The current and future state of companion diagnostics," Pharmgenomics Pers Med, Vol.31, No.87, pp.99-110, 2015.
  17. 신영기, "표적항암제 동반진단키트의 현재와 전망," 생명공학정책연구, Vol.4, 2014.
  18. M. S. Tsao, A. Sakurada, J. C. Cutz, C. Q. Zhu, S. Kamel-Reid, J. Squire, I. Lorimer, T. Zhang, N. Liu, M. Daneshmand, P. Marrano, G. da Cunha Santos, A. Lagarde, F. Richardson, L. Seymour, M. Whitehead, K. Ding, J. Pater, and F. A. Shepherd, "Erlotinib in lung cancer-molecular and clinical predictors of outcome," N Engl J Med, Vol.353, No.2, pp.133-144, 2005. https://doi.org/10.1056/NEJMoa050736
  19. M. Reck, D. Rodriguez-Abreu, A. G. Robinson, R. Hui, T. Csoszi, A. Fulop, M. Gottfried, N. Peled, A. Tafreshi, S. Cuffe, M. O'Brien, S. Rao, K. Hotta, M. A. Leiby, G. M. Lubiniecki, Y. Shentu, R. Rangwala, and J. R. Brahmer, "Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer," N Engl J Med, Vol.375, No.19, pp.1823-1833, 2016. https://doi.org/10.1056/NEJMoa1606774
  20. Ryan Bishop, "Applications of fluorescence in situ hybridization (FISH) in detecting genetic aberrations of medical significance," Bioscience Horizons, Vol.3, No.1, pp.85-95, 2010. https://doi.org/10.1093/biohorizons/hzq009
  21. A. Agarwal, D. Ressler, and G. Snyder, "The current and future state of companion diagnostics," Pharmgenomics Pers Med, Vol.8, pp.99-110, 2015.
  22. S. A. Hardwick, I. W. Deveson, and T. R. Mercer, "Reference standards for next-generation sequencing," Nat Rev Genet, Vol.18, No.8, pp.1473-484, 2017.
  23. S. A. Waldman and A. Terzic, "Companion diagnostics at the intersection of personalized medicine and healthcare delivery," Biomark Med, Vol.9, No.1, pp.1-3, 2015. https://doi.org/10.2217/bmm.14.99
  24. E. Faulkner, L. Annemans, L. Garrison, M. Helfand, A. P. Holtorf, J. Hornberger, D. Hughes, T. Li, D. Malone, K. Payne, U. Siebert, A. Towse, D. Veenstra, and J. Watkins, "Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of The ISPOR Personalized Medicine Special Interest Group," Value Health, Vol.15, pp.1162-1171, 2012. https://doi.org/10.1016/j.jval.2012.05.006