ЭВОЛЮЦИЯ ВЗГЛЯДОВ НА ПАЛЛИАТИВНОЕ ЛЕЧЕНИЕ МЕТАСТАЗИРУЮЩИХ ФОРМ КОЛОРЕКТАЛЬНОГО РАКА В ЭРУ ТАРГЕТНОЙ ТЕРАПИИ
Ключові слова:
колоректальный рак, метастазы, паллиативное лечение, мутация, RAS, BRAF, микросателлитная нестабильность, VEGF, контрольные точки иммунного ответа, МкАТ, таргетные ингибиторы.Анотація
Проанализированы данные исследований и клинических испытаний эффективности сочетания современных химиотерапевтических режимов
(FOLFOX, FOLFIRI) с таргетными препаратами в первой и второй линии
лечения пациентов с метастатическим колоректальным раком (мКРР).
Кдополнительным прогностическим маркерам для оптимизации планов терапии относят мутации генов RAS (KRAS, NRAS) и BRAF, высокий уровень
экспрессии фактора роста эндотелия сосудов (VEGF) и микросателлитную нестабильность (MSI). Отдельные маркеры имеют и предиктивное
значение. Дикий тип генов KRAS и NRAS (RAS-WT) — предиктор чувствительности к анти-EGFR-терапии. MSI — предиктор чувствительности
к препаратам-ингибиторам контрольных точек иммунного ответа. Исследования предиктивной роли мутаций BRAF при мКРР и потенциальной
активности таргетных препаратов, разработанных для других опухолей
с мутацией BRAF, пока не завершены. Уровень VEGF не является предиктором чувствительности к антиангиогенной терапии, но прогностическое
его значение важно. Результаты использования любых сочетаний терапевтических агентов у больных мКРР с первичной опухолью, расположенной в восходящем отделе толстой кишки, хуже, чем в клинических случаях с расположением первичной опухоли в нисходящих отделах. Включение
в схемы лечения пациентов с мКРР RAS-WT анти-EGFR-терапии достоверно повышало показатели ответа на лечение и общей выживаемости
при приемлемом уровне токсичности. Наиболее важный эффект включения анти-EGFR и анти-VEGF-препаратов — улучшение результатов конверсионной терапии: хирургическая резекция метастазов стала возможна соответственно у 17 и 14% больных мКРР. Таким образом, пополнение
современной базы данных о природе опухолевого роста дало возможность
персонализировать лекарственное лечение пациентов с мКРР и извлекать
максимальные преимущества для больных как из давно известных лекарственных препаратов, так и из современных биотехнологических средств.
Посилання
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65 (2): 87–108.
Van der Geest LG, Lam-Boer J, Koopman M, et al. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Met 2015; 32: 457–65. 10.1007/s10585–015–9719–0.
Glimelius B, Cavalli-Bjorkman N. Metastatic colorectal cancer: current treatment and future options for improved survival. Medical approach — present status. Scand J Gastroenterol 2012; 47 (3): 296–314.
Morris EJ, Forman D, Thomas JD, et al. Surgical management and outcomes of colorectal cancer liver metastases. Br J
Surg 2010; 97: 1110–18. 10.1002/bjs.7032.
Andres A, Mentha G, Adam R, et al. Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases. Br J Surg 2015; 102: 691–9. 10.1002/bjs.9783.
de Baere T, Aupérin A, Deschamps F, et al. Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases. Ann Oncol 2015; 26: 987–91. 10.1093/annonc/mdv037.
Klint Å, Engholm G, Storm HH, et al. Trends in survival of patients diagnosed with cancer of the digestive organs in the Nordic countries 1964–2003 followed up to the end of 2006. Acta Oncol 2010; 49: 578–607. 10.3109/02841861003739330.
Langley RR, Fidler IJ. The seed and soil hypothesis revisited-the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 2011; 128: 2527–35. 10.1002/ijc.26031.
Fidler I. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3: 453–8.
Sleeman JP, Nazarenko I, Thiele W. Do all roads lead to Rome? Routes to metastasis development. Int J Cancer 2011; 128: 2511–26. 10.1002/ijc.26027.
Wood SL, Pernemalm M, Crosbie P A, et al. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev 2014; 40: 558–66. 10.1016/j.ctrv.2013.10.001.
Hess KR, et al. Metastatic patterns in adenocarcinoma. Cancer 2006; 106: 1624–33. 10.1002/cncr.21778.
Disibio G, French SW. Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med 2008; 132:931–9. 10.1043/1543–2165132 [931: mpocrf] 2.0.co; 2.
Budczies J, von Winterfeld M, Klauschen F, et al. The landscape of metastatic progression patterns across major human cancers. Oncotarget 2015; 6: 570–83.
Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Scientific Reports 2016; 6: article number: 29765, doi:10.1038/srep29765.
Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment
of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 2005; 23 (22): 4866–75.
Poston GJ, Figueras J, Giuliante F, et al. Urgent need for a new staging system in advanced colorectal cancer. J Clin Oncol 2008; 26 (29): 4828–33.
Hurwitz H, Fehrenbacher L, Novotny W, et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350 (23): 2335–42.
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360 (14): 1408–17.
Van Cutsem E, Kohne CH, Lang I, et al. 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 2011; 29 (15): 2011–9.
Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26 (10): 1626–34.
Kaczirek K, Ciuleanu TE, Vrbanec D, et al. FOLFOX4 plus cetuximab for patients with previously untreated metastatic colorectal cancer according to tumor RAS and BRAF mutation status: updated analysis of the CECOG/CORE 1.2.002 study. Clin Colorectal Cancer 2015; 14 (2): 91–8.
Douillard JY, Oliner KS, Siena S, et al. PanitumumabFOLFOX4 treatment and RAS mutations in colorectal cancer. N
Engl J Med 2013; 369 (11): 1023–34.
Douillard JY, Siena S, Cassidy J, et al. Randomized,
Phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28 (31): 4697–705.
Khattak MA, Martin H, Davidson A, et al. Role of first-line anti-epidermal growth factor receptor therapy compared with antivascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer 2015; 14 (2): 81–90.
Hongchi Wang, Bin Ma, Peng Gao, et al. Efficacy and safety of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer in first-line and second-line therapies: a meta-analysis. Onco Targets Ther 2016; 9: 5405–16.
Heinemann V, von Weikersthal LF, Decker T, et al.FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15 (10): 1065–75.
Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter Phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32 (21): 2240–7.
Venook AP, Niedzwiecki D, Lenz H, et al. CALGB/ SWOG80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) J Clin Oncol 2014; 32 (5s) Suppl; abstract LBA3.
Lenz H, Niedzwiecki D, Innocenti F, et al. CALGB/ SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). J Clin Oncol 2014; 32 (Suppl); abstract LBA3.
Calson RH. Metastatic colorectal cancer: antibody regimens found equivalent. Oncol Times 2014; 36 (13): 28–9.
Stremitzer S, Stift J, Singh J, et al. Histological response, pattern of tumor destruction and clinical outcome after neoadjuvant chemotherapy including bevacizumab or cetuximab in patients undergoing liver resection for colorectal liver metastases. Eur J Surg Oncol 2015; 41 (7): 868–74.
Venook A, Niedzwiecki D, Lenz H, et al. LBA10CALGB/ SWOG 80405: analysis of patients undergoing surgery as part of treatment strategy. Ann Oncol 2014; 25 (Suppl 4): mdu438.8.
Hecht JR, Cohn A, Dakhil S, et al. SPIRITT: a randomized, multicenter, Phase II study of panitumumab with FOLFIRI
and bevacizumab with FOLFIRI as second-line treatment in patients with unresectable wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer 2015; 14 (2): 72–80.
Heinemann V, Niedzwiecki D, Rachel V, et al. Outcomes for FOLFIRI plus bevacizumab (BEV) or cetuximab (CET) in patients previously treated with oxaliplatin-based adjuvant therapy: a combined analysis of data from FIRE-3 and CALGB 80405. J Clin Oncol 2015; 33 (suppl; abstract 3585).
Yang YH, Lin JK, Chen WS, et al. Comparison of cetuximab to bevacizumab as the first-line bio-chemotherapy for patients with metastatic colorectal cancer: superior progression-free survival is restricted to patients with measurable tumors and objective tumor response — a retrospective study. J Cancer Res Clin Oncol 2014; 140 (11): 1927–36.
Modest DP, Stintzing S, von Weikersthal LF, et al. Impact of subsequent therapies on outcome of the FIRE-3/AIO
KRK0306 trial: First-line therapy with FOLFIRI plus cetuximab or bevacizumab in patients with KRAS wild-type tumors
in metastatic colorectal cancer. J Clin Oncol 2015; 33 (32): 3718–26.
Ciardiello F, Bianco R, Caputo R, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res 2004; 10 (2): 784–93.
Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptorblocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001; 61 (13): 5090–101.
Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377 (9783): 2103–14.
Glimelius B, Cavalli-Bjorkman N. Metastatic colorectal cancer: current treatment and future options for improved survival. Medical approach — present status. Scand J Gastroenterol 2012; 47 (3): 296–314.
Feng QY, Wei Y, Chen JW, et al. Anti-EGFR and antiVEGF agents: important targeted therapies of colorectal liver metastases. World J Gastroenterol 2014; 20 (15): 4263–75.
Stintzing S, Modest DP, von Weikersthal LF, et al. LBA11- independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK0306) in the final RAS evaluable population. Ann Oncol 2014; 25 (Suppl 4): mdu438.439.
Bokemeyer C, Kohne CH, Ciardiello F, et al. Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. J Clin Oncol 2014; 32: 5s (suppl; abstract 3505).
Ciardiello F, Lenz H, Kohne CH, et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. J Clin Oncol 2014; 32: 5s (suppl; abstract 3506).
Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009; 27 (35): 5924–30.
Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009; 101 (4): 715–21.
Chan D, Pavlakis N, Price TJ, et al. Impact of chemotherapy partner on efficacy of targeted therapy in metastatic colorectal cancer (mCRC): a meta-analysis. J Clin Oncol 2014; 32: 5s (suppl; abstract 3552).
Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized Phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25 (7): 1346–55.
Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol 2015; 33 (16): 1809–24.
Roskoski RJr. RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun 2010; 399 (3): 313–7.
Zlobec I, Bihl MP, Schwarb H, et al. Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis. Int J Cancer 2010; 127 (2): 367–80.
Tie J, Gibbs P, Lipton L, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAFV600E mutation. Int J Cancer 2011; 128: 2075–84.
Artale S, Sartore-Bianchi A, Veronese SM, et al.Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 2008; 26 (25): 4217–9.
Yuan ZX, Wang XY, Qin QY, et al. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving antiEGFR monoclonal antibodies: a metaanalysis. PLoS One 2013; 8 (6): e65995. doi:10.1371/journal.pone.0065995.
Mao C, Liao RY, Qiu LX, et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep 2011; 38 (4): 2219–23.
Xu Q, Xu AT, Zhu MM, et al. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a meta-analysis. J Dig Dis 2013; 14 (8): 409–16.
Bokemeyer C, Kohne C, Rougier P, et al. Cetuximab with chemotherapy (CT) as firstline treatment for metastatic colorectal cancer (mCRC): analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. J Clin Oncol 2010; 28 (suppl; abstract 3506).
Roth A, Klingbiel D, Yan P, et al. Molecular and clinical determinants of survival following relapse after curative treatment of stage II—III colon cancer (CC): results of the translational study of PETACC 3-EORTC 40993-SAKK 60–00 trial. J Clin Oncol 2010; 28 (suppl; abstr 3504).
Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One 2012; 7 (10): e47054.
Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003; 21 (14): 2787–99.
Custodio A, Feliu J. Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: Beyond KRAS mutations. Crit Rev Oncol Hematol 2013; 85 (1): 45–81.
Niault TS, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis 2010; 31 (7): 1165–74.
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26 (35): 5705–12.
De Roock W, Claes B, Bernasconi D, et al. 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 2010; 11 (8): 753–62.
Fedyanin MJ, Tryakin AA, Tyulandin SA. Perspectives of treatment of patients with colon cancer with a mutation in the BRAF gene. Oncol Coloproctal 2014; (3): 9–16 (in Russian).
Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48: 1466–75.
Seymour MT, Brown SR, Richman S, et al. Addition of panitumumab to irinotecan: results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC). J Clin Oncol 2011; 29 Suppl; abstract 3523.
Tol J, Dijkstra JR, Klomp M, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer 2010; 46: 1997–2009.
Loupakis F, Cremolini C, Salvatore L, et al. FOLFOXIRI plus bevacizumab as firstline treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer 2014; 50 (1): 57–63.
Liu L, Shi H, Bleam MR, et al. Antitumor effects of dabrafenib, trametinib, and panitumumab as single agents and in combination in BRAF-mutant colorectal carcinoma (CRC) models. J Clin Oncol 2014; 32: 5s (suppl; abstr 3513).
Bendell JC, Atreya CE, André T, et al. Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol 2014; 32: 5s (suppl; abstr 3515).
Geel RV, Elez E, Bendell JC, et al. Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the a-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol 2014; 32: 5s (suppl; abstr 3514).
Hong DS, Morris VK, Fu S, et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer. J Clin Oncol 2014; 32: 5s (suppl; abstr 3516).
Corcoran RB, Atreya CE, Falchook GS, et al.Phase 1–2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): Updated efficacy and biomarker analysis. J Clin Oncol 2014; 32: 5s (suppl; abstr 3517).
Tabernero J, Chan E, Baselga J, et al. VE-BASKET, a Simon 2-stage adaptive design, phase II, histology-independent
study in nonmelanoma solid tumors harboring BRAF V600 mutations (V600m): Activity of vemurafenib (VEM) with or without cetuximab (CTX) in colorectal cancer (CRC). J Clin Oncol 2014; 32: 5s (suppl; abstr 3518).
Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11 (2): 141–51. doi: 10.1016/S1074–7613(00)80089–8.
Bogolyubova AV, Efimov GA, Drutskaya MS, Nedospasov SA. Cancer immunotherapy based on the blockade of immune checkpoints. Med Immunol (Russia) 2015; 17 (5): 395–406. doi:10.15789/1563–0625–2015–5-395406 (in Russian).
Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8 (8): 793–800. doi: 10.1038/nm730.
Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer 2013; 108 (8): 1560–5. doi: 10.1038/bjc.2013.117.
Klyuchagina Ju, Sokolov ZA, Baryshnikov AI. The role of the PD1 receptor and its PDL1 and PDL2 ligands in tumor immunotherapy. Oncopediatrix 2017; 4 (1): 50–5 (in Russian).
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
N Engl J Med 2012; 366 (26): 2455–65 (https://doi.org/10.1056/nejmoa1200694).
Ge J, Zhu L, Zhou J, et al. Association between co-inhibitory molecule gene tagging single nucleotide polymorphisms
and the risk of colorectal cancer in Chinese. J Cancer Res Clin Oncol 2015; 141 (9): 1533–44 (https://doi. org/10.1007/s00432–015–1915–4).
Kit ОI, Kirichenko ЕY, Novikova IА, et al. Colorectal cancer immunotherapy: current state and prospects (review). Sovremennye Tehnologii v Medicine 2017; 9 (3): 138–50 (https://doi.org/10.17691/stm2017.9.3.18).
Chung KY, Gore I, Fong L, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol 2010; 28 (21): 3485–90 (https://doi. org/10.1200/jco.2010.28.3994).
Fedyanin MY, Tryakin AA, Tjulandin SA. Role of microsatellite instability in colon cancer. Colorectal Oncol 2012; (3):
–25. DOI:10.17650/2220–3478–2012–0-3–19–25 (in Russian).
Droeser RA, Hirt C, Viehl CT, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 2013; 49 (9): 2233–42 (https://doi. org/10.1016/j. ejca.2013.02.015). ith mismatch-repair deficiency. N Engl J Med 2015; 372 (26): 2509–20 (https:// doi.org/10.1056/nejmoa1500596).
Chung KY, Gore I, Fong L, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol 2010; 28 (21): 3485–90 (https://doi. org/10.1200/jco.2010.28.3994).
Karran P. Mechanisms of tolerance to DNA damaging therapeutic drugs. Carcinogenesis 2001; 22 (12): 1931–7.
Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015; 5 (1): 43–51. doi:10.1158/2159–8290.cd-14–0863.
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366 (26): 2443–54. doi:10.1056/NEJMoa1200690.
Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol 2015; 89 (6): 899–921. doi:10.1007/s00204–
–1474–0.
Gatalica Z, Vijayvergia N, Vranic S, et al. Therapeutic biomarker differences between MSI-H and MSS colorectal cancers. J Clin Oncol 2015; 33 (suppl; abstr 3597).
Gatalica Z, Snyder C, Maney T, et al. (2014) Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomark Prev 2014; 23 (12): 2965–70. doi:10.1158/1055– 9965.epi-14–0654.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26): 2509–20. doi:10.1056/NEJMoa1500596.
Gatalica Z, Vranic S, Xiu J, et al. High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine. Familial Cancer 2016; 15: 405 (https://doi.org/10.1007/s10689–016–9884–6).
