Molecular classification and precision therapy of cancer: immune checkpoint inhibitors
Yingyan Yu()
Department of Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as “genetic interpreters” or “genetic translators” and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.
Moderately or poorly differentiated adenocarcinoma with lymphoepithelial lesion (80.77%)
Yes
Other histology (19.23%)
MSI subtype (64)
(A) Low power: expanding growth pattern of bulky tumor; high power: bulky solid or medullary tumor with lymphocyte infiltration, especially in invasive frontier (B) Low power: expanding growth pattern of bulky tumor; high power: moderately differentiated adenocarcinoma clusters with lymphocyte infiltration, especially in invasive frontier (70.31%) Other histology (29.69%)
Yes
GS subtype (58)
Signet-ring cell carcinoma and its variants, including typical signet-ring cell, small-cell variant, large-cell variant, spindle-cell variant, mucinous variant, and undifferentiated beam variant (namely, poorly cohesive carcinoma) (63.79%)
Unknown
Other histology (36.21%)
CIN subtype (147)
Intestinal-type histology (66.67%) Other histology (33.33%)
Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MD, Niu B, McLellan MD, Uzunangelov V, Zhang J, Kandoth C, Akbani R, Shen H, Omberg L, Chu A, Margolin AA, Van’t Veer LJ, Lopez-Bigas N, Laird PW, Raphael BJ, Ding L, Robertson AG, Byers LA, Mills GB, Weinstein JN, Van Waes C, Chen Z, Collisson EA; Cancer Genome Atlas Research Network, Benz CC, Perou CM, Stuart JM. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 2014; 158(4): 929–944 https://doi.org/10.1016/j.cell.2014.06.049
pmid: 25109877
3
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563–567 https://doi.org/10.1038/nature14011
pmid: 25428504
4
Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, Ma Y, Zhao H, Huang Y, Xue C, Huang P, Hu Z, Zhao Y, Zhang L. Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Med Oncol 2015; 32(3): 86 https://doi.org/10.1007/s12032-015-0501-6
pmid: 25702326
5
Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520(7547): 373–377 https://doi.org/10.1038/nature14292
pmid: 25754329
6
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366(26): 2455–2465 https://doi.org/10.1056/NEJMoa1200694
pmid: 22658128
7
Kim JW, Eder JP. Prospects for targeting PD-1 and PD-L1 in various tumor types. Oncology (Williston Park) 2014; 28(Suppl 3): 15–28
pmid: 25387682
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20(19): 5064–5074 https://doi.org/10.1158/1078-0432.CCR-13-3271
pmid: 24714771
Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015; 5(1): 43–51 https://doi.org/10.1158/2159-8290.CD-14-0863
pmid: 25358689
Yoon K, Lee S, Han TS, Moon SY, Yun SM, Kong SH, Jho S, Choe J, Yu J, Lee HJ, Park JH, Kim HM, Lee SY, Park J, Kim WH, Bhak J, Yang HK, Kim SJ. Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers. Genome Res 2013; 23(7): 1109–1117 https://doi.org/10.1101/gr.145706.112
pmid: 23737375
15
Richman S. Deficient mismatch repair: read all about it. Int J Oncol 2015; 47(4): 1189–1202
pmid: 26315971
16
Arai T, Sakurai U, Sawabe M, Honma N, Aida J, Ushio Y, Kanazawa N, Kuroiwa K, Takubo K. Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach. Gastric Cancer 2013; 16(4): 505–512 https://doi.org/10.1007/s10120-012-0226-6
pmid: 23274922
17
Sinicrope FA, Rego RL, Foster N, Sargent DJ, Windschitl HE, Burgart LJ, Witzig TE, Thibodeau SN. Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers. Am J Gastroenterol 2006; 101(12): 2818–2825 https://doi.org/10.1111/j.1572-0241.2006.00845.x
pmid: 17026563
18
Matthews KS, Estes JM, Conner MG, Manne U, Whitworth JM, Huh WK, Alvarez RD, Straughn JM Jr, Barnes MN, Rocconi RP. Lynch syndrome in women less than 50 years of age with endometrial cancer. Obstet Gynecol 2008; 111(5): 1161–1166 https://doi.org/10.1097/AOG.0b013e31817051d9
pmid: 18448750
19
Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W, Schackert HK, Goergens H, von Knebel Doeberitz M, Goecke TO, Schmiegel W, Buettner R, Moeslein G, Letteboer TG, Gómez García E, Hes FJ, Hoogerbrugge N, Menko FH, van Os TA, Sijmons RH, Wagner A, Kluijt I, Propping P, Vasen HF. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol 2012; 30(35): 4409–4415 https://doi.org/10.1200/JCO.2012.43.2278
pmid: 23091106
20
Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Järvinen HJ, Myrhøj T, Sunde L, Wijnen JT, Lynch HT. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 2008; 123(2): 444–449 https://doi.org/10.1002/ijc.23508
pmid: 18398828
21
Talwalkar VR, Scheiner M, Hedges LK, Butler MG, Schwartz HS. Microsatellite instability in malignant melanoma. Cancer Genet Cytogenet 1998; 104(2): 111–114 https://doi.org/10.1016/S0165-4608(97)00452-4
pmid: 9666803
22
Alvino E, Marra G, Pagani E, Falcinelli S, Pepponi R, Perrera C, Haider R, Castiglia D, Ferranti G, Bonmassar E, Jiricny J, Zambruno G, D’Atri S. High-frequency microsatellite instability is associated with defective DNA mismatch repair in human melanoma. J Invest Dermatol 2002; 118(1): 79–86 https://doi.org/10.1046/j.0022-202x.2001.01611.x
pmid: 11851879
23
Palmieri G, Ascierto PA, Cossu A, Colombino M, Casula M, Botti G, Lissia A, Tanda F, Castello G. Assessment of genetic instability in melanocytic skin lesions through microsatellite analysis of benign naevi, dysplastic naevi, and primary melanomas and their metastases. Melanoma Res 2003; 13(2): 167–170 https://doi.org/10.1097/00008390-200304000-00009
pmid: 12690300
24
Beghelli S, de Manzoni G, Barbi S, Tomezzoli A, Roviello F, Di Gregorio C, Vindigni C, Bortesi L, Parisi A, Saragoni L, Scarpa A, Moore PS. Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 2006; 139(3): 347–356 https://doi.org/10.1016/j.surg.2005.08.021
pmid: 16546499
25
Fang WL, Chang SC, Lan YT, Huang KH, Chen JH, Lo SS, Hsieh MC, Li AF, Wu CW, Chiou SH. Microsatellite instability is associated with a better prognosis for gastric cancer patients after curative surgery. World J Surg 2012; 36(9): 2131–2138 https://doi.org/10.1007/s00268-012-1652-7
pmid: 22669398
26
Lee HS, Choi SI, Lee HK, Kim HS, Yang HK, Kang GH, Kim YI, Lee BL, Kim WH. Distinct clinical features and outcomes of gastric cancers with microsatellite instability. Mod Pathol 2002; 15(6): 632–640 https://doi.org/10.1038/modpathol.3880578
pmid: 12065777
27
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387(10027): 1540–1550 https://doi.org/10.1016/S0140-6736(15)01281-7
pmid: 26712084
28
Sunshine JC, Nguyen PL, Kaunitz GJ, Cottrell TR, Berry S, Esandrio J, Xu H, Ogurtsova A, Bleich KB, Cornish TC, Lipson EJ, Anders RA, Taube JM. PD-L1 expression in melanoma: a quantitative immunohistochemical antibody comparison. Clin Cancer Res 2017; 23(16):4938–4944 https://doi.org/10.1158/1078-0432.CCR-16-1821
pmid: 28428193
29
Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 2016; 9(1): 47 https://doi.org/10.1186/s13045-016-0277-y
pmid: 27234522
30
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372(21): 2018–2028 https://doi.org/10.1056/NEJMoa1501824
pmid: 25891174
31
Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, Goossens M, Ouchene H, Hendriks-Cornelissen SJ, Kwint MP, Hoogerbrugge N, Nagtegaal ID, Ligtenberg MJ. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 2014; 146(3): 643–646.e8 https://doi.org/10.1053/j.gastro.2013.12.002
pmid: 24333619
32
Fadhil W, Ilyas M. Immunostaining for mismatch repair (MMR) protein expression in colorectal cancer is better and easier to interpret when performed on diagnostic biopsies. Histopathology 2012; 60(4): 653–655 https://doi.org/10.1111/j.1365-2559.2011.04021.x
pmid: 22260350
33
Bao F, Panarelli NC, Rennert H, Sherr DL, Yantiss RK. Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma. Am J Surg Pathol 2010; 34(12): 1798–1804 https://doi.org/10.1097/PAS.0b013e3181f906cc
pmid: 21107085
34
Xicola RM, Llor X, Pons E, Castells A, Alenda C, Piñol V, Andreu M, Castellví-Bel S, Payá A, Jover R, Bessa X, Girós A, Duque JM, Nicolás-Pérez D, Garcia AM, Rigau J, Gassull MA; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst 2007; 99(3): 244–252 https://doi.org/10.1093/jnci/djk033
pmid: 17284719
35
Bapat B, Lindor NM, Baron J, Siegmund K, Li L, Zheng Y, Haile R, Gallinger S, Jass JR, Young JP, Cotterchio M, Jenkins M, Grove J, Casey G, Thibodeau SN, Bishop DT, Hopper JL, Ahnen D, Newcomb PA, Le Marchand L, Potter JD, Seminara D; Colon Cancer Family Registry. The association of tumor microsatellite instability phenotype with family history of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2009; 18(3): 967–975 https://doi.org/10.1158/1055-9965.EPI-08-0878
pmid: 19258475
36
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513(7517): 202–209 https://doi.org/10.1038/nature13480
pmid: 25079317
Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, Kelley MC, Sosman JA, Johnson DB, Ribas A, Lo RS. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016; 165(1): 35–44 https://doi.org/10.1016/j.cell.2016.02.065
pmid: 26997480