Clin Colon Rectal Surg
DOI: 10.1055/s-0043-1770717
Review Article

Treatment of Microsatellite-Unstable Rectal Cancer in Sporadic and Hereditary Settings

Cristan E. Anderson
1   Department of Colon and Rectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
,
David Liska
1   Department of Colon and Rectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
› Author Affiliations
Funding Funding for this article was provided in part from the Church-Sheetz Fellowship in Hereditary Colorectal Cancer Syndromes.

Abstract

Microsatellite instability is rare in rectal cancer and associated with younger age of onset and Lynch syndrome. All rectal cancers should be tested for microsatellite instability prior to treatment decisions. Patients with microsatellite instability are relatively resistant to chemotherapy. However, recent small studies have shown dramatic response with neoadjuvant immunotherapy. Patients with Lynch syndrome have a hereditary predisposition to cancer and thus an elevated risk of metachronous cancer. Therefore, while “watch and wait” is a well-established practice for sporadic rectal cancers that obtain a complete clinical response after chemoradiation, its safety in patients with Lynch syndrome has not yet been defined. The extent of surgery for patients with Lynch syndrome and rectal cancer is controversial and there is significant debate as to the relative advantages of a segmental proctectomy with postoperative endoscopic surveillance versus a therapeutic and prophylactic total proctocolectomy. Surgical decision making for the patient with Lynch syndrome and rectal cancer is complex and demands a multidisciplinary approach, taking into account both patient- and tumor-specific factors. Neoadjuvant immunotherapy show great promise in the treatment of these patients, and further maturation of data from prospective trials will likely change the current treatment paradigm. Patients with Lynch syndrome and rectal cancer who do not undergo total proctocolectomy require yearly surveillance colonoscopies and should consider chemoprophylaxis with aspirin.



Publication History

Article published online:
11 August 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260 (5109): 816-819
  • 2 Boland CR, Thibodeau SN, Hamilton SR. et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58 (22) 5248-5257
  • 3 Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol 2012; 27 (09) 1423-1431
  • 4 Herman JG, Umar A, Polyak K. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998; 95 (12) 6870-6875
  • 5 Veigl ML, Kasturi L, Olechnowicz J. et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 1998; 95 (15) 8698-8702
  • 6 Weisenberger DJ, Siegmund KD, Campan M. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006; 38 (07) 787-793
  • 7 Domingo E, Laiho P, Ollikainen M. et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004; 41 (09) 664-668
  • 8 Thiel A, Heinonen M, Kantonen J. et al. BRAF mutation in sporadic colorectal cancer and Lynch syndrome. Virchows Arch 2013; 463 (05) 613-621
  • 9 Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet 2012; 49 (03) 151-157
  • 10 Deng G, Bell I, Crawley S. et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004; 10 (1 Pt 1): 191-195
  • 11 Ligtenberg MJL, Kuiper RP, Chan TL. et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 2009; 41 (01) 112-117
  • 12 National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal (Version 2.2022). Accessed January 31, 2023 at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
  • 13 Salipante SJ, Scroggins SM, Hampel HL, Turner EH, Pritchard CC. Microsatellite instability detection by next generation sequencing. Clin Chem 2014; 60 (09) 1192-1199
  • 14 Samowitz WS, Curtin K, Wolff RK, Tripp SR, Caan BJ, Slattery ML. Microsatellite instability and survival in rectal cancer. Cancer Causes Control 2009; 20 (09) 1763-1768
  • 15 Swets M, Graham Martinez C, van Vliet S. et al. Microsatellite instability in rectal cancer: what does it mean? A study of two randomized trials and a systematic review of the literature. Histopathology 2022; 81 (03) 352-362
  • 16 Papke Jr DJ, Yurgelun MB, Noffsinger AE, Turner KO, Genta RM, Redston M. Prevalence of mismatch-repair deficiency in rectal adenocarcinomas. N Engl J Med 2022; 387 (18) 1714-1716
  • 17 REACCT Collaborative. Microsatellite instability in young patients with rectal cancer: molecular findings and treatment response. Br J Surg 2022; 109 (03) 251-255
  • 18 Poynter JN, Siegmund KD, Weisenberger DJ. et al; Colon Cancer Family Registry Investigators. Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev 2008; 17 (11) 3208-3215
  • 19 Cercek A, Dos Santos Fernandes G, Roxburgh CS. et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res 2020; 26 (13) 3271-3279
  • 20 de Rosa N, Rodriguez-Bigas MA, Chang GJ. et al. DNA mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics. J Clin Oncol 2016; 34 (25) 3039-3046
  • 21 Gryfe R, Kim H, Hsieh ETK. et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000; 342 (02) 69-77
  • 22 Buckowitz A, Knaebel H-P, Benner A. et al. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer 2005; 92 (09) 1746-1753
  • 23 Vilkin A, Halpern M, Morgenstern S. et al. How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation?. Hum Pathol 2014; 45 (10) 2029-2036
  • 24 Seo I, Lee HW, Byun SJ. et al. Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer. J Immunother Cancer 2021; 9 (03) e001610
  • 25 Vyas M, Firat C, Hechtman JF. et al. Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies. Fam Cancer 2021; 20 (03) 201-213
  • 26 Gou Q, Xie Y, Zhang M, Chen Y, Shen Y. Synchronous rectal tumours with different molecular and genetic phenotypes occurring in a patient with Lynch syndrome. Cancer Manag Res 2021; 13: 8009-8015
  • 27 Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18 (09) 1182-1191
  • 28 Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Committee CG. Clinical Guidelines Committee. American gastroenterological association institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology 2015; 149 (03) 777-782 , quiz e16–e17
  • 29 Frank TS. Hereditary cancer syndromes. Arch Pathol Lab Med 2001; 125 (01) 85-90
  • 30 Daina G, Ramos L, Obradors A. et al. First successful double-factor PGD for Lynch syndrome: monogenic analysis and comprehensive aneuploidy screening. Clin Genet 2013; 84 (01) 70-73
  • 31 Karagkounis G, Stocchi L, Lavery IC. et al. Multidisciplinary conference and clinical management of rectal cancer. J Am Coll Surg 2018; 226 (05) 874-880
  • 32 Sauer R, Becker H, Hohenberger W. et al; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351 (17) 1731-1740
  • 33 National Comprehensive Cancer Network. Rectal Cancer (Version 4.2022). Accessed January 31, 2023 at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
  • 34 Kasi A, Abbasi S, Handa S. et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer: a systematic review and meta-analysis. JAMA Netw Open 2020; 3 (12) e2030097
  • 35 Habr-Gama A, Perez RO, Nadalin W. et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240 (04) 711-717 , discussion 717–718
  • 36 Garcia-Aguilar J, Patil S, Gollub MJ. et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol 2022; 40 (23) 2546-2556
  • 37 Carethers JM, Smith EJ, Behling CA. et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004; 126 (02) 394-401
  • 38 Ribic CM, Sargent DJ, Moore MJ. et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349 (03) 247-257
  • 39 Le DT, Uram JN, Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26) 2509-2520
  • 40 Lenz H-J, Van Cutsem E, Luisa Limon M. et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol 2022; 40 (02) 161-170
  • 41 André T, Shiu K-K, Kim TW. et al; KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020; 383 (23) 2207-2218
  • 42 Farchoukh LF, Celebrezze J, Medich D. et al. DNA mismatch repair-deficient rectal cancer is frequently associated with Lynch syndrome and with poor response to neoadjuvant therapy. Am J Surg Pathol 2022; 46 (09) 1260-1268
  • 43 Hasan S, Renz P, Wegner RE. et al. Microsatellite instability (MSI) as an independent predictor of pathologic complete response (PCR) in locally advanced rectal cancer: a National Cancer Database (NCDB) analysis. Ann Surg 2020; 271 (04) 716-723
  • 44 Yuki S, Bando H, Tsukada Y. et al. Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. J Clin Oncol 2020; 38 (15, suppl): 4100-4100
  • 45 Cercek A, Lumish M, Sinopoli J. et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022; 386 (25) 2363-2376
  • 46 Møller P, Seppälä T, Bernstein I. et al; Mallorca Group (http://mallorca-group.org). Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 2017; 66 (09) 1657-1664
  • 47 Herzig DO, Buie WD, Weiser MR. et al. Clinical practice guidelines for the surgical treatment of patients with Lynch syndrome. Dis Colon Rectum 2017; 60 (02) 137-143
  • 48 Lightner AL, Spinelli A, McKenna NP, Hallemeier CL, Fleshner P. Does external beam radiation therapy to the pelvis portend worse ileal pouch outcomes? An international multi-institution collaborative study. Colorectal Dis 2019; 21 (02) 219-225
  • 49 Win AK, Parry S, Parry B. et al. Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol 2013; 20 (06) 1829-1836
  • 50 Kalady MF, Lipman J, McGannon E, Church JM. Risk of colonic neoplasia after proctectomy for rectal cancer in hereditary nonpolyposis colorectal cancer. Ann Surg 2012; 255 (06) 1121-1125
  • 51 Quezada-Diaz FF, Hameed I, von Mueffling A. et al. Risk of metachronous colorectal neoplasm after a segmental colectomy in Lynch syndrome patients according to mismatch repair gene status. J Am Coll Surg 2020; 230 (04) 669-675
  • 52 Schmeler KM, Lynch HT, Chen LM. et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006; 354 (03) 261-269
  • 53 Burn J, Gerdes AM, Macrae F. et al; CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011; 378 (9809): 2081-2087
  • 54 Burn J, Sheth H, Elliott F. et al; CAPP2 Investigators. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet 2020; 395 (10240): 1855-1863