MMR Testing and Treatment Implications

The incidence of early onset colorectal cancer (EOCRC) has been rising prompting the change in change in screening guidelines to 45 years of age for average risk patients. Join us for an in-depth discussion with guest speakers Dr. Andrea Cercek and Dr. Nancy You, where we provide a comprehensive look at the growing challenge of EOCRC.

Hosts:
- Dr. Janet Alvarez - General Surgery Resident at New York Medical College/Metropolitan Hospital Center
- Dr. Wini Zambare – General Surgery Resident at Weill Cornell Medical Center/New York Presbyterian
- Dr. Phil Bauer, Graduating Colorectal Surgical Oncology Fellow at Memorial Sloan Kettering Cancer Center 
- Dr. J. Joshua Smith MD, PhD, Chair, Department of Colon and Rectal Surgery at MD Anderson Cancer Center
- Dr. Andrea Cercek - Gastrointestinal Medical Oncologist at Memorial Sloan Kettering Cancer Center
- Dr. Y. Nancy You, MD MHSc - Professor, Department of Colon and Rectal Surgery at MD Anderson Cancer Center

Learning objectives: 
- Describe trends in incidence of colorectal cancer, with emphasis on the rise of EOCRC.
- Identify age groups and demographics most affected by EOCRC.
- Summarize USPSTF recommendations for colorectal cancer screening.
- Distinguish between screening methods (e.g., colonoscopy, FIT-DNA) and their sensitivity.
- Understand treatment approaches for colon and rectal cancer (CRC)
- Understand the role of mismatch repair (MMR) status in guiding treatment.
- Outline the importance of genetic counseling and testing in young patients.
- Discuss racial, ethnic, and socioeconomic disparities in CRC incidence and outcomes.
- Describe the impact of cancer treatment on fertility and sexual health.
-  Review fertility preservation options.
- Identify the value of integrated care teams for young CRC patients.

References:

1.         Siegel, R. L. et al. Colorectal Cancer Incidence Patterns in the United States, 1974–2013. JNCI J. Natl. Cancer Inst. 109, djw322 (2017). https://pubmed.ncbi.nlm.nih.gov/28376186/
2.         Abboud, Y. et al. Rising Incidence and Mortality of Early-Onset Colorectal Cancer in Young Cohorts Associated with Delayed Diagnosis. Cancers 17, 1500 (2025). https://pubmed.ncbi.nlm.nih.gov/40361427/
3.         Phang, R. et al. Is the Incidence of Early-Onset Adenocarcinomas in Aotearoa New Zealand Increasing? Asia Pac. J. Clin. Oncol.https://pubmed.ncbi.nlm.nih.gov/40384533/
4.         Vitaloni, M. et al. Clinical challenges and patient experiences in early-onset colorectal cancer: insights from seven European countries. BMC Gastroenterol. 25, 378 (2025). https://pubmed.ncbi.nlm.nih.gov/40375142/
5.         Siegel, R. L. et al. Global patterns and trends in colorectal cancer incidence in young adults. (2019) doi:10.1136/gutjnl-2019-319511. https://pubmed.ncbi.nlm.nih.gov/31488504/
6.         Cercek, A. et al. A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers. J. Natl. Cancer Inst. 113, 1683–1692 (2021). https://pubmed.ncbi.nlm.nih.gov/34405229/
7.         Zheng, X. et al. Comprehensive Assessment of Diet Quality and Risk of Precursors of Early-Onset Colorectal Cancer. JNCI J. Natl. Cancer Inst. 113, 543–552 (2021). https://pubmed.ncbi.nlm.nih.gov/33136160/
8.         Standl, E. & Schnell, O. Increased Risk of Cancer—An Integral Component of the Cardio–Renal–Metabolic Disease Cluster and Its Management. Cells 14, 564 (2025). https://pubmed.ncbi.nlm.nih.gov/40277890/
9.         Muller, C., Ihionkhan, E., Stoffel, E. M. & Kupfer, S. S. Disparities in Early-Onset Colorectal Cancer. Cells 10, 1018 (2021). https://pubmed.ncbi.nlm.nih.gov/33925893/
10.       US Preventive Services Task Force. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 325, 1965–1977 (2021). https://pubmed.ncbi.nlm.nih.gov/34003218/
11.       Fwelo, P. et al. Differential Colorectal Cancer Mortality Across Racial and Ethnic Groups: Impact of Socioeconomic Status, Clinicopathology, and Treatment-Related Factors. Cancer Med. 14, e70612 (2025). https://pubmed.ncbi.nlm.nih.gov/40040375/
12.       Lansdorp-Vogelaar, I. et al. Contribution of Screening and Survival Differences to Racial Disparities in Colorectal Cancer Rates. Cancer Epidemiol. Biomarkers Prev. 21, 728–736 (2012). https://pubmed.ncbi.nlm.nih.gov/22514249/
13.       Ko, T. M. et al. Low neighborhood socioeconomic status is associated with poor outcomes in young adults with colorectal cancer. Surgery 176, 626–632 (2024). https://pubmed.ncbi.nlm.nih.gov/38972769/
14.       Siegel, R. L., Wagle, N. S., Cercek, A., Smith, R. A. & Jemal, A. Colorectal cancer statistics, 2023. CA. Cancer J. Clin. 73, 233–254 (2023). https://pubmed.ncbi.nlm.nih.gov/36856579/
15.       Jain, S., Maque, J., Galoosian, A., Osuna-Garcia, A. & May, F. P. Optimal Strategies for Colorectal Cancer Screening. Curr. Treat. Options Oncol. 23, 474–493 (2022). https://pubmed.ncbi.nlm.nih.gov/35316477/
16.       Zauber, A. G. The Impact of Screening on Colorectal Cancer Mortality and Incidence: Has It Really Made a Difference? Dig. Dis. Sci. 60, 681–691 (2015). https://pubmed.ncbi.nlm.nih.gov/25740556/
17.       Edwards, B. K. et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 116, 544–573 (2010). https://pubmed.ncbi.nlm.nih.gov/19998273/
18.       Cercek, A. et al. Nonoperative Management of Mismatch Repair–Deficient Tumors. New England Journal of Medicine 392, 2297–2308 (2025). https://pubmed.ncbi.nlm.nih.gov/40293177/
19.       Monge, C., Waldrup, B., Carranza, F. G. & Velazquez-Villarreal, E. Molecular Heterogeneity in Early-Onset Colorectal Cancer: Pathway-Specific Insights in High-Risk Populations. Cancers 17, 1325 (2025). https://pubmed.ncbi.nlm.nih.gov/40282501/
20.       Monge, C., Waldrup, B., Carranza, F. G. & Velazquez-Villarreal, E. Ethnicity-Specific Molecular Alterations in MAPK and JAK/STAT Pathways in Early-Onset Colorectal Cancer. Cancers 17, 1093 (2025). https://pubmed.ncbi.nlm.nih.gov/40227607/
21.       Benson, A. B. et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. JNCCN 19, 329–359 (2021). https://pubmed.ncbi.nlm.nih.gov/33724754/
22.       Christenson, E. S. et al. Nivolumab and Relatlimab for the treatment of patients with unresectable or metastatic mismatch repair proficient colorectal cancer. https://pubmed.ncbi.nlm.nih.gov/40388545/
23.       Dasari, A. et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. The Lancet 402, 41–53 (2023). https://pubmed.ncbi.nlm.nih.gov/37331369/
24.       Strickler, J. H. et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 24, 496–508 (2023). https://pubmed.ncbi.nlm.nih.gov/37142372/
25.       Sauer, R. et al. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. N. Engl. J. Med. 351, 1731–1740 (2004). https://pubmed.ncbi.nlm.nih.gov/15496622/
26.       Cercek, A. et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol. 4, e180071 (2018). https://pubmed.ncbi.nlm.nih.gov/29566109/
27.       Garcia-Aguilar, J. et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J. Clin. Oncol. 40, 2546–2556 (2022). https://pubmed.ncbi.nlm.nih.gov/35483010/
28.       Schrag, D. et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N. Engl. J. Med. 389, 322–334 (2023). https://pubmed.ncbi.nlm.nih.gov/37272534/
29.       Kunkler, I. H., Williams, L. J., Jack, W. J. L., Cameron, D. A. & Dixon, J. M. Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. N. Engl. J. Med. 388, 585–594 (2023). https://pubmed.ncbi.nlm.nih.gov/36791159/
30.       Jacobsen, R. L., Macpherson, C. F., Pflugeisen, B. M. & Johnson, R. H. Care Experience, by Site of Care, for Adolescents and Young Adults With Cancer. JCO Oncol. Pract. (2021) doi:10.1200/OP.20.00840. https://pubmed.ncbi.nlm.nih.gov/33566700/
31.       Ruddy, K. J. et al. Prospective Study of Fertility Concerns and Preservation Strategies in Young Women With Breast Cancer. J. Clin. Oncol. (2014) doi:10.1200/JCO.2013.52.8877. https://pubmed.ncbi.nlm.nih.gov/24567428/
32.       Su, H. I. et al. Fertility Preservation in People With Cancer: ASCO Guideline Update. J. Clin. Oncol. 43, 1488–1515 (2025). https://pubmed.ncbi.nlm.nih.gov/40106739/
33.       Smith, K. L., Gracia, C., Sokalska, A. & Moore, H. Advances in Fertility Preservation for Young Women With Cancer. Am. Soc. Clin. Oncol. Educ. Book 27–37 (2018) doi:10.1200/EDBK_208301. https://pubmed.ncbi.nlm.nih.gov/30231357/
34.       Blumenfeld, Z. How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries. The Oncologist 12, 1044–1054 (2007).
35.       Bhagavath, B. The current and future state of surgery in reproductive endocrinology. Curr. Opin. Obstet. Gynecol. 34, 164 (2022).
36.       Ribeiro, R. et al. Uterine transposition: technique and a case report. Fertil. Steril. 108, 320-324.e1 (2017).
37.       Yazdani, A., Sweterlitsch, K. M., Kim, H., Flyckt, R. L. & Christianson, M. S. Surgical Innovations to Protect Fertility from Oncologic Pelvic Radiation Therapy: Ovarian Transposition and Uterine Fixation. J. Clin. Med. 13, 5577 (2024).
38.       Holowatyj, A. N., Eng, C. & Lewis, M. A. Incorporating Reproductive Health in the Clinical Management of Early-Onset Colorectal Cancer. JCO Oncol. Pract. 18, 169–172 (2022).

***Behind the Knife Colorectal Surgery Oral Board Audio Review: https://app.behindtheknife.org/course-details/colorectal-surgery-oral-board-audio-review

Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more.  

If you liked this episode, check out our recent episodes here: https://app.behindtheknife.org/listen