Despite advances in population screening, surgical technique, and adjuvant chemotherapy, colorectal cancer remains the second-leading cause of cancer death in the U.S. According to recent estimates, 140,000 Americans were diagnosed with colorectal cancer in 2018, and approximately 35 percent of these cases had regional lymph node involvement; that is, stage III disease at diagnosis.1 The current standard of care for individuals with stage III colon cancer is surgical resection with curative intent followed by adjuvant chemotherapy with the regimen of FOLFOX (fluorouracil, folinic acid, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) for three or six months depending on tumor (T) and nodal (N) risk classification.2 Despite such treatments, approximately 30 percent of patients will succumb to recurrent disease.
Two primary pathways have been described for the development of colorectal cancer: chromosomal instability and microsatellite instability (MSI). MSI occurs in about 15 percent of colorectal cancers and results from deficient DNA mismatch repair (dMMR). Approximately two-thirds of MSI colorectal cancers are sporadic, and one-third are caused by Lynch syndrome. Lynch syndrome is the result of a germline mutation in one of four MMR genes (MLH1, MSH2, MSH6, PMS2) or in EpCAM.3 In sporadic MSI cancers, the MLH1 MMR gene is inactivated by methylation, and such tumors frequently carry BRAF (V600E) point mutations. MSI tumors are more likely to be right-sided colon tumors and poorly differentiated than microsatellite stable tumors, yet are associated with a more favorable prognosis.4 MSI tumors are hyper-mutated, resulting in an abundance of neoantigens that trigger increased numbers of tumor-infiltrating lymphocytes, indicating a robust anti-tumor immune response. Evidence indicates that the immune response fails to eradicate cancer cells because of an overexpression of immune checkpoint proteins by MSI tumors, which inhibit T-cell signaling and function.5 PD-1 (programmed death-1) is one such checkpoint protein that has been successfully targeted by pembrolizumab, an anti-PD-1 antibody, in the treatment of stage IV colorectal cancer with MSI.
PD-L1 (PD-ligand 1) is another checkpoint protein that MSI tumors overexpress, resulting in negative modulation of the host’s anti-tumor immune response. Atezolizumab is a humanized IgG monoclonal antibody that binds to PD-L1, thereby enhancing the T-cell response in immune-activated MSI tumors. This antibody has been administered to more than 3,000 patients in clinical trials with no dose-limiting toxicities observed. The addition of atezolizumab to an oxaliplatin-containing chemotherapy regimen is appealing because evidence suggests that oxaliplatin may prime the immune response by transiently increasing inflammation within tumors. Given that anti-PD-1 treatment results in frequent and durable responses in MSI metastatic colorectal cancers and other solid tumors,6 its evaluation in the adjuvant setting is being evaluated in MSI stage III colon cancers in the ATOMIC trial (Randomized Trial of Standard Chemotherapy Alone or Combined With Atezolizumab as Adjuvant Therapy for Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair). The study hypothesis is that the combination of atezolizumab and FOLFOX may unleash the host immune response to kill hypermutated MSI tumor cells, thus improving upon the results obtained with FOLFOX chemotherapy alone.
The ATOMIC trial (Alliance A021502) is a randomized phase III study of standard chemotherapy (modified FOLFOX-6) alone or in combination with atezolizumab as adjuvant treatment for stage III colon cancer patients with tumors that are deficient DNA MMR with MSI. Eligible patients must have histologically proven stage III adenocarcinoma of the colon (any T, N1 or 2, M0) who have undergone an R0 resection. Deficient MMR status must be evaluated by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) demonstrating loss of one or more proteins. IHC testing may be performed locally or at a reference lab chosen by the study site. Patients with known Lynch syndrome are eligible for this study. Trial stratification includes tumor location (cecum/ascending, descending, sigmoid, or rectosigmoid colon), based on the surgeon’s operative description and other studies. Patients with rectal tumors are excluded from the trial.
Patients must begin adjuvant treatment within 10 weeks of surgical resection and can be enrolled and randomized before starting adjuvant mFOLFOX6 or before the second cycle of adjuvant mFOLFOX6, which serves to allow ample time to obtain results of MMR testing. Patients randomized to the control arm will receive standard of care mFOLFOX6 for 12 cycles (six months), and those randomized to the investigational arm will receive 12 cycles of mFOLFOX6 combined with atezolizumab and will continue atezolizumab as monotherapy for 13 additional two-week cycles to provide sustained activation of the immune system.
The primary endpoint of the study is disease-free survival with secondary endpoints of overall survival, quality of life, and adverse events. The study includes retrospective central confirmation of MMR status. Correlative science objectives are incorporated within the study design and protocol. Patients will be followed for evidence of recurrence every six months for two years after study registration and then annually for three more years. Patients will be followed for survival for eight years.
The surgeon’s role
Surgical resection is the initial treatment for most patients with newly diagnosed colon cancer. The surgeon is responsible for ensuring that the patient’s disease is properly studied by imaging and that pathologic review includes testing of all colon cancers for MMR status.7 This enables decisions regarding further therapy and surveillance to be based on the risk of recurrence. Surgeons should be aware that inhibition of the PD-1/PD-L1 pathway offers the potential to improve outcomes for stage III colon cancer patients with deficient MMR and MSI status. Eligible patients should be counseled regarding participation in this exciting trial.
- National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: Colorectal cancer. Available at: https://seer.cancer.gov/statfacts/html/colorect.html. Accessed December 7, 2018.
- Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378(13):1177-1188.
- Sinicrope FA. Lynch Syndrome-associated colorectal cancer. N Engl J Med. 2018;379(8):764-773.
- Stoffel EM, Boland CR. Genetics and genetic testing in hereditary colorectal cancer. Gastroenterology. 2015;149(5):1191-1203.
- 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.
- Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
- Benson AB, Venook AP, Al-Hawary MM, et al. NCCN guidelines insights: Colon cancer, version 2.2018. J Natl Compr Canc Netw. 2018;16(4):359-369.