Updates in the Treatment of Patients With Colorectal Cancer

Abstract

A number of assays are now available to estimate the prognosis of early-stage colorectal cancer, including multigene assays, the Immunoscore, and circulating tumor DNA (ctDNA). Although the results of these assays may provide prognostic information regarding the risk for recurrence, their use as a predictive assay has not yet been validated. Therefore, although these assays may be useful for prognostication, further validation would be required to include in the NCCN Guidelines. For the treatment of metastatic colorectal cancer, major advances have included the use of checkpoint inhibition in metastatic disease. Studies are currently underway to further define their optimal use.

Aside from the use of targeted therapies, including immune checkpoint inhibitors (ICIs), to treat subsets of patients, the treatment of colorectal cancer (CRC) has remained fairly consistent over the past several years. Most recently, advances in this tumor type have largely centered around new assays that can yield prognostic information for early-stage colon cancer. At the NCCN 2022 Annual Conference, Smitha S. Krishnamurthi, MD, Associate Professor of Medicine, Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, described some of the available prognostic assays and their potential use and limitations in stage II or III colon cancer.

“There is a high degree of variability in the risk of recurrence in early-stage colon cancer. Ideally, we’d like to identify who has been cured by surgery, who will be cured with adjuvant chemotherapy, and who will not benefit from chemotherapy,” she said. “Prognostic and predictive assays, therefore, are of great interest.” During her presentation, Dr. Krishnamurthi also discussed sequencing and selection decisions regarding the use of ICIs for metastatic disease.

Multigene Assays

The multigene ColoPrint assay (Agendia Inc.) is similar to MammaPrint (Agendia Inc.) in breast cancer and uses frozen tissue to examine an 18-gene expression signature. ColoPrint separates stage II into high- and low-risk cancers and has been shown to better discriminate the risk of recurrence compared with traditional risk factors. An ongoing clinical trial has completed enrollment of 785 patients with stage II disease, with the aim of validating ColoPrint to estimate the 3-year relapse rate (ClinicalTrials.gov identifier: NCT00903565).

Another multigene assay is ColDx (Almac Diagnostic Services), which utilizes formalin-fixed paraffin-embedded (FFPE) tissue and examines a DNA microarray signature. This assay was validated in the C9581 trial, which compared observation versus edrecolomab in low-risk stage II colon cancer.1 The ColDX score was found to be strongly associated with risk of recurrence, even more strongly than mismatch repair (MMR) status.

Oncotype DX (Exact Sciences Corporation), or Recurrence Score (similar to that used in breast cancer), is performed on FFPE. This assay identifies genes related to recurrence and treatment benefit. Its development was based on >1,000 specimens from trials of the National Surgical Adjuvant Breast and Bowel Project and a large observational database.2 Altogether, these studies showed the risk of recurrence to be approximately 10% among patients with stage II disease and low Recurrence Scores, and increasing to >20% in those with high Recurrence Scores. Interestingly, the absolute benefit of chemotherapy was proportionally similar across the risk groups (3%–6%) in patients with stage II colon cancer.

Dr. Krishnamurthi summarized the value of ColoPrint, ColDx, and Oncotype DX, noting that they all can increase the precision of recurrence estimates for patients with early-stage colon cancer but are not particularly predictive for response to adjuvant chemotherapy. “They are, therefore, prognostic markers only, and are not recommended in the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Colorectal Cancer,” she said.

Immunoscore

Immunoscore (Veractye) is a standardized scoring system based on CD3 and CD8 immunohistochemical staining at the tumor core and invasive margin. For approximately 1 in 5 patients with stage I–III microsatellite stable (MSS) colon cancer, Immunoscore will be “high,” indicating a high density of T-cell infiltration.3 This indicates that the cancer has an activated immune system, and is associated with a favorable prognosis.

In an international retrospective study of 1,434 patients with stage I–III colon cancer who were receiving standard chemotherapy or observation, Immunoscore predicted recurrence, disease-free survival (DFS), and overall survival better than the AJCC and Union for International Cancer Control (UICC) TNM classification system.4 Among the 27% of patients with stage II disease with low Immunoscores, recurrence risk was 20% compared with 11% for those with intermediate scores and 6% for those with high scores. Time to recurrence significantly differed by Immunoscore, both in MSS tumors (hazard ratio [HR], 0.45 for high vs low; P<.01) and for tumors with microsatellite instability–high (MSI-H) (HR, 0.24 for high vs low; P<.01). In general, patients with MSI-H tumors and high Immunoscores had the best prognosis, she said.

Immunoscore has also been examined prospectively in relation to chemotherapy benefit. Among patients with stage III disease treated with FOLFOX (fluorouracil/leucovorin/oxaliplatin) in the N0147 trial, the 3-year DFS was 83% for patients with intermediate/high Immunoscores and 57% for those with low scores.5

Interestingly, in the IDEA France study, patients with high Immunoscores derived more benefit from 6 months of modified FOLFOX than from 3 months (HR, 0.528; P=.0004), but the duration of chemotherapy was irrelevant in patients with low scores.6 The “surprising” finding—that good-prognosis patients benefited from a longer duration of treatment—is not fully understood and should be considered exploratory, Dr. Krishnamurthi stated.

Immunoscore is currently considered a prognostic marker only and is not recommended in the NCCN Guidelines. “I hope it will be included in clinical trials so we can learn more about it, especially how it may reflect the patient’s response to immunotherapy,” she commented.

Circulating Tumor DNA

Interest is high for circulating tumor DNA (ctDNA), and the guidelines panel “is watching the data carefully” for this “real-time estimate of the patient’s tumor burden,” she said. The isolation and sequencing of ctDNA from a blood sample reveal mutations, copy number variations, fusions, and methylation. These findings indicate the presence or absence of molecular residual disease.

Assays for ctDNA can be performed by next-generation sequencing or PCR. The tests may be customized, tumor-informed assays that require a tumor biopsy or surgical specimen from which tumor is sequenced or tumor-naїve or tumor-agnostic assays (also called plasma-alone assays), which do not require tissue and rely on next-generation sequencing to identify alterations in the blood. Both can detect allele frequencies of 0.01%.7

The tumor-informed assays are potentially more sensitive and specific; sensitivity increases according to the number of genes included. As a customized assay, the turnaround time for these tests is typically longer than for the plasma-alone assays, and the latter require no tumor sequencing and are potentially cost-saving.

Key Studies of ctDNA

Dr. Krishnamurthi summarized the main findings from several key trials of ctDNA in early-stage colon cancer. Tie et al8 applied a tumor-informed test targeting 15 genes and found at least one mutation in 99.6% of patients with stage II disease. Monitoring of patients 4 to 10 weeks after surgery revealed the presence of ctDNA in 9%—patients who were ctDNA-negative were 82% less likely to recur than those who were ctDNA-positive. Among patients with stage III disease, 21% had postoperative ctDNA, and those patients had a 55% risk of recurrence compared with 22% for those who were ctDNA-negative (HR, 3.8; P<.001). This marker had more impact on relapse-free survival than any other clinicopathologic factor; radiologic detection occurred almost 6 months later.

Other studies made similar findings (Table 1).811 Most recently, a 2022 analysis explored tumor-informed whole-exome sequencing on 168 patients with stage III disease.9 For the 14% of patients with ctDNA positivity after surgery, the risk for recurrence was 80%, whereas for those who were ctDNA-negative it was limited to 18%.

Table 1.

Multiple Assays of ctDNA

Table 1.

The largest study to date of ctDNA in colon cancer confirmed its prognostic impact, as well as the power of chemotherapy to ameliorate this risk of disease recurrence. In the recently reported CIRCULATE-Japan study, observational data were from the GALAXY trial of 1,040 patients. Patients underwent surgery (± neoadjuvant therapy) for stage II–IV resectable CRC and were then monitored with ctDNA; some patients received adjuvant chemotherapy and others underwent observation.12 At 12 months, the DFS rate was 55.5% for patients with positive ctDNA 4 weeks after surgery versus 95.2% for those who were ctDNA-negative (HR, 13.3; P<.001).

With adjuvant chemotherapy, 68% of patients cleared ctDNA at 6 months postsurgery compared with only 10% who did not receive adjuvant chemotherapy. In addition, patients with high-risk stage II or III disease and who were ctDNA-positive after surgery were 9 times more likely to be disease-free after chemotherapy; their ctDNA-negative peers had excellent outcomes regardless of chemotherapy, with approximately 95% disease-free at 12 months.

“Thus, ctDNA is not just predicting a recurrence. It’s actually detecting residual disease. It appears to be the most useful prognostic assay, but there are unanswered questions, and we still don’t know if it can guide adjuvant therapy,” she said. Although ctDNA assays can be appropriate for patients seeking more information about their prognosis and these assays are able to perform more sensitive monitoring of disease, they are not yet recommended in the NCCN Guidelines.

Use of ctDNA as a predictive marker is currently being evaluated in a number of studies. For example, the NRG-GI005 (COBRA) trial is examining the use of the LUNAR-2 assay (Guardant Health, Inc.) in patients with stage II colon cancer who do not undergo adjuvant therapy. The United States NRG-GI008 (CIRCULATE-US) trial of the Signatera assay (Natera) is underway in patients with resected colon cancer (ClinicalTrials.gov identifier: NCT05174169). Lastly, a study from Massachusetts General is incorporating immunotherapy and BRAF/MEK inhibitors with chemotherapy (NCT03803553).

Immunotherapy for Metastatic CRC

Immunotherapy with ICIs can be effective in patients with metastatic tumors that have defects in MMR (ie, they are MMR-deficient [dMMR], also labeled MSI-H). These tumors have increased neoantigen loads that lead to CD8 infiltration; have high expression of immune checkpoints, including PD-1, PD-L1, CTLA-4, LAG-3, and IDO; and harbor more mutations compared with tumors that are MMR-proficient (ie, MSS).

For treatment of metastatic dMMR colorectal tumors, 3 anti–PD-1 antibodies—pembrolizumab, nivolumab, and dostarlimab-gxly—and one anti–CTLA-4 antibody—ipilimumab—may be used. In the second line and beyond, response rates to these agents have ranged from 31% to 40% in pivotal studies. Dostarlimab-gxly, the most recently approved agent, demonstrated a response rate of 36% and a median duration of response that was not reached after 12 months of follow-up.13

In the first-line setting, pembrolizumab is FDA-approved based on data from KEYNOTE-177, in which median progression-free survival was 16.5 months with pembrolizumab versus 8.2 months with chemotherapy (HR, 0.60; P=.0002).14 For pembrolizumab, median overall survival was not reached, but was 36.7 months with chemotherapy (HR, 0.74; P=.0359). At 24 months, 83% of the pembrolizumab arm continued to show response to therapy compared with 35% in the chemotherapy arm. Grade ≥3 treatment-related adverse events were seen in 22% of the pembrolizumab arm compared with 66% in the chemotherapy arm.

Combination Nivolumab + Ipilimumab

Could 2 ICIs provide even greater benefit? The combination of nivolumab, 3 mg/kg + ipilimumab, 1 mg/kg, for 4 doses followed by nivolumab, 3 mg/kg, once every 2 weeks is being evaluated in dMMR metastatic CRC. Although efficacy is encouraging, tolerability may be an issue.

In the phase II CheckMate 142 study of previously treated patients, 55% responded to the doublet and 70% were progression-free at 2 years, although 32% developed grade ≥3 treatment-related adverse effects.15 Further evaluating nivolumab/ipilimumab in the first-line setting, Lenz et al16 observed a high response rate of 69% and a 24-month progression-free survival of 73.6%, with an acceptable toxicity (22% grade ≥3).

The GERCOR NIPICOL study examined the duration of single-agent nivolumab after treatment with the doublet and found no appreciable difference in progression-free survival at 1 year (75.4%), 2 years (70.0%), and 3 years (70.0%).17 Three patients were re-treated on disease progression, and 2 experienced response. Overall survival was 84.1% at 1 year and 73.1% at 3 years, suggesting that “1 year of treatment may be adequate,” Dr. Krishnamurthi commented.

For the treatment of metastatic CRC with dMMR/MSI-H tumors, Dr. Krishnamurthi summarized the current clinical use of immunotherapy, stating that in the first line pembrolizumab, nivolumab, or combination nivolumab/ipilimumab is recommended; higher response rates, however, are obtained with combination therapy. Treatment in the second line consists of pembrolizumab, nivolumab, dostarlimab-gxly, or combination nivolumab/ipilimumab. Treatment is typically for a maximum of 2 years, but 1 year may be adequate; the optimal duration is unknown.

Current clinical trials, NRG-GI004 and CheckMate 8HW, are examining the use of PD-1/PD-L1 inhibitors, alone and in combination with other agents, in the first-line setting of MSI-H metastatic CRC (ClinicalTrials.gov identifiers: NCT02997228, NCT04008030).

References

  • 1.

    Niedzwiecki D, Frankel WL, Venook AP, et al. Association between results of a gene expression signature assay and recurrence-free interval in patients with stage II colon cancer in cancer and leukemia group B 9581 (Alliance). J Clin Oncol 2016;34:30473053.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010;28:39373944.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Pagès F, Mlecnik B, Marliot F, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018;391:21282139.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Pagès F, Mlecnik B, Marliot F, et al. . International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018;391:212–-2139.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Sinicrope FA, Shi Q, Hermitte F, et al. Contribution of Immunoscore and molecular features to survival prediction in stage III colon cancer. JNCI Cancer Spectr 2020;4:pkaa023.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Pagès F, André T, Taieb J, et al. Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study. Ann Oncol 2020;31:921929.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol 2019;5:11241131.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 2016;8:346ra92.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Henriksen TV, Tarazona N, Frydendahl A, et al. Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, toward assessment of adjuvant therapy efficacy and clinical behavior of recurrences. Clin Cancer Res 2022;28:507517.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Diehn M, Alizadeh AA, Adams HP, et al. Early prediction of clinical outcomes in resected stage II and III colorectal cancer (CRC) through deep sequencing of circulating tumor DNA (ctDNA) [abstract ]. J Clin Oncol 2017;35(Suppl):Abstract 3591.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Parikh AR, Van Seventer EE, Siravegna G, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer. Clin Cancer Res 2021;27:55865594.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Kotaka M, Shirasu H, Wantanbe J, et al. Association of circulating tumor DNA dynamics with clinical outcomes in the adjuvant setting for patients with colorectal cancer from an observational GALAXY study in CIRCULATE-Japan [abstract ]. J Clin Oncol 2022;40(Suppl 4):Abstract 9.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Andre T, De Braud FG, Jimenez-Rodriguez B, et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient non-endometrial solid tumors: a post-hoc subgroup analysis of patients with colorectal cancer [abstract ]. J Clin Oncol 2022; 40(Suppl 4):Abstract 201.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 15.

    Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/ microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773779.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Lenz HJ, Van Cutsem E, Limon ML, 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;40:161170.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Cohen R, Meurisse A, Pudiarz T, et al. One-year duration of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: long-term follow-up of the GERCOR NIPICOL phase II study [abstract ]. J Clin Oncol 2022;40(Suppl):Abstract 13.

    • Crossref
    • Search Google Scholar
    • Export Citation

Disclosures: Dr. Krishnamurthi has disclosed receiving grant/research support from Aravive, Bristol-Myers Squibb Company, and Natera.

Correspondence: Smitha S. Krishnamurthi, MD, Cleveland Clinic, 9500 Euclid Avenue, CA5-068, Cleveland, OH 44195. Email: krishns3@ccf.org
  • 1.

    Niedzwiecki D, Frankel WL, Venook AP, et al. Association between results of a gene expression signature assay and recurrence-free interval in patients with stage II colon cancer in cancer and leukemia group B 9581 (Alliance). J Clin Oncol 2016;34:30473053.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010;28:39373944.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Pagès F, Mlecnik B, Marliot F, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018;391:21282139.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Pagès F, Mlecnik B, Marliot F, et al. . International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018;391:212–-2139.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Sinicrope FA, Shi Q, Hermitte F, et al. Contribution of Immunoscore and molecular features to survival prediction in stage III colon cancer. JNCI Cancer Spectr 2020;4:pkaa023.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Pagès F, André T, Taieb J, et al. Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study. Ann Oncol 2020;31:921929.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol 2019;5:11241131.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 2016;8:346ra92.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Henriksen TV, Tarazona N, Frydendahl A, et al. Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, toward assessment of adjuvant therapy efficacy and clinical behavior of recurrences. Clin Cancer Res 2022;28:507517.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Diehn M, Alizadeh AA, Adams HP, et al. Early prediction of clinical outcomes in resected stage II and III colorectal cancer (CRC) through deep sequencing of circulating tumor DNA (ctDNA) [abstract ]. J Clin Oncol 2017;35(Suppl):Abstract 3591.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Parikh AR, Van Seventer EE, Siravegna G, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer. Clin Cancer Res 2021;27:55865594.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Kotaka M, Shirasu H, Wantanbe J, et al. Association of circulating tumor DNA dynamics with clinical outcomes in the adjuvant setting for patients with colorectal cancer from an observational GALAXY study in CIRCULATE-Japan [abstract ]. J Clin Oncol 2022;40(Suppl 4):Abstract 9.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Andre T, De Braud FG, Jimenez-Rodriguez B, et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient non-endometrial solid tumors: a post-hoc subgroup analysis of patients with colorectal cancer [abstract ]. J Clin Oncol 2022; 40(Suppl 4):Abstract 201.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 15.

    Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/ microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773779.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Lenz HJ, Van Cutsem E, Limon ML, 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;40:161170.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Cohen R, Meurisse A, Pudiarz T, et al. One-year duration of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: long-term follow-up of the GERCOR NIPICOL phase II study [abstract ]. J Clin Oncol 2022;40(Suppl):Abstract 13.

    • Crossref
    • Search Google Scholar
    • Export Citation
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