Use of Deep Learning to Evaluate Tumor Microenvironmental Features for Prediction of Colon Cancer Recurrence.

Deep learning may detect biologically important signals embedded in tumor morphologic features that confer distinct prognoses. Tumor morphologic features were quantified to enhance patient risk stratification within DNA mismatch repair (MMR) groups using deep learning. Using a quantitative segmentation algorithm (QuantCRC) that identifies 15 distinct morphologic features, we analyzed 402 resected stage III colon carcinomas [191 deficient (d)-MMR; 189 proficient (p)-MMR] from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy. Results were validated in an independent cohort (176 d-MMR; 1,094 p-MMR). Association of morphologic features with clinicopathologic variables, MMR, KRAS, BRAFV600E, and time-to-recurrence (TTR) was determined. Multivariable Cox proportional hazards models were developed to predict TTR. Tumor morphologic features differed significantly by MMR status. Cancers with p-MMR had more immature desmoplastic stroma. Tumors with d-MMR had increased inflammatory stroma, epithelial tumor-infiltrating lymphocytes (TIL), high-grade histology, mucin, and signet ring cells. Stromal subtype did not differ by BRAFV600E or KRAS status. In p-MMR tumors, multivariable analysis identified tumor-stroma ratio (TSR) as the strongest feature associated with TTR [HRadj 2.02; 95% confidence interval (CI), 1.14-3.57; P = 0.018; 3-year recurrence: 40.2% vs. 20.4%; Q1 vs. Q2-4]. Among d-MMR tumors, extent of inflammatory stroma (continuous HRadj 0.98; 95% CI, 0.96-0.99; P = 0.028; 3-year recurrence: 13.3% vs. 33.4%, Q4 vs. Q1) and N stage were the most robust prognostically. Association of TSR with TTR was independently validated. In conclusion, QuantCRC can quantify morphologic differences within MMR groups in routine tumor sections to determine their relative contributions to patient prognosis, and may elucidate relevant pathophysiologic mechanisms driving prognosis. SIGNIFICANCE: A deep learning algorithm can quantify tumor morphologic features that may reflect underlying mechanisms driving prognosis within MMR groups. TSR was the most robust morphologic feature associated with TTR in p-MMR colon cancers. Extent of inflammatory stroma and N stage were the strongest prognostic features in d-MMR tumors. TIL density was not independently prognostic in either MMR group.

Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Ferroptosis: Biology and Role in Gastrointestinal Disease.

Ferroptosis is a form of nonapoptotic cell death that involves iron-dependent phospholipid peroxidation induced by accumulation of reactive oxygen species, and results in plasma membrane damage and the release of damage-associated molecular patterns. Ferroptosis has been implicated in aging and immunity, as well as disease states including intestinal and liver conditions and cancer. To date, several ferroptosis-associated genes and pathways have been implicated in liver disease. Although ferroptotic cell death is associated with dysfunction of the intestinal epithelium, the underlying molecular basis is poorly understood. As the mechanisms regulating ferroptosis become further elucidated, there is clear potential to use ferroptosis to achieve therapeutic benefit.

A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening.

BACKGROUND: Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality. METHODS: We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions. RESULTS: The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7). CONCLUSIONS: In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. (Funded by Guardant Health; ECLIPSE ClinicalTrials.gov number, NCT04136002.).

Improved Risk-Stratification Scheme for Mismatch-Repair Proficient Stage II Colorectal Cancers Using the Digital Pathology Biomarker QuantCRC.

PURPOSE: There is a need to improve current risk stratification of stage II colorectal cancer to better inform risk of recurrence and guide adjuvant chemotherapy. We sought to examine whether integration of QuantCRC, a digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. EXPERIMENTAL DESIGN: ASCO and QuantCRC-integrated schemes were applied to a cohort of 398 mismatch-repair proficient (MMRP) stage II colorectal cancers from three large academic medical centers. The ASCO stage II scheme was taken from recent guidelines. The QuantCRC-integrated scheme utilized pT3 versus pT4 and a QuantCRC-derived risk classification. Evaluation of recurrence-free survival (RFS) according to these risk schemes was compared using the log-rank test and HR. RESULTS: Integration of QuantCRC provides improved risk stratification compared with the ASCO scheme for stage II MMRP colorectal cancers. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared with the ASCO scheme (62.5% vs. 42.2%) without compromising excellent 3-year RFS. The QuantCRC-integrated scheme provided larger HR for both intermediate-risk (2.27; 95% CI, 1.32-3.91; P = 0.003) and high-risk (3.27; 95% CI, 1.42-7.55; P = 0.006) groups compared with ASCO intermediate-risk (1.58; 95% CI, 0.87-2.87; P = 0.1) and high-risk (2.24; 95% CI, 1.09-4.62; P = 0.03) groups. The QuantCRC-integrated risk groups remained prognostic in the subgroup of patients that did not receive any adjuvant chemotherapy. CONCLUSIONS: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance for stage II MMRP colorectal cancers.

Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting.

PURPOSE: Only one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. PATIENTS AND METHODS: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n = 66), we sought to validate data from a U.S. cohort, and performed pooled analysis (n = 104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and with progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. RESULTS: Objective responses were achieved in 38/66 (58%) of patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis (P = 0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P = 0.01). CONCLUSIONS: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients.

Selecting Optimal First-Line Treatment for Microsatellite Stable and Non-Mutated RAS/BRAF Metastatic Colorectal Cancer.

OPINION STATEMENT: Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or panitumumab) or anti-VEGF antibody (bevacizumab). Predictive biomarkers include mismatch repair (MMR) status, and RAS and BRAF mutation status; and important factors in treatment selection include primary tumor location, intent of therapy, and potential toxicity, as well as patient age, comorbidities, and patient preference. To date, single-, double-, or triple-agent cytotoxic chemotherapy all have important roles in appropriately selected patients, with the addition of anti-VEGF or anti-EGFR antibody therapy based on the relevant predictive biomarker. Data indicate that patients with proficient MMR, RAS/BRAF wt mCRC are candidates for an anti-EGFR antibody plus doublet chemotherapy if they have a left-sided primary tumor, or for anti-VEGF (bevacizumab) plus doublet or triplet chemotherapy if they have a right-sided primary tumor. Future studies may provide more predictive biomarkers to further personalize therapy for this heterogeneous disease.

Neoadjuvant Immune Checkpoint Inhibitor Therapy for Localized Deficient Mismatch Repair Colorectal Cancer: A Review.

Importance: Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease. Observations: Multiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy. Conclusions and Relevance: While this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.

Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair-deficient, Advanced Colorectal Carcinomas.

PURPOSE: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction has led to durable responses in fewer than half of patients with mismatch repair-deficient (MMR-d) advanced colorectal cancers. Immune contexture, including spatial distribution of immune cells in the tumor microenvironment (TME), may predict immunotherapy outcome. EXPERIMENTAL DESIGN: Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence (mIF) in primary colorectal cancers with d-MMR (N = 33) from patients treated with anti-PD-1 antibodies. By digital image analysis, density, ratio, intensity, and spatial distribution of PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFßR2, MHC-I, CD14, B2M, and pan-cytokeratin were computed. Feature selection was performed by regularized Cox regression with LASSO, and a proportional hazards model was fitted to predict progression-free survival (PFS). RESULTS: For predicting survival among patients with MMR-d advanced colorectal cancer receiving PD-1 blockade, cell-to-cell distance measurements, but not cell densities or ratios, achieved statistical significance univariately. By multivariable feature selection, only mean number of PD-1+ cells within 10 µm of a PD-L1+ cell was significantly predictive of PFS. Dichotomization of this variable revealed that those with high versus low values had significantly prolonged PFS [median not reached (>83 months) vs. 8.5 months (95% confidence interval (95% CI), 4.7-NR)] with a median PFS of 28.4 months for all patients [adjusted HR (HRadj) = 0.14; 95% CI, 0.04-0.56; P = 0.005]. Expression of PD-1 was observed on CD8+ T cells; PD-L1 on CD3+ and CD8+ T lymphocytes, macrophages (CD68+), and tumor cells. CONCLUSIONS: In d-MMR colorectal cancers, PD-1+ to PD-L1+ receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.

Completion of Genetic Testing and Incidence of Pathogenic Germline Mutation among Patients with Early-Onset Colorectal Cancer: A Single Institution Analysis.

Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16-25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to further characterize PGVs observed in patients with eoCRC. We conducted a retrospective analysis of patients with a history of CRC referred for genetic counseling at Mayo Clinic Rochester between April 2019 and April 2022. Three hundred and three CRC patients were referred to medical genetics, including 124 with a history of eoCRC. Only 84 patients (68%) with eoCRC referred for genetic counseling completed genetic testing, with an average of 48 genes evaluated. PGVs were identified in 27.4% with eoCRC, including 8.3% with Lynch syndrome (LS). Other detected PGVs known to increase the risk of CRC included MUTYH (4.8%), CHEK2 (3.6%), APC, BMPR1A, and TP53 (1.3% each). Among those with aoCRC, 109 patients (61%) completed genetic testing, among which 88% had either a dMMR tumor, personal history of an additional LS malignancy, or family history of LS malignancy, with PGVs detected in 23% of patients. This study reinforces the importance for all patients with CRC, especially those with eoCRC, to undergo germline testing.

Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors.

PURPOSE: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI. EXPERIMENTAL DESIGN: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. RESULTS: In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P < 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08-0.45; P < 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster. CONCLUSIONS: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.

Synchronous Neoplasia Rates at Colonoscopic Diagnosis of Early-Onset vs Average-Onset Colorectal Cancer.

Importance: The incidence of early-onset colorectal cancer (CRC) (age, <50 years) continues to increase globally within high-income countries. Objective: To examine and compare rates of synchronous neoplasia found in patients at colonoscopic diagnosis of early-onset CRC with rates found at diagnosis of average-onset CRC. Design, Setting, and Participants: In this multisite retrospective and cross-sectional study conducted at Mayo Clinic sites and in the Mayo Clinic Health System from January 1, 2012, to December 31, 2022, 150 randomly selected patients with early-onset CRC were identified from the electronic health record and matched with 150 patients with average-onset CRC based on sex and colonoscopic indication. Patients with known hereditary syndromes, past history of CRC, or inflammatory bowel disease were excluded. Main Outcomes and Measures: Colonoscopic findings (polyp size, number, site) and related histopathologic findings (adenoma, advanced adenoma, sessile serrated polyp) were analyzed in association with cancer clinicopathologic features and molecular data (mismatch repair status, KRAS, and BRAFV600E). Results: Among 300 patients (156 men [52%]), the median age at diagnosis was 43 years (IQR, 39-47 years) for those with early-onset CRC and 67 years (IQR, 57-76) for those with average-onset CRC. Overall, 85% of patients were symptomatic at CRC diagnosis. Cancer stage, grade, molecular features, body mass index, and family history did not differ significantly between these groups. Among patients with colon cancer, the overall prevalence of synchronous neoplasia was similar, yet advanced adenomas were 3 times more frequent in those with early-onset vs average-onset cancers (31 of 75 [41%] vs 10 of 75 [13%]; P < .001). This difference was not associated with cancer stage or primary location. Among patients with rectal cancer, nonadvanced adenomas were less frequent among the early-onset group than the average-onset group (21 of 75 [28%] vs 36 of 75 [48%]), and although the prevalence of advanced adenomas was similar (11 of 75 [15%] vs 14 of 75 [19%]), they were more commonly located in the rectum (early onset, 5 of 11 [45%] vs average onset, 1 of 14 [7%]). Patients with early-onset cancer of the colon were significantly more likely than those with early-onset cancer of the rectum to have a synchronous advanced adenoma (31 of 75 [41%] vs 11 of 75 [15%]; P < .001). Conclusions and Relevance: In this cross-sectional study, synchronous advanced adenomas were more commonly found in patients with early-onset colon cancer compared with average-onset colon cancer, and they were distributed throughout the colon. In contrast, advanced adenomas were not increased in patients with rectal cancer and, when detected, were predominantly located in the rectum.

USP10 Regulates ZEB1 Ubiquitination and Protein Stability to Inhibit ZEB1-Mediated Colorectal Cancer Metastasis.

Zinc finger E-box-binding homeobox 1 (ZEB1) is a transcription factor that can promote tumor invasion and metastasis by inducing epithelial-to-mesenchymal transition (EMT). To date, regulation of ZEB1 by RAS/RAF signaling remains unclear, and few studies have examined posttranslation modification of ZEB1, including its ubiquitination. In human colorectal cancer cell lines with RAS/RAF/MEK/ERK activation, an interaction of ZEB1 with the deubiquitinase ubiquitin-specific protease 10 (USP10) was identified whereby USP10 modifies ZEB1 ubiquitination and promotes its proteasomal degradation. Regulation of the USP10-ZEB1 interaction by MEK-ERK signaling was shown whereby constitutive activation of ERK can phosphorylate USP10 at Ser236 to impair its interaction with ZEB1 and enable ZEB1 protein stabilization. Stabilized ZEB1 was shown to promote colorectal cancer metastatic colonization in a mouse tail vein injection model. Conversely, MEK-ERK inhibition blocked USP10 phosphorylation and enhanced the USP10-ZEB1 interaction shown to suppress ZEB1-mediated tumor cell migration and metastasis. In conclusion, we demonstrate a novel function of USP10 in the regulation of ZEB1 protein stability and its ability to mediate tumor metastasis in a preclinical model. IMPLICATIONS: The MEK-ERK-regulated interaction of USP10 with ZEB1 can promote the proteasomal degradation of ZEB1 and thereby suppress its demonstrated ability to mediate tumor metastasis.

Association Between Survival and Metastatic Site in Mismatch Repair-Deficient Metastatic Colorectal Cancer Treated With First-line Pembrolizumab.

Importance: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) shows frequent and durable responses to programmed cell death 1 blockade. While most of these tumors are sporadic and observed in older patients, first-line pembrolizumab data are limited to findings from the KEYNOTE-177 trial (A Phase III Study of Pembrolizumab [MK-3475] vs Chemotherapy in Microsatellite Instability-High [MSI-H] or Mismatch Repair Deficient [dMMR] Stage IV Colorectal Carcinoma). Objective: To investigate outcome with first-line pembrolizumab monotherapy in mostly older patients with dMMR mCRC at a multisite clinical practice. Design, Setting, and Participants: This cohort study included consecutive patients with dMMR mCRC who received pembrolizumab monotherapy between April 1, 2015, and January 1, 2022, at Mayo Clinic sites and the Mayo Clinic Health System. Patients were identified from review of electronic health records at the sites, which included the evaluation of digitized radiologic imaging studies. Intervention: Patients with dMMR mCRC received first-line pembrolizumab, 200 mg, every 3 weeks. Main Outcomes and Measures: The primary study end point was progression-free survival (PFS), which was analyzed using the Kaplan-Meier method and a multivariable stepwise Cox proportional hazards regression model. Clinicopathological features, including metastatic site and molecular data (BRAF V600E and KRAS), were also analyzed along with tumor response rate, which was determined using Response Evaluation Criteria in Solid Tumors, version 1.1. Results: The study cohort included 41 patients (median [IQR] age at treatment initiation, 81 [76-86] years; 29 females [71%]) with dMMR mCRC. Of these patients, 30 (79%) had the BRAF V600E variant and 32 (80%) were classified as having sporadic tumors. Median (range) follow-up was 23 (3-89) months. Median (IQR) number of treatment cycles was 9 (4-20). Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months. Liver as a site of metastasis was associated with significantly poorer PFS vs nonliver metastasis (adjusted hazard ratio, 3.40; 95% CI, 1.27-9.13; adjusted P = .01). Complete and partial responses were observed in 3 patients (21%) with liver metastasis vs 17 patients (63%) with nonliver metastases. Treatment-related grade 3 or 4 adverse events were observed in 8 patients (20%), 2 of whom discontinued therapy; there was 1 treatment-related death. Conclusions and Relevance: This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice. Furthermore, liver vs nonliver metastasis was associated with poorer survival in this patient population, which suggests that the metastatic site has implications for survival outcome.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

PURPOSE: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAFV600E, and mismatch repair status. RESULTS: Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High (P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION: Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.

Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade.

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti-programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.