Care Patterns and Overall Survival in Patients With Early-Onset Metastatic Colorectal Cancer.

PURPOSE: Colorectal cancer (CRC) incidence in patients younger than 50 years of age, commonly defined as early-onset (EO-CRC), is rising. EO-CRC often presents with distinct clinicopathologic features. However, data on prognosis are conflicting and outcomes with modern treatment approaches for metastatic disease are still limited. MATERIALS AND METHODS: We prospectively enrolled patients with metastatic CRC (mCRC) to a biobanking and clinical data collection protocol from 2014 to 2018. We grouped the cohort based on age at initial diagnosis: < 40 years, 40-49 years, and ≥ 50 years. We used regression models to examine associations among age at initial diagnosis, treatments, clinicopathologic features, and survival. RESULTS: We identified 466 patients with mCRC (45 [10%] age < 40 years, 109 [23%] age 40-49 years, and 312 [67%] age ≥ 50 years). Patients < 40 years of age were more likely to have received multiple metastatic resections (odds ratio [OR], 3.533; P = .0066) than their older counterparts. Patients with EO-CRC were more likely to receive triplet therapy than patients > 50 years of age (age < 40 years: OR, 6.738; P = .0002; age 40-49 years: OR, 2.949; P = .0166). Patients 40-49 years of age were more likely to have received anti-EGFR therapy (OR, 2.633; P = .0016). Despite differences in care patterns, age did not predict overall survival. CONCLUSION: Despite patients with EO-CRC receiving more intensive treatments, survival was similar to the older counterpart. However, EO-CRC had clinical and molecular features associated with worse prognoses. Improved biologic understanding is needed to optimize clinical management of EO-CRC. The cost-benefit ratio of exposing patients with EO-CRC to more intensive treatments has to be carefully evaluated.

Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer.

PURPOSE: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection. EXPERIMENTAL DESIGN: A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence. RESULTS: Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 (P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 (P = 0.18); PPV = 53.9%]. CONCLUSIONS: Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.See related commentary by Bent and Kopetz, p. 5449.

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial.

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13-41%) and 20% for PDAC (five of 25; 95% CI, 7-41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19-58%) in CRC and 29% (five of 17; 95% CI, 10-56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

Associations of baseline patient-reported outcomes with treatment outcomes in advanced gastrointestinal cancer.

BACKGROUND: Patient-reported outcomes (PROs) assessing quality of life (QOL) and symptom burden correlate with clinical outcomes in patients with cancer. However, to the authors' knowledge, data regarding associations between PROs and treatment response are lacking. METHODS: The authors prospectively approached consecutive patients with advanced gastrointestinal cancer who were initiating a new treatment. Prior to treatment, patients reported their QOL (Functional Assessment of Cancer Therapy-General [FACT-G], 4 subscales: Functional, Physical, Emotional, Social; higher scores indicate better QOL) and symptom burden (Edmonton Symptom Assessment System [ESAS], Patient Health Questionnaire-4 [PHQ-4]; higher scores represent greater symptoms). Regression models were used to examine associations of baseline PROs with treatment response (clinical benefit or progressive disease [PD] at time of first scan), healthcare utilization, and survival. RESULTS: From May 2019 to April 2020, a total of 112 patients with advanced gastrointestinal cancer were enrolled. For treatment response, 64.3% had CB and 35.7% had PD. Higher baseline ESAS-Physical (odds ratio, 1.04; P = .027) and lower FACT-G Functional (odds ratio, 0.92; P = .038) scores were associated with PD. Higher ESAS-Physical (hazard ratio [HR], 1.03; P = .044) and lower FACT-G Total (HR, 0.96; P = .005), FACT-G Physical (HR, 0.89; P < .001), and FACT-G Functional (HR, 0.87; P < .001) scores were associated with a greater hospitalization risk. Lower FACT-G Total (HR, 0.96; P = .009) and FACT-G Emotional (HR, 0.86; P = .012) scores as well as higher ESAS-Total (HR, 1.03; P = .014) and ESAS-Physical (HR, 1.04; P = .032) scores were associated with worse survival. CONCLUSIONS: Baseline PROs are associated with treatment response in patients with advanced gastrointestinal cancer, namely physical symptoms and functional QOL, in addition to health care use and survival. The findings of the current study support the association between PROs and important clinical outcomes, including the novel finding of treatment response.