Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial.

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.

Willingness to use a wearable device capable of detecting and reversing overdose among people who use opioids in Philadelphia.

BACKGROUND: The incidence of opioid-related overdose deaths has been rising for 30 years and has been further exacerbated amidst the COVID-19 pandemic. Naloxone can reverse opioid overdose, lower death rates, and enable a transition to medication for opioid use disorder. Though current formulations for community use of naloxone have been shown to be safe and effective public health interventions, they rely on bystander presence. We sought to understand the preferences and minimum necessary conditions for wearing a device capable of sensing and reversing opioid overdose among people who regularly use opioids. METHODS: We conducted a combined cross-sectional survey and semi-structured interview at a respite center, shelter, and syringe exchange drop-in program in Philadelphia, Pennsylvania, USA, during the COVID-19 pandemic in August and September 2020. The primary aim was to explore the proportion of participants who would use a wearable device to detect and reverse overdose. Preferences regarding designs and functionalities were collected via a questionnaire with items having Likert-based response options and a semi-structured interview intended to elicit feedback on prototype designs. Independent variables included demographics, opioid use habits, and previous experience with overdose. RESULTS: A total of 97 adults with an opioid use history of at least 3 months were interviewed. A majority of survey participants (76%) reported a willingness to use a device capable of detecting an overdose and automatically administering a reversal agent upon initial survey. When reflecting on the prototype, most respondents (75.5%) reported that they would wear the device always or most of the time. Respondents indicated discreetness and comfort as important factors that increased their chance of uptake. Respondents suggested that people experiencing homelessness and those with low tolerance for opioids would be in greatest need of the device. CONCLUSIONS: The majority of people sampled with a history of opioid use in an urban setting were interested in having access to a device capable of detecting and reversing an opioid overdose. Participants emphasized privacy and comfort as the most important factors influencing their willingness to use such a device. TRIAL REGISTRATION: NCT04530591.

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.

Muscle Loss Is Associated with Overall Survival in Patients with Metastatic Colorectal Cancer Independent of Tumor Mutational Status and Weight Loss.

BACKGROUND: Survival in patients with metastatic colorectal cancer (mCRC) has been associated with tumor mutational status, muscle loss, and weight loss. We sought to explore the combined effects of these variables on overall survival. MATERIALS AND METHODS: We performed an observational cohort study, prospectively enrolling patients receiving chemotherapy for mCRC. We retrospectively assessed changes in muscle (using computed tomography) and weight, each dichotomized as >5% or ≤5% loss, at 3, 6, and 12 months after diagnosis of mCRC. We used regression models to assess relationships between tumor mutational status, muscle loss, weight loss, and overall survival. Additionally, we evaluated associations between muscle loss, weight loss, and tumor mutational status. RESULTS: We included 226 patients (mean age 59 ± 13 years, 53% male). Tumor mutational status included 44% wild type, 42% RAS-mutant, and 14% BRAF-mutant. Patients with >5% muscle loss at 3 and 12 months experienced worse survival controlling for mutational status and weight (3 months hazard ratio, 2.66; p < .001; 12 months hazard ratio, 2.10; p = .031). We found an association of >5% muscle loss with BRAF-mutational status at 6 and 12 months. Weight loss was not associated with survival nor mutational status. CONCLUSION: Increased muscle loss at 3 and 12 months may identify patients with mCRC at risk for decreased overall survival, independent of tumor mutational status. Specifically, >5% muscle loss identifies patients within each category of tumor mutational status with decreased overall survival in our sample. Our findings suggest that quantifying muscle loss on serial computed tomography scans may refine survival estimates in patients with mCRC. IMPLICATIONS FOR PRACTICE: In this study of 226 patients with metastatic colorectal cancer, it was found that losing >5% skeletal muscle at 3 and 12 months after the diagnosis of metastatic disease was associated with worse overall survival, independent of tumor mutational status and weight loss. Interestingly, results did not show a significant association between weight loss and overall survival. These findings suggest that muscle quantification on serial computed tomography may refine survival estimates in patients with metastatic colorectal cancer beyond mutational status.

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.

Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice.

Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.

Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers.

PURPOSE: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer. EXPERIMENTAL DESIGN: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response. RESULTS: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001). CONCLUSIONS: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.