Duma, Narjust

ABSTRACT Enteroendocrine cells (EECs) are specialized sensors of the gastrointestinal (GI) epithelium that regulate gut function and systemic metabolism through hormone secretion. The molecular pathways directing intestinal stem cell (ISC) differentiation into EECs are incompletely understood due, in part, to their rarity. We sought to identify novel regulators of human EEC differentiation using a high-throughput screen of FDA-approved drugs and human duodenal organoids. Two epidermal growth factor receptor inhibitors (EGFRi) commonly used in cancer therapy and known to cause GI side effects, erlotinib and lapatinib, emerged as strong inducers of EEC differentiation, dramatically increasing chromogranin A (CHGA) expression compared to controls, while maintaining ISC function and organoid growth. EGFRi-treated organoids revealed robust and broad upregulation of EEC hormones, including serotonin (5HT), motilin (MLN), and somatostatin (SST), among others. In agreement with these findings, analysis of a patient cohort with lung cancer revealed an association with erlotinib use and increased circulating levels of the above EEC hormones compared to matched controls. Supporting a direct effect of EGFRi on EEC differentiation, mice treated with erlotinib demonstrated increased EEC numbers and hormones and showed EGFRi-associated diarrhea (EAD), a limiting side effect of these medications. Mechanistically, EGFRi induced upregulation of interferon (IFN) signaling targets during early ISC-to-EEC differentiation. Consistent with this, inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) attenuated EGFRi-induced EEC differentiation. These findings provide important insight into EEC differentiation that could inform treatment strategies for EAD, metabolic diseases, and GI diseases. Brief Summary Inhibition of EGFR signaling promotes human ISC-to-EEC differentiation through activation of STAT1 signaling.

Abstract Purpose: In RET-rearranged non–small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. Experimental Design: This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE). Results: Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%. Conclusions: Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.

PURPOSE The primary objective of this randomized, double-blind, placebo-controlled, multicenter phase II study (Alliance A221805) was to screen two doses of duloxetine for preventing sensory oxaliplatin-induced peripheral neuropathy (OIPN). METHODS Participants were randomly assigned 1:1:1 to receive once daily 30 mg duloxetine, 60 mg duloxetine, or placebo. Eligible participants had stage II to III colorectal cancer and no baseline neuropathy, had Eastern Cooperative Oncology Group performance status 0-2, were age 25 years and older, and received oxaliplatin via one of the following doses and schedules: 85 mg/m 2 every 2 weeks (6 or 12 doses) or 130 mg/m 2 every 3 weeks (4 doses). Duloxetine/placebo was taken once daily beginning day 1 of cycle 1 and continued for 17 weeks. The primary end point, a composite response reflecting sensory OIPN symptom severity and onset, was measured in weeks 19-21 using a validated participant-reported outcome survey assessing extremity numbness, tingling, and pain. Response was defined as a participant-reported highest score of ≤2 (ie, 1 = not at all; 2 = a little) on survey items. To be evaluable for the response end point, eligible participants must have initiated oxaliplatin and submitted ≥1 postbaseline OIPN survey. RESULTS Of the 199 participants (n = 66, 30 mg duloxetine; n = 66, 60 mg duloxetine; n = 67, placebo), 46, 47, and 50 (N = 143, 71.8%), respectively, were evaluable for primary end point analysis based on modified intention-to-treat criteria. Participant mean age was 55.1 years (standard deviation = 10.4). Most were White (n = 113, 80.7%) and male (n = 82, 58.6%). The proportion of responders among those receiving placebo (68.0%) was similar to those receiving duloxetine 30 mg (65.2%) or 60 mg (66.0%). Duloxetine adherence rates, measured via pill counts—30 mg (54%), 60 mg (57%), and placebo (59%) groups—were low (<75%). CONCLUSION Duloxetine is not more promising than placebo for preventing sensory OIPN.

PURPOSE Although international medical graduates (IMGs) and Puerto Rican Medical Graduates (PRMGs) comprise an integral part of the health care workforce, these individuals, particularly women, frequently face numerous types of discrimination throughout medical training and independent practice. To our knowledge, we conducted the first cross-sectional study to understand the journeys and consequences of migration faced by IMGs and PRMGs in the US oncology workforce. METHODS We developed a cross-sectional, online survey consisting of 51 multiple choice and open-ended questions that captured demographic information, professional status, period of migration to the United States, location within the United States that participants migrated to, reasons for migration, cultural adaptation, experiences of discrimination during training, and overall professional experiences in the United States. RESULTS The majority of participants cited better education, professional gains, and a lack of opportunities in participants' home country as primary reasons for migration to the United States. However, most participants, particularly women, experienced staunch assimilation to fit the mold of professional American standards; women were also particularly likely to report experiences of racial/ethnic, language, and gender discrimination during oncology training in the United States, which only marginally improved during independent practice. Despite such discrimination, most participants reported excellent professional satisfaction during training and independent practice, although only moderate personal satisfaction. Most participants decided to stay in the United States, citing reasons pertaining to enhanced professional opportunities, whereas those that returned home valued reasons relating to family and quality of life. CONCLUSION Our sobering findings underscore the need for institutional enforcement of an inclusive environment encompassing cultural humility, enactment of programs addressing barriers to socialization, immigration laws, and financial support, creation of IMG-specific support networks, and the sponsorship and promoting of minority women physicians.

PURPOSE KRAS is the most commonly mutated driver oncogene in non–small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS G12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRAS G12C -mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS G12C -mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS G12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Precision immuno-oncology involves the development of personalized cancer treatments that are influenced by the unique nature of an individual’s DNA, immune cells, and their tumor’s molecular characterization. Biological sex influences immunity; females typically mount stronger innate and adaptive immune responses than males. Though more research is warranted, we continue to observe an enhanced benefit for females with lung cancer when treated with combination chemoimmunotherapy in contrast to the preferred approach of utilizing immunotherapy alone in men. Despite the observed sex differences in response to treatments, women remain underrepresented in oncology clinical trials, largely as a result of gender-biased misconceptions. Such exclusion has resulted in the development of less efficacious treatment guidelines and clinical recommendations and has created a knowledge gap in regard to immunotherapy-related survivorship issues such as fertility. To develop a more precise approach to care and overcome the exclusion of women from clinical trials, flexible trial schedules, multilingual communication strategies, financial, and transportation assistance for participants should be adopted. The impact of intersectionality and other determinants of health that affect the diagnosis, treatment, and outcomes in women must also be considered in order to develop a comprehensive understanding of the unique impact of immunotherapy in all women with lung cancer.

ImportanceProstate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity.ObjectiveTo evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials.Data SourcesMEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively.Study SelectionAll phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses.Data Extraction and SynthesisThis study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model.Main Outcomes and MeasuresEnrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population–based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades.ResultsOf 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, −0.06; 95% CI, −0.10 to −0.02; P = .002).Conclusions and RelevanceThe results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.

26 Background: The underrepresentation of minority populations in clinical trials negatively impacts cancer and widens inequities. We aimed to quantify the enrollment disparities in prostate cancer (PC) clinical trials over the last three decades. Methods: MEDLINE and Embase were searched to identify primary reports of prostate cancer RCTs (1989-2020). Data for trial characteristics, the proportion of trials reporting race, ethnicity and age, and the proportion of patients by race, ethnicity and age enrolled in trials were summarized using descriptive statistics. Enrollment incidence ratios (EIR), which compare trial enrollment against global estimates of incidence in age-related subgroups (acquired from the Global Burden of Disease database) and U.S. population-based estimates of racial/ethnic subgroups (acquired from the SEER 18 incidence database) were calculated. Individual trial EIRs were pooled using random-effects meta-analyses to account for the substantial heterogeneity between trials. Multivariable meta-regression was used to explore associations between key trial characteristics and EIR. Annual percentage changes (APC) over the last three decades in enrollment disparities were analyzed using the Joinpoint Regression Analysis. Results: 281 trials from 1989 to 2020 with 99,588 patients were included in this analysis. 107 trials reported race (38%), of which only 25 trials (9%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American. 255 (91%) trials reported mean or median but only 71 trials (25%) specifically reported the enrollment proportion of older adults (age > 65 years). Clinical outcomes by race and age were reported in 9 (8%) and 37 (14%) trials, respectively. Results from meta-analyses showed that Black patients (summary EIR: 0.42 [95% CI: 0.35 - 0.51]), Hispanics (summary EIR: 0.50 [95% CI: 0.37 - 0.68]) and older adults (summary EIR: 0.95 [95% CI: 0.91 - 0.99]) were underrepresented in trials relative to their population estimates. Significantly fewer Black participants (EIR for Black patients = 0.42, EIR for White patients = 0.99; p < 0.0001), Hispanic participants (EIR for Hispanics = 0.50, EIR for non-Hispanics = 1.00; p = 0.001) and older adults (EIR for older adults = 0.95, EIR for younger adults = 1.06; p = 0.037) were enrolled. Representation of Black patients decreased significantly from 1989-2019 (APC: -4.25), while Hispanic representation increased significantly from 2000-2020 (APC: 5.89). Meta-regression showed Black patients were particularly underrepresented in larger-size trials (p < 0.0001). Conclusions: Black representation in PC clinical trials is less than 50% of their expected share based on cancer incidence and it has consistently decreased over last three decades, contributing to the disparities experienced by the population.