A standing platform for cancer drug development using ctDNA-based evidence of recurrence.

The time required to conduct clinical trials limits the rate at which we can evaluate and deliver new treatment options to patients with cancer. New approaches to increase trial efficiency while maintaining rigor would benefit patients, especially in oncology, in which adjuvant trials hold promise for intercepting metastatic disease, but typically require large numbers of patients and many years to complete. We envision a standing platform - an infrastructure to support ongoing identification and trial enrolment of patients with cancer with early molecular evidence of disease (MED) after curative-intent therapy for early-stage cancer, based on the presence of circulating tumour DNA. MED strongly predicts subsequent recurrence, with the vast majority of patients showing radiographic evidence of disease within 18 months. Such a platform would allow efficient testing of many treatments, from small exploratory studies to larger pivotal trials. Trials enrolling patients with MED but without radiographic evidence of disease have the potential to advance drug evaluation because they can be smaller (given high probability of recurrence) and faster (given short time to recurrence) than conventional adjuvant trials. Circulating tumour DNA may also provide a valuable early biomarker of treatment effect, which would allow small signal-finding trials. In this Perspective, we discuss how such a platform could be established.

CDK4/6 Inhibitor Efficacy in ESR1-Mutant Metastatic Breast Cancer.

BACKGROUND: In estrogen receptor-positive metastatic breast cancer, ESR1 mutations (ESR1m) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact ESR1 alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific ESR1 allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1m metastatic breast cancer and associated clinical factors. METHODS: ESR1m were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1m or non-ESR1-mutant (non-ESR1m) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment. RESULTS: One hundred forty-five patients with ESR1m and 612 with non-ESR1m metastatic breast cancer were analyzed. ESR1m and non-ESR1m tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of ESR1 status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1m had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant. CONCLUSIONS: These data suggest ESR1 variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1m metastatic breast cancer.

Data visualization explorer: A tool for participant representation in pivotal trials of FDA-approved medicinal products.

This paper presents a 2015-2021 US Food and Drug Administration (FDA) Drug Trials Snapshots (DTS) Data Visualization Explorer-an interactive data visualization web-based tool (https://arielcarmeli.shinyapps.io/fda-drug-trial-snapshots-data-explorer) built in R and based on publicly available FDA clinical trial participation data and disease incidence data from the National Cancer Institute and Centers for Disease Control and Prevention. FDA data can be explored by race, ethnicity, sex, age group, therapeutic area, pharmaceutical sponsor, and approval year for clinical trials that supported each of the 339 FDA drug and biologic approvals between 2015 and 2021. This work provides several advantages relative to past literature and DTS reports: a dynamic data visualization tool; race, ethnicity, sex, and age group data presented in one place; data on sponsor; and emphasis on data distributions instead of averages. We present recommendations for improved data access, reporting, and communication to assist leaders in making evidence-based decisions to improve trial representation to enhance health equity.

The case for philanthropic investment to increase colorectal cancer screening rates: A novel paradigm to address a public health challenge.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related death despite being highly preventable. Efforts to increase participation in CRC screening have not met national goals. We developed a novel approach: building a business case for philanthropic investment in CRC screening. METHODS: A taskforce representing the public health community, professional societies, charitable foundations, academia, and industry was assembled to: (a) quantify the impact of improving CRC screening rates; (b) identify barriers to screening; (c) estimate the "activation cost" to overcome barriers and screen one additional person; (d) develop a holistic business case that is attractive to philanthropists; and (e) launch a demonstration project. RESULTS: We estimated that of 50 600 CRC deaths annually in the US, 55% occur in 50- to 85-year-olds and are potentially addressable by improvements in CRC screening. Barriers to screening were identified in all patient journey phases, including lack of awareness or insurance and logistical challenges in the pre-physician phase. The cost to activate one person to undergo screening was $25-175. This translated into a cost of $6000-36 000 per CRC death averted by philanthropic investment. Based on this work, the Colorectal Cancer Alliance launched the effort "March Forth" to prevent 100 000 CRC deaths in the US over 10 years, with the first pilot in Philadelphia. CONCLUSIONS: A holistic business plan can attract philanthropy to promote CRC screening. A simple message of "You can save a life from CRC with a $25 000 donation" can motivate demonstration projects in regions with high CRC rates and low screening participation.