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Objective: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF).Methods: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively.Results: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%).Conclusions: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated the prognostic value of circulating tumor DNA (ctDNA); however, the correlation of mean tumor molecules (MTM)/ml of plasma and mean variant allele frequency (mVAF; %) with clinical parameters is yet to be understood. In this study, we analyzed ctDNA data in a pan-cancer cohort of 23 543 patients who had ctDNA testing performed using a personalized, tumor-informed assay (Signatera™, mPCR-NGS assay). For ctDNA-positive patients, the correlation between MTM/ml and mVAF was examined. Two subanalyses were performed: (a) to establish the association of ctDNA with tumor volume and (b) to assess the correlation between ctDNA dynamics and patient outcomes. On a global cohort, a positive correlation between MTM/ml and mVAF was observed. Among 18 426 patients with longitudinal ctDNA measurements, 13.3% had discordant trajectories between MTM/ml and mVAF at subsequent time points. In metastatic patients receiving immunotherapy (N = 51), changes in ctDNA levels expressed both in MTM/ml and mVAF showed a statistically significant association with progression-free survival; however, the correlation with MTM/ml was numerically stronger., (© 2023 Natera, Inc. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment., Methods: A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease., Results: In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression., Conclusion: Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Anal squamous cell carcinoma (SCCA) is an uncommon malignancy with a rising incidence that has a high cure rate in its early stages. There is an unmet need for a reliable method to monitor response to treatment and assist in surveillance. Circulating tumor DNA (ctDNA) testing has shown great promise in other solid tumors for monitoring disease progression and detecting relapse in real time. This study aimed to determine the feasibility and use of personalized and tumor-informed ctDNA testing in SCCA., Patients and Methods: We analyzed real-world data from 251 patients (817 plasma samples) with stages I-IV SCCA, collected between 11/5/19 and 5/31/22. The tumor genomic landscape and feasibility of ctDNA testing was examined for all patients. The prognostic value of longitudinal ctDNA testing was assessed in patients with clinical follow-up (N = 37)., Results: Whole-exome sequencing analysis revealed PIK3CA as the most commonly mutated gene, and no associations between mutations and stage. Anytime ctDNA positivity and higher ctDNA levels (MTM/mL) were associated with metastatic disease (P = .004). For 37 patients with clinical follow-up, median follow-up time was 21.0 months (range: 4.1-67.3) post-diagnosis. For patients with stages I-III disease, anytime ctDNA-positivity after definitive treatment was associated with reduced DFS (HR: 28.0; P = .005)., Conclusions: Our study demonstrates the feasibility of personalized and tumor-informed ctDNA testing as an adjunctive tool in patients with SCCA as well as potential use for detection of molecular/minuteimal residual disease, and relapse during surveillance. Prospective studies are needed to better evaluate the use of ctDNA testing in this indication., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: Circulating tumor DNA (ctDNA) analyses allow for postoperative risk stratification in patients with curatively treated colon and breast cancers. Use of ctDNA in esophagogastric cancers (EGC) is less characterized and could identify high-risk patients who have been treated with curative intent., Methods: In this retrospective analysis of real-world data, ctDNA levels were analyzed in the preoperative, postoperative, and surveillance settings in patients with EGC using a personalized multiplex polymerase chain reaction-based next-generation sequencing assay. Plasma samples (n = 943) from 295 patients at > 70 institutions were collected before surgery, postoperatively, and/or serially during routine clinical follow-up from September 19, 2019, to February 21, 2022. ctDNA detection was annotated to clinicopathologic features and recurrence-free survival., Results: A total of 295 patients with EGC were analyzed, and 212 patients with stages I-III disease were further explored. Pretreatment ctDNA was detected in 96% (23/24) of patients with preoperative time points. Postoperative ctDNA was detected in 23.5% (16/68) of patients with stage I-III EGC within 16 weeks (molecular residual disease window) after surgery without receiving systemic therapy. ctDNA detection at any time point after surgery (hazard ratio [HR], 23.6; 95% CI, 10.2 to 66.0; P < .0001), within the molecular residual disease window (HR, 10.7; 95% CI, 4.3 to 29.3; P < .0001), and during the surveillance period (HR, 17.7; 95% CI, 7.3 to 50.7; P < .0001) was associated with shorter recurrence-free survival. In multivariable analysis, ctDNA status and clinical stage of disease were independently associated with outcomes., Conclusion: Using real-world data, we demonstrate that postoperative tumor-informed ctDNA detection in EGC is feasible and allows for enhanced patient risk stratification and prognostication during curative-intent therapy., Competing Interests: Brandon M. HuffmanStock and Other Ownership Interests: Doximity Vasily N. AushevEmployment: NateraStock and Other Ownership Interests: NateraTravel, Accommodations, Expenses: Natera Griffin L. BuddeEmployment: NateraStock and Other Ownership Interests: NateraTravel, Accommodations, Expenses: Natera Joseph ChaoConsulting or Advisory Role: Lilly, Merck, AstraZeneca, Foundation Medicine, Daiichi Sankyo, Amgen, Bristol Myers Squibb, Astellas Pharma, Turning Point Therapeutics, Roche, Silverback Therapeutics, Novartis, Coherus Biosciences, Geneos, Guardant HealthSpeakers' Bureau: Merck, Bristol Myers SquibbResearch Funding: Merck (Inst), Novonco Therapeutics (Inst), Brooklyn Immunotherapeutics (Inst)Travel, Accommodations, Expenses: Merck, Macrogenics, Foundation Medicine, AmgenOther Relationship: Yiviva Farshid DayyaniEmployment: RocheConsulting or Advisory Role: Genentech/Roche, Array BioPharma, Exelixis, Eisai, QED Therapeutics, SignateraSpeakers' Bureau: Genentech/Roche, Amgen, Eisai, ipsen, Exelixis, Sirtex Medical, Deciphera, Natera, ServierResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Merck (Inst), Genentech (Inst), Taiho Pharmaceutical (Inst), Exelixis (Inst), Ipsen (Inst) Diana HannaConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca Gregory P. BottaHonoraria: NateraConsulting or Advisory Role: NateraSpeakers' Bureau: Natera Daniel V.T. CatenacciHonoraria: Genentech/Roche, Lilly, Amgen, Foundation Medicine, Taiho Pharmaceutical, Guardant Health, Merck, Bristol Myers Squibb, Gritstone Bio, Five Prime Therapeutics, Astellas Pharma, Seattle Genetics, Tempus, Pieris Pharmaceuticals, Daiichi Sankyo/UCB Japan, Zymeworks, QED Therapeutics, Natera, Archer, NovartisConsulting or Advisory Role: Genentech/Roche, Amgen, Merck, Lilly, Taiho Pharmaceutical, Bristol Myers Squibb, Astellas Pharma, Seattle Genetics, Daiichi Sankyo/UCB Japan, Zymeworks, Guardant HealthSpeakers' Bureau: Guardant Health, Genentech, Lilly, Merck, Tempus, Daiichi Sankyo/Astra Zeneca Steven B. MaronStock and Other Ownership Interests: Calithera BiosciencesHonoraria: Vindico Medical Education, Clarion Healthcare, Physicans' Education ResourceConsulting or Advisory Role: Natera, Basilea, Daichi Sankyo, Bicara Therapeutics, Novartis, AmgenResearch Funding: Guardant Health (Inst), Epic Sciences Shifra KrinshpunEmployment: NateraStock and Other Ownership Interests: NateraTravel, Accommodations, Expenses: Natera Shruti SharmaEmployment: NateraStock and Other Ownership Interests: Natera Giby V. GeorgeEmployment: NateraStock and Other Ownership Interests: Natera Meenakshi MalhotraEmployment: NateraStock and Other Ownership Interests: Natera Adham JurdiEmployment: NateraStock and Other Ownership Interests: Natera, Cardiff OncologySpeakers' Bureau: NateraTravel, Accommodations, Expenses: Natera Solomon MoshkevichEmployment: Natera, Mahana TherapeuticsStock and Other Ownership Interests: NateraPatents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera, incTravel, Accommodations, Expenses: Natera Alexey AleshinEmployment: Natera, NateraLeadership: NateraStock and Other Ownership Interests: NateraConsulting or Advisory Role: Mission BioTravel, Accommodations, Expenses: Natera Pashtoon M. KasiConsulting or Advisory Role: Taiho Pharmaceutical (Inst), Ipsen (Inst), Natera, Foundation Medicine, MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, Inflecton Point Biomedical Advisors, QED Therapeutics, Boston Healthcare Associates, SERVIER, Taiho Oncology, Exact Sciences, Daiichi Sankyo/Astra Zeneca, Eisai, Seattle GeneticsResearch Funding: Advanced Accelerator Applications (Inst), Tersera (Inst), Boston Scientific (Inst)Travel, Accommodations, Expenses: AstraZeneca Samuel J. KlempnerThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: TP Therapeutics, Nuvalent, IncHonoraria: NateraConsulting or Advisory Role: Lilly, Astellas Pharma, Bristol Myers Squibb, Pieris Pharmaceuticals, Merck, Daiichi Sankyo/UCB Japan, Sanofi/Aventis, Mersana, Exact Sciences, NovartisResearch Funding: Leap Therapeutics (Inst), BeiGene (Inst), Silverback Therapeutics (Inst)Other Relationship: NCCNNo other potential conflicts of interest were reported.

Introduction: Colorectal cancer (CRC) is a highly prevalent disease, wherein, ~30%-40% of patients with CRC relapse postresection. In some patients with CRC, adjuvant chemotherapy can help delay recurrence or be curative. However, current biomarkers show limited clinical utility in determining if/when chemotherapy should be administered, to provide benefit. Circulating tumour DNA (ctDNA) can measure molecular residual disease (MRD) and relapse with high specificity and sensitivity. This study protocol investigates the clinical utility of ctDNA for optimal use of adjuvant chemotherapy in patients with surgically resected CRC and to detect early disease progression in the surveillance setting., Methods and Analysis: This is a multicentre prospective, observational cohort study. A total of 2000 stage I-IV patients will be enrolled in up to 200 US sites, and patients will be followed for up to 2 years with serial ctDNA analysis, timed with the standard-of-care visits. The primary endpoints are to observe the impact of bespoke ctDNA testing on adjuvant treatment decisions and to measure CRC recurrence rates while asymptomatic and without imaging correlate. The secondary endpoints are MRD clearance rate (MRD+ to MRD-) during or after adjuvant chemotherapy, percentage of patients that undergo surgery for oligometastatic recurrence, survival of MRD-negative patients treated with adjuvant chemotherapy versus no adjuvant chemotherapy (active surveillance), overall survival, examine the number of stage I CRC that have recurrent disease detected postsurgery, and patient-reported outcomes., Ethics and Dissemination: This study has received ethical approval from the Advarra Institutional Review Board (IRB) protocol: Natera-20-041-NCP/3766.01, BESPOKE Study of ctDNA Guided Therapy in Colorectal Cancer (BESPOKE CRC) (Pro00041473) on 10 June 2021. Data protection and privacy regulations will be strictly observed in the capturing, forwarding, processing and storing of patients' data. Publication of any study results will be approved by Natera in accordance with the site-specific contract., Trial Registration Number: NCT04264702., Competing Interests: Competing interests: PMK: consultancy/advisory board: Taiho Oncology, Ipsen, Natera, Foundation Medicine; Research/Trial Support (to institution): BMS, Celgene, AstraZeneca, BTG, Advanced Accelerator Applications, Array Biopharma. AG: Research funding from Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Genentech/Roche, Lilly, Pfizer. SKo: research funding from Amgen, Array BioPharma, Biocartis, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, Sanofi. All other authors are employees of Natera, Inc. with stock/options to own stock on the company. This study is being sponsored by Natera, Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In 2003, the Maimonides Infants & Children's Hospital received a Title VII Residency Training in Primary Care grant to integrate genetic-specific competencies into postgraduate pediatrics education. As part of that endeavor, mandatory yearly genetics objective structured clinical exams (OSCEs) were instituted for third-year residents. This article reports on the first three years of experience with this innovative educational tool.After an overview of genetic concepts, dysmorphology, and communication styles, residents complete a five-station OSCE and receive feedback from standardized patients and from the faculty who observe them. After this clinical exercise, the residents participate in a small-group debriefing session to share strategies for effective communication and clinical case management and to discuss the ethical issues that arise with these genetic cases.In three years, 60 residents have completed the genetics OSCE program. Evaluation data demonstrate that the program has been effective in both introducing genetic-specific challenges and assessing residents' clinical skills. It has helped trainees self-identify both strengths and further training needs. Pre- and postsurveys among the trainees show increased comfort levels in performing 5 of 12 genetic-related clinical tasks.We conclude that genetics OSCEs are an enriching educational tool. Merely providing trainees and practicing physicians with the latest scientific information is unlikely to prepare them for counseling patients about complex genetic issues. Developing proficiency requires focused practice and effective feedback.This article is part of a theme issue of Academic Medicine on the Title VII health professions training programs.