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Baseline clinico-pathological characteristics from patients included versus not included in the ctDNA analysis

Study protocol

Calculation of the neoadjuvant rectal (NAR) score.

Kaplan-Meier estimates of disease-free survival and overall survival according to paired CEA and ctDNA baseline and pre-surgery A. Disease-free survival according to baseline ctDNA and baseline CEA B. Overall survival according to baseline ctDNA and baseline CEA C. Disease-free survival according to pre-surgery ctDNA and pre-surgery CEA D. Overall survival according to pre-surgery ctDNA and pre-surgery CEA pos: positive; neg: negative

Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL.Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics.Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine.Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828–37. ©2012 AACR.

Kaplan-Meier estimates of disease-free survival and overall survival according to pCR and NAR score in the sub-study cohort A. Disease-free survival according to pCR B. Overall survival according pCR C. Disease-free survival according to NAR score D. Overall survival according NAR score

PURPOSE MET exon 14 skipping alterations ( METex14) comprise a diverse set of actionable oncogene drivers in non–small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. RESULTS Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. CONCLUSION METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.

Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)

Background: Liquid biopsy offers a rapid and non-invasive alternative to tissue biopsy for identifying biomarkers. More recently, its application has broadened to include assessment of early response to therapy (i.e. molecular response) and in the early-stage settings, detection of minimal residual disease (MRD) and early disease recurrence1. While circulating tumor fraction (cTF) estimated by somatic mutations is well associated with the tumor progression and prognosis, interference can occur from clonal hematopoiesis of indeterminate potential (CHIP), and for cell-free DNA (cfDNA) samples that lack detectable somatic mutations, somatic tumor fraction cannot be estimated. In this analysis, we demonstrate that epigenomic signatures accurately measure cTF using orthogonal analytes to somatic mutations and enable cTF estimation even in cases without detectable tumor driver variants. Methods: To capture tumor-associated methylated cfDNA, we designed a custom assay of a broad genomic panel (15.2 Mb) targeting unmethylated regions in plasma cfDNA from healthy individuals. We profiled plasma samples from cancer patients with this panel, and utilized machine learning to integrate methylation signals into an estimate of cTF. We benchmarked the accuracy of methylation cTFs on real plasma samples, as well as in-vitro and in-silico titration datasets. Both titration data sets were generated by mixing cfDNA from patients with colorectal cancer (CRC) into the plasma from cancer-free donors, either via titration of CRC cfDNA into cfDNA from cancer-free donors for the in-vitro data, or via computationally mixing reads from CRC patients with those from cancer-free donors for the in-silico data. Results: Our methylation cTF quantified a similar cTF to those derived from well-calibrated genomic tumor driver mutations; across the 670 stage I-IV CRC samples, a strong correlation (Pearson r=0.85) was observed between methylation logit(cTF) and genomic logit(cTF). The methylation cTF was capable of quantifying low cTFs: it quantified a cTF over 0.1% in >99% of the 270 in-vitro and 1,000 in-silico titration samples with true cTFs >0.1%. In contrast, when applied to 2,037 cancer-free samples, less than 5% of the samples resulted in estimated cTFs of >0.1%. Our methylation cTF was more robust than genomic cTF on the 62 in vitro titration samples with true cTFs between 0.3-1%, with a five fold lower coefficient of variation across methylation cTFs compared to genomic cTFs. Conclusions: cTFs from methylated cfDNA may overcome the current limitations of somatic mutation based methods. Our methylation approach is capable of accurately detecting cTFs in tumor-driver positive and negative cases. As we estimate tumor-negative cases to be 30-50% of patients with stage I-III cancer and 15-20% of patients with stage IV cancer, our methylation approach may hold promise for providing better evaluation for patient care and management. Citation Format: William W. Greenwald, Yupeng He, Sai Chen, Tingting Jiang, Anton Valouev, Jun Min, Catalin Barbacioru, Daniel P. Gaile, Dustin Ma, Yvonne Kim, Giao Tran, Indira Wu, Ariel Jaimovich, Victoria Raymond, Rebecca J. Nagy, Han-Yu Chuang. Accurate epigenomic estimates of circulating tumor fraction in large-scale clinical data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3758.

Colorectal cancer (CRC) is the third-most commonly diagnosed cancer among American adults and is estimated to cause the second-most deaths among all types of cancer. However, compliance with the American Cancer Society guidelines for CRC screening remains low. Many authors have studied reasons for screening non-compliance within specific populations, but a consistent understanding of non-compliance among the general population remains elusive. In order to determine the major patient-reported barriers to CRC screening, we conducted a literature review of studies of patient-reported barriers to CRC screening. PubMed and Google Scholar were searched with the terms: “(colorectal cancer OR CRC) AND screening AND (decisions OR uptake OR barriers OR participation OR compliance OR adherence)” and “patient reported barriers to CRC screening”. Inclusion criteria for the literature review were: Original research on patient reported barriers to CRC screening, patient population includes adults with no history of CRC, research quantifies responses. Individual barriers reported in each study were coded into eight author-defined categories of commonly-cited barriers: lack of awareness of screening (awareness), cost of screening (cost), lack of doctor order, psychosocial barriers (fear, embarrassment, disgust, etc.), lack of time for screening (time), logistical problems to screening (logistics), belief that screening is unnecessary (beliefs), and other barriers (other). Of 9,718 studies assessed, 46 met quality and relevance standards. 28 analyzed barriers exclusively in the US; the rest analyzed barriers elsewhere in the world. Worldwide, lack of doctor order was the most commonly cited barrier to CRC screening. In the US, this is followed by awareness, cost, beliefs, logistics, time, psychosocial barriers, and other barriers. Elsewhere in the world, barriers follow a similar order, in particular and from most to least relevant: lack of doctor order, beliefs, psychosocial barriers, awareness, time, logistics, cost, and other barriers. This review shows that lack of doctor order is a significant barrier to screening. Thus, it would appear that the most effective screening compliance intervention would be aimed at clinician education, as increased clinician education should increase screening suggestions made in consultation which appear in this research to have a significant impact on patient behavior. Furthermore, health providers should be cognizant of these patient-reported barriers to CRC screening when developing interventions. Future research should analyze differences in compliance among populations of different socioeconomic status (SES), as low SES is a commonly cited predictor of poor screening compliance. Citation Format: Colin Small, Victoria Raymond, Mark Jacobstein, Kathryn Lang. Understanding patient-reported barriers to colorectal cancer screening: A literature review [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B051.

Whilst advances in clinical research have been made rapidly in the field of oncology research, there remains significant unmet medical need in reaching traditionally under-represented groups (low socioeconomic status, non-academic medical centers, rural populations and ethnic minorities). With the advent of the 21st Century Cures Act, the field of secondary research has become increasingly systematized but issues remain with access, reproducibility, and data ownership. The value of real-world clinico-genomic datasets in understanding the utility of medical interventions in real-world clinical practice cannot be underestimated and is becoming increasingly relevant in therapeutic areas where traditional interventional research is not feasible or economically viable. Current approaches to the execution of ‘real-world data’ studies often lack engagement of subjects and are limited by institutional and technological “data siloes”. The GRECO study is a novel, patient-centered approach to accessing and understanding patient clinical data and developing more comprehensive clinico-genomic datasets. The GRECO study, sponsored by Guardant Health (GH), was designed as a pilot to investigate the feasibility and acceptability of a direct-to-patient approach to gain informed consent from patients to participate in a pragmatic study of individuals with a diagnosis of lung cancer and at least one GH diagnostic test with reported results (taken in the course of routine clinical care). Patients were contacted by a clinical research coordinator by both telephone and email within a 60-day window from the index date and invited to enroll in the study via an online study platform with IRB-approved eConsents and medical records release form. Recruitment of the IRB-approved pilot cohort was completed within six weeks. Medical records and imaging were obtained directly from providers identified by enrolled subjects, data abstracted electronically and manually with source document verification completed to ensure quality, and data reviewed. These data were combined with results from the GH database to develop a clinico-genomic database consisting of data from subjects who have willingly provided consent to have their data collected and studied for research purposes. Based on the result of this pilot, we believe the GRECO approach represents a novel approach to the execution of real-world data studies that engages patients as active and willing participants and results in a more comprehensive view of the longitudinal patient journey. The promise of real-world clinico-genomic data will only be realized fully if the centrality of the patient in the process is remembered. As a responsible data steward and with an organizational commitment to furthering the understanding of cancer and its treatment, GH believes that this novel approach to trial design, real-world data research and patient involvement could benefit many underserved and under-represented groups and bring valuable new insights to clinical care. Citation Format: Linda Higashi, Naveen Kumar, Victoria Raymond, Mark Jacobstein, Kathryn Lang, Colin Small. GRECO: A novel patient-centered research methodology to broaden participation in clinical research [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B040.