92P First-results of the CLIMB360 study, a prospective molecular screening program across multiple cancer types based on circulating tumor DNA (ctDNA)

TPS3650 Background: Trastuzumab deruxtecan, a new HER2-targeting antibody-drug conjugate, has been approved for unresectable or metastatic HER2-positive breast cancer by the Food and Drug Administration. In a phase I/II trial, trastuzumab deruxtecan showed a manageable safety profile and antitumor activity in HER2-positive various cancer types. In addition, a tissue-based HER2 test occasionally cannot identify accurate HER2 status due to spatial and temporal intratumoral heterogeneity, leading to potentially missing an opportunity for responders to receive benefit from anti-HER2-targeted therapy. Circulating tumor DNA (ctDNA) analysis can detect comprehensive somatic genome alterations by assessment of spatial and temporal intratumoral heterogeneity with minimal invasiveness. Methods: We designed an investigator-initiated multicenter phase II basket trial to evaluate efficacy and safety of trastuzumab deruxtecan in advanced solid tumor malignancies with HER2 amplification identified by Guardant360, a 74-gene sequencing ctDNA panel, as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). The key eligibility criteria are as follows: 1) Histopathologically confirmed advanced solid tumor malignancy; 2) Identified HER2 amplification by Guardant360; 3) Failed prior standard therapy. The participants will receive intravenously 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks. The primary endpoint is objective response rate (ORR). The planned sample size is 55-65. A Bayesian model considering the potential heterogeneity across cancer types will be applied to detect ORR of 5% versus 25% to a certain level while maintaining the false-positive error rate in each cancer type at 10%. Furthermore, tumor tissue, ctDNA and circulating tumor cells are serially collected and analyzed to investigate the predictive biomarkers and resistance mechanisms. The trial was activated in late 2019. At the time of the abstract submission, 2 patients have been enrolled. This trial is granted by AMED under Grant Number JP18lk0201084. Clinical trial information: JapicCTI-194707 .

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Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704961114 ◽

2017 ◽

Vol 114 (38) ◽

pp. 10202-10207 ◽

Cited By ~ 195

Author(s):

Joshua D. Cohen ◽

Ammar A. Javed ◽

Christopher Thoburn ◽

Fay Wong ◽

Jeanne Tie ◽

...

Keyword(s):

Gene Mutations ◽

Circulating Tumor Dna ◽

Ductal Adenocarcinoma ◽

Control Cohort ◽

Protein Biomarkers ◽

Pancreatic Cancers ◽

Single Marker ◽

Diagnosis Of Cancer ◽

Cancer Types ◽

Tumor Dna

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests forKRASgene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer.KRASmutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient’s primary tumor (100% concordance). The use ofKRASin conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

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Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing

Journal of Clinical Oncology ◽

10.1200/jco.18.00328 ◽

2018 ◽

Vol 36 (35) ◽

pp. 3459-3465 ◽

Cited By ~ 22

Author(s):

Thomas P. Slavin ◽

Kimberly C. Banks ◽

Darya Chudova ◽

Geoffrey R. Oxnard ◽

Justin I. Odegaard ◽

...

Keyword(s):

Hereditary Cancer ◽

Germline Mutations ◽

Circulating Tumor Dna ◽

Cancer Predisposition ◽

Cancer Genetic Counseling ◽

Predisposition Genes ◽

Average Patient ◽

Cancer Types ◽

Tumor Dna ◽

Hereditary Cancer Predisposition

Purpose To determine the potential for detection of incidental germline cancer predisposition mutations through cell-free DNA (cfDNA) analyses in patients who underwent solid tumor somatic mutation evaluation. Patients and Methods Data were evaluated from 10,888 unselected patients with advanced (stage III/IV) cancer who underwent Guardant360 testing between November 2015 and December 2016. The main outcome was prevalence of putative germline mutations identified among 16 actionable hereditary cancer predisposition genes. Results More than 50 cancer types were studied, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). Average patient age was 63.5 years (range, 18 to 95 years); 43% were male. One hundred and fifty-six individuals (1.4%) had suspected hereditary cancer mutations in 11 genes. Putative germline mutations were more frequent in individuals younger than 50 years versus those 50 years and older (3.0% v 1.2%, respectively; P < .001). Highest yields of putative germline findings were in patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Putative germline mutation identification was consistent among 12 individuals with multiple samples. Patients with circulating tumor DNA copy number variation and/or reversion mutations suggestive of functional loss of the wild-type allele in the tumor DNA also are described. Conclusion Detection of putative germline mutations from cfDNA is feasible across multiple genes and cancer types without prior mutation knowledge. Many mutations were found in cancers without clear guidelines for hereditary cancer genetic counseling/testing. Given the clinical significance of identifying hereditary cancer predisposition for patients and their families as well as targetable germline alterations such as in BRCA1 or BRCA2, research on the best way to validate and return potential germline results from cfDNA analysis to clinicians and patients is needed.

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The mutational landscape of gastrointestinal malignancies as reflected by circulating tumor DNA.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11574 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11574-11574

Author(s):

Paul Riviere ◽

Paul T. Fanta ◽

Sadakatsu Ikeda ◽

Joel Micah Baumgartner ◽

Gregory M. Heestand ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liquid Biopsy ◽

Treatment Options ◽

Circulating Tumor Dna ◽

Genetic Alterations ◽

Ductal Adenocarcinoma ◽

Gastrointestinal Malignancies ◽

Appendiceal Adenocarcinoma ◽

Cancer Types ◽

Tumor Dna

11574 Background: Liquid biopsy of circulating tumor DNA (ctDNA) is a novel method of detecting genetic alterations in cancer patients without tissue acquisition. Methods: Our analysis surveyed the genomic landscape of 213 patients with various gastrointestinal malignancies using next generation sequencing of plasma ctDNA across a 68 gene panel (www.guardanthealth.com/guardant360/). Data analysis was performed following UCSD IRB guidelines for de-identified database (NCT02478931). Results: The most common cancer types were colorectal adenocarcinoma (N = 55 (26%)), appendiceal adenocarcinoma (N = 46 (22%)), hepatocellular carcinoma (N = 31 (15%)), and pancreatic ductal adenocarcinoma (N = 25 (12%)). 70% of patients had discernible alteration(s), and 58% of patients had ≥1 characterized alterations. The median number of characterized alterations per patient was 1 (range 0-13). The number of detected alterations per patient varied between cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had > 1 characterized alteration(s), whereas 76% of patients (35/46) with appendiceal adenocarcinoma had no characterized alterations. Overall, of 123 patients with characterized alterations, > 99% (122/123) had ≥1 hypothetical (experimental or approved) treatment options available. Potentially targetable alterations varied between cancer types, proportionally to the detection rate of characterized alterations. The median percent ctDNA of characterized alterations was 2.50% (IQR 0.76-8.96%). Of interest, 95% of patients (117/123) had distinct molecular portfolios. Altogether, there were 143 unique characterized alterations within 56 genes. Overall concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (105 patients) (https://www.foundationmedicine.com/) in the four most common alterations ( KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Conclusions: Our observations suggest that many patients with gastrointestinal tumors have discernible and pharmacologically tractable ctDNA alterations. Hence, ctDNA assessment through non-invasive liquid biopsy may have an important role in clinical practice.

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Tumor area and microscopic extent of invasion to determine circulating tumor DNA fraction in plasma and detectability of colorectal cancer (CRC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.243 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 243-243

Author(s):

Joerg Bredno ◽

Jafi Lipson ◽

Oliver Venn ◽

Samuel Gross ◽

Alexander P. Fields ◽

...

Keyword(s):

Surface Area ◽

Tumor Size ◽

Clinical Stage ◽

Circulating Tumor Dna ◽

Linear Increase ◽

Model Parameters ◽

Sequencing Data ◽

Multiple Cancer ◽

Genome Bisulfite Sequencing ◽

Cancer Types

243 Background: Circulating Cell-free Genome Atlas (CCGA; NCT02889978) is a multi-center, case-control, observational study with longitudinal follow-up to develop a cfDNA assay in which classifiers were trained on whole-genome bisulfite sequencing (WGBS) and targeted methylation (TM) sequencing data for detection of multiple cancer types. Previously, we showed that the fraction of ctDNA fragments (TF) was a stronger predictor of cancer detection than clinical stage and an equivalent predictor for survival. Given that CRC tumors can be described via surface area (TSA) and microscopic tumor extent (microinvasion), CRC was used as a model to examine the biophysical determinants of TF. Methods: Detection of multiple cancers with WGBS at 98% and TM at > 99% specificity, and methods for determining TF, were previously reported. A model to predict the presence of detectable cfDNA fragments for CRC adenocarcinomas of stages I, II, and III included TSA and microinvasion beyond the subserosa. Predictors were combined assuming a linear increase of cfDNA shedding with tumor size, with scaling factors depending on microinvasion. Model parameters were determined for 27 participants (7, 11, 9 for stages I, II, III, resp.) with WGBS and applied to 40 participants (12, 15, 13 for I, II, III, resp.) with TM assay and information on tumor size and microinvasion. Results: CRC detection at stages I/II/III was 33/46, 61/73, 57/74% for WGBS/TM. TF predicted detection with AUC = 97.6. The model predicted TF as TSA multiplied by 3.81*10−6 / mm2 for tumors that invaded beyond the subserosa (p < 0.001). This was 4.4x higher than estimates for tumors below the subserosa. The model trained on the WGBS assay predicted CRC detection in the TM assay with an AUC of 0.844. Conclusions: This model used TSA (number of tumor cells) and microinvasion (bloodstream access) to predict the fraction of CRC ctDNA fragments in blood without needing to account for stage. Tumors not penetrating the subserosa had low ctDNA shedding that likely limited detection. These findings may generalize to other cancer types, providing principles to predict ctDNA shedding and thus cancer detectability based on microinvasion and surface area. Clinical trial information: NCT02889978.

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