Comprehensive Genomic Profiling Testing Research Articles

Comprehensive Genomic Profiling in Non-Myeloid Hematologic Malignancies Identifies Variants That Can Alter Clinical Practice.

Comprehensive genomic profiling (CGP) is frequently adopted to direct the clinical care of myeloid neoplasms and solid tumors, but its utility in the care of lymphoid and histiocytic cancers is less well defined. In this study, we aimed to evaluate the frequency at which mutations identified by CGP altered management in non-myeloid hematologic malignancies. We retrospectively examined the CGP results of 105 samples from 101 patients with non-myeloid hematologic malignancies treated at an academic medical center who had CGP testing between 2014 and 2021. CGP revealed one or more pathogenic or likely pathogenic variant in 92 (88%) of samples and 73 (72%) of tested patients had one or more mutations with diagnostic, prognostic, or therapeutic significance. The identification of a resistance variant resulted in the suspension of the active treatment or affected subsequent treatment choice in 9 (69%) out of 13 patients. However, the presence of a therapy sensitizing variant only led to consideration of a biomarker-directed therapy in 6 (10%) out of 61 patients. Overall, CGP of non-myeloid hematologic malignancies identified clinically significant variants in 72% of patients and resulted in a change in management in 22% of patients.

A single-institution retrospective study of comprehensive genomic profiling tests based on C-CAT findings for advanced solid cancers

Abstract Background In recent years, as the availability of precision therapies expands, there is increasing reliance on genomic profiling assays to help identify the most appropriate treatment options for patients with advanced cancers. We retrospectively investigated the results of comprehensive genomic profiling tests from the time insurance coverage began until recently and examined the status of genetic analysis. Methods We retrospectively reviewed the analysis results of 300 patients with advanced solid tumors who consented to comprehensive genomic profiling tests from October 2019 to December 2022. Results Of the 300 patients who underwent comprehensive genomic profiling tests, analysis results for 274 patients were obtained, and were reviewed by the Clinical Genome Expert Panel. Six specimens (2%) were discontinued due to patient deaths and deteriorations in general condition. The three most frequently occurring actionable genomic alterations observed were TP53 (47.4%), KRAS (28.1%) and CDKN2A (20.4%). The most common druggable variant was CDKN2A, which was noted in 52 (19%) of 274 patients. The next most common were PIK3CA, BRAF, KRAS and PTEN. The cancer types that showed a greater median number of actionable alterations comprised thyroid cancer, pancreatic cancer and colorectal cancer. Conclusions In conclusion, comprehensive genomic profiling tests have the potential to be valuable in identifying genomic abnormalities. Even if there is no effective treatment at present, it may lead to a treatment in the future. Comprehensive genomic profiling tests should be considered for any cancer.

Strength of Evidence Underlying the CMS-FDA Parallel Review of Comprehensive Genomic Profiling Tests in the Cancer Setting.

Although use of comprehensive genomic profiling (CGP) was approved by a novel CMS/FDA parallel review process, the quality of the supporting evidence is unclear. We evaluated the rigor of the peer-reviewed literature cited in the National Coverage Determination Memorandum for the FoundationOne CDx (F1CDx). We identified studies cited in the memorandum. Two independent researchers evaluated each study and applied a modified version of the Fryback and Thornbury hierarchy[1], an established framework for evaluating the efficacy of diagnostic tests. Studies focused on clinical outcomes were then categorized by study design, guided by recommendations from the Center for Medical Technology Policy. The sample included 113 scientific studies. The majority (n = 60, 53.1%) used CGP outside the course of clinical care, and there was significant heterogeneity in the cancer types assessed and sequencing depth. We found 8 (7.1%) studies that assessed whether clinical care had changed due to CGP testing, and 38 (33.6%) assessed clinical outcomes. After excluding studies that tested for five or fewer genomic alterations, 25 remained in the clinical outcomes sample: Of these, only one included a comparator group that did not receive CGP testing. Only four studies used F1CDx as the primary genomic test, none of which compared the outcomes of patients who did vs did not receive the F1CDx test. The findings indicate gaps in the supporting evidence for broad CGP use in patients with solid tumors. More rigorous studies that assess clinical utility would better inform the approval process for novel diagnostic tests.

Advancing Cancer Care in Colombia: Results of the First In Situ Implementation of Comprehensive Genomic Profiling.

Comprehensive genomic profiling (CGP) identifies genetic alterations and patterns that are crucial for therapy selection and precise treatment development. In Colombia, limited access to CGP tests underscores the necessity of documenting the prevalence of treatable genetic alterations. This study aimed to describe the somatic genetic profile of specific cancer types in Colombian patients and assess its impact on treatment selection. A retrospective cohort study was conducted at Clínica Colsanitas S.A. from March 2023 to June 2024. Sequencing was performed on the NextSeq2000 platform with the TruSight Oncology 500 (TSO500) assay, which simultaneously evaluates 523 genes for DNA analysis and 55 for RNA; additionally, analyses were performed with the SOPHiA DDM software. The tumor mutational burden (TMB), microsatellite instability (MSI), and programmed cell death ligand 1 (PDL1) were assessed. Among 111 patients, 103 were evaluated, with gastrointestinal (27.93%), respiratory (13.51%), and central nervous system cancers (10.81%) being the most prevalent. TP53 (37%), KMT2C (28%), and KRAS (21%) were frequent mutations. Actionable findings were detected in 76.7% of cases, notably in digestive (20 patients) and lung cancers (8 patients). MSI was stable at 82.52% and high at 2.91%, whilst TMB was predominantly low (91.26%). The test has facilitated access to targeted therapies, improving clinical outcomes in Colombian patients. This profiling test is expected to increase opportunities for personalized medicine in Colombia.

Comparison of Results from Two Commercially Available In-House Tissue-Based Comprehensive Genomic Profiling Solutions: Research Use Only AVENIO Tumor Tissue Comprehensive Genomic Profiling Kit and TruSight Oncology 500 Assay

Increased adoption of personalized medicine has brought comprehensive genomic profiling (CGP) to the forefront. However, differences in assay, bioinformatics, and reporting systems and lack of understanding of their complex interplay are a challenge for implementation and achieving uniformity in CGP testing. Two commercially available, tissue-based, in-house CGP assays were compared, in combination with a tertiary analysis solution in a research use only (RUO) context: the AVENIO Tumor Tissue CGP RUO Kit paired with navify Mutation Profiler (RUO) software and the TruSight Oncology 500 RUO assay paired with PierianDx Clinical Genomics Workspace software. Agreements and differences between the assays were assessed for short variants (SVs), copy number alterations (CNAs), rearrangements, tumor mutational burden (TMB), and microsatellite instability (MSI), including variant categorization and clinical trial-matching (CTM) recommendations. Results showed good overall agreement for SV, known gene fusion, and MSI detection. Important differences were obtained in TMB scoring, CNA detection, and CTM. Differences in variant and biomarker detection could be explained by bioinformatic approaches to variant calling, filtering, tiering, and normalization; differences in CTM, by underlying reported variants and conceptual differences in system parameters. Thus, distinctions between different approaches may lead to inconsistent results. Complexities in calling, filtering, and interpreting variants illustrate key considerations for implementation of any high-quality CGP in the laboratory and bringing uniformity to genomic insight results.

Microsatellite Instability-High and High Tumor Mutation Burden Frequencies in Urologic Malignancies Off-Label for Immune Checkpoint Inhibitors in Japan: A Retrospective Single-Institutional Cohort.

Objectives Microsatellite instability-high (MSI-H) and high tumor mutation burden (TMB-high) frequencies were investigated to determine the efficacy and adverse events of pembrolizumab in patients with urologic malignancies (or their equivalents) for which immune checkpoint inhibitors (ICIs) are not covered by Japanese insurance. Methods Between February 2019 and April 2024, patients with urologic malignancies (or their equivalents) treated in our department for whom ICIs were not approved by Japanese insurance were screened with an MSI companion diagnostic kit or comprehensive genomic profiling (CGP). The efficacy of pembrolizumab therapy, presence of adverse events, and outcomes were evaluated retrospectively in patients with MSI-H or TMB-high. Results In total, 44 patients were tested, and the median age at testing was 70 years. Castration-resistant prostate cancer (CRPC) was the most common (n = 31). Overall, 49 tests were performed, including 22 MSI companion diagnostic kits and 27 CGP tests. Of the 49 tests, 1 detected MSI-H, 2 detected TMB-high, and 1 detected simultaneous MSI-H/TMB-high, with detection rates of 4.1% and 11.1% for MSI-H and TMB-high, respectively. A patient with MSI-H CRPC and neuroendocrine differentiation achieved a complete response and a prolonged duration of response to pembrolizumab without adverse events. The duration of response to pembrolizumab was shorter ina patient with TMB-high, and a CRPC patient with simultaneously detected MSI-H/TMB-high had to discontinue pembrolizumab early due to immune-related adverse events. Conclusions Despite the potential benefit of pembrolizumab, MSI-H or TMB-high was less frequently detected in urologic malignancies for which ICIs are not covered by Japanese insurance.

Association of Genetic Alterations with Prognosis in Extramammary Paget's Disease: Insights into the Involvement of somatic CDKN2A variants in Poor Prognosis.

Previous studies reported the mutational landscape in extramammary Paget's disease (EMPD); however, the prognostic implications of genetic alterations remain unexplored. While CDKN2A loss is known to be associated with tumor progression or poor prognosis in some types of cancer, its significance in EMPD has not been investigated. To examine the association between common genetic alterations and prognosis in EMPD. This is a retrospective cohort study analyzing EMPD cases registered until January 2024 in the Center for Cancer Genomics and Advanced Therapeutics database, which is a nationwide database recording clinical data and comprehensive genomic profiling (CGP) test results in Japan. A total of 167 cases were recorded in the database, with CDKN2A loss being the most frequent genetic variant. Survival analysis was conducted on 127 cases. Survival from chemotherapy initiation was analyzed with adjusting for length bias inherent in the database using the Kaplan-Meier estimator, an established adjustment method. Cases with BRCA2-mutant tumors (n=18) had a worse prognosis than those with BRCA2-wild-type tumors (n=109; HR=2.97, 95% CI 1.46-6.01, p=0.003). Additionally, CDKN2A-mutant group (n=72) had a significantly worse prognosis than those with CDKN2A-wild-type group (n=55; HR=1.81, 95% CI 1.06-3.07, p=0.029). Most CDKN2A variants were pathogenic, primarily characterized by loss, while most BRCA2 variants were variants of uncertain significance. In the analysis of survival from CGP enrollment based on Eastern Cooperative Oncology Group performance status (ECOG-PS), cases with ECOG-PS 1 at the time of CGP enrollment had significantly poorer prognosis than those with ECOG-PS 0 (p=0.034; median survival time, 531 vs. 259 days). Somatic CDKN2A variant, mainly exhibiting loss, may be associated with poor prognosis in EMPD. Cases with BRCA2-mutant cancer might also have a worse prognosis in EMPD. In addition, CGP testing before PS deteriorates is preferable, considering the observed median survival of individuals undergoing CGP tests in an ECOG-PS-1 condition was less than 9 months.

Genomic Profiling of Small Intestine Cancers From a Real-World Data Set Identifies Subgroups With Actionable Alterations.

Panel-based comprehensive genomic profiling (CGP) is used in clinical practice worldwide; however, large real-world data (RWD) of patients with advanced small intestine cancer have not been characterized. We investigated differences in the prevalence of clinically relevant alterations across molecularly defined or age-stratified subgroups. This was a collaborative biomarker study of RWD from CGP testing (Foundation Medicine, Inc). Hybrid capture was conducted on at least 324 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. Overall, 1,364 patients with advanced small intestine cancer were available for analyses and were stratified by age (≥40 years/<40 years), microsatellite instability (MSI) status, tumor mutational burden (TMB) status (high ≥10/low <10 Muts/Mb), and select gene alterations. The frequency of alterations was analyzed using a chi-square test with Yate's correction. Genes with frequent alterations included TP53 (59.8%), KRAS (54.8%), APC (27.7%), and CDKN2A (22.4%). Frequent genes with amplifications were MYC (6.7%), MDM2 (5.9%), GATA6 (5.5%), and CCND1 (3.4%). Patients younger than 40 years had significantly lower frequency of APC mutations than those 40 years and older (10.4% v 28.7%; P = .0008). Druggable genomic alterations were detected in 22.3% of patients: BRAF V600E (1.2%), BRCA1 (1.8%), BRCA2 (3.2%), ERBB2 amplification (3.2%), KRAS G12C (3.3%), NTRK1/2/3 fusion (0.07%), MSI-high (7.0%), and TMB-high (12.2%), with no significant differences in the frequency according to age (<40 years v ≥40 years; 22.1% v 22.3%). TMB of 10-20 Mut/Mb was observed in 4.8% of patients, and TMB ≥20 Mut/Mb was seen in 7.3% of the cohort. RWD from clinical panel testing revealed the genomic landscape in small intestine cancer by subgroup. These findings provide insights for the future development of treatments in advanced small intestine cancer.

Real-world clinical and economic outcomes for patients with advanced non-small cell lung cancer enrolled in a clinical trial following comprehensive genomic profiling via liquid biopsy.

Oncology clinical trial enrollment is strongly recommended for patients with cancer who are not eligible for established and approved therapies. Many trials are specific to biomarker-targeted therapies, which are typically managed as specialty pharmacy services. Comprehensive genomic profiling (CGP) of advanced cancers has been shown to detect biomarkers, guide targeted treatment, improve outcomes, and result in the clinical trial enrollment of patients, which is modeled to offset pharmacy costs experienced by US payers, yet payer policy coverage remains inconsistent. A common concern limiting coverage of CGP by payers is the potential of identifying biomarkers beyond guideline-recommended treatments, which creates a perception that insurance companies are being positioned to "pay for research." However, these biomarkers can increase clinical trial eligibility, and specialty pharmacy management may have an interest in maximizing the clinical trial enrollment of members. To investigate if clinical trial enrollment following liquid biopsy CGP for non-small cell lung cancer (NSCLC) is clinically and/or economically impactful from a payer claims perspective. Clinical and economic outcomes were studied using a real-world clinical genomic database (including payer claims data) from patients with NSCLC who enrolled in clinical trials immediately following liquid biopsy CGP (using Guardant360) and matched NSCLC patient controls also tested with liquid biopsy CGP. Real-world overall survival was significantly (log-rank P < 0.0001) better for patients enrolled in clinical trials with similar costs of care, albeit with more outpatient encounters among those enrolled compared with matched controls. The results, together with previous analyses, suggest that, in addition to the clinical benefits associated with targeted therapies directed by CGP and other testing approaches, payers and specialty pharmacy managers may consider clinical trial direction and enrollment as a clinical and economic benefit of liquid biopsy CGP and adopt this into coverage decision frameworks and formularies.

A retrospective machine learning–based analysis of nationwide cancer comprehensive genomic profiling data to identify features associated with recommendation of mutation-based therapy.

e13510 Background: Comprehensive genomic profiling (CGP) has played key roles in cancer precision medicine through optimization of therapeutic interventions based on genomic alterations in cancer cells. However, the probability of discovering mutation-based treatments through CGP remains low. To enhance the effectiveness and efficiency of cancer precision medicine, it is crucial to identify patients who are likely to benefit from CGP tests. This study aims to identify characteristics of patients in which mutation-based treatments are discovered by CGP tests. Methods: We retrospectively analyzed data from 60,655 patients who underwent CGP tests and were registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national data center for cancer CGP in Japan. The C-CAT database covers 99.7% of cancer patients who have undergone CGP tests in Japan. Major cancer types included 10,182 cases of bowel cancer, 8,691 pancreas cancer, 5,062 biliary tract cancer, and 3,777 breast cancer. We developed an eXtreme Gradient Boosting (XGBoost) model using machine learning, and used clinical information as input to predict whether one or more Japanese Pharmaceuticals and Medical Devices Agency (PMDA)-approved drugs are discovered through CGP tests or not. Shapley Additive Explanations (SHAP) was employed to extract significant features that contribute to the model prediction. Results: The prediction model achieved an area under the receiver operating characteristic curve of 0.826 for the overall cancer population. Positive SHAP values were observed for patients with breast (mean SHAP in breast cancer patients: 1.38), lung (1.08), bowel (0.75), and pancreas cancers (0.35), while negative SHAP values were associated with head and neck (-1.75), cervical cancers (-1.54), and brain (-1.33). Positive SHAP values were also associated with presence of liver or lymph node metastasis (0.23, 0.08), shorter intervals between diagnosis and CGP testing or specimen collection and CGP testing, and advanced age. Similar trends were observed in cancer-type-specific prediction models, which also identified their own unique features. In the adolescent and young adult (AYA) age group, primary brain tumors were strongly associated with negative SHAP values (-1.37). Conclusions: Our machine learning-based analysis of nationwide CGP data identified features that predict cases in which mutation-based treatments are discovered by CGP tests, both in the overall cancer population and within specific cancer types and the AYA age group. Expedited CGP testing is recommended for patients who match the identified profile to facilitate early targeted therapy interventions.

Real-world costs and outcomes associated with biomarker testing by comprehensive genomic profiling (CGP) and non-CGP approaches among patients with metastatic non-small cell lung cancer (mNSCLC).

e20598 Background: Guideline-recommended molecular testing is essential for identifying appropriate targeted therapies (Rx) for treatment of mNSCLC patients (pts). Biomarker testing can be performed by single gene tests, small NGS panels (e.g., &lt; 50 genes), or CGP approaches. There is little evidence on the rate of biomarker testing in the real world setting and the impact of different approaches on Rx utilization and cost of care. This study examined real-world utilization of biomarker testing among mNSCLC pts and outcomes with CGP and non-CGP testing. Methods: De-identified administrative claims data from the Optum Labs Data Warehouse were analyzed to identify newly diagnosed adult mNSCLC pts from 1/2018 to 8/2021; the date of the first claim indicating metastasis was the index date. Continuous enrollment in a commercial (COM) or Medicare Advantage (MA) plan with medical and pharmacy benefits for 12 mo prior to (baseline), and ≥6 mo post index date (follow-up) was required; pts with &lt; 6 mo follow-up due to death were included. Initiation of a line of therapy (LOT1) during follow-up was required. We categorized pts based on receipt and type of biomarker testing prior to LOT1: CGP ( &gt; 50 gene panel), non-CGP (5-50 gene panels or single gene testing), or no testing. Differences in receipt of targeted Rx, overall survival (OS), and total overall per patient per month (PPPM) costs during LOT1 were examined with multivariable regression analyses. Results: 9,945 mNSCLC pts (1,970 COM, 7,975 MA) were identified: 5,484 with no testing, 2,215 with CGP, and 2,246 with non-CGP testing prior to LOT1. Biomarker testing rates prior to LOT1 were low (45%) but increased during the study period from 42% to 48% (p &lt;0.01). Testing rates were higher for the COM vs MA population (49% vs 44%, p &lt;0.01). A higher percent of pts with CGP received targeted Rx compared to the non-CGP and no testing group (17% vs 11% and 5% respectively, p&lt; 0.01); after adjustment, CGP pts were still more likely to receive targeted Rx. Compared to the no testing group, OS was more favorable for the CGP [HR 0.8, 95% CI 0.8-0.9] and non-CGP [HR 0.9, 95% CI 0.8-0.9] groups. There was no significant difference in PPPM costs between tested groups: CGP [CR 1.2, 95%CI 1.1-1.2] vs non-CGP [CR 1.1, 95%CI 1.1-1.2]. Conclusions: Rates of biomarker testing among mNSCLC pts are far from optimal despite well-established guideline recommendations and insurance coverage for testing. There was evidence of improved intermediate outcomes (receipt of targeted Rx) with CGP compared to non-CGP or no testing. In addition, OS was improved for tested pts compared to untested. Interventions to help improve biomarker testing are needed. Given the potential benefits of CGP testing (including assessment of biomarkers that cannot be evaluated using small panels), increasing CGP testing may improve outcomes.

Implementation of a comprehensive genomic profiling (CGP) panel for precision oncology at a cancer center in Brazil.

e23520 Background: Assessing molecular alterations in solid tumors is essential for providing the best care in precision oncology. CGP tests utilize next-generation sequencing (NGS) to detect clinically relevant alterations and molecular signatures that are increasingly utilized in cancer careand can be performed in-house, which decreases test turnaround time (TAT) and costs. A paucity of studies have documented the experience of in-house testing at academic centers in Brazil. Methods: The TruSight Oncology (TSO) 500 assay/TSO 500 HRD are research use only (RUO) CGP assays that were validated for the detection of small variants (SVs), copy number variants (CNVs), microsatellite instability (MSI), tumor mutation burden (TMB) and genomic instability score (GIS) in DNA and gene fusions/splice variants in RNA in the NextSeq 500 system. Secondary analysis was performed with Illumina Connected Analytics. Tertiary analysis was performed with Illumina Connected Insights (ICI) and Sophia DDM. TMB ≥ 10mut/Mb was defined as TMB-High and GIS ≥ 42 was homologous recombination deficient (HRD). Results: We performed CGP on 40 FFPE samples (16 with HRD) with variable quality and block age most of which had known alterations detected by other genomics/molecular tests: 17 TNBC (16 paired DNA and RNA, 1 DNA only), 18 lung cancer (13 paired DNA and RNA, 5 DNA only), 1 endometrium cancer (DNA only, POLE mutated, 4 replicates), 1 colorectal cancer (DNA only, MSI unstable) and 11 sarcomas (RNA only). 84%, 84%, 90% and 89% of samples with DNA integrity number (DIN) &gt; 2.5 were qualified for analysis of SVs/TMB, MSI, CNVs, and GIS, respectively, while for samples with DIN &lt; 2.5 these values felt to 47%, 74%, 68% and 43%, respectively. RNA isolated from blocks dated up to 5 y.o. were qualified in 90% of cases while from older blocks only 6%. The 4 replicate (single sample) analysis showed 82% and 83% overall variant concordance in the ICI and Sophia DDM software, respectively. All previously known oncogenic alterations (SVs ≥5% VAF, fusions/splice, MSI, TMB) were detected (qualified samples) and with similar performance in ICI and Sophia, respectively: concordance 0.91/p &lt; 0.0001 vs 0.94/p &lt; 0.0001; sensitivity 100% vs 100%; specificity 98% vs 100%. TMB had 100% concordance with previous TMB results. Of note, 73% (8/11) TNBC samples analyzed for GIS were HRD and 75% (6/8) explained by BRCA1 germline mutation (25%) and BRCA1or RAD51C somatic promoter methylation (75%). Conclusions: This study demonstrates the utility of CGP and HRD testing in identifying multiple molecular alterations in FFPE tissue samples with high sensitivity and specificity. Pre-analytical variables directly impact data generation. BRCA1/RAD51C promoter methylation showed to be a potential biomarker for selecting metastatic TNBC patients for PARP inhibitor therapies. Offering CGP can potentially bring precision oncology to more patients with cancer in Brazil.

Multi-specimen comprehensive genomic profiling for diagnostic disambiguation in advanced and metastatic solid tumors.

e15166 Background: Predictive biomarker testing for therapy selection is the primary intended use of tissue-based comprehensive genomic profiling (CGP) in advanced and metastatic cancer patients. This study aimed to characterize oncologists’ use of multi-specimen CGP to elucidate diagnostic uncertainty in the course of usual care for advanced and metastatic cancer patients. Methods: To assess the nature and extent to which CGP is potentially used for diagnostic disambiguation, we retrospectively identified patients tested at a reference laboratory with CGP at least twice (Illumina TruSight Oncology 500 assay), and the first two serial CGP tests for each patient were selected for study inclusion. We then explored patient demographics, rare ( &lt; 20 cases per 100k individuals) vs common diagnoses, tested tissue characteristics, time between CGP orders, and differences in genomic variant profiles between test pairs to characterize potential diagnostic use cases. Results: In all, 337/15,717 (2.1%) of patients underwent multi-CGP (June 2021-December 2023). All CGP test pairs were performed using different tissue specimens from 2 separate surgical cases (80.7%) or 2 different blocks for the same surgical case (19.3%). Compared to single-CGP, patients with multi-CGP were younger on average (65 vs 68 years), more often female (54.6% vs 50.6%), and had a greater proportion of lung (45.7% v 39.8%), breast (10.7% vs 6.7%), and unknown primary (7.1% vs 5.2%) tumors. CGP test pairs were grouped for comparison by test order diagnoses submitted by oncologists as: (Group 1) 2 different primary tumors (16%); (Group 2) same primary tumor, different histologic subtypes (19%), or; (Group 3) same primary tumor, same histologic subtype (65%). In Group 1, multi-CGP was performed more frequently for patients with a rare diagnosis for at least 1 test compared to Groups 2 and 3 (81.5% vs 43.8% or 19.6%, p &lt; 0.001), especially for cancers of unknown primary origin (31.5% vs 7.8% and 0.9%, p &lt; 0.001). In Groups 1 and 2, testing for both a primary and a metastatic site was twice as common compared to Group 3 (43% and 41% vs 22%, p = 0.017). In Group 3, 80% of patients were represented by common tumor types, and were most often tested &gt; 30 days apart (64.4%). The mean percent overlap in detected genomic variants was lowest for patients in Groups 1 and 2 where patients had 2 different primary diagnoses or 2 different histologies, and highest in Group 3, where patients had the same primary diagnosis and histology for both tests, (41.5%, 54.5%, 60%, p = 0.008). Conclusions: In practice, most multi-CGP testing is ordered serially for a subset of advanced cancer patients with common tumor types. Use of simultaneous multi-CGP for diagnostic decision-making appears to be limited to a fraction of patients representing more rare tumors with distinct diagnostic conundrums, warranting further exploration of clinical utility.

Incorporating precision oncology in everyday clinical practice: First two years of comprehensive genomic profiling (CGP) testing experience in Croatia.

11151 Background: Despite increased availability of modern technologies and evolution of tailored treatment, which has already significantly changed the outcomes in some cancer types, applicability of precision medicine in everyday clinical practice is still emerging and is one of the hot topics. Croatia is among first ones in the World to have entered into force a country-level based project of precision oncology throughout the CGP analysis in everyday clinical work, fully covered by Croatian health insurance. Hence, here we would like to present our data from everyday clinical practice and analyze the penetration of CGP given the opportunity and challenges we had. Methods: The study was observational and retrospective in nature, conducted on a country level among all patients on whose tumor specimens CGP was performed between January 1, 2020 and December 31, 2021. Eligible patients for the CGP analysis were those with metastatic disease, with at least 6-12 months of life-expectancy, with ECOG performance status ≤ 2, and after the recommendation from the multidisciplinary team. The analysis was performed in accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA), through FoundationOneCDx for solid tumors, FoundationOne Liquid in case of insufficient tissue or FoundationOneHeme for sarcomas. Results: There was total of 481 patients with CGP results. Median age was 61 years (IQR 49-69) and 58% of patients were women, while 42% were men. Most commonly tested were gastrointestinal (29.1%) and reproductive tumors (28.9%) with colorectal (19.1%) and uterine cancer (11.2%) as the most prevalent. At least one clinically relevant genomic alteration was found in 48.7% of patients. The most frequent mutations were those of KRAS (27.2%), PIK3CA (12.9%), AR (10.6%), NRAS (10.4%) and PTEN (9.1%) genes. Currently clinically not relevant mutations were found in 51.8% of patients with TP53 gene mutation as the most common (42.8%). According to the Croatian cancer registry, there was around 26 000 cancer related deaths during the investigated period defining population of at least more than 10 000 potentially eligible patients for the CGP analysis. Conclusions: Our results have shown that almost 50% of tested patients could have potential treatment benefit based on the detection of clinically relevant genomic alteration. Unfortunately, taking into consideration country level insurance eligibility criteria for CGP testing and number of potentially eligible cancer patients, we could say that only less than 5% of patients with metastatic disease were tested within first two years and that penetration of CGP is rather low, resulting with a significant number of patients underserved.

CGP-based IO biomarker assessment and treatment utilization across a major US health system.

e23109 Background: Immune checkpoint inhibitors (IO) have become a powerful precision therapy option to treat advanced stage cancer with biomarkers such as PD-L1, tumor mutational burden (TMB), and microsatellite instability (MSI) associated with improved patient response rates. Despite this, many patients do not receive genomic testing for all IO biomarkers. Providence, a large US community health system, developed a pathologist-directed testing protocol where comprehensive genomic profiling (CGP) was routinely used at time of diagnosis for advanced cancer patients. Methods: Advanced cancer patients who received CGP (ProvSeq 523) and IHC testing for PD-L1 between 2019-2023 were included in the study. Patients were required to be treated at Providence and were assessed for presence of IO biomarkers and subsequent therapy selection. Real world data were curated from patient charts and genomic laboratory data by employing a novel natural-language processing (NLP) approach to accelerate abstraction. Results: The study included 2,502 patients (53% female, median age 68y, 83% white). Top 3 tumor types tested were lung (40%), colorectal (9%), and breast (8%). Overall, 58% (N = 1,455) of patients had presence of ≥1 IO biomarker, with 46% (N = 1,155) being PD-L1 positive, and 27% (N = 682) being TMB-H. In PD-L1 negative patients (N = 1,347; 54%), 300 (22%) were TMB-H and 18 (1%) were MSI-H. 53% (N = 767) of patients who harbored an actionable IO biomarker received IO-based therapy. Fewer patients with an IO biomarker received chemotherapy compared to patients without an IO biomarker (23% vs 35%, p &lt; 0.001). Patients who possessed ≥2 IO biomarkers received an IO precision therapy 68% of the time vs 47% in patients with 1 IO biomarker (p &lt; 0.001). In PD-L1 negative patients, 26% (N = 78) of TMB-H patients received IO monotherapy compared to 5% (N = 49) of TMB-L patients. Conclusions: IO biomarker presence is associated with increased precision therapy use. CGP identified many TMB-H patients for IO monotherapy that would have been missed with PD-L1 testing alone. More than half of patients eligible for IO therapy don’t receive it; ongoing analyses will evaluate the impact of pathology-directed reflex testing on IO as well as targeted therapy approaches. [Table: see text]

Insights from C-CAT repository: A novel approach to identifying appropriate patient populations for anticancer drug development using the clinicogenomic nationwide database in Japan.

11159 Background: The integration of Comprehensive Genomic Profiling (CGP) with real-world data (RWD) provides crucial insights for anticancer drug development to achieve precision oncology, therefore, the current global trend to construct as the national projects, yet its clinical impact remains underexplored. The therapeutic efficacy of each line of anti-cancer drug in various cancer types and the relationship between genetic alterations and the effect of anticancer drugs is needed to guide the direction of future drug development promptly and precisely. Methods: A comprehensive analysis was conducted on data from Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository between June 2019 and December 2023. Five genomic profiling assays for CGP testing were reimbursed by nation-wide insurance in Japan. Utilizing the clinicogenomic repository of C-CAT, registered data of therapeutic efficacy of anticancer drug including cytotoxic agents, molecular-targeted agents, and immune checkpoint inhibitors were evaluated in association with genetic alterations. Data on anticancer drug of patients (pts) with recurrent or metastatic disease were included in the analysis. Results: The C-CAT registry data encompassed 60,256 pts across 32 tumor organ sites, classified ontology by the OncoTree over 4.5 years. Of these patients, 30,234 were male, and 30,017 were female, with 5 classified as unknown. In terms of age, 31,919 pts were &lt; 65. The most registered origins were colorectal (n=10,110), pancreas (n=8,069), biliary tract (n=5,030), breast (n=3,744), esophagus/stomach (n=3,734), prostate (n=3,701), ovarian/fallopian tube (n=3,521), lung (n=3,427), and soft tissue (n=2,568). TP53mutations (58.3%, n=35,102) were most prevalent, followed by KRAS (25.8%, n=15,521), APC (19.9%, n=11,919), NOTCH3 (14.1%, n=8,502), and PIK3CA (13.0%, n=7,861). The frequency of BRCA1/2mutation was 4.1% (n=2,479). Overall response rate (ORR) for the first-, second-, third-, and fourth-lines treatment were 35.7%, 23.3%, 19.4%, and 19.2%, respectively. Pts treated with cisplatin or carboplatin in the first-line treatment, who had TP53 mutations, showed a better ORR than those without (44.0% vs. 38.9%, p &lt; 0.001). Similarly, pts with BRCA1/2mutation showed a better ORR than those without (53.9% vs. 41.4%, p &lt; 0.001) in the first-line treatment. Conclusions: This study was the first to report the relationship between genetic alterations and the therapeutic effect of anticancer drugs in each line. This approach based on big data analysis potentially accelerates drug development in the appropriate patient population by identifying significant associations between specific genetic mutations and improved outcomes with certain chemotherapy regimens in various cancers.

Nationwide real-world usage of blood-based (liquid) biomarker testing in Japan.

e23311 Background: Despite the advances in precision oncology with biomarker testing including CGP (comprehensive genomic profiling), not all patients are able to benefit from tissue-guided treatment decisions, underscoring a significant demand for advancements in liquid-based biomarker testing for such patients. However, the treatment landscape based on the application and integration of liquid biopsy in clinical practice has yet to be fully characterized in Japan. Methods: Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter in Japan, was established by the Ministry of Health, Labour and Welfare (MHLW) with the start of cancer genome medicine since June 2019. The database collects the clinical and genomic data from 68,242 patients who underwent CGP by the end of 2023. This study included all patient records who underwent liquid CGP testing using FoundationOne Liquid test from the C-CAT database up to June 2023. Results: We analyzed data from 7,461 records, where the patients had an average age of 65.1 (±12.0) years; 58.8% were male. A majority (51.3%) exhibited an ECOG performance status of 0, and 66.5% reported a family history of carcinoma. Predominant cancer types included pancreatic (1,825; 24.5%), prostate (1,182; 15.8%) and biliary tract cancers (838; 11.2%). Following review by an MTB (molecular tumor board), new treatments were initiated in 5.8% (434) of cases, with targeted therapy (181; 41.7%) and chemotherapy (174; 40.9%) being the primary interventions. Separately, 9 (2.1%) of new treatments post-MTB occurred as part of clinical trials. Median (IQR) durations from specimen collection to MTB, MTB to treatment initiation, and specimen collection to post-MTB treatment were 28 (24-34), 35 (13-64), and 63 (42-94) days, respectively. The largest proportion of biomarker testing occurred after the start of second line of therapy (1,720; 23.1%) Pancreatic and biliary tract cancer patients tend to have biomarker testing at the earlier line, whereas prostate and ovarian cancer patients tend to have at the later line. Conclusions: Although the positioning of liquid CGP testing may differ among cancer types, it is important for patients to select appropriate tissue- and liquid-based biomarker testing at the right timing. Understanding this descriptive landscape of biomarker tests utilized in real-world settings will aid decision-making for addressing unmet needs (e.g., low accessibility to treatment) in cancer genome medicine and its positioning in improving the standard of cancer care.

Genomic landscape of comprehensive genomic profiling in patients with malignant solid tumors in Japan.

Comprehensive genomic profiling (CGP) can aid the discovery of clinically useful, candidate antitumor agents; however, the variant annotations sometimes differ among the various types of CGP tests as well as the public database. The aim of this study is to clarify the genomic landscape of evaluating detected variants in patients with a malignant solid tumor. The present, cross-sectional study used data from 57,084 patients with a malignant solid tumor who underwent CGP at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 1, 2019 and August 18, 2023. The pathogenicity of the variants was annotated using public databases. As a result of re-annotation of the detected variants, 20.1% were pathogenic and 1.4% were benign. The mean number of pathogenic variants was 4.30 (95% confidence interval: 4.27-4.32) per patient. Of the entire cohort, 5.7% had no pathogenic variant. The co-occurrence of the genes depended on the tumor type. Germline findings were detected in 6.2%, 8.8%, and 15.8% of the patients using a tumor/normal panel, tumor-only panel, and liquid panel, respectively, with the most common gene being BRCA2 followed by TP53 and BRCA1. The detected variants should be re-annotated because several benign variants or variants of unknown significance were included in the CGP, and the genomic landscape derived from these results will help researchers and physicians interpret the results of CGP tests. The method of extracting presumptive, germline, pathogenic variants from patients using a tumor-only panel or circulating tumor DNA panel requires improvement.

Abstract PO4-14-03: Results of Comprehensive Genomic Profiling of Metastatic Breast Cancer Patients at a Single Institute in Japan

Abstract BACKGROUND. Comprehensive genomic profiling (CGP) was officially approved by the Japanese National Health Insurance System in June 2019. Currently, three CGP tests are available: FoundationOne CDx (F1CDx), OncoGuide NCC Oncopanel (NCC), and FoundationOne Liquid CDx (F1LCDx). This study examines the clinical significance of CGP testing in patients with metastatic breast cancer (mBC) in Japan. METHODS. The subjects were 105 patients (pts) who underwent CGP testing at our hospital from June 2019 to July 2023. Of these, 64 pts received tissue panels for F1CDx, 25 pts for F1LCDx, and 16 pts for others. Based on the reports from the testing companies and the expert panel committee's review, we evaluated the percentage of patients for whom matched therapy (MT) was recommended, whether MT was performed, and the prognosis of the group of patients for whom MT was performed. Overall survival was analyzed with the log-rank test. RESULTS. Of the 105 patients who underwent CGP testing, 47 pts (44.8%) were recommended MT corresponding to ESCAT(ESMO Scale for Clinical Actionability of molecular Targets) ranking I/II or clinical trials due to genetic alterations, and only 7 pts (6.7%) reached those treatments. Three HER2-negative patients were prescribed anti-HER2 therapy for ERBB2 amplification, one patient was prescribed entrectinib for NTRK fusion, and three patients participated in clinical trial for ERBB2 mutation and FGFR1 rearrangement. If ESCAT ranking beyond I/II and recommended therapy from FoundationOne report (e.g Abemaciclib for CCND1 amplification, Everolimus for PTEN loss)are added, 64 pts (60.1%) were considered these treatments, and 19 pts (18.1%) actually received these treatment. Among these 19 pts, overall survival was significant improved that of patientswho did not reach treatment (21.1 m vs 6.2 m, p=0.0097). CONCLUSIONS. We examined the rate of MT attainment by CGP in mBC at a single institute. We found that the rate of MT attainment with ESCAT ranking I/II, or clinical trials corresponding to genetic mutations, was low. The overall survival of patients who underwent MT, which can be performed by Japanese insurance, was significantly different from that of patients who did not undergo MT. Low accessibility of ESCAT ranking I/II MT may be because, in Japan, CGP testing is available only for patients who have completed or are expected to complete standard therapy. Early use of CGP testing and an increase in clinical trials will be desirable in Japan. Citation Format: Tomomi Kon, Hiroshi Tada, Minoru Miyashita, Akiko Ebata, Narumi Harada-Shoji, Yohei Hamanaka, Miku Sato, Mika Yanagaki, Satoko Tsunokake, Tokiwa Motonari, Asumi Yamazaki, Takanori Ishida. Results of Comprehensive Genomic Profiling of Metastatic Breast Cancer Patients at a Single Institute in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-03.

Abstract PO4-14-04: Comprehensive genomic profiling results in patients with metastatic breast cancer due to germline BRCA1/2 status and their HER2-low status

Abstract Objective: To determine the usefulness of comprehensive genomic profiling testing and the percentage of HER2-low in patients with germline BRCA1/2 (gBRCA1/2) variants metastatic breast cancer. Methods: We included 3404 patients with metastatic recurrent breast cancer who underwent CGP testing from June 2019 to June 2023 in Japan. We examined the proportion of patients with or without recommended therapy, the proportion of patients who received matched therapy, and the proportion of patients with HER2 low by gBRCA1/2 variant due to CGP testing. RESULTS.: Of the 3404 patients, 69 (2.0%) had gBRCA1, 136 (4.0%) had gBRCA 2, 5 (0.1%) had gBRCA1 &amp; gBRCA2, 1807 (53.1%) were negative, and 1388 (40.1%) were untested or unknown. The overall percentage of patients who recommended targeted therapy due to CGP testing was 37.4%(1272/3404), with gBRCA1 at 31.9%(22/69), gBRCA2 at 43.4%(59/136), and gBRCA1&amp;gBRCA2 at 50%(2/4). The percentage of matched therapy performed in the 1st line after the expert panel was 8.3% overall, 2.9% for gBRCA1, 14.0% for gBRCA2, and 0% for gBRCA1&amp;gBRCA2. The rate of tumor mutation burden (TMB) high was 7.4% overall, and gBRCA1 at 2 .9%, gBRCA2 at 9.6%, and gBRCA1&amp;gBRCA2 at 50%. On the other hand, the percentage of HER2-low was 38.3% overall, 29% for gBRCA1, 58.1% for gBRCA2, and 25% for gBRCA1 &amp; gBRCA2. Conclusion.: Germline BRCA2 variants had a higher rate of reaching matched therapy based on CGP test results. The higher rate of TMB high was suggested to be the reason for this. The high percentage of patients with HER2-low is also expected to improve the prognosis. Citation Format: Hiroshi Tada, Minoru Miyashita, Narumi Harada-Shoji, Yohei Hamanaka, Miku Sato, Mika Yanagaki, Satoko Tsunokake, Tokiwa Motonari, Tomomi Kon, Asumi Yamazaki, Takanori Ishida. Comprehensive genomic profiling results in patients with metastatic breast cancer due to germline BRCA1/2 status and their HER2-low status [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-04.