Comprehensive Genomic Profiling Testing Research Articles

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 & 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&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&gBRCA2. The rate of tumor mutation burden (TMB) high was 7.4% overall, and gBRCA1 at 2 .9%, gBRCA2 at 9.6%, and gBRCA1&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 & 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.

Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer.

Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.

Comprehensive genomic profiling of salivary gland carcinoma: Analysis of the Center for Cancer Genomics and Advanced Therapeutics database in Japan.

Comprehensive information on genetic alterations in salivary gland cancer (SGC) is limited. This study aimed to elucidate the genetic and clinical characteristics of patients with SGC using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, a Japanese national genomic database. We analyzed data of 776 patients with SGC registered in the C-CAT database between June 1, 2019, and June 30, 2023. Adenoid cystic carcinoma was the most common histologic type, followed by salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified. Genetic data of 681 patients receiving FoundationOne® CDx were analyzed. We identified specific features of the combination of TP53 and CDKN2A alterations among the histological types. Specific LYN amplification was mainly detected in carcinoma ex pleomorphic adenoma and myoepithelial carcinoma. For SDC, the frequency of ERBB2 and BRAF alterations were higher in cases with metastatic lesions than in those with primary lesions. Although 28.6% patients were offered recommended treatment options, only 6.8% received the recommended treatments. This study highlights the differences in genetic alterations among the histological types of SGC, with comprehensive genomic profiling tests revealing lower drug accessibility. These findings could contribute to the development of personalized treatment for patients with SGC.

Mutational landscape of oral mucosal melanoma based on comprehensive cancer genomic profiling tests in a Japanese cohort

ObjectivesOral mucosal melanoma (OMM) is a rare but aggressive melanoma subtype. Due to its rarity, the genomic landscape of OMM remains unknown despite a relatively thorough understanding of the genetic profile of cutaneous melanoma (CM). In this study, we analyzed the genomic mutational profiles of Japanese patients with OMM and compared them with those of patients with nose/sinuses mucosal melanoma (NMM) and CM to identify potential therapeutic targets. Materials and MethodsWe extracted clinical and genomic information of patients with OMM (n = 15), NMM (n = 63), and CM (n = 413) who underwent comprehensive genomic profiling tests under the National Health Insurance between June 2019 and November 2023 from the Center for Cancer Genomics and Therapeutics database. ResultsThe most frequent genomic alteration identified in OMM was RICTOR (40%) followed by CDK4 (33.3%), MDM2 (33.3%), KDR (30%), KIT (26.7%), and NF1 (26.7%). CDK4 and MDM2 were co-amplified. Gene alterations in MYC and NRAS were the highest in patients with NMM, followed by those with CM, and no MYC alteration was observed in patients with OMM. BRAF V600 mutation, which is frequently observed in patients with CM (23.2%) were only present in 1.6% of patients with NMM and none in patients with OMM. ConclusionThis study clarified the genetic differences between OMM and NMM, and the first to report the frequent occurrence of RICTOR amplification in OMM. This analysis offers insights into the development of personalized therapeutics for OMM.

The Molecular Landscape of Gastric Cancers for Novel Targeted Therapies from Real-World Genomic Profiling.

Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known. We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups. This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥40/<40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥/low <10 Muts/Mb), Epstein-Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate's correction. Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged <40 years (27.7 and 6.2%) than in those aged ≥40 years (14.7 and 4.0%). Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

Feasibility of comprehensive genomic profiling using endoscopic ultrasound-guided tissue acquisition with a 22-gauge Franseen needle.

Comprehensive genomic profiling (CGP) test for solid tumors is now increasingly utilized in clinical practice, especially in pancreatobiliary cancer, and specimens obtained by endoscopic ultrasound-guided tissue acquisition (EUS-TA) are often submitted for tissue-based CGP test. In this study, we evaluated the feasibility of EUS-TA using a 22-gauge Franseen needle for the CGP test. Consecutive patients with solid tumors who underwent EUS-TA using a 22-gauge Franseen needle, and whose tissue samples were pre-checked for suitability for CGP test, were included in this single-center, retrospective analysis. The success rates of appropriate sample collection for CGP evaluated by pathologists (1st quality control) and CGP test (2nd quality control) were evaluated. In addition, The EUS-TA slides were evaluated for the tissue area and tumor area content, using the image software. A total of 50 cases, with 78% of pancreatic cancer, were included in the analysis. A median of 3 passes of EUS-TA were performed with an adverse event rate of 4%. The success rates for 1st and 2nd quality control for CGP tests were 86% and 76%, respectively. The image analyses suggested EUS-TA specimen did not always fulfill CGP test criteria, with 18% of tissue area ≥16 mm2 and 38% of tumor area content ≥20%, even in cases with successful CGP tests. The suction method yielded a significantly larger amount of DNA but without a significant difference in the multivariate analysis. The present study demonstrated the feasibility of EUS-TA using a 22-gauge Franseen needle for CGP test.

Comprehensive Genomic Testing: Tissue Stewardship and Best Practices

Biomarker-driven targeted therapies have shaped the oncology treatment landscape for patients with advanced solid tumors over the past decade. Comprehensive genomic profiling (CGP) has played a key role in precision medicine as it enables simultaneous identification of multiple biomarkers to guide cancer diagnosis, therapy selection, and prognostication. As a result, tissue stewardship for successful CGP testing is paramount. In addition, widespread adoption of less invasive sampling techniques leaves less diagnostic tissue for additional or future testing as smaller biopsies are acquired. To help oncology care practitioners overcome these challenges, this paper provides an overview of current genomic testing methodologies and offers guidelines on best practices for tissue stewardship and preanalytic practices for successful CGP testing and efficient turnaround times for laboratory tests.

Abstract 6457: The real-world data of comprehensive genomic profiling tests with tissue specimens from lung cancer patients in Japan

Abstract Introduction: Molecularly targeted therapy improves prognosis of lung cancer patients with specific genomic alterations, and thus it is important to identify actionable genomic alterations leading to appropriate therapy. In Japan, comprehensive genomic profiling (CGP) tests have been covered by insurance since June 2019. 99.7% of the CGP data under insurance coverage have been registered with the nationwide database: Center for Cancer Genomics and Advanced Therapeutics (C-CAT). C-CAT data include CGP test results and clinical information such as companion diagnostic results for EGFR, ALK, ROS1, and BRAF as well as therapeutic history. The aim of this study is to evaluate the usefulness of CGP tests for identifying actionable genomic alterations in real-world lung cancer patients. Methods: Among the 3,240 lung cancer patients registered in the C-CAT database by September 2023, 2,076 non-small cell lung cancer cases were tested using tissue specimens and analyzed retrospectively. The analysis was based on the levels of evidence defined by C-CAT. Level A indicated approved drugs for the particular cancer type, while level C indicated approved drugs or presence of positive clinical trials regardless of cancer type. Level F indicated that the genomic alteration was an oncogenic marker. Results: The cases were divided into two groups: 335 cases with known genomic alterations with positive results from companion diagnostic tests or use of specific inhibitors and 1,741 cases without. Genomic alterations with level A, A to C, and A to F were identified in 430 cases (24.7%), 1174 cases (67.4%), and 1718 cases (98.7%) with unknown genomic alterations, respectively. Genomic alterations with level A included rearrangement of RET (43 of 1741 cases, 2.5%), ALK (14 cases, 0.8%), ROS1 (8 cases, 0.5%), and NTRK1 (2 cases, 0.1%), and mutations of EGFR (124 cases, 7.1%), MET (38 cases, 2.2%), ERBB2 (122 cases, 7.0%), KRAS G12C (66 cases, 3.8%), and BRAF V600E (15 cases, 0.9%). Genomic alterations with level C included mutations in KRAS (185 cases, 10.6%), PIK3CA (99 cases, 5.7%), BRAF (55 cases, 3.2%), and PTEN (32 cases, 1.8%) and amplifications in ERBB2 (147 cases, 8.4%) and MET (68 cases, 3.9%). Among cases with known genomic alterations, ALK and ROS1 fusion genes were not detected in 11 of 49 (22.4%) and 17 of 46 (37.0%), while EGFR and BRAF mutation was not detected in 11 of 218 (5.0%) and 3 of 4 cases (75.0%), respectively. The detection rate of fusion genes was lower than that of mutated genes (70.5% vs 93.7%, p&amp;lt;0.001). Conclusion: In non-small cell lung cancer patients with unknown driver genes, driver oncogenes with corresponding approved therapy were found in a quarter of the patients. CGP tests offer the possibility of increasing the opportunities of receiving new therapies. CGP tests may have a lower detection rate for fusion genes compared with other mutations. Citation Format: Koki Fujii, Momoko Morishita, Michiko Ueki, Hiroaki Ikushima, Hideaki Isago, Kousuke Watanabe, Katsutoshi Oda, Hidenori Kage. The real-world data of comprehensive genomic profiling tests with tissue specimens from lung cancer patients in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6457.

Abstract 6460: Incidence of pathogenic germline variants and presumed germline pathogenic variants in Japanese lung cancer patients using comprehensive genomic profiling tests

Abstract Introduction: Pathogenic germline variants (PGVs) and presumed germline pathogenic variants (PGPVs) are often detected with comprehensive genomic profiling (CGP) tests. Using the Center for Advanced Cancer Genomics and Therapeutics (C-CAT) database, we investigated the incidence of PGV and PGPV detected by CGP tests in Japanese lung cancer patients. Methods: Among 3,240 lung cancer cases registered in C-CAT between June 2019 and August 2023, 321 were tumor/normal paired NCC Oncopanel (NOP), 773 were FoundationOne Liquid CDx (F1L), and 2,145 were tumor-only FoundationOne CDx (F1CDx). We analyzed cancer susceptibility genes in accordance with the national guideline. In F1L and F1CDx, PGPV was determined based on variant allele frequency (VAF) and medical history. Differences between groups in the detection of PGV and PGPV were tested using chi-squared test, and differences in age were tested using t-test. Results: The incidence of PGV in NOP and PGPV in F1L and F1CDx were 4/321 (1.2%), 36/773 (4.7%), and 141/2145 (6.6%), respectively (NOP vs F1L vs F1CDx; p = 0.001 NOP vs F1L; p = 0.006, NOP vs F1CDx; p &amp;lt; 0.001, F1L vs F1CDx;p=0.190). The 4 PGVs detected by NOP were in the ATM, BRCA2, MSH6, and TP53 genes. Notably, two out of four patients were in their 30s while the other two were in their 70s. In the F1L dataset, 36 patients (4.7%) had PGPV: 8 patients (1.0%) had PALB2, 6 patients (0.8%) had BRCA2, and 4 patients (0.5%) had CHEK2 variants. In the F1CDx dataset, 141 had PGPV: 19 patients (0.9%) each had BRCA1 or BRCA2 variants and 18 patients (0.8%) had PALB2 variant. There was no significant age difference between PGPV(-) and PGPV(+) patients (F1L:63.3 vs. 62.4 years; p = 0.938, F1CDx: 65.5 vs 65.0 years; p = 0.749). Most cases with PGV or PGPV were non-small cell lung cancer: 4/4 in NOP, 34/36 in F1L, and 110/141 in F1CDx. Discussion: The incidence of PGV in lung cancer patients was at least 1% and found in both younger and older patients. A circulating tumor DNA panel and a tumor-only tissue panel detected PGPVs at a significantly higher rate than detection of true PGVs by tumor/normal paired tissue panel, suggesting the use of tumor/normal paired panels may mitigate the burden of both patients and clinicians with concerns from false positive PGPV. The majority of detected PGV/PGPV were in homologous recombination repair genes. Citation Format: Michiko Ueki, Kousuke Watanabe, Momoko Morishita, Koki Fujii, Hiroki Ikushima, Hideaki Isago, Katsutoshi Oda, Hidenori Kage. Incidence of pathogenic germline variants and presumed germline pathogenic variants in Japanese lung cancer patients using comprehensive genomic profiling tests [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6460.

Abstract 2933: Use of artificial intelligence to facilitate reporting of comprehensive genomic profiling tests

Abstract Background: Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since 2019, and all test results must be discussed by molecular tumor boards (MTBs). More than 60,000 patients have taken the CGP tests at over 200 government-designated hospitals by November 2023. Streamlining decision-making by MTBs and standardizing interpretation of test results is important. We evaluated the performance of Chrovis, an annotation algorithm for reporting CGP tests. Methods: We retrospectively reviewed the reporting process of all approved CGP tests done at The University of Tokyo Hospital and its 12 affiliated hospitals between December 2019 and November 2023. Chrovis referenced several public knowledge databases and used natural language processing to annotate each genetic variant and generated reports using the automated program. The MTB reviewed all reports with the addition of clinical information and made any necessary changes Recommendations on disclosure of germline findings were made in accordance with the national guideline. Results: Among the 2,819 Chrovis reports created, 1,927 were tumor-only FoundationOne CDx (F1CDx), 483 were tumor/normal paired NCC Oncopanel (NOP), and 409 were FoundationOne Liquid CDx (F1Liquid) panels. Among them, 603 changes in 496 reports (17.6% of all reports) were made by the MTB. The most common type of change was germline disclosure with 208 changes (7.4%), followed by clinical trial information (196 changes, 7.0%) and pathogenicity (107 changes, 3.8%). Gene alterations that led to most changes in germline disclosure were TP53, SMAD4, CDKN2A, TERT, and NF2 (42, 22, 16, 13, and 13 changes, respectively). Changes in clinical trial information were frequently observed in TP53, NF1, BRAF, ERBB2, and KRAS (25, 20, 19, 16, and 16 changes, respectively). F1CDx required the greatest number of changes (404/1927, 21.0%) followed by F1Liquid (53/409, 13.0%) and NOP (39/483, 8.1%) (p &amp;lt; 0.001). Changes to germline disclosure were made in 9.1% of F1CDx reports, 5.4% of F1Liquid reports, and 2.1% of NOP reports (p &amp;lt; 0.001). Changes to clinical trial information were made in 8.3%, 4.4%, and 3.9%, respectively (p &amp;lt; 0.001). Conclusions: Chrovis-generated CGP reports did not require any changes in 82%s, suggesting that artificial intelligence reporting may lessen the burden of MTBs while contributing to its standardization. Recommendation for germline disclosure requires manual supervision, and improvements in clinical trial databases are required to correctly recommend genomically matched trials to patients. Citation Format: Hidenori Kage, Takashi Aoki, Aya Shinozaki-Ushiku, Kousuke Watanabe, Nana Akiyama, Hideaki Isago, Miho Ogawa, Kazunaga Ishigaki, Hiroshi Kobayashi, Takuya Miyagawa, Jun Omatsu, Yuki Saito, Kazuhito Sasaki, Yasuyoshi Sato, Yusuke Sato, Nobumi Suzuki, Shota Tanaka, Motohiro Kato, Masahiko Tanabe, Kenji Tatsuno, Tetsuo Ushiku, Kunihiro Nishimura, Hiroyuki Aburatani, Katsutoshi Oda. Use of artificial intelligence to facilitate reporting of comprehensive genomic profiling tests [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2933.

Abstract 5036: Analytical and clinical validity of Northstar Select, a quantitatively enhanced liquid biopsy assay for comprehensive genomic profiling of solid tumors

Abstract Background: Liquid biopsy assays have emerged as vital tools in precision oncology. Among these assays, Comprehensive Genomic Profiling (CGP) tests in particular have improved treatment selection for late-stage solid tumor cancer patients by allowing for the detection via circulating tumor DNA (ctDNA) of somatic mutations in the tumor, many of which have corresponding targeted therapies. However, technical restrictions in the performance of such tests have limited their utility when ctDNA signal is low. BillionToOne’s Northstar Select assay is a new CGP test that achieves increased performance by addressing these limitations. Innovation: By using Quantitative Counting Template (QCT) technology, Northstar Select is able to track the yield of multiple processing steps, contributing to the higher sensitivity of the assay by maximizing the number of decoded molecules after sequencing. In addition, it employs chemistry and panel design optimizations, as well as novel algorithms for SNV, indel, CNV, fusion, and MSI calling to increase sensitivity and specificity. Analytical Performance: The performance of Northstar Select surpasses that of other commercially available tests for multiple mutation types, detecting more pathogenic and actionable mutations at low tumor DNA fraction while maintaining similarly high specificity. In analytical validation (N=103), limit of detection was determined to be 0.13-0.16% variant allele fraction (VAF) for SNVs and indels, 2.11 copies for copy number amplifications, 1.8 copies for copy number losses, 0.35% VAF for fusions, and 0.07% tumor fraction for MSI. Clinical Performance: Northstar Select was determined to have high clinical utility as well, with a study of clinical samples (N=481) from a variety of tumor types yielding &amp;lt;2% of reports with 0 mutations detected. A head-to-head comparison with other commercial liquid biopsy assays on a subset of the clinical samples (N=192) showed that the assay detected 115 additional pathogenic mutations in total, leading to a higher proportion of patients with at least one pathogenic mutation detected (90%) compared to comparators (79%). Conclusion: These results demonstrate that the Northstar Select assay is an innovative and high-performing diagnostic for treatment selection in oncology, leveraging quantitative approaches in process design, chemistry, and bioinformatics to offer superior analytical and clinical performance compared to the current landscape of liquid biopsy CGP tests. Citation Format: Xavier Bower, Jan Wignall, Joyce Zhu, Naomi Searle, Matthew Varga, Emilio Rosas-Linhard, Jason Luong, Esther Lin, Marie Simon, John ten Bosch, Wen Zhou. Analytical and clinical validity of Northstar Select, a quantitatively enhanced liquid biopsy assay for comprehensive genomic profiling of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5036.

Abstract 3889: Genomic landscape of gynecologic cancers with poor prognosis in Japan, an analysis of the national database of comprehensive genomic profiling tests

Abstract Objective: Comprehensive genomic profiling (CGP) tests were approved in Japan in June 2019 under universal health insurance coverage for cancer patients who have finished (or almost finished) standardized treatment. All the data are collected to the “Center for Cancer Genomics and Advanced Therapeutics (C-CAT)” under written informed consent. Up to date, over 60,000 CGP data have been deposited with a 99.7% consent rate. This study aims to analyze mutational landscape of gynecologic cancers, especially with poor prognosis, by using this database. Methods: We analyzed CGP datasets from 3,006 gynecologic cancer patients using FoundationOne® CDx (F1CDx), the most commonly tested in Japan. This study was ethically approved by our institutional ethics committee (#2021341G) and the Information Utilization Review Board of C-CAT (#CDU2022-026N). Results: Endometrial cancers (n=561) showed high rates of tumor mutational burden-high (TMB-H) (13.9%) and MSI-high (MSI-H) (10.8%), especially in endometrioid carcinomas. POLE exonuclease mutations were less frequent (1.4%) compared to TCGA data (7%), while TP53 mutations were more common (54.4% vs. 29% in TCGA), suggesting the impact of prognosis of the molecular subtypes. Other frequently mutated genes included PIK3CA (41%), PTEN (35%), ARID1A (31%) and KRAS (26%). In 839 cervical cancers, TMB-H prevalence was 14.2%, with low MSI-H at 1.5%. TMB-H was significantly higher in squamous cell carcinomas (20.6%) than adenocarcinomas (8.3%). Frequent mutations included PIK3CA (32%), STK11 (20%), TP53 (20%), KRAS (14%), and CDKN2A (11%). TP53 mutations were significantly higher than TCGA data (&amp;lt;5%), particularly in mucinous carcinomas (60%), indicating a prevalence of HPV-independent tumors with poorer prognosis. Actionable mutations were generally more frequent in adenocarcinomas than in squamous cell carcinomas, including KRAS (32.2%), TP53 (29.4%), CDKN2A (18.3%), and ERBB2 (16.7%). In 1,606 ovarian cancers, the ratio of TMB-H was 5.0%, and MSI-H was 1.2%. TMB-H rates varied between 3.3-6.5% across histological types, while the ratio of MSI-H was significantly lower in serous carcinomas (0.3%) than non-serous carcinomas. Pathogenic mutations in the POLE exonuclease domain were rare in cervical (0.0%) and ovarian (0.2%) cancers. Conclusion: The C-CAT database offers insights into the mutational landscape of various cancers and histological subtypes, especially those with poor prognosis, highlighting the unmet needs for drug development in these gynecologic cancers. Citation Format: Qian Xi, Hidenori Kage, Miho Ogawa, Asami Matsunaga, Akira Nishijima, Kenbun Sone, Kei Kawana, Katsutoshi Oda. Genomic landscape of gynecologic cancers with poor prognosis in Japan, an analysis of the national database of comprehensive genomic profiling tests [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3889.

Abstract 2555: Real-world data analysis of comprehensive genomic profiling using plasma samples from non-small cell lung cancer patients

Abstract Introduction: Comprehensive genomic profiling (CGP) tests which use plasma samples can detect driver mutations and are recommended when tissue samples are unavailable. Multiple studies have shown that plasma CGP tests can result in genomically matched treatment for cancer patients, especially in gastrointestinal cancer. However, data for non-small cell lung cancer (NSCLC) remain limited. Methods: We searched the database of the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), which comprised 99.7% of the CGP data under insurance coverage in Japan. NSCLC patients analyzed with FoundationOne Liquid CDx (F1LCDx) between August 1 2021 to July 31 2023 were included, all of whom were previously treated. Result: 694 patients with NSCLC underwent liquid biopsy. Among them, 572 cases were adenocarcinoma, and 71 were squamous cell carcinoma. The median age was 68 years (range: 24-93), and 423 patients were male. Pathogenic or likely pathogenic EGFR mutations, ALK rearrangements, ROS1 rearrangements, MET exon 14 skipping mutations, BRAF V600E, RET fusions, ERBB2 mutations, and KRAS G12C were detected in 174 cases (25.1%), 18 cases (2.6%), 2 cases (0.3%), 9 cases (1.3%), 3 cases (0.4%), 7 cases (1.0%), 26 cases (3.7%) and 17 cases (2.4%), respectively. Among the 499 patients without known driver mutations, driver mutations were detected by F1LCDx in 60 patients (12.0%). The detection rate of each driver oncogene is shown in Table 1. Conversely, among the 174, 20, 9 and 3 patients with known EGFR, ALK, ROS1, or BRAF V600E alterations, F1LCDx showed false negative results in 48 (27.6%), 10(50.0%), 8 (88.9%), and 3 cases (100%) (EGFR/BRAF vs. ALK/ROS1, p = 0.001), respectively. Conclusion: In patients without known driver oncogenes, mutations associated with approved therapeutic implications were detected in 12.0%. The detection of gene rearrangements using liquid biopsy may be limited compared with genetic mutations. Genomic profiling detected by FoundationOne Liquid CDx Cases (%) EGFR, known EGFR, unknown ALK, known ALK, unknown ROS1, known ROS1, unknown BRAF V600E, known BRAF V600E, unknown Detected by F1LCDx 126 (72.4) 48 (9.2) 10 (50.0) 8 (1.2) 1 (11.1) 1 (0.15) 0 3 (0.43) Undetected by F1LCDx 48 (27.6) 472 (90.8) 10 (50.0) 666 (98.8) 8 (88.9) 684 (99.9) 3 (100) 688 (99.6) Total 174 520 20 674 9 685 3 691 Citation Format: Momoko Morishita, Koki Fujii, Michiko Ueki, Hiroaki Ikushima, Hideaki Isago, Kousuke Watanabe, Katsutoshi Oda, Hidenori Kage. Real-world data analysis of comprehensive genomic profiling using plasma samples from non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2555.

Evaluation of pancreatic cancer specimens for comprehensive genomic profiling.

Inadequate specimen quality or quantity hinders comprehensive genomic profiling in identifying actionable mutations and guiding treatment strategies. We investigated the optimal conditions for pancreatic cancer specimen selection for comprehensive genomic profiling. We retrospectively analyzed 213 pancreatic cancer cases ordered for comprehensive genomic profiling and compared results from pancreatic biopsy, liver biopsy of pancreatic cancer metastases, pancreatectomy, liquid, and nonliver metastatic organ specimens. We examined preanalytical conditions, including cellularity (tumor cell count/size). The successfully tested cases were those that underwent comprehensive genomic profiling tests without any issues. The successfully tested case ratio was 72.8%. Pancreatic biopsy had the highest successfully tested case ratio (87%), with a high tumor cell percentage, despite the small number of cells (median, 3425). Pancreatic biopsy, liver biopsy of pancreatic cancer metastases, and non-liver metastatic organ had higher successfully tested case ratios than that for pancreatectomy. Liver biopsy of pancreatic cancer metastases and pancreatectomy cases with tumor size (mm2 ) × tumor ratio (%) > 150 and >3000, respectively, had high successfully tested case ratios. The success of comprehensive genomic profiling is significantly influenced by the tumor cell ratio, and pancreatic biopsy is a potentially suitable specimen for comprehensive genomic profiling.

An approach for improvement of the accuracy of cancer gene panel testing.

Tissue-based comprehensive genomic profiling (CGP) is increasingly being employed for genotype-directed therapies in patients with advanced cancer. However, tissue availability may limit their potential applications. In Japan, the cost of cancer gene panel tests is covered by public insurance for patients diagnosed with advanced solid tumors once in their lifetime. Therefore, it is essential to improve the success rate (reportability) and accuracy of CGP tests. The purpose of this study was to identify the factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data. This study included 159 samples analyzed using tumor-only panel FoundationOne® CDx cancer genome profiling (F1CDx) and 85 samples analyzed using matched-pair panel OncoGuide™ NCC Oncopanel system (NCCOP) at St. Marianna University Hospital. Sample characteristics (fixation conditions, storage period, histology, tumor cell ratio, and genomic tumor cell content), CGP performance, and quality control status were evaluated across all 244 tested samples. In 237/244 samples (97.1%), CGP testing results were successfully obtained [F1CDx, 99.4% (158/159) and NCCOP, 92.9% (79/85)]. An increased number of fibroblasts, inflammatory cells, and necrotic tumor cells, long-term storage, and/or prolonged fixation of tissue sections were involved in the unreported results and/or qualified CGP results. In addition, a negative correlation between median insert size values and ΔΔCq was observed in the NCCOP system. We identified various factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data, suggesting that thorough selection and preparation of tissue sections could optimize CGP and maximize useful information.

Real-world data on the comprehensive genetic profiling test for Japanese patients with metastatic castration-resistant prostate cancer.

comprehensive genomic profiling test has been covered by Japanese health insurance since June 2019. However, no real-world data on the test have been reported with a focus on Japanese patients with prostate cancer. we retrospectively reviewed the data of 45 consecutive patients with metastatic castration-resistant prostate cancer, who underwent the comprehensive genomic profiling tests at Kitasato University Hospital between August 2019 and December 2022. Patients' characteristics, prevalence of gene alterations and therapeutic impact of genotype-matched therapy were assessed. genomic data were obtained using a tissue-based test (n=32) and liquid-based test (n=13). Actionable genomic alternations were identified in 51.1% of patients, and 22.2% were treated with genotype-matched therapy. The main reason for not receiving genotype-matched therapy was disease progression, accounting for 46.2% (6/13). Kaplan-Meier analysis showed significantly longer overall survival after the comprehensive genomic profiling tests in patients with genotype-matched therapy under public insurance (17.8%, n=8) than those without it (median: not reached vs. 18.1months; P=0.003). Five (62.5%) out of the eight patients with genotype-matched therapy under public insurance had BRCA1 or 2 deleterious alteration. Multivariate analyses showed that BRCA deleterious alteration (17.8%, n=8) was an independent risk factor for shorter time to castration-resistant prostate cancer (hazard ratio: 2.46, 95% confidence interval: 1.04-5.87; P=0.041), and no patients with the alteration had ≤5 bone metastases. the results of this study showed the promising survival outcomes in patients with genotype-matched therapy under public insurance, even in the castration-resistant prostate cancer setting. Further detection of promising therapeutic target gene is expected to increase the number of patients who reach genotype-matched therapies.

Disease characteristics, survival outcomes, and tumor molecular landscape in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) harboring CDK12 alterations (CDK12a) receiving intensified androgen deprivation therapy (ADTi).

189 Background: CDK12 is one of the homologous recombination repair ( HRR) genes involved in genomic stability. The presence of CDK12a has been associated with worse survival outcomes in pts with metastatic prostate cancer [PMID: 32988971; 32462107]. However, the impact of CDK12a on outcomes in pts with mHSPC undergoing ADTi with doublets has never been reported. Herein, we sought to assess this impact while evaluating disease characteristics and tumor molecular landscape. Methods: This was a retrospective IRB-approved study. Eligibility: pts with mHSPC undergoing ADTi with either docetaxel or an androgen receptor pathway inhibitor (ARPI) (i.e., abiraterone, enzalutamide, apalutamide) harboring pathogenic CDK12a on comprehensive genomic profiling (CGP) of primary prostate tissue, metastatic lesion, or on cell-free DNA. Descriptive statistics were used for clinical features and survival outcomes. Optimal PSA response (PSA-R) was defined as PSA ≤ 0.2 ng/ml. Progression-free survival (PFS) was defined from the start of therapy for mHSPC to progression (per PCWG-3) or death from any cause. Overall survival (OS) was defined from treatment initiation for mHSPC to death from any reason or censored at the last follow-up. Concurrent genomic alterations with a frequency ≥ 10% were reported. Results: Of 323 pts with mHSPC receiving ADTi doublet with CGP testing, 19 pts harbored CDK12a and were included. The median age at diagnosis was 66.1 (56 – 77), with 63.2% of pts receiving ADTi with an ARPI. Baseline characteristics are summarized in the Table. Overall, 7 pts (36.8%) achieved an optimal PSA-R by 6 months (mo). The median PFS was 18.8 mo (95% CI 4.2 – 33.4 mo), and the median OS was 33.1 mo (95% CI 9.5 – 56.7 mo). CGP was performed on primary tissue (84.2%), followed by metastatic lesion (10.5%) and blood (5.3%). PIK3CA and TP53 were the most frequent associated genomic alterations (15.8%), followed by ARID1A, CTNNB1, RB1, and TMPRSS2 (10.5%). Conclusions: This is the first real-world study to report outcomes of pts with mHSPC and tumor CDK12a undergoing ADTi with doublets. We show these pts to have inferior outcomes than those enrolled in the registration trials of mHSPC with ADTi. Upon external validation in larger cohorts, these hypothesis-generating data may guide future clinical trial design for these pts, their preferential selection for trials, and counseling and prognostication in the clinic. [Table: see text]

Patient survey on cancer genomic medicine in Japan under the national health insurance system.

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy.