Comprehensive Genomic Profiling Testing Research Articles

Current Clinical Practice of Precision Medicine Using Comprehensive Genomic Profiling Tests in Biliary Tract Cancer in Japan.

With the recent advances of next generation sequencing technologies, comprehensive genomic profiling (CGP) tests, which are designed to measure more than hundreds of cancer-related genes at a time, have now been widely introduced into daily clinical practice. For the patients whose tumor samples are not fit for tissue-based CGP tests, a blood-based CGP test (liquid biopsy) is available as an alternative option. Three CGP tests, “OncoGuide NCC™Oncopanel System (124 genes)”, “FoundationOne®CDx (324 genes)”, and “Founda-tionOne®CDx Liquid (324 genes)”, are now reimbursed by public insurance in 233 hospitals designated for cancer genomic medicine in Japan. In biliary tract cancer, the prevalence of druggable variants is relatively higher compared to other cancer types and the European Society for Medical Oncology recommends routine use of CGP tests for advanced biliary tract cancer to guide treatment options. The latest National Cancer Center Network guideline lists eight druggable markers (NTRK fusion, MSI-H, TMB-H, BRAF V600E, FGFR2 fusions/rearrangement, IDH1 mutations, RET fusion, and HER2 overexpression) and matched therapies. In Japan, matched therapies for four markers (NTRK, MSI-H, TMB-H, and FGFR2) are reimbursed by public insurance (as of September 2022). The progress of genomic profiling technology will contribute to the improvement of the dismal clinical outcomes of this disease in the future.

Clinical utility of comprehensive genomic profiling tests for advanced or metastatic solid tumor in clinical practice.

Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p=0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p=0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers.

Real-World Comprehensive Genomic Profiling Success Rates in Tissue and Liquid Prostate Carcinoma Specimens.

Challenges with sequencing tissue samples from patients with prostate cancer have been reported in clinical trials. To assess the success rate of comprehensive genomic profiling (CGP) for prostate cancer patients, we analyzed a real-world cohort who underwent sequencing of their prostate tissue sample as well as a subset of patients with a reflex liquid biopsy. Overall, a significant majority (82%) of tissue prostate carcinoma samples yielded reportable CGP results. Of those samples that were unsuccessful, most (75%) were inadequate samples that did not meet pre-established criteria to advance into sequencing. For cases where liquid CGP was performed if tissue CGP was unsuccessful, mutations that were likely attributable to prostate carcinoma were observed in most cases and all cases were successful in generating a report. These results suggest that, for CGP testing, prostate cancer tissue is a reasonable matrix type and that liquid samples can be effectively used as an alternative to tissue.

Chronological improvement in precision oncology implementation in Japan.

In Japan, comprehensive genomic profiling (CGP) tests for refractory cancer patients have been approved since June 2019, under the requirement that all cases undergoing CGP tests are annotated by the molecular tumor board (MTB) at each government-designated hospital. To investigate improvement in precision oncology, we evaluated and compared the proportion of cases receiving matched treatments according to CGP results and those recommended to receive genetic counseling at all core hospitals between the first period (11 hospitals, June 2019 to January 2020) and second period (12 hospitals, February 2020 to January 2021). A total of 754 and 2294 cases underwent CGP tests at core hospitals in the first and second periods, respectively; 28 (3.7%) and 176 (7.7%) patients received matched treatments (p< 0.001). Additionally, 25 (3.3%) and 237 (10.3%) cases were recommended to receive genetic counseling in the first and second periods, respectively (p< 0.001). The proportion was associated with the type of CGP test: tumor-only (N= 2391) vs. tumor-normal paired (N= 657) analysis (10.0% vs. 3.5%). These results suggest that recommendations regarding available clinical trials in networked MTBs might contribute to increasing the numbers of matched treatments, and that tumor-normal paired rather than tumor-only tests can increase the efficiency of patient referrals for genetic counseling.

EP16.02-003 Real World Experience and Feasibility of Tissue Informed CGP and ctDNA Testing in a Cohort of NSCLC Patients

Circulating tumor DNA (ctDNA) analysis is a promising approach for treatment response monitoring in patients with NSCLC. Additionally, comprehensive genomic profiling (CGP) is playing an integral role in the optimal management of this disease across stages. In this study, we analyzed patients with stage I-IV NSCLC who underwent serial monitoring with a personalized, tumor-informed ctDNA assay with or without concomitant CGP, with a focus on real-world feasibility and clinical utility.

An Overview of Comprehensive Genomic Profiling Technologies to Inform Cancer Care

&#x0D; Horizon Scan reports provide brief summaries of information regarding new and emerging health technologies; Heath Technology Update articles typically focus on a single device or intervention. This Horizon Scan summarizes the available information regarding emerging comprehensive genomic profiling (CGP) technologies for informing cancer treatments.&#x0D; These technologies are based on next-generation sequencing platforms, which can characterize up to hundreds of genes and other genomic information with a single sample. Emerging tests are also compatible with minimally invasive liquid biopsies that use fluids such as blood samples to support clinical decision-making. CGP could be an alternative or a complement to conventional testing that uses single-biomarker assays or limited gene panels.&#x0D; Some emerging CGP tests available in Canada, the US, and Europe are being considered to inform the treatment of non–small cell lung cancer (NSCLC) because it has the highest number of identified biomarkers. Most identified studies have examined CGP use with NSCLC.&#x0D; The emerging evidence about the clinical and cost-effectiveness of CGP technologies for either NSCLC or other cancer types remains uncertain. Without randomized trials and robust study designs, it is not yet well-established whether the additional costs and technical requirements of CGP may provide better clinical outcomes compared with conventional molecular testing.&#x0D; This Horizon Scan also provides considerations for health systems about testing infrastructure, training for health care professionals, and understanding different patients’ perspectives should CGP or other next-generation sequencing technologies become more widely used in Canada.&#x0D;

PSY4-3 Discussion on the appropriate timing of comprehensive genomic profiling test in Japan

In Japan, the comprehensive genomic profiling (CGP)tests were covered by insurance in June 2019, and more than 23,000 cases have been tested so far. On the other hand, only 8.1% of patients were reported to have received treatment, suggesting that the benefits of CGP test may not be fully utilized. In Japan, CGP tests are indicated for patients with solid tumors who have no standard treatment or who failed all standard treatment (including those expected to failure). This situation has been pointed out that access to drugs may be poor due to the timing of last-line treatment.

ON1-4 Referral patient pathway from distant hospitals in precision oncology

Precision oncology has made progress in recent years and is currently at the heart of revolutionizing cancer research. In May 2019, two comprehensive genomic profiling (CGP) tests were approved with reimbursement in Japan: FoundationOne CDx Cancer Genomic Profile and OncoGuide NCC Oncopanel System, which are fully covered by the national health insurance system. It has been reported that only 3.7% of patients received sequencing-directed therapy (Sunami et al., Int J Clin Oncol, 2021). The Ministry of Health, Labor and Welfare reported that in 2021, only 8.1% of patients received sequencing-directed therapy after CGP tests.

PSY4-2 Prospective of patient-proposal healthcare services with multiple targeted agents

Since June 2019, 3 comprehensive genomic profiling (CGP) tests have been covered by public medical insurance in Japan, and a body of cancer genomic medicine has been establishing such 12 designate core hospitals throughout Japan. However, when genomic abnormalities are detected by CGP tests, some patients can't receive treatments due to the lack of molecular targeted drugs to be covered by public medical insurance for the diseases. It has been our urgent issue. In October 2019, we started a basket/umbrella-type clinical trial based on the result of CGP test (NCCH1901).

Comprehensive genomic profiling in advanced/metastatic colorectal cancer: number needed to test and budget impact of expanded first line use

Aims Use of comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC) is limited. We estimated impacts of expanded 1 L CGP, using the Tempus xT test, on detection of actionable alterations and testing budgets in a modeled US health plan over two-years. Materials and methods A decision analytic model was developed to estimate the impact of replacing 20% of usual testing (a mix of CGP and non-CGP) with Tempus xT CGP. Actionable alterations for matched treatments or clinical trial included KRAS, NRAS, RAF, BRAF, deficient mismatch repair (dMMR)/microsatellite instability (MSI), NTRK, RET, EGFR, HER2, MET, PIK3CA and POLE1. Costs included initial and repeat testing, physician-associated and administrative costs. Results In a hypothetical five-million-member plan, 50% Medicare and 50% commercial, 1,112 new cases of mCRC were expected per year. Of these, 566 (51%) would undergo 1 L molecular testing, with 55 re-tested upon progression. Based on current testing rates, there were an expected 521 missed opportunities for genomically informed treatment (47% of new cases), with 442 missed due to lack of testing and 79 due to testing without CGP. Replacing 20% of usual testing with Tempus xT CGP was associated with up to a $0.003 per member per month testing cost increase (net total cost of $202,102 for the five-million-member plan) and 15.5 additional patients with an opportunity for genomically informed care (12.7 patients for treatment and 2.8 for clinical trial). The testing total cost (initial test, repeat test, biopsy and physician services, and administrative cost) to put one additional patient with mCRC on matched therapy or matched clinical trial was estimated to be $13,005. Number needed to test to identify one actionable alteration with Tempus xT CGP versus usual testing was 7.8 patients. Limitations Conservative assumptions were made for inputs with limited evidence. Based on high concordance rates with dMMR/MSI status, tumor mutational burden (TMB) status was not calculated separately. Conclusions Replacing 20% of usual testing with Tempus xT CGP was associated with a small incremental testing cost and can identify meaningfully more actionable alterations.

Abstract 5735: Druggable gene alterations in Japanese patients with rare malignancy

Abstract Background: In the absence of a current standard of care, precision oncology with next-generation sequencing provides an important therapeutic option for patients with rare malignancy. Here, we sought to establish the clinical relevancy of comprehensive genomic profiling (CGP) for patients with rare malignancy. Methods: We reviewed 341 patients who underwent CGP (FoundationOne CDx; OncoGuide NCC OncoPanel System)in our institution between 2019 and 2021. Cases were classified as common or rare malignancy based on the Rare Cancers in Europe (RARECARE) definition (incidence of &amp;lt;6 cases per 100,000 individuals). We analyzed the genomic features in the rare malignancy cohort, including gene mutations, gene fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Gene variants, amplifications, and fusions categorized as evidence level A using Clinical Interpretations of Variants in Cancer (CIViC) and MD Anderson Knowledge Base for Precision Oncology were considered as druggable alterations. CGP testing was used to calculate overall survival (OS) to death or at the last follow-up. Results: With the exception of 7 unclassifiable cases, rare malignancy accounted for 149 of the 334 cases (45%), with the most common being female genital cancers (32%), followed by digestive cancers (24%), sarcoma (16%), and others (28%). Many (83%) of the patients with rare malignancy harbored at least one pathogenic/likely-pathogenic variant. The commonly mutated genes were TP53 (41%), PIK3CA (20%), ARID1A (14%), and KRAS (13%). ERBB2amplification was detected in 6% of patients (median copy number, 8). Gene fusion in EWSR1 was found in 4% of patients (sarcoma) and in FGFR2 in 1% (cholangiocarcinoma and salivary duct carcinoma). TMB-high (≥10 mut/Mb) and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 36 patients; this percentage was not significantly different to that of common malignancy (24% vs. 17%, P=0.10). The common druggable alterations were BRAF V600E (n=10), ERBB2 amplification (n=9), PIK3CA E542K (n=6), and BRCA1/2 variant (n=6). There was no significant difference in OS between the rare and common malignancy groups (1-year OS rate: 62% vs. 46%, P=0.24). Conclusion: In this study, the ratio of rare malignancy was higher than that typically found in previous epidemiological studies (about 20%-25%). We observed no adverse impact for OS, which might be due to the high number of patients (n=48) with intractable pancreatic cancer. Remarkably, &amp;gt;20% of patients harbored a potential druggable alteration. Our results suggest the clinical relevance of CGP for patients with rare malignancy, and its potential utility to provide clues for future clinical development. Citation Format: Akihiro Ohmoto, Naomi Hayashi, Ippei Fukada, Masumi Yamazaki, Mayu Yunokawa, Akiyoshi Kasuga, Eiji Shinozaki, Arisa Ueki, Akiko Tonooka, Kengo Takeuchi, Seiichi Mori, Kazuma Kiyotani, Shunji Takahashi. Druggable gene alterations in Japanese patients with rare malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5735.

Identification of clinically actionable biomarkers via routine comprehensive genomic profiling across a large community health system.

e15035 Background: Precision therapies and immunotherapies have revolutionized cancer care, with novel genomic biomarker-associated therapies being introduced into clinical practice rapidly. We assessed the utility of comprehensive genomic profiling (CGP)-based testing for identifying biomarkers associated with approved therapies, and therapies in precision medicine basket clinical trials (CT) across a large cohort of advanced cancer patients in the Providence health system. Methods: Advanced cancer patients were tested utilizing the Providence CGP workflow between 2019-2021. Clinical actionability was assessed for CGP and compared with results from an in silico 50-gene panel based on a previously utilized lab-developed test at Providence. Clinical actionability was assessed based on OncoKB and alterations were assigned as: FDA recognized (Level 1), standard of care (Level 2), FDA approved/investigational drug in another indication or having compelling clinical evidence (Level 3). CT matching was assessed based on enrollment criteria for ASCO-TAPUR, NCI-MATCH and My Pathway CTs at time of testing. Pooled electronic medical record and genomic data were curated and standardized. Results: Of the 3,218 advanced cancer patients tested with CGP, 52% were female, 80% were white, and median age was 67 years. Across 31 tumor types, the most commonly tested were lung (26%), bowel/colon (16%), and breast (9%). Overall, 48% of patients tested with CGP harbored at least one actionable biomarker (OncoKB Levels1/2/3). Clinical actionability was significantly higher in the CGP cohort compared to the in silico cohort based on presence of at least one Level 1 biomarker (45% vs. 19%, p &lt; 0.001). CGP cohort had higher proportion of patients with multiple/co-occurring Level 1 biomarkers compared to in silico cohort (20% vs. 9%, p &lt; 0.001). Of the most prevalent tumor types, 57% lung, 94% bowel/colon, and 37% breast had Level 1 alterations with CGP testing. Notably, 49% of CGP cohort vs. 23% in silico cohort (p &lt; 0.001) harbored a biomarker matching to one or more arms of the three basket CTs. Conclusions: CGP and small panel testing can both identify patients eligible for approved therapies and/or basket CTs with CGP having significantly higher clinical actionability and CT eligibility. We expect value of CGP to increase as biomarker actionability transforms clinical practice.

Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study.

e21114 Background: Biomarker testing for patients with aNSCLC includes testing for specific alterations in single genes, hotspot multigene panels, or CGP. Historically, CGP has been used following progression on early lines of systemic therapy to identify genomic alterations not captured by single-gene/hotspot testing, or to determine clinical trial(CT) eligibility. We compared the proportion of patients with genomic alterations for which FDA has approved targeted therapies(TT) (actionable alterations) identified through CGP vs. single-gene/small panel(“small panel”) testing in the real-world setting. Methods: In a retrospective study, patients initially diagnosed-with/progressed-to aNSCLC between 1/1/2015-12/31/2020, treated in the US community health setting, were categorized based on small panel or CGP testing. Patients were followed until the earliest of last contact/death/study-end on 9/30/2021. Testing between 30 days prior to initial NSCLC diagnosis and end of follow-up was used to determine actionability based on OncoKB levels, and eligibility for two basket-CTs(ASCO-TAPUR, NCI-MATCH). Results: Of 7,242 aNSCLC patients in this study, 5,154 (72%) received molecular testing (50% only small panel; 14% CGP; and 7% with an unknown size panel), 22% of patients remained untested and 7% were tested for only PD-L1. Among CGP-tested patients evaluated for tumor mutational burden (TMB), 18% were classified as TMB-High. &gt; 75% of patients presented with advanced cancer at initial diagnosis, 51% were female, 50% were White, and median age was 68 years. Molecular testing rate increased from 9% to 20%(CGP) and 42% to 51%(small panel) between 2015–2020. The proportion of patients with ≥1 actionable biomarker was significantly higher with CGP than small panels (34%vs.15%; p &lt; 0.001). Of tested patients. the proportion of CT eligible patients was also significantly greater for CGP than small panels (56%vs.4%; p &lt; 0.001). The proportion of tested patients that received an FDA-approved TT or immunotherapy(IO) within 30 days of testing was higher in CGP cohort compared to small panel (9%vs.3%; p &lt; 0.001). Conclusions: Although rates of CGP and small panel testing are increasing over time, overall molecular testing remains underutilized, and the proportion of patients who received TT/IO post-testing is low. Use of CGP is associated with higher identification of actionable biomarkers and patients receiving TT/IO, and CT eligibility.

Pathogenic fusion detection in solid malignancies utilizing RNA-DNA based comprehensive genomic profiling (CGP) testing.

3078 Background: Gene fusions caused by chromosomal rearrangements comprise a key category of oncogenic driver mutations. However, given the diverse array of potentially novel loci where each proto-oncogene can translocate, many assays including DNA-based CGP have technical limitations that disallow the detection of all relevant fusion partners potentially leading to false negatives. Hybrid Capture RNA sequencing renders a more comprehensive evaluation of genes and allows detection of novel and known fusion partners. Here we assessed the impact of utilizing in-house CGP testing with a paired RNA-DNA hybrid assay in the identification of pathogenic fusions and their potential clinical actionability for patients with solid tumors across a large US health system. Methods: Patients in the Providence health system diagnosed with advanced solid tumor malignancies over a two-year period (2019-2021) received reflex CGP testing at the time of diagnosis utilizing an internally validated workflow. DNA/RNA sequencing results as well as histology and staging information were curated from deidentified electronic medical records and in-house databases, and tumor types were mapped to OncoTree tissue categories. Potential clinical actionability was assessed based on OncoKB therapeutic levels 1-3 and clinical trial eligibility matched to the biomarker inclusion criteria for ASCO TAPUR, NCI-MATCH and MyPathway studies (both without time limits and at time of testing). Results: The median patient age at diagnosis was 67 years, 52% of patients were female, and the majority (80%) were white. Across all tested advanced solid tumors, 6.7% (217/3218) were found to harbor a pathogenic fusion. The tumor types most enriched in this set of pathogenic fusions were prostate (30%), lung (27%), CUP (10%) and breast (9%). 29% (n = 64) of the identified pathogenic fusions were identified as actionable based on OncoKB criteria (levels 1-3), and 31% (n = 69) matched to one or more arms in the ASCO TAPUR, NCI-MATCH or MyPathway basket clinical trials. The most frequent actionable fusion driver genes identified were ALK (12%), FGFR 1-3 (12%), RET (7%) NTRK 1-3 (3%), and ROS1 (2%) and a subset of these key drivers were fused with novel gene pairs. A subset of fusions co-occurred with other targetable biomarkers, with the most common comprising tumor mutational burden high (TMB-H) (13%), PIK3CA (7%) and high microsatellite instability (MSI-H) (2%). Conclusions: In-house CGP testing utilizing an RNA-DNA based assay identified actionable fusion targets across tumor types, with many novel fusion partners that may be undetectable by prior generation sequencing assays. While many of these actionable targets are rare individually, the expanding totality of actionable gene alterations supports the growing utility of CGP for identifying patients who are candidates for approved targeted therapies and clinical trials.

Impact of learning program on treatment recommendations by molecular tumor boards and an artificial intelligence-based annotation system: A prospective study.

11032 Background: Treatment recommendations (TRs) by molecular tumor boards (MTBs) based on comprehensive genomic profiling tests are crucial for enrolling cancer patients in genotype-matched trials. Our previous study of Japanese designated ‘Core’ hospitals using simulated cases showed that TRs for biomarkers with high evidence levels (ELs) were highly concordant between central consensus and MTBs, whereas those with low ELs showed low concordance, indicating that a learning program (LP) about obtaining information on matched trials, particularly for those with low ELs, is needed to improve the quality of TRs by MTBs (Kage H. ESMO 2021). Therefore, we conducted a nationwide prospective study to investigate the clinical utility of an LP for MTBs in designated ‘Hub’ hospitals and explore the efficacy of an artificial intelligence (AI)-based annotation system. Methods: Fifty simulated cases were randomly divided into 2 groups (pre- and post-tests) by the central statistician, stratified by high vs. low ELs. Each MTB at ‘Hub’ hospitals (group), treating physicians at ‘Core’ hospitals (individual), and an AI company were eligible. Each participant made TRs for the first 25 cases, then participated in the LP, and made TRs for the second 25 cases. The online LP shared the methodology of making the optimal TRs and showed central consensus TRs for simulated cases. The primary endpoint was the proportion of MTBs that met prespecified ‘accreditation’ criteria for the second 25 cases: &gt; 90% concordance for high ELs and &gt; 40% for low ELs. Expected and threshold proportions of ‘accreditation’ MTBs were 50% and 20%, respectively, and the planned sample size was 24 MTBs. The improvements in concordance rates in TRs on post-tests were key secondary endpoints. The concordance rate of TRs with the AI system was an exploratory endpoint. Results: From May to December 2021, 47 participants applied, and 42 (27 MTBs, 14 individuals, and an AI company) were eligible. The primary ‘accreditation’ rate of MTBs was 55.6% (95% CI, 35.3-74.5%, p &lt; 0.001), and the ‘accreditation’ rate of individuals was 35.7% (95% CI, 12.8-64.9%, p = 0.17). TR concordance rates improved significantly, from 57.5% (95% CI, 51.7-63.1%) to 65.7% (95% CI, 59.2-71.6%) [odds ratio (OR): 1.23, p = 0.04]. A prespecified subgroup analysis showed an improved concordance rate for biomarkers with low ELs for MTBs (OR, 1.32: 95% CI, 1.00-1.73), but not for individuals (OR, 1.11: 95% CI, 0.75-1.63). TR concordance rates with the AI system were 80% (95% CI, 60.0-91.4%) and 84% (95% CI, 64.3-93.9%) for pre- and post-tests, respectively. Conclusions: This LP significantly improved the quality of TRs by MTBs, potentially leading to providing more matched trials to cancer patients. TRs by the AI system showed higher concordance with central consensus TRs than MTBs, suggesting the clinical utility of AI-based TRs over those by MTBs.

An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for patients with pre-treated, BRCA-mutated, unresectable/recurrent biliary tract, pancreatic, and other gastrointestinal cancers (NIR-B trial).

TPS4174 Background: Recent comprehensive genomic profiling tests have revealed therapeutic target molecules. However, because many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. In order to overcome this patient identification barrier, the SCRUM-Japan, nationwide large-scale genomic profiling platform, efficiently has been performed umbrella- and basket-type clinical trials. Among the platforms, we have reported that there are BRCA1/2-mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is an anticancer drug belonging to poly(ADP-ribose) polymerase (PARP) inhibitors. Niraparib has been shown to be selective for PARP1/2, to be more cytotoxic among other PARP inhibitor because of its PARP trapping activity. Methods: This is an investigator-initiated, multicenter, three-cohort phase 2 study. Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (cohort A), pancreatic cancers (cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Primary endpoint is the investigator-assessed objective response rate in each cohort with a threshold-response rate of 10% and an expected response rate of 35%. Key secondary endpoints are progression-free survival, overall survival, disease control rate, duration of response, and safety. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL receive 200 mg of niraparib, orally once daily. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. The trial was initiated in January 2021 with enrollment being ongoing. Thirty-three out of planned 60 patients (cohort A/B/C; 25/25/10, respectively) have been enrolled as of December 2021. Funding: Takeda Pharmaceutical Co., Ltd. Clinical trial information: jRCT2011200023.

The Molecular Landscape of Pancreatobiliary Cancers for Novel Targeted Therapies From Real-World Genomic Profiling.

Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC. To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care. A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden-high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients. We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing.

Clinical Application of Comprehensive Genomic Profiling Tests for Diffuse Gliomas.

Simple SummaryCancer patients suffer from recurrence after the completion of standard treatments and exhaustion of treatment options. The comprehensive genomic profiling test (CGPT) is a platform that enables those patients to access the eligible promising therapeutic agents based on their genomic aberrations, using next-generation sequencing. Though CGPTs have been utilized since 2019 in Japan, only limited findings have been available about their use for glioma patients. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients, especially the clinical actionability, which means the probability of being able to receive appropriate molecular targeting therapeutic agents. In our cohort, the clinical actionability was 18.5%, which was compatible with the results of previous reports for tumors other than glioma. We confirmed that CGPT is also useful for glioma patients, and our result will encourage a future increase of CGPT use in our clinical practices.Next-generation sequencing-based comprehensive genomic profiling test (CGPT) enables clinicians and patients to access promising molecularly targeted therapeutic agents. Approximately 10% of patients who undergo CGPT receive an appropriate agent. However, its coverage of glioma patients is seldom reported. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients in our institution, especially the clinical actionability. We analyzed the genomic aberrations, tumor mutation burden scores, and microsatellite instability status. The Molecular Tumor Board (MTB) individually recommended a therapeutic agent and suggested further confirmation of germline mutations after considering the results. The results of 65/104 patients with glioma who underwent CGPTs were reviewed by MTB. Among them, 12 (18.5%) could access at least one therapeutic agent, and 5 (7.7%) were suspected of germline mutations. A total of 49 patients with IDH-wildtype glioblastoma showed frequent genomic aberrations in the following genes: TERT promoter (67%), CDKN2A (57%), CDKN2B (51%), MTAP (41%), TP53 (35%), EGFR (31%), PTEN (31%), NF1 (18%), BRAF (12%), PDGFRA (12%), CDK4 (10%), and PIK3CA (10%). Since glioma patients currently have very limited standard treatment options and a high recurrence rate, CGPT might be a facilitative tool for glioma patients in terms of clinical actionability and diagnostic value.

Clinical Benefit of Comprehensive Genomic Profiling for Advanced Cancers in India.

PURPOSEComprehensive genomic profiling (CGP) assay is increasingly used in low-middle–income countries to detect clinically relevant genomic alterations despite its clinical benefits not being well known. Here, we describe the proportion of patients with advanced cancer in India who received targeted therapy for an actionable genetic alteration identified on CGP assays.METHODSThis was a multicenter, retrospective cohort study in adult patients with advanced nonhematologic malignancies who underwent a CGP test. If patients received a targeted therapy for ≥ 6 months, they were considered to have obtained a clinical benefit from the medication, whereas those continuing for ≥ 12 months were considered to have attained an exceptional response. Descriptive statistics were used to describe the proportion of patients with subsequent targeted therapy.RESULTSDuring 2019-2020, 12 medical oncologists provided CGP reports for 297 patients; 221 met the inclusion criteria. Patients received a median of two lines (range: 0-5) of prior systemic therapy. On the basis of the CGP assay, 21 patients (10%) received targeted therapy. Among them, 33% was for human epidermal growth factor receptor 2 (HER2) amplification (nonbreast cancer) and 19% for HER2 or epidermal growth factor receptor exon 20 insertion mutation (lung cancer). After excluding patients with HER2 or epidermal growth factor receptor exon 20 insertions, 8% of 217 patients received targeted therapy. In the overall cohort of 221 patients, clinical benefit was seen in nine patients (4%), of whom two were exceptional responders (1%).CONCLUSIONWe observed that in a low-middle–income country setting, 10% of patients received targeted therapy on the basis of CGP assay. Only 4% of patients who underwent CGP testing obtained a clinical benefit.

Abstract P5-13-02: Serially biopsied BRCA1/2 mutant breast tumors frequently acquire alterations in BRCA1, BRCA2, and CREBBP

Abstract Introduction Tumors with alterations in BRCA1 or BRCA2 (BRCAm) are sensitive to poly ADP ribose polymerase inhibitors (PARPi), with significant benefit in ovary, breast, prostate, and pancreatic cancers. Despite strong early responses on PARPi, many patients eventually exhibit relapse. Previous literature has identified BRCA1/2 reversion as a common class of acquired alteration in the resistance setting; however, additional resistance pathways have not been well characterized. Here, we examined 100 BRCAm patients who were profiled with serial biopsy during clinical care to identify possible therapy resistance alterations. Methods Comprehensive genomic profiling (CGP) was carried out in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA). Tissue biopsy CGP was performed on FFPE blocks examining at least 324 genes for all classes of alterations (FoundationOne® and FoundationOne® CDx). Liquid biopsy CGP was performed examining at least 62 genes (FoundationACT®, FoundationOne®Liquid).One hundred breast cancer patients with baseline BRCAm were serially profiled with CGP testing during routine clinical care (n=50 tissue then liquid; n=50 tissue for both tests). As a comparator, we examined 1,294 patients without a baseline BRCAm (BRCAwt) profiled with serial biopsy (n = 585 tissue then liquid; n=709 tissue for both tests). Co-occurrence analyses (Fisher’s exact) were run on the full research dataset, including 12,198 breast-biopsied (local) and 16,586 metastatic-biopsied samples. All classes of genomic alterations were included in the analysis. Results Of the serially biopsied samples, 7.2% (100/1,394) had baseline BRCAm. In patients with baseline BRCAm, acquired alterations were frequently observed in BRCA1/2 (17%), ESR1 (16%), TP53 (15%), MYC (12%), CREBBP (10%), RB1 (9%), PIK3CA (9%), and NF1 (5%). To understand if any of these are specific to the BRCAm population, we compared the milieu of acquired alterations to a serially biopsied BRCAwt cohort (n=1,294). While many of the alterations were common and shared across both cohorts, likely due to endocrine therapy use, acquired alterations in BRCA1, BRCA2, and CREBBP were specifically enriched in the BRCAm population (all p&amp;lt;0.005). Acquired BRCA1/2 mutations were predicted reversion mutations and spanned a range of mechanisms, including large deletion/rearrangement events that remove the exon of the truncal mutation, point mutations that change a nonsense BRCA1/2 to a missense event, upstream indels that revert the frame of the truncal BRCA1/2 event, and splice site mutations that lead to a skipping of the truncal BRCA1/2. Of note, a majority of cases with a reversion involved a rearrangement event (9/17; 53%). For patients with a baseline BRCA1/2 short variant mutation, there was a trend towards a higher rate of reversion in BRCA2 v BRCA1 (23.1% v 18.5%, p&amp;gt;0.05). Acquired BRCAm were never observed in cases with baseline deletion of BRCA1/2. The high rate of acquired CREBBP alterations was specific to the BRCAm population (10% BRCAm v 1% BRCAwt; p = 0.0013), suggesting a possible role for CREBBP in platinum or PARPi resistance. Consistent with this, BRCAm and CREBBP significantly co-occur in the metastatic setting (Odds ratio, OR = 1.6; p = 0.016) but not in the local setting (OR = 1.1; p = 0.68). Conclusions Analysis of serially biopsied BRCAm breast cases revealed frequent acquisition of BRCA1/2 reversion mutations and CREBBP alterations that are not frequently observed in BRCAwt samples. Additional studies are warranted to investigate the possible role of CREBBP in PARPi therapy resistance. Citation Format: Ethan Sokol, Smruthy Sivakumar, Brennan Decker, Jeffrey Ross, Priti Hegde. Serially biopsied BRCA1/2 mutant breast tumors frequently acquire alterations in BRCA1, BRCA2, and CREBBP [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-02.