bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the genomic landscape of PIK3CA alterations from 121,221 adult patients with cancer: The next tissue-agnostic target?
Authors: Coleman Niamh , Roszik Jason , Reddy Neha K. , Subbiah Vivek 
Published: June 2022

3088 Background: The PI3K–AKT–mTOR signaling pathway is frequently dysregulated in cancer and small molecule inhibitors targeting various nodes in the pathway have been pursued for decades. Activating mutations in PIK3CA are recognized potent drivers of oncogenesis, though the landscape of PIK3CA fusions and amplifications has yet to be well-defined. The field has been hampered by issues such as resistance and poor tolerance, however several isoform-specific PI3K inhibitors have now received regulatory approval and allosteric pan-mutant and specific mutant selective Inhibitors of PI3Kα are being investigated in early phase clinical trials. Here, we present a comprehensive analysis of PIK3CA alterations in pan-cancer adult malignancies. Methods: We analyzed 136096 samples from 121221 patients available from AACR Project GENIE v.11 database for the prevalence of PIK3CA mutations, fusions and copy number alterations in a range of cancer types. Results: 15712 alterations in PIK3CA were detected in profiled tumor samples (12%), in 14774 of patients profiled (12%), most frequently in endometrial (44% of 4135 cases), anal (35% of 286 cases), breast (35% of 14218 cases), cervical (27% of 761 cases) and colorectal cancer (20% of 3743 cases). PIK3CA alterations identified included 17740 mutations (11%) (including duplicate mutations in patients with multiple samples). 16685 missense mutations were identified (12%);14953 were identified as missense in driver mutation (likely oncogenic)(90% of missense); 1,732 were missense of variants of uncertain significance (VUS) using OncoKB database (11%). Missense mutations most frequently involved codons 545(3347, 20% of missense), codon 1047 (3644, 22%) and codon 542 (1881, 11%). 237 truncating mutations were identified (0.2%), 442 in-frame deletions, 29 in-frame insertion mutations. PIK3CA fusions were observed in 0.06% of tumor samples and were most identified in breast, colorectal, lung, GBM and ovarian cancer (24%, 17%, 13%, 7% and 6% of identified PIK3CA fusions respectively). PIK3CA fusions were most commonly intragenic fusions(36%);common fusion partners included TBL1XR1, FNDC3B and NAALADL2(17%, 7%, 5% of identified PIK3CA fusions, respectively). PIK3CA fusions were identified as VUS, aside from KMT2C-PIK3CA (2%) . PIK3CA amplification high level gain occurred in 0.5% of samples tested(662), deletion occurred in 0.16%(21). Conclusions: Activating PIK3CA mutations occur frequently across cancer types and could be considered for tissue-agnostic drug development. PIK3CA fusion and amplification events are extremely rare. Most PIK3CA missense mutation variants are described as oncogenic, while fusions are described as VUS, which may limit the impact of precision oncology for patients with this alteration. Further functional characterization of PIK3CA variants and basket trial enrollment are warranted.
Genomic and clinical characteristics of MET alterations in solid tumors among the 10,475 Chinese patients.
Authors: Li Yaping , Li Mingwei , Zhang Yanrui , Hao Xueyu , Zhang Yun , Liang Xiayuan , Lou Feng , Cao Shanbo , Wang Huina 
Published: June 2022

3115 Background: Somatic alterations of the MET oncogene are emerging as an attractive target in human cancers, thus, understanding the molecular epidemiology of MET alterations is essential. While the occurrence of MET exon 14 skipping mutations (MET ex14) in US lung cancer patients is well defined, it is not widely published for Chinese patients. In addition, reports on the occurrence of METex14 outside lung cancer and other clinically relevant MET alterations across all cancers are limited. Methods: The MET ex14 alterations and amplification data of 10475 Chinese cancer patients from 16 types of cancer were obtained in Acronmed database, including non-small cell lung cancer (NSCLC, n = 5719), Hepatocellular carcinoma (HCC, n = 511), colorectal cancer (CRC, n = 1779), renal cell carcinoma (RCC, n = 1169), Gastric carcinoma (GC, n = 679), etc. Genomic profiling of DNA was performed through a next-generation sequencing. Results: Of all pan-cancer patients, 141 cases (1.3%) with MET alterations were identified, including MET Amp (0.9%) and MET ex14 (0.7%). Compared to Western population (̃3%), the frequency of MET alterations is much lower in Chinese cancer patients (1.3%). MET Amp were most commonly found in HCC (1.7%), GC (1.3%), NSCLC (0.7%), RCC (0.7%), CRC (0.2%). MET ex14 occurred most in NSCLC (0.5%), HCC (0.3%), CRC (0.2%). HCC were significantly to have MET Amp than NSCLC (P = 0.01), while MET ex14 mutations were more likely to be observed in NSCLC (p = 0.02). We further analyzed the MET mutation characteristics of NSCLC. The most frequently co-mutated genes in MET ex14 cohort were TP53 (48%,15/31), KMT2B (23%,7/31) and EGFR (16%, 5/31). Except for TP53 (65%,22/34) and EGFR (56%,19/34) mutations. Interestingly,other gene mutations were rare in the patients with MET Amp. In addition, MET ex14 patients showed significant lower EGFR mutation comparing to the MET amp patients (P = 0.002). Conclusions: Our study demonstrated a landscape of MET alterations among the Chinese population. MET mutations occurs in a variety of solid tumors, indicating that these patients may benefit from MET inhibitors.
Inference of sample-specific genetic interactions to increase accuracy of indication prioritization in oncology clinical trials and facilitate exploration of combined therapy opportunities.
Authors: Jenna Sarah , Lemaçon Audrey , Dehghani Mehrnoush , Renaut Sébastien , Baniré Diallo Abdoulaye 
Published: June 2022

3123 Background: Precision oncology is growing rapidly in parallel with advances in high throughput sequencing. Development of new anti-cancer therapies is, however, still associated with low efficacy issues, leading to phase II and III clinical trial failures. Improved methodologies are required to identify clinical and molecular patient profiles associated with good drug response to inform decisions on indication prioritization. Methods: We used a sample-specific Genetic Interaction Graph Inference (ssGI2) algorithm, integrating bulk tumor transcriptomic data as well as data collected from 120 public databases and scientific literature in oncology, to infer genetic interactions (GI). More than 10,000 genes from 17,000 samples, covering 195 oncology ICD10 codes, were used to infer GIs for each individual sample. GIs involving a given drug target are selected from a compendium of 17,000 networks of 2M GIs each, and ranked based on their prevalence in the patient cohort and data-support. The mean Z-scored expression of genes from the top ranked GIs were subsequently used to predict drug response for each patient and to calculate the response rate for each indication. Detailed information on each drug target’s genetic interactors was used to characterize the drug’s mechanisms of action and explore opportunities for combined therapies. We investigated our method's ability to predict good responders using four FDA approved immune and targeted therapies (pembrolizumab, nivolumab, ipilimumab and sorafenib) across seven clinical studies. Importantly this methodology is suitable for drugs with no clinical studies available. Results: Our results show that the prediction of good responders can be achieved with Precision-Recall AUC on average 13% higher than predictions based on drug target expression level solely, in five out of seven studies. Also, for each drug target, between 30 to 140 genetic interactors with good performance (Precision=0.92; Recall=0.61) were identified, suggesting potential synergistic effects of drugs, some of which have already been confirmed by clinical studies on combined therapies. Conclusions: Our ssGI2-derived signatures are powerful predictors of good response to a drug even without available clinical data. Applying this methodology at a pre-clinical stage will significantly de-risk clinical trials, particularly for novel therapies, and could also support investigation of new combined therapies.
Insights of clinical significance from solid tumor profiles with FoundationOneCDx.
Authors: Heilmann Andreas M , Riess Jonathan W. , McLaughlin-Drubin Molly , Creeden James , Alexander Brian Michael , Erlich Rachel 
Published: June 2022

3126 Background: FoundationOne CDx (F1CDx) is a US FDA-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. Tumor profiling with F1CDx detects genomic findings with evidence of additional clinical significance. This study analyzes the breadth and impact of clinical decision insights from F1CDx clinical reports across solid tumors. Methods: F1CDx consecutive reports (n = 109,695) were retrospectively analyzed for the type and frequency of clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures in common cancer types and across solid tumors. Predictive markers were defined as therapeutically relevant markers in drug labels or NCCN guidelines or targets of ESCAT evidence Tier I/II (Mateo et al., 2018; PMID: 30137196). Prognostic and diagnostic markers were determined in accordance with NCCN, ESMO, or WHO guidelines. We also describe the frequency and targets of interventional clinical trials with targeted therapies or immune checkpoint inhibitors that were matched to tumor profiles based on clinical or strong preclinical evidence. Results: Predictive genomic findings of clinical significance were identified in more than half of non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC), and melanoma (MEL) tissue samples; over a third of ovarian cancer (OC), urothelial carcinoma (UC), and head and neck squamous cell carcinoma (HNSCC); approximately a fourth of prostate cancer (PC), gastro-esophageal adenocarcinoma (GEA), cholangiocarcinoma (CA), and glioma (GL) samples; and one in 18 pancreatic adenocarcinoma (PA) samples (Table). Prognostic markers were reported for patients with NSCLC (18%), CRC (10%), BC (16%), PC (25%), CA (8.1%), MEL (24%), GL (74%), or HNSCC (7.1%). Diagnostic markers were frequently detected for patients with GL and noted for patients with BC, GEA, or MEL (Table). Interventional clinical trials were evidence-matched to most F1CDx tumor profiles (89%, range 82% in PC to 99% in PA), with the targets of approved therapies accounting for a small subset of targets in clinical development. Conclusions: F1CDx reports support clinical decision making by interpreting predictive, prognostic, and diagnostic markers according to professional guidelines as well as investigational markers for the enrollment in clinical trials. [Table: see text]
Identification of homologous recombination deficiency (HRD) by RAD51 in a tumor molecular profiling program for precision medicine.
Authors: Llop-Guevara Alba , Arce-Gallego Sara , Oliveira Mafalda , Simonetti Sara , Viaplana Cristina , Grau Juan Francisco , García-Duran Carmen , Pimentel Isabel , Martínez Paola , Jimenez Jose , Dienstmann Rodrigo , Nuciforo Paolo , Carles Joan , Vivancos Ana , Oaknin Ana , Saura Cristina , Aguilar Susana , Mateo Joaquin , Balmaña Judith , Serra Violeta 
Published: June 2022

3137 Background: Tumor molecular profiling by panel sequencing helps to identify candidate patients for precision oncology. Mutations in genes of the homologous recombination repair (HRR) pathway confer DNA repair deficiency and sensitivity to DNA damaging agents, such as PARP inhibitors (PARPi) or platinum-based drugs. RAD51 nuclear foci is a biomarker of functional HRR deficiency (HRD). We aimed to incorporate the RAD51 test in an academic molecular profiling program to identify HRD tumors beyond genetic testing. Methods: We included patients with metastatic breast cancer (TNBC, ER+ <60y, 3rd line HER2+ BC), newly diagnosed high-grade epithelial ovarian cancer (HGOC) and metastatic and/or castration-resistant prostate adenocarcinoma (PC) undergoing tumor/germline genetic testing. A customized capture-based targeted sequencing of 450 genes was performed in FFPE tumor samples. RAD51 was manually stained by immunofluorescence and functional HRD was defined as RAD51 score ≤10%. Results: Between January 2021 and January 2022, tumor panel sequencing was performed in 279 tumors. Panel sequencing was informative in 264/279 (95%) samples and the RAD51 test was evaluable in 81/90 (90%). In total, 77 samples were evaluable for both tumor/germline sequencing and RAD51, namely 42 BC, 16 HGOC and 19 PC (Table 1). Functional HRD by RAD51 was observed in 15/77 (20%) cases. Panel sequencing identified 17/77 (22%) cases carrying HRR gene alterations, of which nine were confirmed as HRD by RAD51. In BC, 2/6 tumors with HRD by RAD51 did not carry a germline or tumor mutation in HRR genes. HRD tumor profiling triggered the germline analysis of one hereditary BRCA2 BC patient. Four g BRCA1/2 BC with HRD by RAD51 became HRR proficient (HRP) at PARPi progression. In addition, the RAD51 test identified 2/5 HGOC and 2/4 PC tumors as HRD despite not carrying a tumor HRR gene mutation. Conclusions: RAD51 testing is feasible in an established molecular profiling program and complements gene panel sequencing results by providing evidence of functional HRR status. In particular, the RAD51 test extends the identification of HRD tumors beyond those with HRR gene mutations and captures HRR restoration after PARPi treatment. We aim to expand the analysis of RAD51 to other tumor types.[Table: see text]
Next-generation sequencing (NGS) for identifying actionable molecular alterations in patients with newly diagnosed and recurrent IDHwt-glioblastoma (GBM): A large mono-institutional experience.
Authors: Padovan Marta , Maccari Marta , Bosio Alberto , Vizzaccaro Salvatore , Cestonaro Ilaria , Corrà Martina , Caccese Mario , Cerretti Giulia , Fassan Matteo , Zagonel Vittorina , Lombardi Giuseppe 
Published: June 2022

3139 Background: NGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment. Methods: From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOneCDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase. Results: We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. Incidence of actionable molecular alterations in newly diagnosed and relapsed GBM samples is described in the Table. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing. Conclusions: NGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples. [Table: see text]
Do early phase trials predict clinical efficacy in subsequent phase III biomarker-enriched randomized trials?
Authors: Udayakumar Suji , Thomson Sasha , Abdul Razak Albiruni Ryan , Chan Kelvin K. 
Published: June 2022

3152 Background: Efficacy endpoints of randomized controlled trials (RCT) are commonly used as the basis of regulatory drug approvals. Recently, promising results in early phase trials have resulted in approval of biomarker-targeted therapies. We examined if early phase trial results were associated with efficacy in subsequent biomarker-enriched RCTs. Methods: All cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Trials were eligible if a biomarker was used to select a patient population for treatment with a targeted agent. Associated early phase trials were included if they matched the RCT in treatment setting and patient population. Trials pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We assessed difference in endpoints using summary measures (e.g., average, range). We examined whether early phase trials results were associated with RCT results using logistic regression. Results: The search yielded 2,157 unique phase III RCTs and 27 RCTs met eligibility criteria pairing with associated early phase trials, where 17 RCTs met their primary endpoint. The most common biomarkers were EGFR+ (n = 8), HER2+ (n = 5) and PD-L1 (n = 5). Based on average difference of trial pairs, ORR was similar between trials (1.59%, 95% CI = -2.5-5.6, p = 0.50) and median PFS was slightly higher in early phase trials (1.95 months, 95% CI = 0.91-2.99, p < 0.05). On an individual pair basis, there was large range of variability in the difference between early phase trials and RCTs for ORR (range = -23.9-20.2%) and median PFS (range = -0.8-7.4 months). The probability of the RCT meeting its primary endpoint is 50% or 95%, when the early phase trial ORR is 41.2% (95% CI = 35.2-47.1%) or 77.7% (95% CI = 71.7-83.6%), respectively. Conclusions: Through comparison of early phase trials and subsequent phase III RCT, we found that, overall, ORR has minimal bias in early phase trials, and median PFS appears to be slightly overestimated. Substantial variability in results for trial pairs suggests that, on an individual basis, results in early phase trial can be inconsistent with results in subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs for decision-making as the predictive ability of early phase trials is limited.
Pembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D.
Authors: Kim Richard D. , Tehfe Mustapha , Kavan Petr , Chaves Jorge , Kortmansky Jeremy S. , Chen Eric Xueyu , Lieu Christopher Hanyoung , Wong Lucas , Fakih Marwan , Spencer Kristen Renee , Zhao Qing , Predoiu Raluca , Li Chenxiang , Carpenter David , Leconte Pierre , Chiorean E. Gabriela 
Published: June 2022

3521 Background: Response to antiPD-1 monotherapy is poor in patients (pts) with advanced microsatellite stable (MSS)/mismatch-repair proficient (pMMR) CRC. Combination of chemotherapy with antiPD-1 pembro may potentiate the antitumor immune response and provide greater antitumor activity than either agent alone. Combination of pembro and mFOLFOX7 or FOLFIRI in the ongoing phase 1b multicohort KEYNOTE-651 (NCT03374254) study in metastatic MSS/pMMR CRC showed antitumor activity. We present results with approximately 20 mo of additional follow-up. Methods: Pts had metastatic MSS/pMMR CRC and were previously untreated (cohort B) or received 1 prior line including a fluoropyrimidine + oxaliplatin (cohort D). Pts received pembro 200 mg Q3W + mFOLFOX7 Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI Q2W (cohort D). Primary end points were safety (DLT) and RP2D. Secondary end point was ORR per RECIST v1.1 by investigator review. DOR, DCR, and PFS per RECIST v1.1, and OS were exploratory end points. Results: Median study follow-up (range) at data cutoff (Oct 15, 2021) was 30.2 mo (25.0-43.6) for cohort B (n = 31) and 33.5 mo (25.2-43.2) for cohort D (n = 32). Treatment was discontinued in 29 pts (94%) in cohort B and 28 pts (88%) in cohort D, mostly because of PD (61% and 66%, respectively). At prior analysis (Feb 10, 2020), RP2D was confirmed as the starting dose in both cohorts; no new DLT had occurred. In cohort B, gr 3/4 TRAEs occurred in 18 pts (58%), most commonly neutropenia and decreased neutrophil count (both n = 5; 16%); 19 pts (61%) discontinued drug because of a TRAE. In cohort D, gr 3/4 TRAEs occurred in 17 pts (53%), most commonly, neutropenia (n = 7; 22%), diarrhea and fatigue (both n = 4; 13%); 3 pts (9%) discontinued drug because of a TRAE. There were no gr 5 TRAEs in either cohort. Efficacy by cohort and KRAS mutation status are below (Table). PD-L1 data and DNA/RNA-based biomarker data including GEP, consensus signatures, TMB, and LoF mutations will be included in the presentation. Conclusions: After 2.5 y of follow-up, the combination of pembro with either mFOLFOX7 or FOLFIRI continued to demonstrate a manageable safety profile with no new safety signals. Efficacy data from these single-arm cohorts appear comparable to historical data for current SOC. Clinical trial information: NCT03374254. [Table: see text]