bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Estimating the impact of reducing the age of colorectal cancer screening on cancer incidence, mortality, and costs in Canada using OncoSim.
Authors: Kalyta Anastasia , Loree Jonathan M. , De Vera Mary A. , Peacock Stuart , Telford Jennifer J. , Brown Carl J , Donnellan Fergal , Gill Sharlene
Published: June 2022

3526

Background: Organized colorectal cancer (CRC) screening programs currently cover Canadians aged ≥50 at average-risk of developing CRC and have contributed to declining CRC incidence. Rising incidence of early-onset CRC in individuals < 50 has led to lowering of the recommended screening start age to 45 rather than 50 in some jurisdictions. We used OncoSim, a publicly-available simulation tool, to model the effects of earlier screening initiation on Canadian CRC incidence, mortality and healthcare costs. Methods: OncoSim uses Canadian population and cancer registry data to simulate a representative sample of individuals from birth to death. We modeled four scenarios: no screening in average-risk individuals, screening initiation at age 50, initiation age lowered to 45 in 2022, and initiation age lowered to 40 in 2022. Each includes 32 million simulated participants. In the model, average-risk screening involves biennial FIT, available to all simulated participants regardless of family history with participation of 60% at the first recruitment attempt and 80% for repeat screening. Participants with a family history in all 4 scenarios were eligible for additional screening by colonoscopy every 5 years. Results: In our model, earlier screening yields reduced CRC incidence and mortality with increasing benefit over time. By 2051, screening initiation at age 45 or 40 reduces age-standardized incidence by 3.4% and 4.8% respectively, and age-standardized mortality by 3.3% and 4.6% respectively, compared to initiation at age 50. Screening initiation at age 45 yields 3,848 additional quality-adjusted life-years (QALYs) in 2051 at a cost of $9,350 per QALY gained and a 5% increase in colonoscopies performed. Initiation at age 40 yields 6,255 additional QALYs at $16,350 per QALY gained and a 9% increase in colonoscopies. The difference in screening costs compared to screening from age 50 is consistent year-to-year after 2024. In 2051 screening costs increase by $75mil and $155mil per year with initiation at ages 45 and 40 respectively, while costs of cancer management (including diagnosis, treatment, recurrence, palliative and end of life care) decrease by $42mil and $57mil respectively. Conclusions: Our model predicts that lowering the CRC screening initiation age for average-risk Canadians to 45 or 40 could reduce CRC incidence and mortality. Costs per QALY gained are high in the first few decades but decrease over time. Costs are modest after 30 years of screening compared to other life-preserving interventions such as dialysis. Our results suggest that lowering the screening age in Canada may be warranted, but further investigation is needed to assess capacity for increased colonoscopy demand.
Analysis of plasma angiogenesis factors on the efficacy of first-line (1L) chemotherapy (chemo) combined with biologics in RAS wild-type metastatic colorectal cancer (mCRC): Results from GI-SCREEN CRC Ukit study.
Authors: Yuki Satoshi , Sunakawa Yu , Yamazaki Kentaro , Shirasu Hiromichi , Taniguchi Hiroya , Masuishi Toshiki , Shiozawa Manabu , Bando Hideaki , Nishina Tomohiro , Yasui Hisateru , Ohta Takashi , Takahashi Naoki , Denda Tadamichi , Esaki Taito , Kawakami Hisato , Satake Hironaga , Takashima Atsuo , Abe Yukiko , Nomura Shogo , Yoshino Takayuki
Published: June 2022

3530

Background: Angiogenesis factors have been reported as prognostic and predictive biomarkers of angiogenesis inhibitors for mCRC (Weickhardt AJ. Br J Cancer 2015. Tabernero J. Ann Oncol 2018). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemo in 1L treatment in patients (pts) with RAS wild-type mCRC. Methods: Serial plasma samples were prospectively collected at the time points of pre- and post-treatments in mCRC pts receiving biologics in either 1L or 2nd-line (2L) chemo. From Sep 2017 to Dec 2020, 497 pts were enrolled [1L chemo plus bevacizumab (1L BEV, n=102), 1L chemo plus anti-EGFR antibody (1L aEGFR, n=100), 2L chemo plus bevacizumab (n=100), 2L FOLFIRI plus RAM (n=99), 2L FOLFIRI plus aflibercept (n=85) and other treatment (n=11)]. Total of 17 plasma angiogenesis factors (HGF, PlGF, VEGF-A, VEGF-D, Angiopoietin-2, IFN-γ, IL-6, IL-8, sNeuropilin-1, TSP-2, OPN, sVEGFR1, sVEGFR2, sVEGFR3, sICAM-1, sVCAM-1, and TIMP-1) were analyzed by the multiplex assay with Luminex® technology. Interactions of their pre-treatment measurements with treatment groups on PFS and OS were assessed via Cox proportional hazards model. The strength of interactions was estimated using a propensity score weighting analysis, and the continuous plasma angiogenesis variables were categorized according to the median. The significance level in the interaction was defined as p≤0.1. Results: 133 pts were included in adjusted RAS wild-type 1L cohort (1L BEV: n=33, 1L aEGFR [reference]: n=100). Baseline characteristics of adjusted RAS wild-type 1L cohort were as follows; median age 64 years; male 62.4%; left-sided tumor 88.7%; triplet chemo 15.0%. Propensity-score weighted Cox model for OS showed significant interactions in IL-8 (median 8.03 pg/mL, high: HR 1.738, p=0.0838, Low: HR 0.479, p=0.2624, interaction p=0.0283), sVEGFR-1 (median 1,350 pg/mL, high: HR 0.333, p=0.1770, Low: HR 1.311, p=0.3004, interaction p=0.0777), and sVCAM-1 (median 1,020,000 pg/mL, high: HR 0.100, p=0.0558, Low: HR 1.616, p=0.1765, interaction p=0.0011). In terms of PFS, there were significant interactions in IL-8 (high: HR 1.322, p=0.0418, Low: HR 0.517, p=0.0528, interaction p=0.0752) and sVCAM-1 (high: HR 0.285, p=0.0414, Low: HR 1.200, p=0.7725, interaction p=0.0156). Conclusions: Pre-treatment plasma IL-8 and sVCAM-1 could be predictive biomarkers for efficacy of biologics combined with chemo in 1L treatment of RAS wild-type mCRC. Clinical trial information: UMIN000028616. [Table: see text]
Molecular characteristics of advanced colorectal cancer and multi-hit PIK3CA mutations.
Authors: Cecchini Michael , Sokol Ethan , Vasan Neil , Pavlick Dean C. , Huang Richard S.P. , Pelletier Maureen , Levy Mia Alyce , Pusztai Lajos , Lacy Jill , Eder Joseph Paul , Zhang Janie Yue , Ross Jeffrey S.
Published: June 2022

3535

Background: Approximately 20% of colorectal cancer (CRC) has an activating mutation in the PIK3CA oncogene. PIK3CA codes for the catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα), which ultimately activates the AKT and mammalian target of rapamycin (mTOR) pathway. The PI3Kα inhibitor alpelisib has been approved for breast cancer where a single PIK3CA activating mutation is sufficient for response. However, two activating mutations (multi-hit) in the PIK3CA allele substantially increases PI3Kα signaling compared to single hot spot mutations and results in exceptional response to PI3Kα inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in CRC to identify patients potentially susceptible to PI3K inhibitors. Methods: Tissue-based comprehensive genomic profiling (CGP) was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA) on all-comers during the course of routine clinical care from 2013-2021. Approval was obtained from the Western Institutional Review Board (Protocol No. 20152817). Hybrid capture was carried out for at least 324 cancer-related genes, including PIK3CA. Results: We identified 48,836 patients with advanced CRC who underwent Foundation Medicine testing and 846 (1.7%) patients with multi-hit PIK3CA mutations. Additional clinical and molecular data was available for 41,154 of these patients of which 710 (1.7%) had multi-hit PIK3CA and 7627 (19%) had any deleterious PIK3CA mutation . The local colon tumor was used for sequencing in 70% of cases and a separate site in 30% of cases. Patients with PIK3CA multi-hit mutations were 53% male with a median age of 60 (interquartile range 50-70). The microsatellite status was available for 697 of 710 patients with multi-hit PIK3CA and 123/697 (18%) were microsatellite instability-high. The Table outlines the genes with cooccurring mutations of >10% prevalence for multi-hit PIK3CA CRC, including the clinically relevant mutations in KRAS (65%) and BRAF (13%). The four most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%) and R88Q (7.1%). The most common variant pair was E542K with E545K in 4.7% of multi-hit cases. Conclusions: Double-hit mutations in PIK3CA are seen in 1.7% of advanced CRC patients and may represent a subset of patients that may have enhanced sensitivity to PI3K inhibitors. Given the high prevalence of CRC in the United States and worldwide this represents a clinically meaningful prevalence of multi-hit PIK3CA. Future investigation on the clinical utility of PI3K inhibitors may be warranted in multi-hit PIK3CA CRC.[Table: see text]
Negative hyperselection for mutations associated with anti-EGFR antibody resistance in RAS wildtype metastatic colorectal cancer (mCRC): Evaluation of the PANAMA trial (AIO-KRK-0212, maintenance therapy with 5-FU, folinic acid (FU/FA) with or without panitumumab).
Authors: Kind Andreas Jay , Modest Dominik Paul , Sers Christine , Mamlouk Soulafa , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Von Weikersthal Ludwig Fischer , Goekkurt Eray , Reinacher-Schick Anke C. , Kasper Stefan , Kurreck Annika , Hoppe Beeke , Held Swantje , Heinemann Volker , Horst David , Jarosch Armin , Stintzing Sebastian , Trarbach Tanja , Stahler Arndt
Published: June 2022

3536

Background: We evaluated the prognostic and predictive impact of DNA mutations related to anti-EGFR antibody resistance in patients of the PANAMA trial, which compared Panitumumab (Pmab) and FU/FA versus FU/FA maintenance therapy after Pmab-FOLFOX induction therapy in RAS wild-type (wt) mCRC. Methods: Next generation panel sequencing was conducted on 201 of 248 tumors obtained prior to study inclusion from the full analysis set using the Cancer Hotspot Panel v2 on an Illumina MiSeq system. Hyperselection covered mutations of the following genes: KRAS, NRAS, BRAF, HER2, PTEN, AKT1, PIK3CA. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier and Cox-regression (log rank test). Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: From 201 tumors, 41 (20.4 %) carried at least one mutation: KRAS: 7 (3.5%), BRAF: 23 (11.4%), PTEN: 4 (2.0%), AKT1: 2 (1.0%), PIK3CA: 12 (6.0%), with 6 tumors harboring co-occuring mutations. No mutations were found in NRAS and HER2. Negative hyperselection (wt for all genes) was associated with (numerically) favourable prognosis in terms of PFS (HR 0.79 (95% CI 0.55 – 1.12), p=0.184), OS (HR 0.61 (95% CI 0.40 – 0.95), p=0.028) and ORR (39.4% vs. 29.3%, p=0.279). The benefit of adding Pmab to FU/FA during maintenance was limited to the hyperselection wt subgroup, with significantly longer PFS (9.9 vs. 6.0 months, 0.64 (95% CI 0,46 – 0.90), p = 0.011), numerically longer OS and significantly higher ORR (49.4% vs 26.6%, p=0.009) compared to FU/FA (Table). Conclusions: Mutations related to resistance concerning anti-EGFR antibodies were detected in 41 of 201 (20.4%) of analysed tumors and associated with a worse prognosis compared to hyperselected wt tumors. Negative hyperselection may aid in the identification of patients with relevant benefit from maintenance therapy including Pmab. [Table: see text]
BRAF-mutant metastatic colorectal cancer: Prognostic and predictive value of primary tumor location—A pooled analysis of the AIO studies FIRE-1, CIOX, XELAVIRI, FIRE-3, and VOLFI.
Authors: Alig Annabel Helga Sophie , Heinemann Volker , Stintzing Sebastian , Geissler Michael , von Weikersthal Ludwig , Decker Thomas , Kaiser Florian , Moosmann Nicolas , Heinrich Kathrin , Held Swantje , Holch Julian Walter , Stahler Arndt , Kurreck Annika , Reinacher-Schick Anke C. , Tannapfel Andrea , Klauschen Frederick , Jung Andreas , Giessen-Jung Clemens , Modest Dominik Paul
Published: June 2022

3576

Background: Primary tumor location (PTL: left vs. right) is an established prognostic marker in metastatic colorectal cancer (mCRC) and has predictive impact for anti-EGFR antibody (mAb) efficacy in patients with RAS ( KRAS and NRAS) wild-type (WT) mCRC. This analysis of five pooled studies evaluates PTL as a prognostic and - concerning anti-EGFR mAb efficacy - predictive marker in BRAF V600E-mutant/ RAS WT and mCRC. Methods: The analysis is based on individual patient data of five pooled 1st-line studies with varying treatment strategies: the pooled population comprises of BRAF V600E-mutant/ RAS WT ( BRAFmt) mCRC with known PTL. For analysis, treatment was stratified into two groups: treated with or without anti-EGFR mAb. Dichotomous variables (overall response rate, ORR; characteristics) were compared by Chi-Square or Fisher’s exact test and time-to event endpoints (progressive-free survival, PFS; overall survival, OS) by Kaplan-Meier method, log rank test and Cox regression. Results: Of 102 patients (pts) with BRAFmt mCRC, 55 pts (54%) presented with right-sided primary tumors (RPT), 47 (46%) presented with left-sided primary tumors (LPT). Pts with RPT were more likely to be female ( p= 0.04). ORR was inferior in RPT compared to LPT (35% vs. 55%; p= 0.04). No difference was seen in PFS (HR 0.8 (95% CI 0.6-1.3; p= 0.32) or OS (HR 0.8; 95% CI 0.8-1.3; p= 0.46). In male pts PTL trended to be associated with longer OS (HR 0.6; 95% CI 0.3-1.0; p= 0.06). 25 pts with RPT (45%) and 21 with LPT (45%) received anti-EGFR mAb. In pts with LPT anti-EGFR mAb based treatment was associated with higher ORR (81% vs. 35%; p< 0.01). No effect was seen in RPT (ORR 35% vs. 36%; p= 0.82). Anti-EGFR mAb treatment resulted in inferior PFS in RPT (HR 2.0; 95% CI 1.1-3.5; p= 0.02) and showed a trend towards improved PFS in LPT (HR 0.6; 95% CI 0.3-1.1; p= 0.11). Pts with RPT had a worse OS when treated with anti-EGFR mAb (HR 1.8; 95% CI 1.0-3.1; p= 0.05), whereas pts with LPT appeared to have a favorable outcome when treated with an anti-EGFR mAb containing regimen (HR 0.4; 95% CI 0.2-0.7; p< 0.01). Conclusions: This exploratory analysis of five studies suggests that PTL has limited prognostic impact in BRAFmt mCRC but might carry predictive information regarding anti-EGFR mAb efficacy in a 1st-line treatment setting. Further prospective studies are needed to validate these results and to grasp the differences in the heterogeneous group of BRAFmt pts. Clinical trial information: FIRE-1 was before mandatory registration, NCT00254137, NCT00433927, NCT01249638, NCT01328171.
Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer (mCRC).
Authors: Arai Hiroyuki , Yang Yan , Millstein Joshua , Denda Tadamichi , Ou Fang-Shu , Innocenti Federico , Takeda Hiroyuki , Doi Ayako , Horie Yoshiki , Umemoto Kumiko , Izawa Naoki , Wang Jingyuan , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Wu Zhang , Venook Alan P. , Sunakawa Yu , Lenz Heinz-Josef
Published: June 2022

3586

Background: HSP90 mediated chaperoning is a well-conserved biological mechanism for stabilization and activation of kinases. More than 60% of human kinases including VEGFR, CRAF, CSF1R, and FGFR are target of HSP90 (client kinases), whereas EGFR is non-client. CDC37 is a specific co-chaperone determining selectivity of client kinases recognized by HSP90. We hypothesized that gene expression levels of CDC37 have predictive values for anti-angiogenic therapies in mCRC. Methods: The subjects of this study were mCRC patients treated with regorafenib (REGO, Japanese retrospective cohort) and those treated with bevacizumab (BEV) or cetuximab (CET) in combination with first-line chemotherapy (CALGB/SWOG 80405 trial cohort). CDC37 expression levels were measured using RNA isolated from FFPE samples by nCounter gene expression profiling (Nanostring) and HiSeq 2500 (Illumina) in the Japanese and CALGB/SWOG 80405 cohorts, respectively. Overall survival (OS) and progression-free survival (PFS) were compared between patients with high CDC37 expression ( CDC37-H) and those with low expression ( CDC37-L), grouped by median cutoff value in each cohort. Results: In total, 484 patients were included (50 treated with REGO, 227 treated with BEV, and 207 treated with CET). In REGO-treated patients, CDC37-H showed significantly better OS (median 11.3 vs 6.0 months, adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.11-0.54, p <0.01) and PFS (median 3.5 vs 1.9 months, adjusted HR 0.51, 95% CI 0.28-0.94, p = 0.03) compared to CDC37-L. Similarly, in BEV-treated patients, CDC37-H showed significantly better PFS (median 13.5 vs 9.6 months, adjusted HR 0.59, 95% CI 0.43-0.79, p <0.01) and numerically better OS (median 34.1 vs 29.4 months, adjusted HR 0.81, 95% CI 0.60-1.11, p = 0.20) compared to CDC37-L. However, in CET-treated patients, CDC37-H and CDC37-L patients showed similar OS (median 33.7 vs 26.1 months, adjusted HR 1.00, 95% CI 0.73-1.38, p = 0.98) and PFS (median 11.3 vs 11.0 months, adjusted HR 1.08, 95% CI 0.81-1.45, p = 0.60). Significant interaction was observed between CDC37 expression and treatment in terms of PFS in the CALGB/SWOG 80405 cohort ( p = 0.01). Conclusions: Our results suggest patients with CDC37-dependent ( CDC37-H) tumors may derive more benefit from REGO and BEV both of which target HSP90 client kinases or signaling pathways, but not from CET which target HSP90 non-client kinase. Further validation studies are warranted to develop a novel personalized approach for targeted therapies based on CDC37 expression in mCRC patients. Support: U10CA180821, U10CA180888; Pfizer, Genentech; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00265850.
Using cell-free circulating tumor DNA (cfDNA) to identify guideline-relevant biomarkers for therapy selection in 14,000 patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Kasi Pashtoon Murtaza , Tan Benjamin R. , Nguyen Timmy Q. , Starr Jason S. , Bucheit Leslie A. , Drusbosky Leylah , Weipert Caroline
Published: June 2022

3601

Background: Two cfDNA assays are FDA-approved for use in advanced cancer pts across solid tumors. While several NCCN guidelines recommend cfDNA as a valid and useful method for molecular testing, the utility varies by cancer type. Despite the growing number of molecular alterations pertinent to first-line treatment in mCRC, current guidelines offer little guidance on the use of cfDNA in mCRC. Here we assess the ability of cfDNA to detect guideline-relevant actionable biomarkers informative for first-line therapy selection and beyond in patients with mCRC. Methods: We queried consecutive samples from advanced cancer pts with a diagnosis of CRC who underwent testing via a commercially available cfDNA assay (Guardant360) from September 2018 to January 2022. Validation and content of this assay has been previously described. To enrich for less heavily treated pts, we limited analysis to those whose first cfDNA test was done during the study period and only included the pt’s first test. The maximum variant allele fraction (maxVAF) for each test was used as a proxy for tumor shed and was compared between cancers with a Mann-Whitney test. The frequency of suspected germline alterations was assessed only in pts who received testing via a panel version with expanded mismatch repair (MMR) gene coverage. Tissue frequencies for select biomarkers were obtained from the MSK-IMPACT Clinical Sequencing Cohort in cBioPortal. Results: In total, 14,345 pts with mCRC received their first cfDNA test during the study period, with 92% of pts (13,190) having >1 cfDNA alteration detected. Median age was 62 and 44% of pts were female. The frequencies of key biomarkers are listed in Table 1. The median maxVAF was 5.6%, compared to 2.5% and 1.8% for pts with advanced gastric and NSCLC, respectively (p = < 0.0001 for both). The average turnaround time (TAT) for tests was 7 calendar days. Conclusions: cfDNA results from pts with mCRC demonstrated detection of biomarkers essential to first-line treatment decisions at a frequency comparable to what has been reported via tissue genotyping. mCRC pts had significantly higher tumor shed compared to other cancer types with guidelines that recommend cfDNA as an option for molecular testing, suggesting a potential gap in coverage. Tissue availability in mCRC does not guarantee comprehensive testing is completed quickly (compared to the 7-day TAT seen for cfDNA here), making it an attractive alternative strategy for first-line therapy selection in mCRC. [Table: see text]
Computerized features of tumor diversity on pre-chemoradiation MRI are associated with pathologic complete response in rectal cancers: A multi-institutional study.
Authors: Singh Sneha , DeSilvio Thomas , Purysko Andrei , Paspulati Raj M , Friedman Ken , Liska David , Stein Sharon , Krishnamurthi Smitha S. , Viswanath Satish Easwar
Published: June 2022

3608

Background: Neoadjuvant chemoradiotherapy (nCRT) prior to total mesorectal excision (TME) reduces the risk of local recurrence and is a standard-of-care treatment for patients with locally advanced rectal cancer. Previous studies have indicated up to 30% of patients who undergo TME demonstrate a pathologic complete response (pCR) to nCRT [2], but current serum markers and clinical evaluation have limited utility in predicting benefit from nCRT. In this study, we evaluated if tumor diversity features on baseline pre-treatment MRI were predictive of pCR in rectal cancers. Methods: Pre-nCRT T2-weighted MRIs from 126 patients who later underwent nCRT and TME (without neoadjuvant chemotherapy) were retrospectively collected from 2 institutions. 69 patients (14 pCR, Institution 1) formed the training cohort D1, while 57 patients (10 pCR, Institution 2) formed the independent holdout validation cohort D2. Response groupings were based on AJCC tumor regression grade (TRG) evaluation where pCR corresponded to no residual tumor cells in excised histopathologic specimens after nCRT (i.e. TRG0) and non/partial response otherwise (TRG1-3). Computerized tumor diversity algorithms extracted measurements of fractal dimensions, surface topology, and persistent homology from annotated tumor regions on MRI to quantify visual patterns, spatial geometry, and prolonged structural similarity. Top tumor diversity features identified via Wilcoxon rank-sum testing were used to train a random forest (RF) machine learning classifier to predict the likelihood of pCR using D1 and then independently evaluated for predicting pCR in D2. Results: Machine learning analysis identified 5 tumor diversity measurements associated with pCR on pre-nCRT MRI. The associated RF classifier for pCR achieved an AUC of 0.98 (95% CI, 0.9808-0.9949) in D1 and an AUC of 0.9117 in hold-out validation on D2. This corresponded to predicting 100% of non/partial response prior to nCRT as well as 80% of pCR patients via tumor diversity features on pre-nCRT MRI. Conclusions: Computerized tumor diversity features on pre-nCRT MRI can predict pathologic complete response to nCRT in rectal cancers. These findings need to be validated in larger multi-institutional cohorts to establish independent predictive utility of MRI-based biomarkers, which could aid in the selection of patients who will see maximal response from neoadjuvant therapy and avoid unnecessary surgery.
Disproportionate morbidity and mortality in African American and Asian patients from colorectal cancer: A nationwide analysis.
Authors: Franco Jorge , Franco Diana , Farooq Umer , Ma Irene
Published: June 2022

3628

Background: Published literature points towards the disproportionate prevalence of colorectal cancer (CRC) in ethnic groups. Racial minorities are also prone to higher mortality due to inequalities in access to healthcare. Therefore, we examined the disparities in hospital-related outcomes among racial groups from CRC. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with CRC. We compared various outcomes stratified by racial groups with White as the reference group. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses and included: gender, Charlson Comorbidity Index, median household income for patients’ zip codes, hospital location/region/bedside, and insurance status. Results: Out of 732,492 included patients, 72.77% White, 13.66% African American (AA), 9.91% Hispanics, and 3.65% Asians were in the cohort. AA and Asians had higher mortality odds than White, while Hispanics had mortality similar to White. AA had a lower mean length of stay by 0.74 days than White. All racial groups incurred higher mean total charges compared to White. AA and Hispanics had lower odds of undergoing colectomy. Overall, all racial groups had high morbidity compared to White. Among subgroups, the odds of morbidity markers (sepsis, lower GI bleed, and acute renal failure) were higher in AA and Asians than Hispanics. Post-op adhesions and DVT/PE were not significantly different among racial groups. Conclusions: AA and Asians disproportionately suffer from higher mortality from colorectal cancer than Hispanics and White. Lower colectomy rates (a definitive CRC treatment) in AA and higher in-hospital complication burden in Asians are possible explanations; however, further research needs to establish if race-specific genomics are also responsible for disparities. [Table: see text]
Impact of immune-related adverse events (irAEs) on PD-1/L1 inhibitors efficacy in advanced esophageal cancer.
Authors: Qin Wenru , Wang Linlin
Published: June 2022

4061

Background: The recent development of Immune checkpoint inhibitors (ICIs) has improved treatment outcomes for patients with esophageal cancer, although it may initiate autoimmune-related disorders in some patients. Across disease sites, patients who experience irAEs while on therapy with anti-PD-1 and anti-PD-L1 antibodies have been documented to experience improved outcomes as measured by overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Methods: We reviewed the medical records and the following characteristics of patients were collected: age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), stage, histology, history of surgery, metastatic sites, therapy line, presence of target lesion according to the response evaluation criteria in solid tumors (RECIST) version 1.1, LDH level before initiating ICIs treatment. We divided the patients treated with ICIs into two groups based on occurrence of irAEs. We compared the efficacy between the irAE - and irAE + groups. Results: There were total 295 patients. Of all the patients, 143 patients (50.2%) suffered from irAEs. The median patient age was 60 years (range, 36–84). Baseline characteristics including gender, ECOG PS, tumor location, history of surgery, histology, number of organs with metastases, site of metastases, therapy line, history of drinking, history of smoking between patients with or without irAE were not significantly different. The most frequent irAEs were Anemia(71/295, 24.07%), Pneumonitis (55/295, 18.64%), Cardiovascular toxicities (35/295, 11.86%). There were no grade 5 adverse events related to immunotherapy. Objective response was observed in 92 patients (31.19%), 54 of the 143 patients with irAEs had objective response (37.76%) in contrast with 38 of the 152 cases without irAEs (25.00%). Median PFS in patients with irAEs was 10.27 months and 6.2 months in those without irAEs (p<0.001). Median OS in patients with irAEs was 15.4 months and 9.2 months in those without irAEs(p<0.001).Multivariate analyses identified an ECOG PS ≥2, cycles ≤8, and without irAEs as independent poor prognostic factors (p=0.003, p <0.001 and p=0.011). Multivariate analysis demonstrated that ECOG PS ≥2, Therapy line≥22nd,without radiation and absence of irAEs were associated with a poor overall survival(p=0.022, p=0.006, p. <0.001 and p=0.002). Multivariable analysis also revealed that Cycles>8, Radiation and Antiangiogenic therapy were positively associated with occurrence of irAEs(p<0.001, p=0.002, p=0.025). Conclusions: In advanced esophageal cancer treated with PD-1/L1 inhibitors., patients with irAEs showed a markedly improved efficacy over patients without irAEs.
Toripalimab combined with gemcitabine and S-1 in the first-line treatment of advanced biliary tract cancer.
Authors: Li Wei , Wang Yueqi , Yu Yiyi , Li Qian , Wang Yan , Zhang Chenlu , Xu Xiaojing , Guo Xi , Cui Yuehong , Hao Qing , Huang Lujia , Liu Houbao , Liu Tianshu
Published: June 2022

4081

Background: Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs), but the overall effect needs to be further improved. This study intended to explore the safety and efficacy of toripalimab combined with chemotherapy in the first-line treatment of advanced BTCs. Methods: This single-arm, phase II clinical trial enrolled patients with advanced BTCs who had not received systemic treatment. Toripalimab combined with chemotherapy were applied as first-line treatment: toripalimab (240 mg, iv, d1), gemcitabine (1000 mg/m2, iv, d1&d8), and S-1 (40-60mg bid po, d1-14, Q21d). The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) and safety. The study explored the association between response with PD-L1 expression, tumor mutational burden (TMB) and genetic variations identified by next-generation sequencing (NGS) of peripheral blood. Results: 50 patients were enrolled from January 2019 to August 2021 with a median follow-up time of 24.0 months (4.3-31.0). The median PFS was 7.0 months (95%CI: 5.0-8.9 months); median OS was 15.0 months (95%CI: 11.6-18.4 months). Of the 49 patients who completed the evaluation for tumor response, the ORR was 30.6% (95%CI: 17.2%-44.0%), and the disease control rate was 87.8% (95%CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%) and immune-related colitis (2%).Among them, the Grade III/IV immune-related adverse events irAEs) worthy of attention included were skin rash and immune-related colitis. There was no significant difference in PFS and OS among intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder cancer. Exploratory study showed that patients with CPS≥1 had longer PFS. However, there was no significant correlation between TMB and PFS. Conclusions: Toripalimab combined with gemcitabine and S-1 (GS) has shown good safety in the first-line treatment of advanced BTCs. Although the primary endpoint did not reach the preset goal, toripalimab plus GS as first-line treatment has shown encouraging data of PFS and OS in patients with advanced BTC, which is worthy for further verification. Biomarker analysis showed that the expression level of PD-L1 could predict the curative effect. Clinical trial information: NCT03796429.