EGFR Alterations Research Articles

Biomarkers for monitoring patients with cardiac amyloidosis during transthyretin-stabilizer therapy

Abstract Introduction Cardiac amyloidosis is characterized by deposition of amyloid fibrils in the heart, leading to structural abnormalities and functional impairments resulting in heart failure. Amyloid transthyretin amyloidosis cardiomyopathy (ATTR-CM) is the most common form with increasing incidence due to growing awareness and improved diagnosis. The ATTR stabilizer tafamidis serves as the first specific therapy approved for ATTR-CM, and many promising substances are in late-stage clinical trials. With growing numbers of patients receiving stabilizer therapy, valid tools for monitoring treatment response and detecting disease progression are currently lacking. Here, we aim to assess systemic and cardiac biomarkers in patients receiving stabilizer therapy. Method All individuals diagnosed with ATTR-CM at our university hospital, were systematically assessed for eligibility in this study. We enrolled patients who were undergoing therapy with tafamidis. Biomarkers including Hemoglobin (Hb), Creatinine, estimated glomerular filtration rate (eGFR), International Normalized Ratio (INR), C-reactive protein (CRP), Troponin and NT-proBNP were examined at baseline and during 6 and 12 months follow-up. Wilcoxon signed rank test was used for statistical analysis. The study was approved by the local ethics committee (23-11500-BO). Results 194 patients were included in the analysis with median age of 80 (76-83) years (86,6% male). Results showed an impaired renal function at baseline (all mean ± SD) with creatinine 1.24 ± 0.46 mg/dl and eGFR 58.64 ± 18.24 ml/min/kg with statistically significant increase after 6 months in creatinine (1.31 ± 0.51 mg/dl, p<0.001) and eGFR (55.06 ± 17.65 ml/min/kg, p<0.001) and after 12 months (creatinine 1.35 ± 0.54 mg/dl, p<0.001, eGFR 53.27 ± 17.68 ml/min/kg, p<0.001). Hb showed a significant increase after 6 (13.61 ± 1.78 g/dl, p<0.001) and 12 months (13.6 ± 1.79 g/dl, p<0.001), compared to baseline (13.41 ± 1.71 g/dl, p<0.001). Comparison of baseline values for CRP (0.08 ± 1.18 mg/dl), Troponin (86.33 ± 190.6 ng/l), NT-pro BNP (4703 ± 4385 pg/ml) and INR (1.25 ± 0.46) after 6 (CRP p=0.28, Troponin p=0.7, NT-pro BNP p=0.97, INR p=0.91) and 12 months (CRP p=0.12, Troponin p=0.59, NT-pro BNP p=0.78, INR p=0.28) showed no significant changes. Conclusion Although troponin and BNP are routinely used and recommended as biomarker for monitoring patients with ATTR-CM, the diagnostic value may be insufficient to assess therapy response. Results emphasize the need to identify new biomarkers to adequately reflect the specific aspects of ATTR-CM disease progression. This study reveals significant alterations in creatinine and eGFR due to a worsening of kidney function, but an increase of Hb, suggesting a potential indicator for treatment response. Future research should explore innovative approaches like proteomic analysis as promising approach for both diagnostic and prognostic biomarkers.

Cost-effectiveness of next-generation sequencing for advanced EGFR/ALK-negative non-small cell lung cancer

ObjectivesThis study aimed to evaluate the cost-effectiveness of next-generation sequencing (NGS) versus sequential single-gene testing (SGT), including the long-term costs and survival outcomes of relevant treatments for advanced EGFR/ALK-negative non-small cell lung cancer (NSCLC). Materials and MethodsWe developed a decision tree linked to a partitioned survival model to estimate the clinical outcomes and costs over the five-year analysis period. The decision tree consisted of treatment types based on molecular biomarker (ROS1, BRAF, NTRK, MET, RET, and KRAS alterations) test results. The probability of receiving each targeted therapy was estimated based on 1) the testing rate, 2) the proportion of alterations detected, and 3) the proportion of patients receiving treatment consistent with the testing results. We estimated the long-term overall survival and progression-free survival for each treatment using parametric estimation by reconstructing patient-level data from clinical trials. The costs of testing, drugs, administration, physician visits, monitoring, adverse events, post-progression, and end-of-life care were included. The utility values were obtained from a previous study. The incremental cost-effectiveness ratio (ICER) was used to evaluate the cost-effectiveness of NGS within a threshold of $38,701 (50,000,000 KRW) per quality-adjusted life year (QALY). ResultsThe incremental life-years (LYs) and QALYs for the NGS group versus the SGT group were 0.028 and 0.023, respectively. The total medical cost for the NGS group was $8,375 higher than that for the SGT group. The difference in drug costs accounted for most of the differences in total medical costs. NGS was not cost-effective compared to sequential SGT, with an ICER of $300,233/LY and $359,405/QALY, respectively. ConclusionsNGS is not cost-effective for advanced EGFR/ALK-negative NSCLC, but has a survival benefit over sequential SGT. Our findings provide a basis for decision-making regarding the coverage and clinical utilization of NGS in regions where EGFR alterations are prevalent.

Contrast-enhanced ultrasound-guided percutaneous transhepatic cholangiodrainage is a safe and effective procedure for patients with malignant biliary obstruction and stage 3 chronic kidney disease

ObjectivesThis study aimed to validate the efficacy and safety of contrast-enhanced ultrasound-guided percutaneous transhepatic cholangiodrainage (CEUS-PTCD) as a biliary drainage procedure in patients with malignant biliary obstruction and stage 3 chronic kidney disease (CKD3). Materials and methodsBetween January 2019 and December 2023, 634 patients who underwent CEUS-PTCD were retrospectively enrolled in this study. During the procedure, imaging parameters such as the maximum diameter of the dilated bile duct, presence of ascites, detailed findings from CEUS, and clinical outcomes were meticulously recorded. Laboratory results, including serum bilirubin levels, liver function tests, and estimated glomerular filtration rate (eGFR), were evaluated in one day before and three days after procedure. The aforementioned parameters were compared using the paired-sample t test and the Wilcoxon test. ResultsA total of 66 (10.41 %) patients with malignant biliary obstruction and CKD3 were included in the final analysis (median age: 66, range: 30–89 years, 46 males and 20 females). Procedure records indicated that 23 patients (34.8 %) had a maximum biliary duct dilation diameter of ≤ 4 mm, while 5 patients (7.6 %) exhibited mild ascites. Additionally, 24 patients (36.4 %) had ultrasound contrast agent entry into both the biliary duct and bloodstream. All patients successfully achieved external bile drainage following CEUS-PTCD, with no significant complications observed during or after the intervention. Post-procedure, there was a statistically significant reduction in all previously elevated serum bilirubin and liver enzyme levels (P-values were less than 0.05). Furthermore, no statistically significant alterations in eGFR were observed prior to or following CEUS-PTCD across all patients (P = 0.295), including comparisons between groups with and without the ultrasound contrast agent into the bloodstream (P = 0.254). ConclusionCEUS-PTCD is a safe and effective biliary drainage procedure for patients with malignant biliary obstruction and CKD3.

Adenosquamous Carcinoma of the Lung: Survival, Radiologic Findings, PD-L1, and Driver Mutations.

Background: Adenosquamous carcinoma of the lung (ASC) is a rare non-small-cell lung cancer (NSCLC) subtype combining components of squamous cell carcinoma (SCC) and adenocarcinoma (AC). Data on ASC, particularly in Caucasian populations, are limited. Methods: We reviewed clinicopathological and radiological characteristics of ASC patients diagnosed between 1996 and 2023. Patients were classified into AC-predominant ASC (AC-ASC) and SCC-predominant ASC (SCC-ASC) groups for analysis. Results: Among the 66 patients included, the median overall survival was 41.7 (95% CI, 25.0-54.4), while it was 48.1 (95% CI, 27.3-88.0) in patients treated with curative surgery (n = 44) and 15.3 (95% CI, 6.5-42.6) months for palliative patients (n = 22). The five-year survival rates were 39% and 26%, respectively. Recurrence occurred in 43% of stage I patients and was associated with worse survival (HR 3.303 (95% CI, 1.10-9.89) p = 0.033). AC-ASCs (n = 17) more frequently showed air-bronchogram (p = 0.002) and pleural effusions (p = 0.054) compared to SCC-ASCs (n = 26). SCC-ASCs exhibited more vascular invasion (p = 0.006) and PD-L1 values between 1 and 49% (TPS) (p = 0.032). The subtype did not influence survival. EGFR and ALK alterations were found in 17% and 2% of patients, respectively. Conclusions: Despite early-stage disease, ASC patients had a high recurrence rate, associated with worse survival. Clinicopathologic differences between AC-ASCs and SCC-ASCs did not influence survival.

The role of molecular biomarkers in recurrent glioblastoma trials: an assessment of the current trial landscape of genome-driven oncology

For glioblastoma patients, the efficacy-targeted therapy is limited to date. Most of the molecular therapies previously studied are lacking efficacy in this population. More trials are needed to study the actual actionability of biomarkers in (recurrent) glioblastoma. This study aimed to assess the current clinical trial landscape to assess the role of molecular biomarkers in trials on recurrent glioblastoma treatment. The database ClinicalTrials.gov was used to identify not yet completed clinical trials on recurrent glioblastoma in adults. Recruiting studies were assessed to investigate the role of molecular criteria, which were retrieved as detailed as possible. Primary outcome was molecular criteria used as selection criteria for study participation. Next to this, details on moment and method of testing, and targets and drugs studied, were collected. In 76% (181/237) of the included studies, molecular criteria were not included in the study design. Of the remaining 56 studies, at least one specific genomic alteration as selection criterium for study participation was required in 33 (59%) studies. Alterations in EGFR, CDKN2A/B or C, CDK4/6, and RB were most frequently investigated, as were the corresponding drugs abemaciclib and ribociclib. Of the immunotherapies, CAR-T therapies were the most frequently studied therapies. Previously, genomics studies have revealed the presence of potentially actionable alterations in glioblastoma. Our study shows that the potential efficacy of targeted treatment is currently not translated into genome-driven trials in patients with recurrent glioblastoma. An intensification of genome-driven trials might help in providing evidence for (in)efficacy of targeted treatments.

Effect of SGLT2 inhibitors on kidney function of type 2 diabetes patients during Ramadan: A systematic review.

SGLT2 inhibitors are known for their osmotic diuretic effect, and their use by Muslim patients with type 2 diabetes during the fasting month of Ramadan may pose an increased risk of volume depletion, potentially impacting renal function. We conducted a systematic review registered on PROSPERO (registration number CRD42020204582) of studies published between 2013 and January 2023, sourced from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. The study selection criteria included controlled studies that reported the use of SGLT2 inhibitors (SGLT2i) by fasting adult type 2 diabetes patients and provided data on creatinine or estimated glomerular filtration rate (eGFR) as outcomes. Two prospective observational studies, encompassing a total of 359 participants, of which 197 utilized SGLT2 inhibitors, were identified. Our findings indicated that the use of SGLT2 inhibitors during Ramadan did not result in a significant alteration in eGFR. In one study by Hassanein et al., the mean changes in eGFR for the SGLT2i group, as compared to the non-SGLT2i group, were -1.2 ± 19.4 and 3.1 ± 14.8, respectively (p = 0.06). In a study by Shao et al., the least squares mean changes for eGFR in the SGLT2i group, compared to the non-SGLT2i group, were -6.0 ± 1.5 (95% CI, -8.9 to -3.1) and -4.2 ± 1.6 (95% CI, -7.3 to -1.1), respectively (p = 0.39). Despite the limited number of observational studies available, our analysis suggests that the use of SGLT2 inhibitors by type 2 diabetes patients during Ramadan does not appear to significantly impact kidney function.

A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell Lung Cancer (CCTG IND.242A): A Substudy of the IND.242 Platform Master Protocol

Molecularly targeted agents are increasingly being studied in the treatment of early-stage non-small cell lung cancer (NSCLC) to try and improve cure. However, phase 3 data on neoadjuvant therapy have largely been conducted in a biomarker agnostic manner with inconsistent exclusion of EGFR and ALK alterations. Our objective was to develop IND.242 as a large-scale neoadjuvant platform trial to introduce novel agents into the preoperative window for molecularly-defined NSCLC patient populations. Given that KRAS G12C mutations are common in the overall NSCLC patient population, ranging from 9.4% to 13% of cases across different cohorts, and may be associated to worse prognosis, the initial IND.242A Substudy was designed to test neoadjuvant JDQ443 (opnurasib), a selective KRAS G12C inhibitor. This current trial report describes the multicenter, Canadian Cancer Trials Group (CCTG)-led IND.242 neoadjuvant phase 2 platform master protocol and its first Substudy (IND.242A) of neoadjuvant opnurasib KRAS G12C inhibitor for patients with surgically resectable NSCLC (AJCC 8th edition stage IA2 to IIIA). In IND.242A, a maximum of 27 patients will be accrued in participating Canadian sites. The primary objective is the rate of major pathological response (MPR) following neoadjuvant opnurasib. Secondary objectives include safety and tolerability of the treatment regimen, objective response rate (ORR) by RECIST 1.1 for the neoadjuvant treatment period, pathological complete response (pCR) rate, event-free survival (EFS) at 2 years, and surgical outcomes. Exploratory objectives are to explore patient related outcomes (PROs) and identify potential predictive biomarkers of response and mechanisms of resistance on tissue and peripheral blood samples.

Targeted DNA Sequencing in Diagnosis of Malignant Phyllodes Tumors With Emphasis on Tumors With Keratin and p63 Expression

The differential diagnosis of malignant spindle cell neoplasms in the breast most frequently rests between malignant phyllodes tumor (MPT) and metaplastic carcinoma (MBC). Diagnosis of MPT can be challenging due to diffuse stromal overgrowth, keratin (CK) and/or p63 immunopositivity, and absent CD34 expression, which can mimic MBC, especially in core biopsies. Distinction of MPT from MBC has clinical implications, with differences in surgical approach, chemotherapy, and radiation. In this study, we evaluated MPTs (78 tumors, 64 patients) for stromal CK, p63, and CD34 expression and profiled a subset (n = 31) by targeted next-generation DNA sequencing, with comparison to MBC (n = 44). Most MPTs (71%) were CK+ and/or p63+, including 32% CK+ (25/77 focal) and 65% p63+ (32/66 focal, 10/66 patchy, and 1/66 diffuse). Thirty percent of MPTs expressed both CK and p63 (20/66), compared with 95% of MBCs (40/42, P < .001). CK and/or p63 were positive in CD34+ and CD34− MPTs. Recurrent genetic aberrations in MPTs involved TERT, TP53, MED12, CDKN2A, chromatin modifiers, growth factor receptors/ligands, and phosphoinositide-3 kinase (PI-3K) and MAPK pathway genes. Only MED12 (39%, 12/31) and SETD2 (13%, 4/31) were exclusively mutated in MPTs and not MBCs (P < .001 and P = .044, respectively), whereas PIK3R1 mutations were only found in MBCs (37%, 13/35, P < .001). Comparative literature review additionally identified ARID1B, EGFR, FLNA, NRAS, PDGFRB, RAD50, and RARA alterations enriched or exclusively in MPTs vs MBCs. MED12 was mutated in MPTs with diffuse stromal overgrowth (53%, 9/17), CD34− MPTs (41%, 7/17), and CK+ and/or p63+ MPTs (39%, 9/23), including 36% of CD34− MPTs with CK and/or p63 expression. Overall, MED12 mutation and/or CD34 expression were observed in 68% (21/31) MPTs, including 61% (14/23) of CK+ and/or p63+ tumors. Our results emphasize the prevalence of CK and p63 expression in MPTs and demonstrate the diagnostic utility of next-generation DNA sequencing, especially in MPTs with confounding factors that can mimic MBC.

Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer

IntroductionNo definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. MethodsWe retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). ResultsSixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 – 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0–22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21–34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2–23.9; p = 0.019). ConclusionChemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests.

Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years. Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.

Identification and Treatment of Lung Cancer Oncogenic Drivers in a Diverse Safety Net Setting

IntroductionAdvances in the testing and treatment of patients with non-small cell lung cancer (NSCLC) harboring oncogenic drivers have improved outcomes. Little is known about testing and treatment patterns in diverse patient populations. MethodsWe conducted a retrospective study in a diverse cohort of patients treated in the John Peter Smith safety net healthcare system. We determined patterns of blood- and tissue-based testing and treatment of patients with EGFR and ALK alterations. Cox proportional-hazards regression models were used to assess the impact of EGFR and ALK testing. ResultsA total of 220 patients were included, 97 (44%) were non-Hispanic White, 72 (33%) were Black, 28 (13%) were Hispanic, and 23 (10%) were Asian. EGFR and ALK testing increased over time from 55% and 52%, respectively, in 2017 to 87% and 82%, respectively, in 2021. Frequency of EGFR alterations were highest in Asian patients (45%) and comparable among other groups (6-13%). Frequency of ALK alterations were highest in Hispanic (13%), and Asian (11%) patients, and were 2% for both Black and non-Hispanic White patients. In a multivariate model, lack of testing was associated with worse survival (aHR 1.6; P = .003) and testing positive for EGFR (aHR 0.43; P = .01) or ALK (aHR 0.28; P = .04) was associated with improved survival. Race and ethnicity were not associated with survival differences. ConclusionAs molecular testing for oncogenic mutations in NSCLC increases, druggable alterations such as ALK and EGFR can be identified in all race-ethnicity groups and are associated with improved outcomes.

Landscape of Concomitant Driver Alterations in Classical EGFR-Mutated Non-Small Cell Lung Cancer.

Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored. We profiled concomitant driver alterations of EGFR+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with EGFR+ NSCLC. Out of the total patient population, 334 patients had EGFR mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing EGFR mutations include KRAS at 53.9%, followed by ERBB2 at 24.3%, MET at 16.5%, and BRAF at 3.3%. KRAS mutations in concomitant drivers were frequently hyperexchange mutations (25.6% v 8.2%, P < .001), compared with KRAS single drivers. EGFR/ERBB2 drivers exhibited a higher incidence of ERBB2 amplification (40.7% v 16.5%, P < .001) and p.S310F/Y mutations (44.4% v 4.3%, P < .001) compared with ERBB2 alone. EGFR/MET drivers had a higher frequency of MET amplification (71.4% v 43.3%) than MET single drivers. At the genomic level, the median number of additional concurrent mutations was four, with TSC2 (4%), CD274 (1%), and TP53 (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that EGFR mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant MET amplification exhibited worse prognosis. These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.

Ancestry-associated co-alteration landscape of KRAS and EGFR-altered non-squamous NSCLC

Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.

Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer

BackgroundMobocertinib, an EGFR exon 20 insertion (Ex20ins)–specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown. MethodsTo investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation. ResultsEGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response. ConclusionsOur study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.

Landscape of Clinically Relevant Genomic Alterations in the Indian Non-small Cell Lung Cancer Patients

BackgroundThe genomic landscape of non-small cell lung cancer (NSCLC) in the Indian patients remains underexplored. We revealed distinctive genomic alterations of Indian NSCLC patients, thereby providing vital molecular insights for implementation of precision therapies. MethodsWe analyzed the genomic profiles of 325 lung adenocarcinoma and 81 lung squamous carcinoma samples from Indian patients using targeted sequencing of 50 cancer related genes. Correlations between genomic alterations and clinical characteristics were computed using statistical analyses. Additionally, we identified distinct features of Indian NSCLC genomes by comparison across different ethnicities. ResultsOur genomic analysis revealed several noticeable features of Indian NSCLC patients. Alterations in EGFR (45.8%), TP53 (27.4%), ALK (11.4%) and KRAS (10.2%) were predominant in adenocarcinoma, with 68% eligible for targeted therapies. Squamous carcinoma exhibited prevalent alterations in TP53 (40.7%), PIK3CA (17.3%), and CDKN2A (8.6%). We observed higher frequency of EGFR alterations (18.5%) in lung squamous carcinoma patients, significantly distinct from other ethnicities reported till date. Beyond established correlations, we observed 60% of PD-L1 negative squamous patients harbored TP53 alterations, suggesting intriguing therapeutic implications. ConclusionsOur data revealed unique genomic variations of adenocarcinoma and squamous carcinoma patients, with significant indications for precision medicine and clinical practice of lung cancers. The study emphasizes the importance of clinical utility of NGS for routine diagnostics.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

Current status of precision oncology in adult glioblastoma.

The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor inadults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E-mutated GBM benefit from BRAF/MEK-inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (< 10%) of targeted treatments. Efficacy was observed in one-third and currently appears to be limited to BRAF-, VEGFR-, and mTOR-directed treatments. Advancing precision oncology for GBM requires consideration of pathways instead of single alterations, new trial concepts enabling rapid and adaptive drug evaluation, a focus on drugs with sufficient bioavailability in the CNS, and the extension of target discovery and validation to the tumor microenvironment, tumor cell networks, and their interaction with immune cells and neurons.

Molecular Characteristics and Pretreatment Neutrophil-to-Lymphocyte Ratio as Predictors of Durable Clinical Benefit from Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer

BackgroundPrior research in non-small cell lung cancer (NSCLC) has shown that tumors with specific driver mutations may be less likely to respond to immune checkpoint inhibitors (ICI). In this analysis, we evaluated the characteristics of patients with durable clinical benefit (DCB) to ICI compared to those with no durable clinical benefit (NDB), with emphasis on the role of molecular alterations in EGFR, ALK, and ROS1 and pretreatment neutrophil-to-lymphocyte ratio (NLR). MethodsWe retrospectively collected clinical characteristics and outcomes for patients who initiated ICI monotherapy for advanced NSCLC at Stanford University between April 2015 and May 2018. Patients were classified as having DCB if time on ICI therapy was greater than or equal to 180 days, or NDB if less than 180 days. Outcomes included best radiographic benefit while on ICI and survival from time of ICI initiation. ResultsOf 123 patients treated with ICI for NSCLC, 28 patients had DCB (23%), while 95 had NDB (77%). Median overall survival from initiation of ICI in the 33 patients with molecular alterations in EGFR (n = 31), ALK, or ROS1 and NLR of 5.9 or higher was 2.0 months, compared to 8.1 months in patients with these genomic alterations and NLR less than 5.9. Median overall survival in patients without alterations in EGFR, ALK, or ROS1 and NLR of 5.9 or higher was 4.3 months, compared to 12.1 months in patients with NLR less than 5.9 (P = .023). ConclusionsElevation in pretreatment NLR was associated with significantly lower overall median survival from initiation of ICI, particularly when in combination with NSCLC with alterations in EGFR, ALK, or ROS1. This finding could influence clinical practice as NLR is readily available through routine blood testing.

HGG-16. PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA OF METHYLATION-BASED RTK2A AND RTK2B SUBCLASSES PRESENT DISTINCT RADIOLOGICAL AND HISTOMOLECULAR FEATURES

Abstract BACKGROUND Diffuse pediatric-type high-grade gliomas (pedHGG), H3-wildtype and IDH-wildtype, encompass three main methylome-based subclasses: pedHGG-MYCN, -RTK1A/B/C, and -RTK2A/B. Since their first description in 2017, tumors of pedHGG-RTK2A/B have not been further characterized and their clinical significance is unknown. METHODS A not yet published cases series on pedHGG with a gliomatosis cerebri (GC) growth pattern showed an increased incidence of pedHGG-RTK2A/B (n=18/40). We assembled a cohort of 14 additional methylation-based pedHGG-RTK2A/B tumors and pooled them with the GC tumors providing centrally reviewed radiological, histological, and molecular characterization. RESULTS Our cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 RTK2A (78%) and seven RTK2B (22%) cases. The median age was 11.6 years (4-17) with an overall survival of 15.9 months (interquartile range 12.1-25.8). Of the additional unselected cases with available imaging (10 of 14), seven showed a GC phenotype at diagnosis or follow-up. In addition, pedHGG-RTK2B tumors exhibited bithalamic involvement (6/7, 86%). Histopathology confirmed a diffuse glial neoplasm in all cases with prominent angiocentric features in both subclasses. Most tumors (24/29, 83%) diffusely expressed EGFR, notably with a focal perivascular enhancement. Cells of pedHGG-RTK2A lacked Olig2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed Olig2. Loss of ATRX expression occurred in four pedHGG-RTK2B samples (57%). In sequencing analyses (RTK2A: n=18, RTK2B: n=5), EGFR alterations (n=15/23, 65%; predominantly point mutations) were commonly found in both subclasses. Mutations in BCOR (n=14/18, 78%), SETD2 (n=7/18, 39%), and TERT promoter (n=6/18, 33%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 mutations (4/5, 80%). CONCLUSIONS In conclusion, genotype-phenotype correlations in a multicenter series of pedHGG-RTK2A/B tumors revealed a highly diffuse-infiltrating tumor frequently exhibiting a GC phenotype. The two subclasses share particular histomolecular features (EGFR alterations, angiocentric pattern), whereas they differ in specific characteristics (pedHGG-RTK2A: Olig2 negativity, BCOR and SETD2 mutations; pedHGG-RTK2B: ATRX and TP53 alterations).

DIPG-44. DIFFUSE MIDLINE GLIOMA, H3K27-ALTERED: A COMPREHENSIVE CLINICAL AND BIOMOLECULAR LANDSCAPE OF THE NON-PONTINE TUMORS

Abstract BACKGROUND Since 2016, the WHO classification of CNS tumors groups all midline gliomas with H3K27me3 loss under the term diffuse midline glioma (DMG), H3K27-altered. Molecular characteristics enable their sub-classification based on driver mutations, co-driver mutations and epigenetic alterations. Predominantly studied in the pons (Diffuse Intrinsic Pontine Glioma, DIPG), where these are mainly pediatric tumors with a median overall survival (OS) of one year, fewer studies have been conducted on non-pontine DMG (npDMG), prompting this study to clinically and biologically characterize these gliomas and compare them with DIPG. METHODS Retrospective monocentric study from 1994 to 2022, including pediatric and adult patients diagnosed with npDMG, H327-altered with neuropathological confirmation at Sainte Anne Hospital in Paris, France. Comparative literature review of cases of npDMG and series of DIPG. RESULTS 108 patients were included (54.7% male, median age 13.05-years [2.4-59.3]). The most frequent location was monothalamic (62.9%), followed by bithalamic, spinal, cerebellar, bulbo-medullar and other. H3K27M mutation was found in 85.2% of cases, EZHIP overexpression in 14.8% and EGFR alteration (mutation and/or amplification) in 16.7%. EZHIP-overexpressing patients were younger than H3K27M-mutated patients, as were EGFR-altered patients compared to those without EGFR alteration. Along with data from the literature, npDMG are older at diagnosis and have a slightly longer median OS (15 months [0.1-247.2]) than DIPG. Positive prognosis factors upon univariate analysis included longer time from symptom onset until diagnosis, treatment with ONC201, re-irradiation upon relapse, microcalcifications, proliferative index &amp;gt;10%, MAP kinase alteration and absence of TP53 mutation and EGFR amplification. However, surgery quality did not impact OS. CONCLUSIONS npDMG is a heterogeneous group of gliomas, affecting all ages, which can develop in diverse locations, with an overall poor prognosis. Despite shared clinical, immuno-histochemical and molecular properties with DIPG, recent molecular biology advancements reveal distinct subtypes within DMG, with varying prognoses, challenging the unified classification.