Molecular Profiling of Olfactory Neuroblastoma Using the AACR Project GENIE Database.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international data-sharing consortium focused on enabling advances in precision oncology through the gathering and sharing of tumor genetic sequencing data linked with clinical data. The project’s history, operational structure, lessons learned, and institutional perspectives on participation in the data-sharing consortium are reviewed. Individuals involved with the inception and execution of AACR Project GENIE from each member institution described their experiences and lessons learned. The consortium was conceived in January 2014 and publicly released its first data set in January 2017, which consisted of 18,804 samples from 18,324 patients contributed by the eight founding institutions. Commitment and contributions from many individuals at AACR and the member institutions were crucial to the consortium’s success. These individuals filled leadership, project management, informatics, data curation, contracts, ethics, and security roles. Many lessons were learned during the first 3 years of the consortium, including on how to gather, harmonize, and share data; how to make decisions and foster collaboration; and how to set the stage for continued participation and expansion of the consortium. We hope that the lessons shared here will assist new GENIE members as well as others who embark on the journey of forming a genomic data–sharing consortium.

e18142 Background: Follicular thyroid carcinoma (FTC), the second most common thyroid cancer, is diagnostically challenging due to overlapping features with benign adenomas, often requiring histologic review. While surgery and +/- adjuvant radioiodine ablation are standard therapy, radioiodine resistance underscores the need to define molecular drivers for targeted therapies. Using the AACR GENIE database, this study characterizes FTC’s mutational landscape to identify prognostic markers and therapeutic targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE)® database was accessed from cBioPortal (v16.1-public) on July 22, 2024 to identify all patients with FTC. The most common gene mutations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg False Discovery Rate (FDR) correction. Results: The cohort comprised 168 follicular thyroid cancer (FTC) samples from 161 patients. The patient population was predominantly female (n=101, 62.7%) and adult (n=149, 92.5%), with a smaller pediatric subset (n=18, 11.2%). By race, the cohort consisted primarily of White (n=107, 66.5%) and Black (n=13, 8.1%) patients, with the remaining patients (n=41, 25.4%) categorized as Asian, other, or unspecified. Samples were derived from primary (n=89, 55.3%) and metastatic (n=64, 39.8%) tumors. The most frequent mutations were observed in NRAS (33.9%, n=57), TERT (22.6%, n=38), DICER1 (15.5%, n=26), HRAS (11.9%, n=20), and PTEN (10.7%, n=18). Mutual exclusivity was found between NRAS and HRAS (p<0.001) and between NRAS and DICER1 (p=0.02). NRAS mutations were detected in 29.2% of primary tumors (n=26/89) and 42.2% of metastatic samples (n=27/64). DICER1 mutations were more prevalent in primary tumors (16.1%, n=10/62) compared to metastatic disease (2.0%, n=1/51; p<0.02). Mutations in BOD1L1 , UMODL1 , CDH23 , and NCOR2 were enriched in females (p<0.001). DICER1 mutations were more frequent in pediatric samples (44.4%, n=8/18) than in adult samples (4.6%, n=5/109; p<0.001), while TERT mutations were almost exclusively present in adults (p<0.001). NRAS was the most common mutation in adults (35.3%, n=53/150), whereas DICER1 was the most common in pediatric patients (44.4%, n=8/18). Conclusions: This study reveals NRAS and TERT as key drivers of FTC, with NRAS linked to metastatic progression and DICER1 enriched in pediatric and primary tumors. The mutual exclusivity of NRAS/HRAS and NRAS/DICER1 suggests divergent oncogenic pathways. Sex-specific mutations (e.g., BOD1L1 , NCOR2 ) and pediatric-adult disparities highlight the need for demographic-tailored therapies. These findings prioritize NRAS and TERT as targets for novel inhibitors or immunomodulators, particularly in radioiodine-resistant or metastatic FTC.

Anaplastic ependymoma (AE) is a rare and aggressive central nervous system tumor that predominantly affects children and remains inadequately characterized at the genomic level. This study aimed to delineate the genomic and demographic landscape of histologically defined AE while identifying potential therapeutic targets. We conducted a retrospective analysis of AE cases from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository via cBioPortal, examining recurrent somatic mutations, copy number alterations, mutation co-occurrence, and exploratory sex- and race-based enrichment using descriptive and non-parametric statistics. The most frequent alterations included mutations in the telomerase reverse transcriptase (TERT) promoter, followed by recurrent changes in lysine methyltransferase 2D (KMT2D), lysine methyltransferase 2A (KMT2A), lysine methyltransferase 2C (KMT2C), E1A binding protein p300 (EP300), additional sex combs like 1 (ASXL1), and SET domain containing 2 (SETD2), indicating significant disruption of chromatin remodeling. Recurrent alterations in tumor protein p53 (TP53), ataxia telangiectasia mutated (ATM), and cyclin-dependent kinase inhibitor 2A (CDKN2A) suggested dysregulation of the p53 and DNA damage response pathways. Additionally, alterations in notch receptor 1 (NOTCH1) and notch receptor 2 (NOTCH2) indicated aberrant NOTCH signaling. Neurofibromin 2 (NF2) mutations were observed in male patients, and exploratory subgroup differences emerged across racial groups. Overall, AE appears to be driven by recurrent alterations in chromatin remodeling, p53, DNA damage response, and NOTCH signaling pathways, highlighting these areas as priorities for future biological validation and therapeutic investigation.

Purpose: The first comprehensive analysis of the detailed clinico-genomic landscape of the breast cancer (BC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). Methods: We analyzed 1, 045 BC patients treated at three GENIE-participating institutions. Breast cancer patients in the GENIE registry aged 18-56 at sequencing and with tumor(s) sequenced between 2013 and 2018 were randomly chosen for curation using the PRISSMM framework. Sites of distant metastasis were captured from imaging and pathology reports. A previously published cohort of older patients was used as a point of comparison in identifying age-related differences. Overall survival (OS) was estimated for patients with advanced disease. Results: Clinical and genomic features were compared across the four subtypes HR+/ HER2 - (N=660), HR+/HER2+ (N=138), HR-/HER2+ (N= 74), and TNBC (n = 173). The age distribution was similar across subtypes, HR+/HER2+ had the highest percentage of patients ages 18-39 (HR+/HER2-: 28%, HR+/HER2+: 39%, TNBC: 33%, HR-/HER2+ 35%). The most frequently altered genes in the cohort were TP53 (HR+/HER2-: 33%, HR+/HER2+: 58%, TNBC: 95%, HR-/HER2+ 80%), PIK3CA ( HR+/HER2-: 35%, HR+/HER2+: 33%, TNBC: 8%, HR-/HER2+ 15%), and ERBB2 (HR+/HER2-: 3%, HR+/HER2+: 71%, TNBC: 2%, HR-/HER2+ 84%). Analysis of patients with metastatic disease (n=818) revealed robust associations with OS and TP53 (HR = 1.87, SF = 100%), ERBB2 amplification (HR = 0.61, SF = 98%), MYC (HR = 1.09, SF = 52%), FGFR2 (HR=0.89, SF = 49.3%), MAP3K1 (HR = 0.94, SF = 35%), DDR2 (HR = 1.09, SF = 33%) and ESR1 (HR=1.07, SF = 32.7%). In a comparison of older and younger patients with HR+/HER2- subtype, we found that mutations in TP53 (18-39: 35% vs >60: 22%), GATA3 (18-39: 21% vs >60: 10%), and MAP2K4 (18-39: 10% vs >60: 4%) were significantly (q<0.1) more prevalent among younger patients. Conversely, PIK3CA (18-39: 31% v >60: 48%), CDH1 (18-39: 3% v >60: 21%), and MAP3K1 (18-39: 5% v >60: 12%) showed higher alteration rates in seniors. These trends were consistent at pathway level with higher alteration of p53 (18-39: 44% vs >60: 29%) and PI3K (18-39: 46% vs >60: 62%). In patients with any distant metastases, we calculated the metastatic burden, or the number of distant metastases reported in key sites of interest. Patients with a history of adrenal Metastasis had a higher metastatic burden (49/61, 80.3% with at least 4 distinct sites recorded) than those with no adrenal metastasis recorded (326/764, 42.6% with at least 4 distinct sites recorded). Conclusions: The GENIE BPC cohort provides a comprehensive clinico-genomic dataset enriched with younger patients with BC, providing a valuable source to improve our understanding of age-related clinical and genomic characteristics and their impact on real-world patient outcomes. Citation Format: Evan Seffar, Brooke Mastrogiacomo, Alex Paynter, Protiva Rahman, Jesus Fuentes Antras, Sonya A. Reid, Nikolaus Schultz, Michael J. Hassett, Ben Park, Shawn Sweeney, Walid K. Chatila, Pedram Razavi. The GENIE BPC BRCA Cohort: a real-world repository of standardized clinical and genomic data for young patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1118.

8534 Background: Mutations in the human epidermal growth factor receptor 2 (ERBB2; HER2) are oncogenic in lung adenocarcinoma (LUAD). An FDA-approved drug, trastuzumab deruxtecan, is now available as second line treatment (rx) of patients (pts) with HER2 mutated NSCLC. HER2 activation occurs via gene mutation (mt), gene amplification (amp), or protein overexpression. Further information is needed about HER2 alterations (alt) and the potential association with rx response. The purpose of this study is to describe the genomic landscape of a cohort of pts with HER2 alt LUAD in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). Methods: In a cohort of 16,241 NSCLC LUAD pts available in GENIE v.13.0, we analyzed the association of HER2 alt (mt/amp) with alt in other driver genes. Also, we assessed the relationship between HER2 alt and expression levels using TCGA and CPTAC cohorts (566 and 110 pts), and prognosis using GENIE NSCLC BPC cohort (1,846 pts). Results: LUAD pts were classified as having KRASmt (K; 6426 pts; 31.9%), EGFRmt (E; 5256 pts; 26%) or EML4-ALK fusion (A; 102 pts; 0.5%). The remainder were classified as “KRAS/EGFR/ALK other (KEAother).” HER2mt (6.06%) and amp (2.06%) were more frequent in the KEAother cohort(p<0.001). HER2 amp were also found more frequently in the E deletion(del) mt cohort (1.63%), compared to KA cohorts (p<0.001). Additionally, there was significant co-occurrence of HER2 mt and HER2 amp (OR 6.49; p<0.001) in the KEAother cohort. HER2mt/amp had significant odds of co-occurrence with TP53 alt (OR 1.43; p<0.001), CDKN2A del (OR 2.15; p<0.001), TERT amp (OR 2.37; p<0.001), RB1 alt (OR 1.6; p<0.001). Additionally, HER2 amp co-occurred with TP53 alt (OR 4.0; p<0.001), CDKN2A del (OR 3.44; p<0.001), while HER2 mt co-occurred with CDKN2A del (OR 2.03; p<0.001), TERT amp (OR 2.43; p<0.001). BRAF mts were mutually exclusive with HER2 mt/amp (OR 2.31; p<0.001) and HER2 mt (OR 1.93; p<0.001). In the E cohort, there was a significant rate of HER2 mt or amp co-occurring with RB1 alt (OR 2.95; p<0.001). Despite limited survival data in the GENIE database, HER2 mt and amp had a trend toward inferior mOS (HER2mt 29.4 months vs HER2amp 27.8 months vs HER2wt 51.0 months), but this difference was not statistically significant. High HER2 mRNA expression is associated with increased age, while low expression is associated with stage IV disease. Pts with high HER2 expression that never smoked, have a trend toward inferior mOS (p=0.19), but this is based on a limited number of pts (n=18). Conclusions: HER2 mts are found in 1-4% of pts with NSCLC but can be identified in up to 6% of KEAother NSCLC. In contrast to prior reports, there was a significant rate of co-occurring HER2 mt and HER2 amp. BRAF mts were mutually exclusive with both HER2 mt and amp. Further analysis using the Caris database is planned to evaluate clinical outcomes by HER2 alt, co-mts, and prior rx received.

Large gene profiling program is feasible, but challenging.

<div>AbstractPurpose:<p>We describe the clinical and genomic landscape of the non–small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC).</p>Experimental Design:<p>A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies.</p>Results:<p>In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with <i>EGFR</i> (20%), <i>KRAS</i> G12C (13%), and oncogenic fusions (<i>ALK, RET</i>, and <i>ROS1</i>; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9–19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5–11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1–8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2–2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7–2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; <i>P</i> = 0.03; <i>n</i> = 247 patients).</p>Conclusions:<p>The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.</p></div>

<div>Abstract<p>The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally.</p>Significance:<p>AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 2007</a></i></p></div>

Purpose:We describe the clinical and genomic landscape of the non–small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC).Experimental Design:A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies.Results:In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9–19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5–11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1–8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2–2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7–2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients).Conclusions:The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.

Background: Limited information is available about treatments and clinical outcomes among men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbor DNA damage repair (DDR) mutations. Methods: This retrospective chart review study included men diagnosed with mCRPC with ≥1 DDR mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the initiation of a new therapy in this period, in patients who developed castration-resistant disease and progressed while receiving androgen deprivation therapy. Data on all available lines of therapy post-index were collected. Outcomes reported include time to treatment discontinuation for any reason (TTTD) and overall survival (OS), which were assessed using Kaplan-Meier analyses. Results for tumor response-related endpoints are forthcoming. Results: A total of 138 patients with mCRPC met the inclusion criteria. The mean age at index was 68 years, and 76% of patients were White. The median follow-up time was 27.1, 15.9, 11.3, and 9.4 months for 1L, 2L, 3L, and 4L+ therapy, respectively. Common sites of metastases included bone (74%), lymph nodes (69%), and lungs (10%). Common tumor DDR mutations included CDK12 (48%), BRCA2 (23%), ATM (21%), and BRCA1 (8%). Assessment of germline mutations was conducted in 114 (83%) patients; the most common was BRCA2 (8%). First-line (1L) treatment information was available for 119 (86%) patients, 2L for 101 (73%), and 3L for 75 (54%) patients. Novel hormonal therapy (NHT; 55%) and taxane chemotherapy (20%) were most common in 1L. Enzalutamide (35%) and abiraterone acetate (14%) were the most frequently used NHTs. Compared to 1L, the proportion of patients receiving NHTs was lower in 2L (33%) and 3L (17%), while the proportion of patients receiving taxanes was higher (36% in 2L and 31% in 3L). In 3L, poly ADP-ribose polymerase (PARP) inhibitors were used in 21% of patients. Median TTTD was 5.6 months (95% CI: 4.2, 7.2) in 1L, 3.9 months (95% CI: 3.0, 4.6) in 2L, and 4.0 months (95% CI: 3.3, 4.7) in 3L. Median OS was 36.3 months (95% CI: 30.7, 47.8) from the start of 1L, 21.1 months (95% CI: 15.6, 29.3) from the start of 2L, and 14.1 months (95% CI: 9.5, 20.5) from the start of 3L. Conclusions: These findings provide real-world insights about treatment patterns and clinical outcomes among patients with mCRPC harboring DDR mutations. Such insight may provide a helpful benchmark for research aimed at improving clinical outcomes, particularly in later lines of therapy. Citation Format: David B. Solit, Niharika B. Mettu, Shannon J. McCall, Mallika Dhawan, Priyanka J. Bobbili, Maral DerSarkissian, Jasmina Ivanova, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Tracy Guo, Mei Sheng Duh, William K. Oh. Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 930.

Background: While there is growing interest in targeted therapy for non-small cell lung cancer (NSCLC) in perioperative settings, data on key oncogenic driver mutations is limited in early-stage NSCLC. This real-world database study aims to evaluate the prevalence of select genomic alterations in stage I-III NSCLC. Methods: From the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) V2.1-consortium dataset, we included adult patients with a confirmed diagnosis of NSCLC who had genomic testing using stage I-III NSCLC tissue samples. Descriptive statistics were used to summarize baseline characteristics and the prevalence of select genomic alterations. Results: A total of 465 patients were included in this study, of whom 61% were female, 85% were white, 19% were never smokers, and 77% had adenocarcinoma. Less than 2% of the study population had BRAF V600E, HER2 activating mutations, HER2 amplification, MET amplification, HER3 amplification, RET fusion, ALK fusion, or ROS1 fusion. Among genomic alterations with a prevalence of 2% or higher, such as EGFR sensitizing mutations, KRAS G12C, MET exon 14 skipping, STK11, KEAP1, and TP53, some variations in prevalence were observed across baseline patient and disease characteristics such as race, smoking status, and histology (Table 1). Conclusion: The prevalence of key oncogenic drivers and its relationship to select baseline disease characteristics among patients with early-stage NSCLC are similar to those of advanced NSCLC observed in other real-world clinico-genomic databases. Table 1. Prevalence of Select Genomic Alterations in Stage I-III NSCLC (N=465) Prevalence of Positive Biomarker Status (%) EGFR KRAS G12C MET Exon 14 Skipping STK11* KEAP1* TP53 Overall 17.6 12.7 4.5 16.0 11.0 52.7 Gender Male 7.1 9.3 5.5 18.5 18.5 59.6 Female 24.5 15.9 3.9 14.3 6.3 48.2 Race White 15.6 14.1 4.5 16.5 12.0 53.7 Black 15.0 5.0 5.0 22.2 11.1 60.0 Asian 44.0 4.0 8.0 8.3 4.2 44.0 Smoking Status Never smoker 41.4 1.2 6.9 4.7 1.2 36.8 Former smoker 13.7 16.0 4.6 17.4 12.9 52.4 Current smoker 5.7 12.9 1.4 23.9 15.4 72.9 Histology Adenocarcinoma 20.1 14.3 4.6 18.1 10.4 46.0 Squamous cell carcinoma 0 2.9 4.4 4.6 14.1 86.8 *The numbers of patients tested for STK11 and KEAP1 were 457 and 445, respectively. Citation Format: Ke Zu, Jiemin Ma, Cai Chen, Christine Pierce. The prevalence of key oncogenic driver mutations in stage I-III non-small cell lung cancer: Results from the AACR GENIE BPC dataset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4977.

Background: The phosphatidylinositol-3-kinase (PI3K) pathway, driven by the PIK3CA gene, is crucial for tumor initiation, growth, proliferation and therapy resistance. PIK3CA mutations (PIK3CAm) occur in ∼35% of all breast cancers (BC), most commonly in estrogen receptor positive (ER+) and HER2-negative BC. In HER2-positive (HER2+) BC, these mutations are found in ∼25-30% of cases. Although PIK3CAm are linked to lower rates of pathological complete response (pCR) in the neoadjuvant setting for HER2+ patients (pts), the prognostic significance of somatic PIK3CAm remains unclear. In the recently presented phase 3 Destiny Breast09 trial, the presence of a PIK3CAm was identified as a marker of early progression in HER2+ metastatic BC (mBC) on first line therapy with trastuzumab/pertuzumab monoclonal antibody therapy. We, therefore, aimed to evaluate the impact of PIK3CAm status on clinical outcomes in HER2+ BC pts receiving first- and second-line therapy. Methods: We analyzed clinico-genomic data from the BC cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (version 1.2), which includes pts diagnosed between 18-56 years of age who underwent tumor sequencing between 2013 and 2020. We included adult HER2+ BC pts who had received at least one line of therapy. The primary outcomes were overall survival (OS) and progression-free survival (PFS). We used Kaplan-Meier curves to estimate and compare OS and PFS. Univariable and multivariable Cox proportional hazard regressions were used to compare outcomes between patient groups, accounting for line of therapy. Subgroup analysis was performed according to TNM stage and PIK3CA wild type (wt) vs PIK3CAm. Results: We included 212 pts, of which 58 (27.3%) had a documented PIK3CAm. Of the 212, 62 were mBC, of which 15 (26%) had PIK3CAm. The median age at diagnosis was 43. Most patients were White (77%), Non-Hispanic (95%), and initial TNM stage II BC diagnosis (33%). Statistically significant differences between PIK3CAm and PIK3CAwt were observed in use of endocrine therapy (78% vs 62%, p=0.04) as well as the median time to distant metastasis (38 vs 22 months, p= 0.01). The observed median OS for the overall cohort starting from the date of first-line therapy, was 121.8 months. Median OS between pts with PIK3CAm and PIK3CAwt did not significantly differ (121.8 vs. 125.1 months, p=0.42). In the multivariable Cox regression, line of therapy was not significantly associated with an increased risk of death. The observed median PFS for the overall cohort from start of first-line therapy was 14.2 months. These results showed a trend by PIK3CAm status: 20.3 months for PIK3CAwt and 6.9 months for PIK3CAm (p=0.4). Multivariable Cox regression also revealed a higher associated risk of progression for patients with PIK3CAm on their second line of therapy (HR = 2.65, 95% CI 1.02-6.94). These findings were consistent in the subgroup analysis by TNM stage (Stages I-III and Stage IV). Conclusion(s): In this real-world cohort of HER2+ BC patients, PIK3CA mutations were not associated with worse median OS but demonstrated a trend toward shorter median PSF survival in early lines of therapy. Multivariable analysis revealed that patients with PIK3CAm receiving second-line therapy had a statistically significant 2.6-fold increased associated-risk of disease progression. These findings suggest the presence of a PIK3CAm may serve as a negative predictive biomarker for treatment duration in HER2+ disease. Given that approximately 30% of HER2+ BC harbor PIK3CAm, our results support prioritizing clinical investigation of PI3K inhibitors in combination with anti-HER2 therapy in the first-line metastatic setting for HER2+/PIK3CA-mutant BC to optimize treatment sequencing and potentially delay disease progression. Citation Format: N. Stabellini, S. D. de Oliveira, T. Mizukami, A. J. Montero. Impact of somatic PIK3CA Mutations on clinical outcomes in HER2-Positive Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-06-23.

Background/AimT-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers.Materials and MethodsThis study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001.ResultsFrequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations.Conclusion This study provides a comprehensive genomic profile of T-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development.

Background: Limited information is available about real-world treatment patterns and survival among patients with metastatic breast cancer (mBC) with BRCA1/2 mutations. BRCA1/2 mutations, which are involved in the repair of DNA double-strand breaks, are rare. Since 2018, PARP inhibitors (olaparib and talazoparib) have been approved for the treatment of patients with germline BRCA-mutated HER2-negative locally advanced and/or mBC. Methods: This retrospective chart review study included adults diagnosed with mBC with ≥1 oncogenic somatic BRCA1/2 mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at 3 oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the first initiation of a new therapy for mBC in this period (which could be first-line [1L] or subsequent line of therapy). Data on all available lines of therapy post-index were collected. Treatments received in different lines of therapy for mBC and overall survival (OS) were described separately for patients with HR-positive/HER2-negative (HR+/HER2-) mBC, triple negative mBC (TNBC), and HER2-positive (HER2+) mBC. OS from the start of each line of therapy was assessed using Kaplan-Meier analysis. Results: A total of 48 women with mBC met the inclusion criteria. The mean age at index was 58 years; 73% of women were White. Common sites of metastases included lymph nodes (56%), bone (52%), and lungs (31%). Somatic BRCA1 mutation was detected in 48% and BRCA2 mutation was detected in 54% of women. Assessment of germline BRCA mutations was conducted in 25 (52%) women; 2 (8%) of assessed women tested positive for germline BRCA mutations. 29 (60%) of women had HR+/HER2- mBC, 9 (19%) had TNBC, 9 (19%) had HER2+ mBC, and 1 woman had unknown HER2 status. Treatments received in different lines of therapy for mBC and OS from start of each line of therapy by HR and HER2 status are reported in Table 1. Common treatments for women with HR+/HER2- mBC included endocrine-based therapy, and chemotherapy. Women with TNBC were most often treated with chemotherapy. Women with HER2+ mBC most often received endocrine-based therapy in 1L; chemotherapy or HER2-targeted combination therapy in second-line (2L); and chemotherapy or HER2-targeted monotherapy in third-line (3L). Median OS from the start of 1L therapy was 37.5 months among women with HR+/HER2- disease; 20.0 months for women with TNBC; and 51.7 months for women with HER2+ disease. Conclusions: These findings provide real-world insights about treatment patterns and survival among women with mBC and BRCA1/2 mutations. Further studies with larger sample sizes are needed to confirm these findings. Table 1. Treatment patterns and survival by line of therapy, HR, and HER2 status among patients with BRCA1/2 mutated mBC Citation Format: Priyanka Bobbili, Jasmina Ivanova, David B. Solit, Niharika Mettu, Shannon McCall, Mallika Dhawan, Maral DerSarkissian, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha J. Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Mianzhao Guo, Mei Sheng Duh, William Oh. Real-world treatment patterns and survival among adults with metastatic breast cancer with BRCA1/2 mutations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-30.

TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib