PTEN Mutations Research Articles

Abstract 936: Clinicogenomic predictors for the pattern of failure in high-grade glioma

Abstract Background: High-grade gliomas, the most common primary brain tumors, are highly lethal, and treatment options remain limited. Despite advances in genomic technologies, there are few molecular biomarkers to guide precision medicine for high-grade glioma. Here, we aimed to identify the clinicogenomic features associated with its prognosis and recurrence patterns. Materials/Methods: Our single-institution retrospective analysis included 223 patients diagnosed with high-grade gliomas who underwent next-generation sequencing targeting 82 brain tumor-relevant genes. We categorized them according to the 2021 WHO classification, and their clinicopathological statuses, treatment characteristics, survival, and genomic profiles were analyzed. Results: The most common genomic variants were TERT promoter (51%), TP53 (39%), IDH1/2 (18%), NF1 (13%), ATRX (12%), PTEN (11%), PIK3CA (9%), SETD2 (7%), and H3F3A (6%) mutation. Regarding copy number variants, amplification of EGFR (21%), PDGFRA (11%), CDK4 (9%) and loss of CDKN2A/2B (55%), PTEN (29%), 19q (17%), NF2 (14%), and RB1 (10%) were the most common copy number aberrations. At a median follow-up of 18 months (range, 2-54 months), 174 patients (78%) had progression or recurrences. A total of 15.2% of our patients were re-classified under the 2021 WHO classification, and there was a clear separation of overall survival(OS) and progression-free survival(PFS) curves between grade 3 and 4 groups using the revised grading system. On multivariate cox regression analysis, MYCN amplification (HR 6.08, p = 0.002) and SETD2 mutation (HR 0.19, p =0.06) were independent predictors of OS and PFS. Conclusion: The assessment of genomic characteristics in conjunction with the pattern of failure for high-grade glioma aids in identifying patients who are likely to benefit from personalized medicine. The 2021 WHO grading system explains survival differences between grade 3 and 4 tumors better than the 2016 WHO classification dose. We identified SETD2 mutation and MYCN as prognostic biomarkers with potential therapeutic implications in patients with high-grade glioma. Citation Format: Joo Ho Lee, Byung-Hee Kang, Seungbok Lee. Clinicogenomic predictors for the pattern of failure in high-grade glioma [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 936.

891 Next Generation Sequencing Mutational Profiles of Gliomas Presenting With and Without Seizure

INTRODUCTION: Seizures are among the most common presentation of gliomas in adults, but much remains unknown regarding the relationship between underlying tumor biology and epileptic activity. METHODS: We conducted a single-center retrospective review of 140 adult patients who underwent surgical management of glioma with next generation sequencing of tumor samples obtained 2016-2020. Univariate odds ratios were computed for relevant cohort characteristics. RESULTS: Among patients with documented seizure history, 71 (51.1%) presented with seizures while 68 (48.9%) did not. At time of diagnosis, patients presenting with seizure were younger (47 vs 60.5, p = 0.0001) and had more recurrent disease (60.6% vs 16.7%, p < 0.0001). Patients presenting with seizure had fewer glioblastomas (OR: 0.2 [0.09-0.41], p < 0.0001) but more astrocytomas (OR: 4.78 [1.68-13.65], p = 0.0038) and oligodendrogliomas (OR: 3.47 [1.07-11.27], p = 0.0557). Of the top 15 most common mutations in our cohort, patients presenting with seizure had fewer instances of IDH1 (OR: 5.26 [2.44-11.32], p<0.0001), polysomy 7/monosomy 10 (OR: 0.48 [0.24-0.95], p = 0.0523), and PTEN mutation (OR: 0.46 [0.22-0.98], p = 0.0646), but more instances of 1p/19q codeletion (OR: 3.47[1.07-11.27], p = 0.0557), ATRX (OR: 2.54 [1.15-5.59], p = 0.0315) and CIC (OR: 13.63 [1.72-107.97], p = 0.0046) mutations. Notably, mutations in NF1 (OR: 0.73 [0.28-1.88)], p = 0.6753), TP53 (OR: 1.1 [0.56-2.15], p = 0.9194), TERT (OR: 0.63 [0.31-1.28], p = 0.2679), CDKN2A/B (OR: 0.61 [0.31-1.21], p = 0.2154), and EGFR (OR: 0.49 [0.21-1.13], p = 0.1396) were not associated with seizure presentation. CONCLUSIONS: ATRX and CIC mutations are positively associated with seizure presentation while polysomy 7/monosomy 10 and PTEN mutations are negatively associated. Future analysis of this cohort is needed to better characterize the influence of tumor mutational profile on preoperative as well as postoperative seizure activity.

MP17-19 GENE MUTATIONS AMONG PROSTATE CANCER PATIENTS WITH A SMOKING HISTORY

You have accessJournal of UrologyCME1 Apr 2023MP17-19 GENE MUTATIONS AMONG PROSTATE CANCER PATIENTS WITH A SMOKING HISTORY Ahmed El-shafie, Allison H. Feibus, Mohammed Al-Toubat, Navid Lelani, SeyedBehzad Jazayeri, Kashyap Koul, Robert A. Marino, Mark Bandyk, Joseph Costa, and K. C. Balaji Ahmed El-shafieAhmed El-shafie More articles by this author , Allison H. FeibusAllison H. Feibus More articles by this author , Mohammed Al-ToubatMohammed Al-Toubat More articles by this author , Navid LelaniNavid Lelani More articles by this author , SeyedBehzad JazayeriSeyedBehzad Jazayeri More articles by this author , Kashyap KoulKashyap Koul More articles by this author , Robert A. MarinoRobert A. Marino More articles by this author , Mark BandykMark Bandyk More articles by this author , Joseph CostaJoseph Costa More articles by this author , and K. C. BalajiK. C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003237.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tobacco smoking has been established as a risk factor for a majority of cancers, representing one of the most important modifiable risk factors. However, the association between smoking and prostate cancer (PCa) remains unclear. We compared gene mutations using a next generation sequencing (NGS) database of smokers and non-smokers with PCa. METHODS: Data is derived from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry. We included 1832 men with PCa in our study cohort, categorized as either smokers or non/never smokers. We compared the frequency of mutations (point mutations, copy number variations and structural variants) of 47 genes between the 2 groups. We also studied the association of the gene mutations with overall survival. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with mortality. RESULTS: Within the study cohort, 1007 (55%) patients were non-smokers and the remaining 825 (45%) were smokers. Patients with a smoking history had a higher percentage of somatic mutations in PREX2 (p=0.018), PTEN (p=0.02), AGO2 (p=0.03), and KMT2C (p=0.04) compared to non-smokers. In contrast, non-smokers had a higher percentage of somatic mutations in APC (p=0.02) and KMT2A (p=0.04) compared to smokers. The mortality rate was significantly higher among the smoker population (p=0.006). The presence of metastatic disease at the time of diagnosis (OR 2.26, p<0.001), smoking history (OR 1.32, p=0.02), and PTEN somatic gene mutation (OR 1.89, p<0.001) were independent predictors of mortality among patients diagnosed with PCa (Table 1). CONCLUSIONS: PCa patients with a tobacco smoking history had significantly higher somatic mutations of PREX2, KMT2C, AGO2, and PTEN genes. Moreover, PTEN somatic gene mutation is linked to mortality among patients with PCa (Figure 1). Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e220 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmed El-shafie More articles by this author Allison H. Feibus More articles by this author Mohammed Al-Toubat More articles by this author Navid Lelani More articles by this author SeyedBehzad Jazayeri More articles by this author Kashyap Koul More articles by this author Robert A. Marino More articles by this author Mark Bandyk More articles by this author Joseph Costa More articles by this author K. C. Balaji More articles by this author Expand All Advertisement PDF downloadLoading ...

PD04-03 GENETIC AND PATHWAY ALTERATIONS OF PROSTATE CANCER: FROM LOCALIZED TO METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD04-03 GENETIC AND PATHWAY ALTERATIONS OF PROSTATE CANCER: FROM LOCALIZED TO METASTATIC PROSTATE CANCER Chang Eil Yoon, Seung Ah Rhew, Hyeok Jae Kwon, Dongho Shin, and Ji Youl Lee Chang Eil YoonChang Eil Yoon More articles by this author , Seung Ah RhewSeung Ah Rhew More articles by this author , Hyeok Jae KwonHyeok Jae Kwon More articles by this author , Dongho ShinDongho Shin More articles by this author , and Ji Youl LeeJi Youl Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although prostate cancer is one of the most commonly diagnosed male cancer, because of it’s heterogeneity the treatment options are limited and the prognosis varies widely. Recently, interest in genetic analysis and targeted therapy has been increasing. In particular, Mutation in DNA repair pathways, such as BRCA1/2 genes, has been found to be associated with poor prognosis. Accordingly, the purpose of this study was to identify genetic mutations in patients with localized and metastatic prostate cancer, and to analyze the association between these genes and each patient's clinical course. METHODS: We analyzed 74 patients diagnosed with prostate cancer. Tissue specimens were obtained from prostate biopsy or surgical excision, and were analyzed through Next-generation sequencing at Seoul St. Mary's Hospital between July 1, 2021 and September 31, 2022. We retrospectively evaluated baseline characteristics including PSA score, TNM staging, Gleason’s score and the clinical course including additional treatment and biochemical recurrence. RESULTS: The patients are classified as follows: 49 localized prostate cancer and 25 metastatic prostate cancer. The average age of the patients and initial PSA values were 69.8±8.4 years and 155.6±588.1 ng/dL. 8p copy number alteration (24.3%), and SPOP(18.9%), IGF2R (17.6%), BRCA2(12.2%), NOTCH2(10.8%) gene mutations were most frequently detected gene mutations. BRCA2, NOTCH2 mutations showed a significant relationships with high M stage (p=0.041, 0.001 respectively) and high Gleason's score. (p= 0.01, 0.043 respectively. KMT2C (associated with histone methyltransferase) and TP53 (known as Tumor suppressor gene) mutations also showed high frequency (21.6%, 13.5% respectively), with KMT2C frequently found in local prostate cancer (p=0.011) and TP53 frequently found in metastatic prostate cancer (p=0.046). Although the incidence was low, PI3K pathway aberrations including PTEN (4.1%) and PIK3CA (5.4%) gene mutation was identified. Both were associated with high Gleason’s score (p=0.002, 0.048 respectively). CONCLUSIONS: Through genetic analysis of prostate cancer, it was possible to analyze numerous gene mutations, and to find clinically significant mutations. Several genes, such as BRCA2, NOTCH2 and TP53 gene mutations have been found to be associated with advanced prostate cancer. The prognosis of prostate cancer can be predicted by genetic analysis, and the better prognosis can be expected through the application of a proper targeted therapy for each pathway alterations. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e143 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chang Eil Yoon More articles by this author Seung Ah Rhew More articles by this author Hyeok Jae Kwon More articles by this author Dongho Shin More articles by this author Ji Youl Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Mesonephric-like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric-like carcinosarcomas.

To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract. We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components. Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component.

Molecular genetics of diffuse sclerosing papillary thyroid cancer.

Diffuse sclerosing papillary thyroid cancer (DSPTC) is rare, with limited data on its molecular genetics. We studied the molecular genetics of a cohort of DSPTC. DNA was isolated from paraffin blocks of 22 patients with DSPTC (15 females, 7 males, median age 18 years, range 8-81). We performed PCR-based Sanger sequencing and a gene panel next-generation sequencing (NGS) to characterize the genomic landscape of these tumors. We classified genetic alterations to definitely or probably pathogenic. Definitely pathogenic are genetic alterations that are well known to be associated with PTC. Probably pathogenic are other alterations in genes that were reported in The Cancer Genome Atlas or the poorly differentiated and anaplastic thyroid cancer datasets. Three tumors were tested only by Sanger sequencing and were negative for BRAFV600E, HRAS, KRAS, NRAS, TERT promotor, PTEN and PIK3CA mutations. The other 19 tumors tested by NGS showed definitely pathogenic alterations in ten patients (52.6%): 2/19 (10.5%) BRAFV600E, 5/19 (26.3%) CCDC6-RET (RET/PTC1), 1/19 (5.3%) NCOA4-RET (RET/PTC3), 1/19 (5.3%) STRN-ALK fusion and 2/19 (10.6%) TP53 mutations. Probably pathogenic alterations occurred in 13/19 tumors (68.4%) and included variants in POLE (31.6%), CDKN2A (26%), NF1 (21%), BRCA2 (15.8%), SETD2 (5.3%), ATM (5.3%), FLT3 (5.3%), and ROS1 (5.3%). In one patient, the gene panel showed no alterations. No mutations were found in RAS, PTEN, PIK3CA, or TERT promotor in all patients. There was no clear genotype/phenotype correlation. In DSPTC, fusion genes are common, BRAFV600E is rare, and other usual point mutations are absent. Pathogenic and likely pathogenic variants in POLE, NF1, CDKN2A, BRCA2, TP53, SETD2, ATM, FLT3 and ROS1 occur in about two-thirds of DTPTC.

HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis

ObjectiveHER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. Methods2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. ResultsHER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. ConclusionsHER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.

Clinical characterization and genomic landscape of gynecological cancers among patients attending a Chinese hospital.

Gynecological cancers are the most lethal malignancies among females, most of which are associated with gene mutations. Few studies have compared the differences in the genomic landscape among various types of gynecological cancers. In this study, we evaluated the diversity of mutations in different gynecological cancers. A total of 184 patients with gynecological cancer, including ovarian, cervical, fallopian tube, and endometrial cancer, were included. Next-generation sequencing was performed to detect the mutations and tumor mutational burden (TMB). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were also conducted. We found that 94.57% of patients had at least one mutation, among which single nucleotide variants, insertions and InDels were in the majority. TP53, PIK3CA, PTEN, KRAS, BRCA1, BRCA2, ARID1A, KMT2C, FGFR2, and FGFR3 were the top 10 most frequently mutated genes. Patients with ovarian cancer tended to have higher frequencies of BRCA1 and BRCA2 mutations, and the frequency of germline BRCA1 mutations (18/24, 75.00%) was higher than that of BRCA2 (11/19, 57.89%). A new mutation hotspot in BRCA2 (I770) was firstly discovered among Chinese patients with gynecological cancer. Patients with TP53, PIK3CA, PTEN, and FGFR3 mutations had significantly higher TMB values than those with wild-type genes. A significant cross was discovered between the enriched KEGG pathways of gynecological and breast cancers. GO enrichment revealed that the mutated genes were crucial for the cell cycle, neuronal apoptosis, and DNA repair. Various gynecological cancer types share similarities and differences both in clinical characterization and genomic mutations. Taken together with the results of TMB and enriched pathways, this study provided useful information on the molecular mechanism underlying gynecological cancers and the development of targeted drugs and precision medicine.

Real-World Evaluation of Disease Progression After CDK 4/6 Inhibitor Therapy in Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

Cyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER-) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2- patients with MBC. We retrospectively reviewed the medical records of patients with HR+/HER2- MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models. We identified 140 patients with HR+/HER2- MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN. This study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2- MBC.

DICER1-associated central nervous system sarcoma: A comprehensive clinical and genomic characterization of case series of young adult patients.

DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described "primary DICER1-associated CNS sarcoma" (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy. We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed. Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months. DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.

Identification and Characterization of Metabolic Subtypes of Endometrial Cancer Using a Systems-Level Approach.

Endometrial cancer (EC) is the most common gynecological cancer worldwide. Understanding metabolic adaptation and its heterogeneity in tumor tissues may provide new insights and help in cancer diagnosis, prognosis, and treatment. In this study, we investigated metabolic alterations of EC to understand the variations in metabolism within tumor samples. Integration of transcriptomics data of EC (RNA-Seq) and the human genome-scale metabolic network was performed to identify the metabolic subtypes of EC and uncover the underlying dysregulated metabolic pathways and reporter metabolites in each subtype. The relationship between metabolic subtypes and clinical variables was explored. Further, we correlated the metabolic changes occurring at the transcriptome level with the genomic alterations. Based on metabolic profile, EC patients were stratified into two subtypes (metabolic subtype-1 and subtype-2) that significantly correlated to patient survival, tumor stages, mutation, and copy number variations. We observed the co-activation of the pentose phosphate pathway, one-carbon metabolism, and genes involved in controlling estrogen levels in metabolic subtype-2, which is linked to poor survival. PNMT and ERBB2 are also upregulated in metabolic subtype-2 samples and present on the same chromosome locus 17q12, which is amplified. PTEN and TP53 mutations show mutually exclusive behavior between subtypes and display a difference in survival. This work identifies metabolic subtypes with distinct characteristics at the transcriptome and genome levels, highlighting the metabolic heterogeneity within EC.

Characteristics of PTEN Mutation in Thyroid Tumours: A Retrospective Chart Review

While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies are aggressive. This multicenter study involved 316 patients who underwent preoperative molecular testing, and subsequent lobectomy or total thyroidectomy at two quaternary care hospitals. A four-year retrospective review was performed on the 16 charts of patients that opted for surgery following a positive PTEN mutation on molecular testing results from January 2018 to December 2021. Of the total 16 patients, 37.5% (n = 6) had malignant tumours, 18.75% (n = 3) had non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), and 43.75% (n = 7) had benign disease. Aggressive features were detected in 33.33% of the malignant tumours. Malignant tumours were found to have a statistically significant higher allele frequency (AF). The aggressive nodules were all poorly differentiated thyroid carcinomas (PDTCs) with copy number alterations (CNAs) and the highest AFs.

Comparison of clinicopathological and genomic profiles in anal squamous cell carcinoma between Japanese and Caucasian cohorts

Anal squamous cell carcinoma (ASCC) is a rare tumor of the gastrointestinal tract. We aimed to compare the genetic backgrounds and their effect on clinical outcomes between Japanese and Caucasian patients with ASCC. Forty-one patients diagnosed with ASCC at the National Cancer Center Hospital were enrolled and evaluated for clinicopathological features, human papillomavirus (HPV) infection, HPV genotypes, p16 expression, PD-L1, and association of p16 status with the efficacy of concurrent chemoradiotherapy (CCRT). Target sequencing for hotspot mutations in 50 cancer-related genes was performed using genomic DNA from 30 available samples. Of 41 patients, 34 were HPV-positive (among them, HPV 16 was predominant; 73.2%); 38 patients were p16-positive (92.7%); and 39 patients received CCRT, of whom 36 were p16-positive and three p16-negative. p16-positive patients showed better complete response than p16-negative patients. Among 28 samples, 15 showed mutations in PIK3CA, FBXW7, ABL1, TP53, and PTEN; no difference in mutation profiles between the Japanese and Caucasian cohorts was observed. Actionable mutations were detected in both Japanese and Caucasian patients with ASCC. Genetic backgrounds, such as the HPV 16 genotype and PIK3CA mutations, were common regardless of ethnicity. p16 status may be a prognostic biomarker for CCRT in Japanese patients with ASCC.

Abstract P4-09-12: Baseline and End-of-Treatment Biomarkers in Patients With PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From BYLieve Study Cohorts A and B

Abstract Introduction: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is mutated in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). PIK3CA mutations are associated with resistance to endocrine therapy (ET) and worse overall survival. Alpelisib (ALP), an α-selective PI3K inhibitor and degrader, is indicated in combination with fulvestrant (FUL) for pts with PIK3CA-mutated (mut) HR+, HER2− ABC following progression on/after ET-based treatments. In the Phase 2, open-label, 3-cohort, noncomparative BYLieve study, clinical benefit of ALP in combination with ET was observed in the post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) setting in pts with PIK3CA-mut, HR+, HER2− ABC. Here we report the results of a biomarker analysis using paired baseline (Cycle 1 Day 1) and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples from pts in BYLieve Cohorts A and B. Methods: In the BYLieve study, pts with PIK3CA-mut, HR+, HER2− ABC had CDK4/6i + aromatase inhibitor (Cohort A; N=127) or CDK4/6i + FUL (Cohort B; N=126) as treatment immediately prior to receiving ALP + FUL and ALP + letrozole, respectively. In this biomarker analysis, gene alterations were detected in ctDNA at baseline and EOT using next-generation sequencing (PanCancer V2 panel). Pts included in this interim analysis had confirmed PIK3CA mutations and matched baseline/EOT samples with enough sequencing coverage and ctDNA fraction to detect mutations at both time points. ctDNA fractions, tumor mutation burden (TMB) distributions, genomic landscapes, gain/loss of PIK3CA and estrogen receptor 1 (ESR1), chromosome 8/11 amplification profiles, and alterations in PI3K pathway and potential CDK4/6i resistance markers were assessed across time points. Sample sizes were small; results should thus be interpreted with caution. Results: Forty-three pts were included in the Cohort A biomarker population and 40 pts were included in Cohort B. ctDNA fraction was numerically higher at EOT compared with baseline in both cohorts; further analyses will be presented. In Cohort A, no significant differences were observed in TMB at EOT compared with baseline (P=0.21). In Cohort B, TMB was higher at EOT compared with baseline (P=0.053). Chromosome 8/11 amplifications were consistent between baseline and EOT for both cohorts. Small variations were observed in ESR1/PIK3CA mutations between baseline and EOT on both cohorts (Table). The status of potential CDK4/6i resistance markers was relatively unchanged at EOT (Table). Loss-of-function mutations in PTEN, a known PI3K inhibitor resistance marker, increased from 9% at baseline to 14% at EOT in Cohort A and from 12% at baseline to 22% at EOT in Cohort B. Conclusions: Between baseline and EOT, only small variations in gene alterations in PIK3CA-mutated HR+, HER2– ABC were observed in the post-CDK4/6i setting. As the disease progressed, increases in loss-of-function mutations in PTEN at EOT in both Cohorts A and B suggested loss of PTEN in PI3K pathway may drive resistance to ALP. Early intervention with ALP, when the tumor is particularly driven by PIK3CA oncogenic mutations and before it develops more genomic complexity, may potentially provide better clinical outcomes. Table. Gene Alteration Gain/Loss at Baseline/EOT Across Cohorts A and B Citation Format: Dejan Juric, Nicholas Turner, Sherene Loi, Fabrice Andre, Stephen K. Chia, Komal Jhaveri, Patrick Neven, Rebecca Dent, Eva Ciruelos, Mukta Joshi, Estelle Roux, Heather Patino, Murat Akdere, Hope Rugo. Baseline and End-of-Treatment Biomarkers in Patients With PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From BYLieve Study Cohorts A and B [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 P4-09-12.

Abstract PD5-10: PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype of all breast cancers. However, unlike other breast cancer subtypes, current treatments for TNBC are restricted and this scarcity of viable options is the key contributor to the poorer prognosis. Despite early response, almost all the targeted drugs tested in TNBC eventually fail due to the development of resistance. Patients’ data have shown that the expression level of Mediator kinases CDK8 and CDK19 are elevated in TNBC, and that higher expression of CDK8/19 is correlated with more advanced diseases and worse prognosis. Selective CDK8/19 inhibitor SNX631, when used as a single agent, inhibited the growth of several TNBC cell lines in vitro, cell-derived xenografts (CDXs) as well as patient derived xenografts (PDXs) in vivo, suggesting the potential of targeting CDK8/19 in treating TNBC. We also analyzed the effect of CDK8/19 inhibition on the outcome of treatment with mTORC1 inhibitor everolimus (RAD001), an approved drug for several cancers with mutations of PTEN or PI3KCA. SNX631 exhibited a synergistic effect in combination with everolimus on suppressing TNBC cell growth in vitro. In vivo treatment with everolimus alone achieved a strong tumor growth inhibition in TNBC xenograft models but all the tumors eventually resumed growth, indicated the development of resistance. Significantly, the addition of a CDK8/19 inhibitor prevented the emergence of in vivo everolimus resistance both in CDX and PDX tumors upon treatment for up to 150 days, suggesting a potential for extending remission or even achieving cures in TNBC. Transcriptomic analysis demonstrated that this effect was due to the prevention of transcriptional reprogramming associated with everolimus resistance in tumor cells. Citation Format: Xiaokai Ding, Hao Ji, Amanda C. Sharko, Juergen Loskutov, Zachary Mack, Jadyn Myers, Mengqian Chen, Elena Pugacheva, Igor Roninson, Eugenia Broude. PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer [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 PD5-10.

Abstract HER2-12: HER2-12 Genomic and Transcriptomic Landscape of HER2-Low Breast Cancer

Abstract Introduction: Breast cancer has pioneered precision medicine with prognostic and predictive subtypes, defined by immunohistochemistry (IHC). Novel therapeutic strategies have led to the emergence of HER2-Low (H2L) as a new entity, defined as tumors with HER2 IHC score of 1+ (&amp;gt;10% cell stained), as well as those with 2+ (&amp;gt;10% cell stained) with paired negative in-situ hybridization (ISH) assay. H2L has been reported to represent up to half of all breast cancer. Further investigation into the mutational landscape of H2L compared to historical subtypes is needed to understand the clinical and biologic factors driving mechanisms of resistance and to consider post-progression treatment options within H2L populations. Methods: The Caris Life Sciences database was used to identify H2L breast tumors by IHC and CISH and evaluated for mutations detected by DNA next-generation sequencing (NextSeq 592-gene panel or NovaSeq whole exome panel). PD-L1 expression was tested by IHC (SP142 IC ≥ 1%). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high ≥ 10 mutations per Mb). Statistical significance was determined using Fisher’s-Exact/Mann Whitney/X2 test with Benjamini-Hochberg-correction-adjusted p value (q value) of &amp;lt;0.05. Results: A total of 19789 breast tumors were included in this study. Using standard definitions, 12480 were defined as hormone receptor positive (HR+), 7309 hormone receptors negative (HRneg), 5564 were TNBC, and 1784 HER2 positive (HER2pos). 4349 cases were also identified as H2L, which included 3403 HR+H2L and 946 HRneg H2L. H2L was 22% (4349/19789) of total population; 27% (3403/12480) of the HR+ population and 12.9% (946/7309) of the HRneg population. Within the H2L tumors, when stratified by HR status, we observed in the HR+H2L tumors an increased frequency of amplifications in CCND1 (15.6% vs 5.0%), FGF3 (13.3% vs 4.7%), FGF4 (13.3% vs 4.2%), FGF19 (14.4% vs 4.7%), ZNF703 (15.6% vs 4.4 %), NSD3 (12.9% vs 5.2%), ADGRA2 (13.1% vs 5.3%), FGFR1 (11.7% vs 3.6%) and EMSY (5.2% vs 1.4%) compared to the HRnegH2L tumors. TP53 mutations were strikingly higher in the HRnegH2L group (74.4% vs 25.0%) compared to HR+H2L tumors. Markers of IO response also showed elevated positivity in PD-L1 (39.6% vs 19.5%) however, no difference was detected in TMB-H status in HRnegH2L tumors compared to HR+H2L tumors, all q&amp;lt;0.05. The genomic landscape differed when comparing HR+HER2pos tumors to HR+H2L tumors. Significantly more prevalent alterations in HR+HER2pos included amplifications in RNF43 (4.4% vs 1.4%), RARA (13.6% vs 0.1%), MLLT6 (19% vs 0.0%), MYC (6.1% vs 2.7%), DDX5 (10.1% vs 2.0%), CLTC (10.4% vs 3.3%) as well as TP53 (64.0% vs 25.0%) mutations and PD-L1 expression (26.6% vs 19.5%). Furthermore, mutations in PTEN (2.5% vs 7.8%), MAP3K1 (2.8% vs 7.1%), ESR1 (4.4% vs 14.3%), CDH1 (5.2% vs 16.4%), AKT1 (0.0% vs 4.3%) were elevated in the HR+H2L tumors compared to the HR+HER2pos tumors, all q&amp;lt;0.05. Interestingly, when the HRnegH2L tumors were compared to TNBC subtype differences were seen in the mutation rate of PIK3CA (33.5% vs 16.7%; q&amp;lt;0.0001), a master regulator of cell growth, and tumor suppressor gene TP53 (74% vs 86%). Conclusions: With some exceptions, H2L breast cancer shared genomic features with its more classically defined subset of either HR+ or HRneg disease. Notable differences in PIK3CA (an actionable mutation) and TP53 (a prognostic alteration) warrant additional assessment, as do amplifications variable between HR+H2L and HR+Her2pos groups. Our findings add tremendously to the current understanding of the molecular profile of the H2L subgroup and comparison to the classically defined breast cancer subgroups. Genomic risk assessments after progression on novel therapeutics will be needed to better define implications for mechanisms of resistance. Citation Format: Rani Bansal, Julie McGrath, Phil Walker, Matias A. Bustos, Estelamari Rodriguez, Sarah L. Sammons, Melissa K. Accordino, Jane Meisel, Margaret Gatti-Mays, Emily Hsu, Kate I. Lathrop, Virginia Kaklamani, Matthew Oberley, W. Michael Korn, Stephanie L. Graff. HER2-12 Genomic and Transcriptomic Landscape of HER2-Low Breast Cancer [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 HER2-12.

Abstract P3-05-25: Clinical Factors associated with Survival Outcomes in Patients with Metaplastic Breast Cancer

Abstract Background Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer (BC) defined by presence of both epithelial and mesenchymal components. Most are triple negative but are often chemo-refractory and associated with poor survival outcomes compared to non-metaplastic triple negative BC. Advances in therapy have led to improvements in survival outcomes of patients (pts) with BC over the last decade. Our multicenter retrospective study aims to assess (1) progression free survival (PFS) and overall survival (OS) (2) factors predictive of survival outcomes in MBC pts Methods We performed a retrospective analysis of pts diagnosed with MBC from 1997-2021 at Mayo Clinic (Florida, Arizona and Rochester) under IRB approval. Kaplan-Meier method was used to estimate OS and PFS at 1, 3 and 5 years. Cox regression models were used to examine the association between risk factors and survival outcomes. All tests were two-sided with p value &amp;lt; 0.05 considered statistically significant Results We evaluated 158 pts with MBC. Median age and tumor size was 61 (range: 20-91) years and 2.8 (range: 0.5-21) cm, respectively, with 80% of pts being postmenopausal. At diagnosis, 14.6% of pts had clinical T3/T4 disease, 16.4% were clinically node-positive, and 6.3% (10 pts) had distant metastases (DM). Spindle cell histology was seen in 36 pts. Most MBC pts were triple-negative (68.3%), high grade (77.2%) and high Ki-67 (36/47; 76.5%). Of the 61 pts tested for germline mutation, 8 (13.1%) were positive, with BRCA1/2, PTEN, NBN, CHEK2, and BARD1 mutations. Most pts had lumpectomy (53.8%), followed by simple mastectomy (38.5), and modified radical mastectomy (7.7%). Majority of pts had sentinel lymph node biopsy (71.8%). Adjuvant radiation therapy was performed in 65.6% of pts. Pathologic complete response (pCR) was noted in 4/38 (10.5%) evaluable pts who received neoadjuvant chemotherapy (NACT). Residual cancer burden (RCB) scores of 2 and 3 were seen in 76.2% of evaluable pts. Median follow-up time was 2.2 years (range: 6 days-24.6 years). Overall, 1-, 3-, and 5-year OS was 93.3%, 81.7%, and 76.0%, while PFS was 80.8%, 67.9%, and 60.9%, respectively. The presence of DM at diagnosis [HR 38.55 (11.18, 132.93), p &amp;lt; 0.001] and spindle cell histology (SC) [HR 2.57 (1.19, 5.53), p = 0.02] predicted worse OS in multivariable analysis. Inferior PFS was predicted by DM [HR 18.84 (6.53, 54.35), p &amp;lt; 0.001], SC [HR 2.46 (1.25, 4.86), p = 0.009], and node-positivity at diagnosis [HR 3.65 (1.5, 8.89), p = 0.004]. The 5-year OS and PFS were 22.2% and 0% for DM pts versus 80.0% and 65.6% for non-DM pts. The 5-year OS and PFS were 71.5% and 54.7% for SC pts versus 81% and 66.6% for non-SC pts. 5-year OS and PFS for NACT pts was 67.3% and 52.6% for NACT pts versus 78.2% and 62.8% for non-NACT pts. Age at diagnosis, menopausal status, family history of BC, grade, stage, tumor size, hormone-receptor and HER2 status, and use of NACT were not found to be significantly associated with OS or PFS in multivariate analysis. Conclusion This study is one of the largest and most recent review of institutional experiences with MBC. Overall, OS at 5 years was improved compared to prior older studies of MBC but still remains very low for those with DM, representing an area of unmet clinical need. SC and DM correlated with worse outcomes for both PFS and OS. Additionally, node positivity at diagnosis was a predictor of worse PFS. In contrast, no association was seen between survival and tumor size, stage, hormone receptor-positivity, HER2 receptor-positivity. The low pCR rates following NACT in our study are consistent with reported literature. Further, use of NACT does not impact survival, suggesting pts with resectable disease should proceed with surgery first. Citation Format: Siven Chinniah, Raza Zarrar, Zhuo Li, Kostandinos Sideras, Alvaro Moreno-Aspitia, Saranya Chumsri, Rohit Rao, Sarah McLaughlin, James Jakub, Emmanuel Gabriel, Sanjay Bagaria, Laura Vallow, Santo Maimone, Pooja Advani. Clinical Factors associated with Survival Outcomes in Patients with Metaplastic Breast Cancer [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 P3-05-25.

Loss of CDKN2A/B is a Molecular Marker of High-grade Histology and is Associated with Aggressive Behavior in Acinic Cell Carcinoma

Acinic cell carcinoma (AciCC) is a rare salivary gland cancer with excellent prognosis in most cases. However, a subset of patients will develop distant metastasis and die of disease. Recently, a 2-tiered grading scheme in AciCC was proposed to recognize patients at risk of poor outcome. We performed a genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined programmed death ligand 1 (PD-L1) expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade (HG) and 21 low-grade AciCCs. Forty-three cases were subjected to targeted exome sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. PD-L1 immunohistochemistry was performed in 33 cases. Tumor mutation burden was low with a median of 1 and 2 mutations in low-grade and HG AciCCs, respectively. CDKN2A/B was the most frequently altered gene, and loss-of-function mutations were found only in HG but not in low-grade AciCCs (18/31 [58.1%] vs 0/12 [0%], P < .001). CDKN2A/B alterations were significantly associated with distant metastasis, which occurred in 16/18 (88.9%) CDKN2A/B mutants versus 11/25 (44%) wild-type cases (P = .004, Fisher exact test). Sequential profiling of multiple temporally distant samples from the same patient demonstrated intratumor heterogeneity, including the detection of CDKN2A/B deletion in the second, in HG metastasis only. ATM and PTEN mutations were detected in 6/31 (19.4%) and 5/31 (16.1%); ARID2, BIRC3, and FBXW7 mutations each in 4/31 (12.9%); and TP53, MTAP, and FAT1 each in 3/31 (9.7%) HG AciCC. PD-L1–positive labeling was more common in HG AciCC (9/17, 52.9% vs 3/16, 18.9%, P = .071). CDKN2A/B mutations in AciCC represent a molecular marker of HG histology and disease progression, providing a rationale for further studies to determine their prognostic and therapeutic significance in this salivary gland cancer. AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered to be a treatment option for a subset of patients with AciCC.

Development and validation of a gene expression signature based on RB1, PTEN,and TP53 in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

236 Background: Alterations on the tumor suppressor genes (TSG) RB1, PTEN and TP53 are associated with treatment resistance and aggressive clinical evolution of prostate cancer patients (pts). We developed and assessed the role of a TSG gene expression signature in mHSPC pts. Methods: This is a multicenter retrospective biomarker study in mHSPC pts receiving different therapies. RB1, PTEN and TP53 mutations were assessed by targeted sequencing and its gene expression was determined by the nCounter platform in FFPE tumor samples. Normalized and transformed (z-score) expression data of a training cohort was used to establish the cut-off for RB1, PTEN and TP53 expression, those cut-offs were then applied to the other cohorts. TSGlow was considered when ≥2 out of 3 TSG presented low expression, and TSGwt in the remaining cases. TSG signature was correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: Overall, 297 pts (baseline characteristics are shown) were included: 125 treated with ADT+Docetaxel (ADT+D) (54 and 71 in training and validation cohorts, respectively), 93 with ADT, and 79 with ADT+Abiraterone or Enzalutamide (ADT+A/E). Training cohort pts were tested for both, gene expression and targeted sequencing of TSG. Pts with low expression of PTEN showed higher frequency of PTEN mutations (p&lt;0.05). TSGlow (14 (25.9%) out of 54 pts) had a worse CRPC-FS (14.3 vs. 21.7 months (m); HR 2.2 (95% CI, 1.1 - 4.4), p=0.022). In the validation cohort, 7 (9.9%) pts were TSGlow and had a worse CPRC-FS (11.7 vs. 20 m, HR 2.5 (95% CI, 1.1 - 5.5), p=0.027) and OS (27.6 vs 58.1 m, HR 3.5 (95% CI, 1.3 - 9.5) p=0.012). TSGlow signature was independently associated with CPRC-FS (HR 2.66 (95% CI, 1.17 - 6.06), p=0.02) and OS (HR 3.67 (95% CI, 1.33 - 10.10), p=0.012). In the ADT and ADT+A/E cohorts, 20 (21.5%) and 14 (17.7%) pts were TSGlow, respectively. TSGlow was not predictive of either CRPC-FS (p=0.23 and p=0.242, respectively) or OS (p=0.091 and p=0.66, respectively). We analyzed together high-volume pts from both ADT+D and ADT cohorts. TSGlow pts (16, 10.74%) treated with ADT+D had a CRPC-FS (13.6 m) similar to pts treated with ADT (TSGlow = 14.5 m and TSGwt = 12.8 m). Moreover, TSGwt pts treated with ADT+D had a better CRPC-FS (19.3m) (p=0.022) and OS (ADT/TSGlow = 31.7 m, ADT/TSGwt = 38.6 m, ADT+D/TSGlow = 31.5 m, ADT+D/TSGwt = 52.2 m, p=0.07). Conclusions: A TSG gene expression signature is predictive of taxanes benefit in mHSPC pts and may be useful to personalize the treatment in this setting. [Table: see text]

DNA alterations in papillary renal cancer.

725 Background: The characterisation of DNA alternations in papillary renal cancer (PRC) is unclear. The CALYPSO trial (NCT02819596) prospectively evaluated combination therapy of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) in PRC. The trial showed high response rates (RR) in the MET-driven population. Here we explore the relationship between MET, PD-L1 and TMB in these tumours and the relevance of other biomarkers including PIK3CA, PTEN and KRAS. Methods: FoundationOne analysis from 41 samples of PRC patients enrolled on the CALYPSO trial was performed. The relevance of co-positivity between MET/PD-L1 and MET/TMB as well as analysis of other DNA alterations such as PIK3CA, PTEN and KRAS was explored. Outcome parameters were correlated with RR, PFS and OS. Results: 41% of patients were MET-driven, 66% were PD-L1+ (vCPS≥1) and 3% were TMB &gt;10mut/Mb. Further testing used TMB ≥ median (2.52mut/Mb) 32% of patients were both MET-driven and PD-L1+. 17% of patients were both MET-driven and TMB ≥ median. RR and survival outcomes for combinations are shown in the table. The overall RR in MET driven and non-MET-driven patients was 52.9% and 13%, respectively. The median PFS and OS in the MET-driven group was 12.0 months (95% CI: 2.9-19.4) and 27.4 months (95% CI: 9.3-not reached [NR]), respectively, compared to a median PFS and OS in the non-MET-driven group of 2.7 months (95% CI: 0.5-5.0) and 7.5 months (95% CI: 0.0-16.0), respectively. PIK3CA, PTEN and KRAS mutations occurred in 1, 4 and 2 patients, with RR of 0% (0/1), 25% (1/4) and 50% (1/2), in the PIK3CA, PTEN and KRAS groups, respectively. Conclusions: MET-driven papillary cancers have low mutational burden, but high PD-L1 expression. Small patient numbers limit definitive conclusions, but responses occur irrespective of the immune biomarkers investigated. Other DNA alterations are rare and did not appear to influence outcomes in this cohort. These data support the design of the SAMETA trial (NCT05043090), further investigating the savolitinib and durvalumab combination. [Table: see text]