Gastroesophageal Adenocarcinoma Research Articles

A Review of Type III Gastroesophageal Junction Adenocarcinoma and the Importance of Early Detection of Gastric Cancer

A Review of Type III Gastroesophageal Junction Adenocarcinoma and the Importance of Early Detection of Gastric Cancer

Abstract PO1-18-06: Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST

Abstract Background The introduction of trastuzumab has dramatically changed outcomes in patients with human epidermal growth factor receptor 2 positive (HER2+) cancer. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. Combination of anti-HER2 antibodies with other immunotherapies is likely to improve the quantity and quality of responses. BI-1607 is a human monoclonal antibody (mAb) targeting FcRIIB (CD32b) with antagonistic function capable of blocking the inhibitory function of FcRIIB on immune effector cells. BI-1607 has been engineered to lack a glycan in position N297Q in the constant domain (Fc), and thus cannot interact with FcγRs through its Fc. Given its high specificity and affinity for FcγRIIB, BI-1607 blocks other antibodies’ binding to FcγRIIB. As a result, BI-1607 is expected to shift tumor cells coated antibodies (here anti-HER2) to selectively engage activating FcγRs, thus augmenting FcγR-dependent therapeutic activity (ADDC, ADCP). Tumor-associated macrophages express high levels of FcγRIIB and are a major target of BI-1607 in the tumor microenvironment. This concept was demonstrated in preclinical in vivo models showing increased efficacy of the combination therapy with the murine surrogate of BI-1607 and an anti-HER2, an anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and an anti-CD20 (rituximab) as compared to monotherapy. It important to note that BI-1607 will have no single-agent activity. Instead, its clinical use will be in combination with other immunotherapies and tumor-targeting antibodies such as trastuzumab. The choice of trastuzumab as the combination agent in this trial was based on promising preclinical studies, a recognized need for additional options for those patients who fail to respond or stop responding to trastuzumab, and promising results from the newly approved Fc-engineered anti-HER2 mAb margetuximab. Ultimately, if shown to be safe and effective in combination with trastuzumab, BI-1607 can also be used in combination with other cytotoxic or immunomodulatory antibodies for cancer treatment. Methods This is a Phase 1/2a, first-in-human, open-label, multicenter, dose-escalation, consecutive-cohort study of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors. Phase 1 aims to assess safety and tolerability and to determine the RP2D of BI-1607 in combination with trastuzumab. Phase 2a will explore efficacy at RP2D of BI-1607 in combination with trastuzumab in two separate expansion cohorts, a) in subjects with locally advanced or metastatic HER2+ breast cancer and b) in subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. Eligible patents must have a HER2+ locally advanced unresectable or metastatic solid tumors and have received standard of care or be intolerant to standard of care antineoplastic therapy, with progressive disease after the last line of treatment. Accrual/Planned Accrual As of June 222d, 2023 10 patients have been treated into trial and dosed with BI-1607 and trastuzumab at doses from 75-900 mg every 3 weeks (Q3W) in Phase 1. Phase 2a will enroll 15 subjects each in two cohorts of HER2+ advanced/metastatic breast cancer or HER2+ gastric/GEJ adenocarcinoma respectively. For information regarding the study, please contact: anna.ropenga@bioinvent.com Citation Format: Javier Cortés, Araceli Priego, Elena Garralda Cabanas, Katerin Rojas Lamito, Simon Lord, Thorsten Goetze, Sherko Küemmel, Simon Crabb, Marie Borggren, Ingrid Karlsson, Linda Mårtensson, Anna Ropenga, Ingrid Teige, Johan Wallin, Björn Frendeus, Andres McAllister. Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-06.

68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study

IntroductionAccurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly...

Neoadjuvant chemoimmunotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma.

Patients suffering from locally advanced gastric or gastroesophageal junction adenocarcinoma often face a high postoperative recurrence rate. Despite aggressive treatment, less than 50% survive beyond five years. Ongoing clinical studies are exploring ways to prolong patient survival, revealing that perioperative chemotherapy can extend both the period of recurrence-free survival and overall survival for this group of patients. Currently, combining chemotherapy and immune checkpoint inhibitors has become a critical treatment approach for advanced gastric or gastroesophageal junction adenocarcinoma. However, the effectiveness of this approach in locally advanced patients remains unverified. This article delves into the latest research concerning the use of perioperative chemotherapy coupled with immune checkpoint inhibitors in locally advanced gastric or gastroesophageal junction adenocarcinoma treatment, and highlights prospective challenges and discusses how to best identify patients who may benefit from combined chemotherapy and immune checkpoint inhibitor therapy.

Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.

BCAT1, IKZF1 and SEPT9: methylated DNA biomarkers for detection of pan-gastrointestinal adenocarcinomas

Introduction Methylated circulating tumour DNA (ctDNA) blood tests for BCAT1/IKZF1 (COLVERA) and SEPT9 (Epi proColon) are used to detect colorectal cancer (CRC). However, there are no ctDNA assays approved for other gastrointestinal adenocarcinomas. We aimed to characterize BCAT1, IKZF1 and SEPT9 methylation in different gastrointestinal adenocarcinoma and non-gastrointestinal tumours to determine if these validated CRC biomarkers might be useful for pan-gastrointestinal adenocarcinoma detection. Methods Tissue DNA methylation data from colorectal (COAD, READ), gastroesophageal (ESCA, STAD), pancreatic (PAAD) and cholangiocarcinoma (CHOL) adenocarcinoma cohorts within The Cancer Genome Atlas were used for differential methylation analyses. Clinicodemographic predictors of BCAT1, IKZF1 and SEPT9 methylation, and the selectivity of hypermethylated BCAT1, IKZF1 and SEPT9 for colorectal adenocarcinomas in comparison to other cancers were each explored with beta regression. Results Hypermethylated BCAT1, IKZF1 and SEPT9 were each differentially methylated in colorectal and gastroesophageal adenocarcinomas. IKZF1 was differentially methylated in pancreatic adenocarcinoma. Hypermethylated DNA biomarkers BCAT1, IKZF1 and SEPT9 were largely stable across different stages of disease and were highly selective for gastrointestinal adenocarcinomas relative to other cancer types. Discussion Existing CRC methylated ctDNA blood tests for BCAT1/IKZF1 and SEPT9 might be usefully repurposed for use in other gastrointestinal adenocarcinomas and warrant further prospective ctDNA studies.

Abstract CT259: Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors

Abstract Background: MDNA11 is an albumin-fused ‘beta-enhanced not-alpha’ IL-2 agonist engineered to preferentially expand and activate CD8+ T and NK cells with minimal impact on Tregs. The ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) is a global Phase 1/2 study evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of MDNA11, both as single agent and in combination with a PD-1 inhibitor, in pre-treated patients with advanced solid tumors. Method: The ABILITY-1 study (NCT05086692) comprises monotherapy dose escalation/evaluation with a modified 3+3 design (enrollment complete); monotherapy dose expansion (enrolling); combination with pembrolizumab dose escalation (enrolling) followed by combination expansion. Thirty participants were enrolled in the monotherapy cohorts (3, 10, 30, 60, 90, and 120 μg/kg, IV, Q2W): 23 in dose escalation and 7 in dose evaluation. To enhance tolerability, step-up dosing with 2 or 3 priming doses was implemented starting at 60 μg/kg. Primary endpoints were incidence and severity of adverse events (AEs) and secondary endpoints included PK, PD, and tumor response (RECIST 1.1 and iRECIST). Results: As of December 22, 2023, 30 patients were enrolled in dose-escalation/evaluation, comprising 16 melanoma, 3 NSCLC, 3 PDAC, 2 RCC, 2 sarcoma, 2 ovarian cancer, 1 tonsillar squamous cell carcinoma and 1 gastro-esophageal adenocarcinoma. No dose-limiting toxicities (DLTs) were observed. Most common treatment related AEs were infusion-related reactions (53.3%), primarily grade 1-2, encompassing pyrexia (43.3%), nausea (33.3%), chills (33.3%), hypotension (30%), and fatigue (26.6%) that resolved within 48-72 hours. PK analysis showed sustained dose-dependent increase in serum concentration of MDNA11 with repeat doses. PD evaluation showed robust and durable dose-dependent increase in lymphocyte counts without eosinophilia. Immune effector cells, particularly CD8+ T cells, showed durable expansion with evidence of activation markers (CD25, ICOS and OX40) peaking at the 90 μg/kg dose. Single-agent anti-tumor activity was evident among 26 evaluable patients with confirmed partial responses (PRs) in a PDAC (MSI-H) patient (60 μg/kg cohort) and a melanoma patient (90 μg/kg cohort) as well as 8 (30.7%) stable disease (SD) including 3 melanoma patients with durable SD (>6 months, >8 months, >1.5 years). Based on the combined safety, PK, PD and preliminary anti-tumor activity, a recommended dose for expansion (RDE) of 90 μg/kg (preceded by priming doses of 30 and 60 μg/kg; Q2W) was selected for the ongoing monotherapy dose expansion of the ABILITY-1 study. Conclusions: MDNA11 was well-tolerated with no DLTs observed at all dose levels up to 120 μg/kg. With study currently ongoing, single agent clinical activity was evident with an ORR of 7.7% and Clinical Benefit Rate (CBR) of 19.2% (2 PRs + 3 SDs > 6 months) in dose escalation to date. Monotherapy dose expansion at 90 μg/kg and combination dose escalation with pembrolizumab are enrolling. Citation Format: Victoria G. Atkinson, Jesus F. Antras, Philippe Bedard, Warren Brenner, Jacqueline Brown, Charlotte R. Lemech, Peter Lloyd, Kim Margolin, Matthen Mathew, John J. Park, Sajeve Thomas, Przemyslaw Twardowski, Humphrey Gardner, Amy Prawira, Melissa Coello, Walead Ebrahimimizadeh, Minh D. To, Rosemina Merchant, Sudhir Madduri Karanam, Arash Yavari, Lillian L. Siu, Hussein A. Tawbi, Paolo A. Ascierto. Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT259.

Abstract CT104: Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors

Abstract Background: In the dose escalation phase of a first-in-human phase 1 study (NCT03564691), the anti-ILT4 IgG4 monoclonal antibody MK-4830 + pembrolizumab (pembro) had a manageable safety profile and demonstrated promising antitumor activity in patients (pts) with previously treated advanced solid tumors, including those with PD on immunotherapy. Here, we present safety, efficacy, and biomarker analyses for MK-4830 + pembro for the previously treated pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma (HNSCC), and gastric cancer cohorts of the expansion phase. Methods: Eligible pts were aged ≥18 y with metastatic pancreatic adenocarcinoma and 1-3 lines of prior therapy (cohort A), unresectable glioblastoma and 1 prior line of therapy (cohort B), recurrent or metastatic HNSCC that progressed on a platinum-based chemotherapy and PD-(L)1 inhibitor (cohort C), or recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that progressed on ≥2 prior chemotherapy regimens (cohort I). Pts in cohorts A, B, and I had not previously received a PD-(L)1 inhibitor. All pts received MK-4830 800 mg + pembro 200 mg Q3W for 35 cycles or until PD, unacceptable toxicity, or study withdrawal. Primary objectives were to evaluate safety and ORR per RECIST v1.1 (cohorts A, C, and I) or Response Assessment in Neuro-Oncology (RANO) criteria (cohort B) by investigator assessment. Exploratory objectives included evaluating DOR and PFS per RECIST v1.1 (cohorts A, C, and I) or RANO criteria (cohort B) by investigator assessment. Results: At data cut-off (September 27, 2023), 33 pts were enrolled and received treatment in cohort A, 20 pts in cohort B, 35 pts in cohort C, and 35 pts in cohort I. Median follow-up duration was 38.4 mo (range, 35.5-39.9) in cohort A, 34.1 mo (32.3-36.2) in cohort B, 37.5 mo (33.4-42.1) in cohort C, and 29.5 mo (22.3-36.4) in cohort I. Treatment-related adverse events (TRAEs) occurred in 15 pts (45%) in cohort A, 13 pts (65%) in cohort B, 19 pts (54%) in cohort C, and 16 pts (46%) in cohort I; grade 3 or 4 TRAEs occurred in 3 pts (9%), 0 pts, 2 pts (6%), and 4 pts (11%), respectively. No deaths due to TRAEs occurred. ORR was 6% (95% CI, 1-20) in cohort A, 5% (0-25) in cohort B, 0% (0-10) in cohort C, and 20% (8-37) in cohort I. Median DOR was 14.3 mo (range, 14.0-14.7) in cohort A, 7.4 mo (7.4-7.4) in cohort B, and 9.6 mo (3.0-27.6+) in cohort I. Median PFS was 1.9 mo (95% CI, 1.6-2.0) in cohort A, 1.2 mo (1.1-1.4) in cohort B, 2.2 mo (1.9-4.1) in cohort C, and 1.4 mo (1.3-3.0) in cohort I. Conclusions: In pts with select previously treated advanced or metastatic solid tumors, MK-4830 + pembro had a manageable AE profile but no significant antitumor activity beyond that historically observed with pembro monotherapy. Other treatment options must be explored for these difficult-to-treat tumors. Citation Format: Lillian L. Siu, Marta Gil-Martin, Byoung Chul Cho, Ruth Perets, John Hilton, Ravit Geva, Iwona Lugowska, Martin Gutierrez, Marcelo Bonomi, Rafal Dziadziuszko, Drew Rasco, Eytan Ben-Ami, Cristina P. Rodriguez, Shabana Siddiqi, Nicole Myer, Leah Suttner, Douglas Wilson, Ombololaji O. Akala, Maria de Miguel. Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT104.

Abstract LB417: Leveraging advanced human lung models to explore mechanisms underlying T-DXd-associated interstitial lung disease (ILD)

Abstract Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved for several indications, including HER2-positive unresectable or metastatic breast cancer that progressed on two or more prior therapies, HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen and HER2-mutant unresectable or metastatic non-small cell lung cancer (USPI-ENH-C9-1122-r006). While the safety profile of T-DXd is manageable, ILD is an important identified risk and considered as an Adverse Event (AE) of special interest (Powell et al ESMO Open 2022). The therapeutic options for patients that develop ILD are limited to steroid medications, including prednisone and methylprednisolone. Hence, a greater understanding of T-DXd-associated ILD pathophysiology has the potential to guide alternative interventions to prevent ILD progression and improve patient care. Here, we used advanced human lung models to explore if T-DXd can affect pulmonary epithelial cell homeostasis and function. Transcriptome and gene set enrichment analysis of bronchial epithelial cells cultured under air-liquid interface (ALI) conditions revealed that genes and pathways associated with senescence, inflammation, and barrier integrity were dysregulated upon treatment with T-DXd. These transcriptomic findings linked to senescence and inflammation were confirmed in follow-up ALI experiments where T-DXd was shown to activate the p53 pathway, and upregulate pro-senescence, -inflammatory and -fibrotic mediators. Similarly, T-DXd activated senescence- and inflammation-associated markers in a microphysiological alveolar lung-on-chip system, thus indicating that T-DXd has similar effects in alveoli epithelia. In addition, T-DXd induced epithelial injury of ALI cells, which was reflected by loss of barrier function and release of epithelial damage markers. These changes were also accompanied by upregulation of mesenchymal cell markers, suggesting cells transition to a partial epithelial-to-mesenchymal phenotype. Whereas the payload (deruxtecan; DXd) and IgG control antibody-DXd conjugate (IgG-DXd) could recapitulate effects measured with T-DXd on lung epithelial cells, trastuzumab did not have any effect, suggesting limited contribution of HER2 targeting to T-DXd-induced epithelial changes in the experimental models used. Altogether, these data demonstrate that DXd can drive epithelial mechanisms and pathways associated with pulmonary fibrosis, inflammation, and damage, which are dysregulated events observed in ILD. Ongoing studies aim to evaluate the translation of these discoveries to the clinic and to support the development of novel therapeutic strategies to manage or prevent ILD. Citation Format: Ingrid Lua, Lin Jia, Jeff Chen, Kevin Contrepois, Mary McFarlane, Anton I. Rosenbaum, Peter Newham, Sonia Terrillon. Leveraging advanced human lung models to explore mechanisms underlying T-DXd-associated interstitial lung disease (ILD) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB417.

Association Between Body Composition and Survival in Patients With Gastroesophageal Adenocarcinoma: An Automated Deep Learning Approach.

Body composition (BC) may play a role in outcome prognostication in patients with gastroesophageal adenocarcinoma (GEAC). Artificial intelligence provides new possibilities to opportunistically quantify BC from computed tomography (CT) scans. We developed a deep learning (DL) model for fully automatic BC quantification on routine staging CTs and determined its prognostic role in a clinical cohort of patients with GEAC. We developed and tested a DL model to quantify BC measures defined as subcutaneous and visceral adipose tissue (VAT) and skeletal muscle on routine CT and investigated their prognostic value in a cohort of patients with GEAC using baseline, 3-6-month, and 6-12-month postoperative CTs. Primary outcome was all-cause mortality, and secondary outcome was disease-free survival (DFS). Cox regression assessed the association between (1) BC at baseline and mortality and (2) the decrease in BC between baseline and follow-up scans and mortality/DFS. Model performance was high with Dice coefficients ≥0.94 ± 0.06. Among 299 patients with GEAC (age 63.0 ± 10.7 years; 19.4% female), 140 deaths (47%) occurred over a median follow-up of 31.3 months. At baseline, no BC measure was associated with DFS. Only a substantial decrease in VAT >70% after a 6- to 12-month follow-up was associated with mortality (hazard ratio [HR], 1.99 [95% CI, 1.18 to 3.34]; P = .009) and DFS (HR, 1.73 [95% CI, 1.01 to 2.95]; P = .045) independent of age, sex, BMI, Union for International Cancer Control stage, histologic grading, resection status, neoadjuvant therapy, and time between surgery and follow-up CT. DL enables opportunistic estimation of BC from routine staging CT to quantify prognostic information. In patients with GEAC, only a substantial decrease of VAT 6-12 months postsurgery was an independent predictor for DFS beyond traditional risk factors, which may help to identify individuals at high risk who go otherwise unnoticed.

Chemotherapy Plus Atezolizumab Pre- and Post-Resection in Localized Esophageal or Gastroesophageal Junction Adenocarcinomas: A Phase I/II Single-Arm Study.

Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24-31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel.

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice.

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel.

The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1–14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8–89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Abstract 4643: A novel epigenomic profiling assay reveals disease biology and therapeutic targets in gastro-esophageal cancer from 1 ml of plasma

Abstract INTRODUCTION: Gastro-esophageal adenocarcinoma (GEA) is an aggressive and heterogeneous disease with a poor prognosis. Targeted therapies have failed largely due to challenges associated with biopsy collection, tumor antigen heterogeneity, and accurately distinguishing transcriptionally distinct esophageal, GE junction or gastric tumor types. We developed a novel, multimodal liquid biopsy assay that profiles genome-wide transcriptional activation. Here, we deploy this assay to define clinically relevant insights in a cohort of GEA patients. METHODS: 1 ml of plasma from whole blood samples was used to assess genome-wide enhancer, promoter and DNA methylation loci in 11 GEA patients (Stage III: 1, Stage IV: 10) and 7 healthy volunteers. 6 patients were confirmed as HER2+ based on standard tissue IHC/ISH methods. ctDNA estimation was performed using the ichorCNA algorithm on low pass whole genome sequencing data. A multimodal HER2 classifier developed previously using genome-wide features including HER2 was used to predict HER2 status of the GEA samples. RESULTS: Epigenomic profiling and comparison of GEA and healthy volunteer plasma samples revealed distinct genome-wide transcriptional activation patterns associated with gastroesophageal adenocarcinoma, including (i) the characteristic upregulation of HER2, FGFR2 and VEGF (ii) SOX2, KLF4, GATA6 transcription factor circuitry, and (iii) DNA methylation at the CHFR and MGMT promoters. We then explored if epigenomic profiling of liquid biopsies could infer the activation status of antibody-drug conjugate (ADC) targets currently under investigation in GEA cancers. Simultaneous examination of multiple target genes including HER2, HER3, TROP2, CLDN18, CEACAM5 and MET demonstrated patient-specific differences and dynamic range in transcriptional activation of a subset of these target genes. Finally, we investigated if HER2 status could be assigned accurately and quantitatively from a liquid biopsy using the multimodal HER2 classifier. HER2 positivity by IHC was predicted accurately in 8/11 samples corresponding to an area under the ROC curve (AUC) greater than 0.85. Discordance between plasma and tissue HER2 calls could be partially attributed to variability associated with tumor site/section used for tissue collection, IHC staining, and time between biopsy collection and blood draw. CONCLUSIONS: We demonstrate the feasibility of comprehensive epigenomic profiling from low input volume of 1ml of plasma to provide a snapshot of the tumor’s transcriptional state to derive clinically actionable insights. The HER2 classifier overcomes several of the challenges with IHC profiling by providing a uniform and quantitative measurement of HER2 activation. This non-invasive assay provides an accurate reflection of tumor transcriptional biology that can inform optimal patient selection strategies. Citation Format: Jonathan Beagan, Aparna Gorthi, Anthony D'Ippolito, Travis Clark, Michael Coyne, Tyrone Tamakloe, Amy Donahue, Baovy Tran, Hyun-Hwan Jeong, Kristian Cibulskis, Hathairat Sawaengsri, Corrie A. Painter, Juliann Chmielecki, J Carl Barrett, Mosammat Faria Afreen, Aditya Pandey, Ilexa Ashley Schechter, Martin S. Taylor, Matthew R. Strickland, Matthew Eaton, Samuel J. Klempner. A novel epigenomic profiling assay reveals disease biology and therapeutic targets in gastro-esophageal cancer from 1 ml of plasma [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 4643.

Abstract 6846: Tumor cell metaplastic programs and failure of T cell remodeling drive resistance and progression to frontline chemoimmunotherapy in advanced gastric cancer

Abstract Adding aPD1 to 5-FU/platinum in advanced gastroesophageal adenocarcinomas (GEA) has yielded modest and heterogeneous results. Understanding cooperativity between these two treatment modalities will inform novel combination treatments for GEA. Towards this end, we conducted a trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in previously untreated advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab we transcriptionally profiled 358,067 single cells and obtained TCR-sequences from single tumor-resident T cells. Stratifying patients into slow- (> 6 months) and fast-progressing (< 6 months) groups based on progression-free survival allowed us to quantify differences in immune, stromal and epithelial subpopulations across treatment time points. Using topic modeling with consensus non-negative matrix factorization (cNMF), we identified gene expression programs in each population at each time point and developed a methodology to verify the stability of those programs across the cohort using cross-validation. Faster clinical progression featured decreased M1-like macrophage repolarization and increased MUC5A and MSLN containing metaplasia programs in tumor cells. We next selected features from cell state gene programs and identified trajectories of tumor cells across a spectrum of treatment sensitive and resistant states. We identified several factors that correlated with these trajectories and regulons that may be influencing them. After pembrolizumab we observed slower progression was associated with further increased CD8 T cell infiltration with increased CXCL13+ T cells. We next calculated covarying programs between patient samples at each time point and performed permutation testing to identify which programs (and respective cell types they were expressed in) were significantly correlated to infer the presence of multicellular tumor communities. We found that the tumor cell interferon program co-varied with the CXCL13 T cell program, and the emergence of a covarying module with tumor-reactive CXCL13 program expression happens as early as after the first dose of chemotherapy. To better understand the behavior of tumor reactive T cells within the tumor microenvironment, we leveraged TCR-sequencing data to study T cell clonality and diversity across treatment time points and between fast and slow progressors. Our data provide an invaluable resource to dissect chemoimmunotherapy response in tumor cells, understand T cell behavior and propose strategies to drive anti-tumor immune hub formation to expand the portion of patients benefiting from immunotherapy approaches. Citation Format: Samuel J. Wright, Minae An, Byung Hoon Min, You Jeong Heo, Milan Parikh, Lynn Bi, Hyuk Lee, Taejun Kim, Song-Yi Lee, Jeonghyeon Moon, Ryan J. Park, Matthew R. Strickland, Woong Yang Park, Won Ki Kang, Kyoung-Mee Kim, Seung Tae Kim, Arnav Mehta, Samuel J. Klempner, Jeeyun Lee. Tumor cell metaplastic programs and failure of T cell remodeling drive resistance and progression to frontline chemoimmunotherapy in advanced gastric cancer [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 6846.

Abstract 2535: Development of Claudin 18.2 IHC 14G11 pharmDx as a clinical trial assay for the clinical development of anti-claudin 18.2 monoclonal antibody osemitamab (TST001) in gastric and gastroesophageal junction adenocarcinoma

Abstract Clone 14G11 is a mouse anti-Claudin 18.2 monoclonal antibody developed by Transcenta. The antibody was generated against a linear epitope located on the extracellular domain of loop1 and has a binding site that overlaps with the binding site of therapeutic antibody Osemitamab. It was selected to further develop for the detection of Claudin 18.2 expression in human cancer. Agilent Technologies, Inc. is developing Claudin 18.2 IHC 14G11 pharmDx as an immunohistochemical (IHC) assay for the detection of Claudin 18.2 protein in gastric and gastroesophageal junction (GEJ) adenocarcinoma in support of clinical studies conducted by Transcenta Therapeutics. Analytical verification for Claudin 18.2 IHC 14G11 pharmDx included sensitivity, specificity, and precision assessment. Testing was performed on human formalin-fixed, paraffin-embedded (FFPE) gastric and GEJ tissues using Autostainer Link 48 with EnVision FLEX visualization system. Biomarker expression was evaluated using Tumor Proportion Score (TPS). TPS is defined as the percentage of viable invasive tumor cells that exhibit convincing partial or complete membrane staining at any intensity. Sensitivity testing of 102 commercially procured FFPE gastric/GEJ specimens demonstrated a broad dynamic range of Claudin 18.2 positivity that covered TPS from 0% to 100%. Specificity tests confirmed specific targeting of the Claudin 18.2 protein in a variety of normal and abnormal tissues. For laboratory precision testing, which evaluated the assay variability in relation to run, instrument, operator, and reagent lot, ≥ 95% of TPS values were within expected variability limits for each parameter. For observer precision testing, two-sided 95% confidence intervals were ≥ 85% for negative, positive, and overall agreements when assessing two clinical cutoffs. These results demonstrated the Claudin 18.2 IHC 14G11 pharmDx assay can provide reliable and reproducible results in day-to-day testing. Analytical verification testing indicates Claudin 18.2 IHC 14G11 pharmDx is a sensitive, specific, and precise assay for detecting Claudin 18.2 in gastric and GEJ adenocarcinoma. Claudin 18.2 IHC 14G11 pharmDx for Investigational Use Only/for Performance Evaluation Only will be used for patient selection in the upcoming phase III trial of gastric/GEJ adenocarcinoma where applicable ethics committee and regulatory approvals have been granted. Citation Format: Hayley Alderson, Katie Lefley, Lesly Fregoso, Achintya Bharadwaj, Dan Castellanos-McKenney, Siena Tabuena-Frolli, Donna Kell, Xinlai Yao, Xueming Qian, Li Xu, Caroline Germa, Emin Oroudjev. Development of Claudin 18.2 IHC 14G11 pharmDx as a clinical trial assay for the clinical development of anti-claudin 18.2 monoclonal antibody osemitamab (TST001) in gastric and gastroesophageal junction adenocarcinoma [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 2535.

Abstract 6400: Tislelizumab combined with XELOX as a neoadjuvant therapy for locally advanced gastric and gastroesophageal junction adenocarcinomas: A prospective, phase II trial

Abstract Background: Combing anti-PD-(L)1 antibody with chemotherapy in neoadjuvant therapy of gastric/gastroesophageal junction (G/GEJ) adenocarcinomas is a promising strategy, but clinical data are remain insufficient. Whether immunotherapy biomarkers in previous studies (TMB, MSI, PD-L1, etc.) have equivalent predictive value for G/GEJ remains to be verified. In this phase II clinical trial of tislelizumab in combination with chemotherapy, potential therapy-related biomarkers in tumor samples, and changes in the tumor microenvironment during treatment were analyzed, and a predictive model for efficacy was developed. Methods: This was a prospective, single-center, single-arm, phase II trial. Patients with G/GEJ adenocarcinomas (stage cT3-4aN+M0) were treated with PD-1 inhibitor tislelizumab in combination with oxaliplatin plus capecitabine (XELOX) as neoadjuvant treatment for 2 or 3 cycles. The primary endpoint was the major pathological response (MPR). The secondary endpoints included pathological complete response (pCR) rate, R0 resection rate, and safety. Tumor samples underwent RNA-sequencing (Amoy Diagnostics Co Ltd, Xiamen, China), to identify potential biomarkers, and a predictive model was developed to explore factors influencing tumor response and survival. Results: 28 patients were enrolled; mean age was 59.5 years (SD = 8.2), 19 (67.9%) patients were male; 14 (50.0%) patients with primary tumor location in the stomach, and 14 (50.0%) patients with primary tumor location in the GEJ. All patients were EB virus negative. Except one patient with PMS2 loss, 27 patients were pMMR. Nine (32.1%) patients achieved MPR after treatment, with four (14.3%) of them achieved pCR. The R0 resection rate was 96.4%, with 14 (50.0%) patients achieved objective response. No serious adverse events were reported. The most common grade 2 TRAEs during neoadjuvant treatment were anemia (5 of 28, 17.86%) and nausea (3 of 28, 10.71%). Analysis of differentially expressed genes revealed enrichment of the antigen processing and presentation pathway in the MPR group, while the TGF-β signaling pathway was enriched in the non-MPR group. Notably, the differential immune microenvironment analysis also uncovered significant differences in the TGF-β signature between the MPR and non-MPR groups. Additionally, a therapeutic response prediction model (HT score) was developed with an AUC of 0.98 (0.932-1) in the training set, and its performance was validated in publicly available datasets. Conclusion: Tislelizumab combined with XELOX holds promise as a neoadjuvant therapy for resectable G/GEJ adenocarcinomas, especially for EBV- and pMMR population, offering a well-tolerated safety profile. Moreover, the HT score has the potential to predict treatment efficacy in this regimen. Trial registration numbers: NCT05507658 and NCT05508399. Citation Format: Haikun Zhou, Tao Han, Lei Tuo, Qingchuan Yang, Ruiqi Gao, Pengfei Yu, Jiangpeng Wei, Changbin Zhu, Jin Wang, Peng Cheng, Xiang Kang, Sihui Pi, Hui Liu, Xiaoxi Pan, Xiaohua Li, Gang Ji. Tislelizumab combined with XELOX as a neoadjuvant therapy for locally advanced gastric and gastroesophageal junction adenocarcinomas: A prospective, phase II trial [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 6400.

Abstract 6568: PTCH1 loss-of-function alterations: Mutational landscape and therapeutic outcomes to hedgehog pathway inhibitors in non-canonical histologies

Abstract Background: Loss-of-function (LOF) alterations of the PTCH1 tumor suppressor gene represent canonical events involved in basal cell carcinoma (BCC) oncogenesis. Hedgehog pathway inhibitors (HPIs) are approved for the treatment of advanced BCC, but genomic characterization and therapeutic outcomes remain limited in tumor agnostic cohorts. Methods: Using the MSK Clinical Sequencing Cohort, we performed a mutational landscape analysis of PTCH1 LOF alterations in non-BCC histologies, including Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) annotation, and analyzed response and progression-free survival (PFS) with HPIs. Results: Out of 115,619 samples, 1972 samples from advanced solid tumors with PTCH1 LOF alterations were identified. Excluding 1306 variants of unknown significance (VUSs) using OncoKB knowledge base as well as 44 BCC samples, a total of 622 samples from 570 patients with oncogenic PTCH1 alterations were identified across histologies. In addition, 124 patients received ≥1 line(s) of HPI at our institution between 2013 and 2023, including 16 patients with non-BCC histologies presenting PTCH1 alterations. At the patient level (n=570), PTCH1 LOF alterations were present across 33 primary sites, including colorectal cancer (CRC; 34%; n=192), endometrial cancer (17%; n=98), gastroesophageal adenocarcinomas (ADC) (8%; n=46), non-small cell lung cancer (NSCLC; 6%; n=34) and soft tissue sarcomas (STS; 4%; n=25). At the sample level (n=622), TMB ≥10 was seen in 83% (n=516), including 324 samples with MSI-high status. PTCH1 alterations most frequently involved frameshift (fs) indels (69%; n=429), followed by nonsense mutations (18%; n=114), splice site mutations (8%; n=47) and fusions (5%; n=32). Recurrent fs events involved S1203Afs*52 (24%; n=150) and R1308Efs*64 (14%; n=89), among others. When comparing monoallelic (monoall) vs biallelic (biall) PTCH1 alterations through FACETS annotation, monoall showed a strong association with higher TMB (p<0.01) whereas biall were associated with higher loss of heterozygosity (LOH; p<0.01). In the 16 non-BCC patients treated with HPIs, histologies included lung squamous cell cancer (SCC; n=4), cutaneous SCC (n=2), medulloblastoma (n=2), carcinosarcoma (n=2), osteosarcoma, chondrosarcoma, chordoma, sebaceous ADC, anal SCC and CRC (each n=1). TMB ≥10 was seen in 31% (n=5), all of which were MSI-low. Tumor regressions on HPI were seen in 50% (n=8), including lung SCC, cutaneous SCC, sebaceous ADC and medulloblastoma, with median time to response of 3.6 months (mo). Median PFS on HPI was 3.9 mo and median OS was 22.7 mo. Median PFS was higher in patients with TMB ≥10 vs TMB <10 (11.8 vs. 1.8 mo, p=0.02). Conclusion: PTCH1 LOF alterations appear actionable in non-BCC cutaneous/adnexal primaries, lung SCC and medulloblastoma, including TMB-high tumors. Citation Format: Antoine Desilets, Matteo Repetto, Soo Ryum Yang, Monica Chen, Dazhi Liu, Nikhil Rizvi, Ezra Rosen, Alan L. Ho, Alexander Drilon, Yonina R. Murciano-Goroff. PTCH1 loss-of-function alterations: Mutational landscape and therapeutic outcomes to hedgehog pathway inhibitors in non-canonical histologies [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 6568.

Abstract 1046: Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types

Abstract The S-methyl-5′-thioadenosine phosphorylase (MTAP) gene is located at 9p21 and is often co-deleted with CDKN2A. Because homozygous MTAP deletions result in a complete expression loss, MTAP immunohistochemistry (IHC) can be used for detection of homozygous deleted cells. MTAP IHC is of diagnostic utility for the distinction of mesotheliomas (often 9p21 deleted) from benign mesothelial proliferations. Moreover, evidence is emerging that MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting several different pathways that depend on a functional MTAP gene and also causes resistance to immune checkpoint inhibitors. To determine the prevalence of complete MTAP expression loss and to assess the diagnostic utility of MTAP IHC, a tissue microarray containing 17,078 samples from 149 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by IHC. All cases with complete MTAP loss were validated by fluorescence in situ hybridization (FISH). In normal tissues, MTAP was ubiquitously expressed resulting in a cytoplasmic and nuclear MTAP staining. At least one case with a complete MTAP expression loss was observed in 87 of 149 (58%) tumor categories. MTAP staining was most commonly lost in neuroendocrine neoplasms of various sites (up to 80%), Hodgkin’s lymphoma (38%), mesothelioma (24-30%), bilio-pancreatic adenocarcinomas (9-36%), urothelial neoplasms (19-29%), malignant melanoma (14-21%), mucinous carcinoma of the ovary (27%), squamous cell carcinomas of various organs of origin (up to 24%), various types of sarcomas (up to 20%), adenocarcinoma of the lung (11%), gastro-esophageal adenocarcinomas (2.6-11%), and in various types of non-Hodgkin’s lymphomas (up to 14%). FISH validation identified homozygous 9p21 deletions in 90-98% of cases with MTAP expression loss in most tumor categories including urothelial neoplasms, mesotheliomas, and pancreatic cancers, and others. There were, however, also tumor types such as neuroendocrine tumors and Hodgkin’s lymphomas that always lacked 9p21 deletions. In summary, our data provide a comprehensive overview on MTAP expression in cancer and show a strong link between MTAP expression loss and homozygous 9p21 deletions in most tumor entities. These cancers might most benefit from cancer drugs targeting MTAP deficiency. The absence of 9p21 deletions in other entities with frequent MTAP expression loss demonstrates that other mechanisms can cause significant MTAP downregulation. Whether these tumors benefit from targeting MTAT deficiency remains to be determined. Citation Format: Natalia Gorbokon, Maximilian Lennartz, Doris Hoeflmayer, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Florian Viehweger, Florian Lutz, Christoph Fraune, Andreas M. Luebke, Claudia Hube-Magg, Franziska Büscheck, Anne Menz, Ria Schlichter, Till Krech, Andrea Hinsch, Eike Burandt, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H. Marx, Patrick Lebok, David Dum, Sarah Minner, Frank Jacobsen, Till S. Clauditz, Christian Bernreuther, Martina Kluth. Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types [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 1046.