HER2 Overexpression Research Articles

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Temporal and spatial heterogeneity of HER2 status in metastatic colorectal cancer

BackgroundHER2-targeted therapies have recently emerged as an option in the management of metastatic colorectal cancer (mCRC) overexpressing HER2. However, data regarding HER2 status in primary CRC and its corresponding liver metastases are limited, potentially influencing clinical decisions. Therefore, the aim of this study was to compare the HER2 status in primary CRC and paired liver metastases.MethodsPatients with mCRC who were operated from their primary colorectal cancer and their corresponding synchronous or metachronous liver metastases, in the digestive surgery department of Besançon University Hospital, between April 1999 and October 2021, were included. Tissue microarrays were constructed from matched primary CRC and liver metastastic tissue samples. HER2 status was assessed by immunohistochemistry and in situ hybridization according to Valtorta’s criteria.ResultsA series of 108 paired primary CRC and liver metastases, including a series of multiple liver metastases originating from the same patients (n = 24), were assessed. Among the primary CRC, 89 (82.4%), 17 (15.8%) and 2 (1.8%) cases were scored 0, 1 + and 2 + respectively. In liver metastases, 99 (91.7%), 7 (6.5%) and 2 (1.8%) were scored 0, 1 + and 2, respectively. Overall, there was a 19% discrepancy rate in HER2 status between primary CRC and metastases, which increased to 21% in cases with multiple synchronous or metachronous liver metastases in a given patient. No significant difference was found between metachronous and synchronous metastases regarding the HER2 status (p = 0.237).ConclusionsOur study highlights the temporal and spatial heterogeneity of HER2 status between primary CRC and corresponding liver metastases. These findings raise the question of a sequential evaluation of the HER2 status during disease progression, to provide the most suitable treatment strategy.

From Intractable to Treatable: Milestones and Horizons in the Management of HER2+ Breast Cancer

The human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family that initiates various signalling pathways that control cell proliferation and tumourigenesis. Historically, approximately 15% of breast cancers have been characterized by overexpression or amplification of HER2, known as “HER2+” breast cancers. This subtype has been associated with an adverse prognosis, along with a high risk of recurrence and worse survival outcomes. However, with the discovery and subsequent development of HER2‑targeted therapies, the clinical course of HER2+ breast cancers has fundamentally changed. Optimizing therapeutic strategies using existing and emerging HER2-targeted therapies to build upon these advances remains a major priority for clinical development and treatment delivery. In 1998, the American Food and Drug Administration (FDA) and Health Canada approved trastuzumab, the first HER2-targeted therapy. Trastuzumab, a monoclonal antibody that binds to the HER2 receptor, has demonstrated clinical activity and improved outcomes in patients with metastatic HER2+ breast cancer when combined with chemotherapy. Following soon after, the first trial of adjuvant trastuzumab (HERA) demonstrated improvements in outcomes when combined with chemotherapy for early HER2+ breast cancer. More than 25 years after its first approval, trastuzumab retains a central role in the treatment of both early and advanced HER2+ breast cancer and has provided a backbone for both new therapeutic combinations (eg. with small molecule inhibitors of HER2) and new classes of therapeutic agents (antibody drug conjugates [ADC]). These successors of trastuzumab are currently redefining the HER2+ treatment landscape in both advanced and early breast cancer.

Current and Emerging Treatment Options for HER2‑Positive Gastroesophageal Cancer

Gastroesophageal cancer (GEC) is the fifth most common cancer and the second most common cause of cancer-related mortality, with 1.3 million annual deaths worldwide. The global incidence is increasing, particularly among younger patients. GEC can be classified into subtypes based on anatomic location, histology, molecular characteristics, or tumour biology and genomics. In approximately 20% of all GECs overexpression of HER2 is identified. The landscape of treatment options in this patient population is evolving rapidly. This review summarizes the progress of HER2-directed therapies for advanced disease and highlights future directions in targeting the disease. The epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinase receptors, EGFR/HER1, HER2/neu, HER3, and HER4, all have an extracellular ligand-binding domain, lipophilic transmembrane domain, and an intracellular domain with tyrosine kinase activity, binding to these receptors results in activation of downstream RAS/MAPK and PI3K/AKT pathways. In turn, this induces cell proliferation, differentiation, migration, and survival. The phase III Trastuzumab for Gastric Cancer (ToGA) trial reported the incidence of HER2-positive gastric cancer to be 22%. Therefore, targeting HER2 and its downstream signaling pathways holds important potential as a therapeutic strategy. Figure 1 illustrates potential targeting mechanisms that will be discussed in this review.

Radiomics in esophagogastric junction cancer: A scoping review of current status and advances

PurposeThis scoping review aimed to understand the advances in radiomics in esophagogastric junction (EGJ) cancer and assess the current status of radiomics in EGJ cancer. MethodsWe conducted systematic searches of PubMed, Embase, and Web of Science databases from January 18, 2012, to January 15, 2023, to identify radiomics articles related to EGJ cancer. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies using the Radiomics Quality Score (RQS) and the METhodological RadiomICs Score (METRICS) tool, respectively. ResultsA total of 120 articles were retrieved from the three databases, and after screening, only six papers met the inclusion criteria. These studies investigated the role of radiomics in differentiating adenocarcinoma from squamous carcinoma, diagnosing T-stage, evaluating HER2 overexpression, predicting response to neoadjuvant therapy, and prognosis in EGJ cancer. The median score percentage of RQS was 34.7% (range from 22.2% to 38.9%). The median score percentage of METRICS was 71.2% (range from 58.2% to 84.9%). ConclusionAlthough there is a considerable difference between the RQS and METRICS scores of the included literature, we believe that the research value of radiomics in EGJ cancer has been revealed. In the future, while actively exploring more diagnostic, prognostic, and biological correlation studies in EGJ cancer, greater emphasis should be placed on the standardization and clinical application of radiomics.

HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review.

Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.

Discovery of Potent and Selective Covalent Inhibitors of HER2WT and HER2YVMA.

HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.

Integrin β3 Reprogramming Stemness in HER2-Positive Breast Cancer Cell Lines.

HER2-positive breast cancer, characterised by overexpressed HER2 levels, is associated with aggressive tumour behaviour and poor prognosis. Trastuzumab is a standard treatment; however, approximately 50% of patients develop resistance within one year. This study investigates the role of ITGβ3 in promoting stemness and resistance in HER2-positive breast cancer cell lines (HCC1954 and SKBR3). The findings demonstrate that chronic exposure to trastuzumab upregulates stem cell markers (SOX2, OCT4, KLF4, NANOG, SALL4, ALDH, BMI1, Nestin, Musashi 1, TIM3, CXCR4). Given the documented role of RGD-binding integrins in drug resistance and stemness, we specifically investigated their impact on resistant cells. Overexpression of ITGβ3 enhances the expression of these stem cell markers, while silencing ITGβ3 reduces their expression, suggesting a major role for ITGβ3 in maintaining stemness and resistance. Further analysis reveals that ITGβ3 activates the Notch signalling pathway, known for regulating stem cell maintenance. The combination of trastuzumab and cilengitide, an integrin inhibitor, significantly decreases the expression of stem cell markers in resistant cells, indicating a potential therapeutic strategy to overcome resistance. These results identify the importance of ITGβ3 in mediating stemness and trastuzumab resistance through Notch signalling in HER2-positive breast cancer, offering new approaches for enhancing treatment efficacy.

Advances in Small-Molecule Dual Inhibitors Targeting EGFR and HER2 Receptors as Anti-Cancer Agents

Abstract: As members of the protein tyrosine kinase family, the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) play essential roles in cellular signal transduction pathways. Overexpression or abnormal activation of EGFR and HER2 can lead to the development of various solid tumors. Therefore, they have been confirmed as biological targets for the development of anticancer drugs. Due to the fact that many cancers are highly susceptible to developing resistance to single-target EGFR inhibitors in clinical practice, dual inhibitors that target both EGFR and HER2 have been developed to increase efficacy, reduce drug resistance and interactions, and improve patient compliance. Currently, a variety of EGFR/HER2 dual inhibitors have been developed, with several drugs already approved for marketing or in clinical trials. In this review, we summarize recent advancements in small-molecule EGFR/HER2 dual inhibitors by focusing on structure-activity relationships and share novel insights into developing anticancer agents.

Targetable ERBB2/HER2 Mutations in Gynecologic Malignancies: Clinicopathological, Immunohistochemical, and Molecular Correlations.

Targeted anti-HER2 therapy has been recently added to the standard treatment recommendations in endometrial serous carcinoma. Current eligibility requires testing for HER2 overexpression and/or gene amplification by immunohistochemistry and by fluorescence in situ hybridization. However, clinical trials have also demonstrated the efficacy of anti-HER2 drugs against activating ERBB2/HER2 mutations in a variety of solid tumor types, and fam-trastuzumab deruxtecan is now approved by the US Food and Drug Administration for HER2-mutant non-small cell lung cancer. This study aimed at evaluating the detailed clinical, histomorphological, immunohistochemical, and molecular characteristics of gynecologic malignancies with ERBB2/HER2 mutations. We identified 16 tumors with 19 ERBB2/HER2 mutations in our departmental archives: 11 endometrial primaries, 2 endocervical adenocarcinomas, 1 ovarian mucinous adenocarcinoma, 1 tubo-ovarian undifferentiated carcinoma, and 1 high-grade endometrioid adenocarcinoma of Mullerian origin. ERBB2/HER2 mutations most often involved the tyrosine kinase domain (52.6%), and the most frequent specific mutation was R678Q (31.6%), involving the juxtamembrane domain. More than half (54.5%) of endometrial carcinomas and half of all tumors were MMR-deficient, resulting from MSH6 loss in all but 2 tumors. None of the tumors (0%) were POLE-mutated, while 18.8% were TP53-mutated. HER2 IHC was negative (score 0 or 1+) in 12 tumors (67%) and equivocal (score 2+) in 4 tumors (33%), whereas none of the tumors were scored as HER2 3+. Score 2+ was associated with R678Q, L755S, I767M mutations, and ERBB2/HER2 rearrangement with a breakpoint in exon 23. Concurrent ERBB2/HER2 amplification was identified in 2 endometrial carcinomas, with HER2/CEP17 ratios of 3.1 and 3.5. We also queried the cBioportal database, which revealed 70 ERBB2/HER2-mutant gynecologic tumors with a total of 77 ERBB2/HER2 mutations, most often involving the active site of the tyrosine kinase domain (n=36; 46.8%), and the most common specific mutation was S310F (n=20; 26%), located in the extracellular domain. Our results provide important details regarding the clinicopathological and molecular associations of potentially actionable ERBB2/HER2 mutations in endometrial carcinoma and other gynecological cancer types and contribute to addressing clinical treatment needs and improving pathology testing recommendations in the future.

Whole genome sequencing of HER2-positive metastatic extramammary Paget’s disease: a case report

BackgroundExtramammary Paget’s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape.MethodsImmunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed.ResultsNotable copy number gains (log2FC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event.ConclusionWhole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.

Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .

Efficacy and safety of disitamab vedotin (RC48) combined with camrelizumab and S-1 for neoadjuvant therapy of locally advanced gastric cancer with HER2 overexpression: Preliminary results of a prospective, single-arm, phase II study.

e16100 Background: A combination of HER2-targeted therapy, immunotherapy and chemotherapy is being explored in the perioperative treatment of gastric/gastric junction (GC/GEJ) adenocarcinoma.Disitamab vedotin (RC48), a HER2-directed antibody-drug conjugate (ADC), demonstrated significant anti-tumor activity. Moreover, data suggest that the combination of RC48 with immunotherapy exhibits a synergistic effect. Therefore, we conducted the study to investigate the effects of combining RC48 with camrelizumab and S-1 in the neoadjuvant setting for locally advanced, resectable GC/GEJC with HER2 overexpression. Methods: In this prospective, phase II, single-arm study, we included patients with histologically confirmed, resectable gastric/gastric junction adenocarcinoma (GC/GEJ) staged as cT3-4aN1-3M0 according to the TNM 8th edition, and demonstrating HER2 overexpression (IHC 3+ or IHC 2+). Participants received three cycles of treatment on a three-weekly basis (Q3W). Surgical resection was scheduled to occur 3-4 weeks following the completion of neoadjuvant therapy. The primary endpoint was the pathological complete response (pCR) rate; the secondary endpoints included the major pathological response (MPR) rate, clinical downgrading rate, disease-free survival (DFS), overall survival (OS), and safety. Results: Between Sep 18, 2022 and Feb 2, 2024, a total of 23 patients were enrolled. Seven patients had not completed neoadjuvant treatment.Two patients refused surgery due to organ preservation. Two patients refused study therapy after 2 cycles of neoadjuvant treatment. 12 patients who experienced D2 resection, 6 (50%) achieved MPR, including 4 (33.3%) with pCR (ypT0N0M0).The R0 resection rate was 100%. Median DFS and OS have not been reached. The most common reported AEs (grade≥3) were decreased neutrophil count (10%), bowel obstruction (5%), ALT increased (5%) and AST increased (5%). There have been no treatment-related mortalities documented. Conclusions: The preliminary findings suggest that the neoadjuvant combination of RC48, camrelizumab and S-1 presents a promising and safe treatment option for locally advanced resectable GC/GEJ adenocarcinoma with HER2 overexpression. Clinical trial information: ChiCTR2300075446.

Influence of neoadjuvant regimen on the prognosis of locally advanced gastric and gastroesophageal junction cancer with HER2 overexpression.

e16082 Background: The relative high recurrence rate in locally advanced gastric or gastroesophageal junction (G/GEJ) cancer with Her2 overexpression after surgery, along with the absence of a standard neoadjuvant treatment protocol, necessitates exploration of novel approaches for this patient population. Methods: In this study, we conducted a retrospective analysis of clinical characteristics, postoperative pathological results, and survival data for patients who underwent neoadjuvant treatment and subsequent surgery at our center from September 2020 to December 31, 2022. The inclusion criteria were as follows: 1) pathologically confirmed adenocarcinoma of the G/GEJ; 2) diagnosed as cT3-4 or N+ by enhanced CT and endoscopic ultrasound; 3) Her2 immunohistochemistry 3+ or 2+ with Fish positive in biopsy specimens; 4) discussed in a multidisciplinary team for the need for neoadjuvant treatment; 5) received 2-4 cycles of neoadjuvant therapy; 6) underwent radical D2 surgery; 7) had complete follow-up data. Results: Seventy-three patients met the inclusion criteria, with 19 receiving chemotherapy + anti-PD-1, 10 receiving chemotherapy + anti-Her2, and 44 receiving chemotherapy alone. Their pCR rates were 31.6%, 10%, and 2.3%, respectively (P = 0.003); MPR rates were 42.1%, 30%, and 11.4% (P = 0.022). As of the last follow-up on December 31, 2023, the median DFS for the chemotherapy group was 18.1 months (95% confidence interval 14.9-21.3); median DFS for the other two groups had not been reached. DFS analysis revealed differences in median DFS among different neoadjuvant treatment regimens (P = 0.025); further pairwise comparisons indicated that this difference mainly stemmed from the chemotherapy + anti-Her2 group compared to the chemotherapy group. Conclusions: In locally advanced gastric and gastroesophageal junction cancer with Her2 overexpression, neoadjuvant chemotherapy combined with anti-Her2 treatment improves the pCR rate and prolongs DFS compared to neoadjuvant chemotherapy alone.

The role of determining HER2neu status in patients with gastric cancer.

e16067 Background: Over the past two decades, gastric cancer has continued to maintain a leading position in both incidence and mortality rates among all malignant neoplasms in the Republic of Kazakhstan. Recent data indicate that amplification or overexpression of the HER2 gene is detected in 7-34% of gastric cancer cases, significantly impacting treatment outcomes. Studying a specific group of patients with HER2 overexpression in gastric cancer is of great interest in clinical oncology. Research aim: To examine the long-term treatment outcomes in patients with gastric cancer depending on the status and level of HER-2 expression in real clinical practice. Methods: Analysis was conducted on 172 formalin-fixed paraffin-embedded samples of gastric adenocarcinoma and gastroesophageal junction carcinoma, subjected to immunohistochemical examination to determine HER2 protein expression. Patients' ages ranged from 18 to 85 years, with a mean age of 61.7 years; among them, 106 (61.6%) were male and 66 (38.4%) were female. Of the 172 patients, 64 (37.2%) had primary tumors located at the gastroesophageal junction, while 108 (62.8%) had tumors located in the body of the stomach. Based on differentiation grade, the majority were G3-100 (50%), G2-91 (45%), G1-9 (5%). HER2 testing was performed on the Ventana BenchMark Ultra platform using the HER2 (4B5) antibody. Results: HER2 overexpression was detected in 26 (15.1%) of the 172 patients. Patients with HER2 2+ non-amplified were 6 (3.5%), HER2 2+ amplified were 8 (4.6%), HER2 1+ was detected in 19 (11%) cases, and HER2 0 was found in 121 (80.9%) cases. Long-term results revealed statistically significant differences, notably the highest overall survival rate in patients with HER-2 overexpression compared to HER-2 low and absence of HER-2. The HER2 3 (+FISH/SISH) variant was significantly more prevalent in 84.6% compared to HER2 0 in 52%, and HER2 1 in 48%, p < 0.05. Comparison of Her2 status using the chi-square method in groups revealed probable differences concerning tumor localization, with a criterion value of 0.034; morphological form (criterion value = 5.83); and differentiation grade (criterion value = 10.05). Conclusions: These results underscore the importance of further HER2 research in gastric cancer and gastroesophageal junction carcinoma for the development of personalized therapeutic strategies.

The tumor immune profile of bladder cancer (BC) with HER2 over-expression and the investigation into RC48-ADC versus BCG in high-risk non-muscle invasive BC with HER2 over-expression.

The tumor immune profile of bladder cancer (BC) with HER2 over-expression and the investigation into RC48-ADC versus BCG in high-risk non-muscle invasive BC with HER2 over-expression.

Population based assessment of HER-2 and PD-L1 positivity in gastric and gastroesophageal junction adenocarcinomas in a Canadian population.

e16038 Background: Current standard of care for advanced gastric and gastroesophageal cancers combines systemic chemotherapy with either human epidermal growth factor receptor 2 (HER-2) or programmed death ligand 1 (PD-L1) targeting therapy. New data is emerging that for patients whose tumours are positive for both HER-2 overexpression and have a PD-L1 combined positive score (CPS) >1%, combining all three treatment modalities results in superior outcomes. There is limited international data, and no Canadian data, exploring the frequency of patients who have tumours that are both HER-2 and PD-L1 positive who will be eligible for this novel treatment approach. Objective: To determine the proportion of patients in Nova Scotia with HER-2 positive gastric and GEJ adenocarcinomas who have a PD-L1 CPS score above established clinical thresholds. Methods: A retrospective review of PD-L1 and HER-2 status for all patients diagnosed with gastric and GEJ adenocarcinomas in Nova Scotia between June 3, 2022 and August 13, 2023 was completed. PD-L1 CPS was evaluated using the 28-8 assay and was considered positive if >1%. HER-2 overexpression was evaluated by immunohistochemistry and in cases with equivocal expression, status was based on fluorescence in situ hybridization. Results: Over the study period, 56 cases of gastric and 42 cases of GEJ adenocarcinoma were identified for a total of 98 cases. The median age of the study population was 73 years (range 38 - 91). 73 patients (74%) were male and 25 patients (26%) were female. HER-2 expression was evaluated in 92 cases, and PD-L1 CPS was evaluated in 95 cases. 19 cases (21%) were HER-2 positive and 86 cases (91%) were PD-L1 positive. 17 HER-2 positive cases were also PD-L1 positive (89%). Conclusions: This study provides population level data in a Canadian context on patients with gastric and GEJ adenocarcinoma with respect to HER-2 overexpression and PD-L1 status. This data will be helpful in planning allocation of clinical and financial resources as a new standard of care for these patients is established.

Retrospective analysis of factors impacting efficacy of patients with later stage breast cancer receiving neoadjuvant therapy.

e12624 Background: Neoadjuvant treatment is the current standard of care for patients with early breast cancer (EBC), especially for patients with later stage breast cancer (LBC). We conducted this retrospective study to summarize the correlation between pathologic complete response (pCR), disease-free survival (DFS), overall survival (OS) and clinical impacting factors of patients with later stage received neoadjuvant treatment. Methods: We retrospectively analyzed the clinical data of patients receiving neoadjuvant treatment at the Department of Breast Oncology, Peking University Cancer Hospital from Jan. 2013 to Feb. 2022. Statistical analyses were carried out using IBM SPSS Statistics. We calculated pCR rate, DFS and OS. Pearson’s χ2 or Fisher’s exact tests were used for comparison of categorical variables. DFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox regression was used to identify factors impacting on survival. All p values were two sided and p<0.05 was considered to denote statistical significance. Results: Of 198 patients, most of them were in stage II (115/198, 58.1%), followed by stage III (79/198, 39.9%) and stage I (4/198, 2.0%), The pCR rates for different molecular subtypes were 31.6% TNBC, 29.7% for HR-Her2+ BC, 26.1% for HR+Her2+ BC and 1.3% for HR+Her2- BC, respectively (p=0.000). The median DFS of patients with or without pCR was 59.63 months (95%CI: NA-NA) and 29.83 months (95%CI: 21.31-38.35), respectively (p=0.012). DFS of patients who were cT1 [59.63 months (95%CI: 37.95-81.31)] or cT2 [39.56 months (95%CI: 24.19-54.93)] was significantly longer than that of patients who were cT3-4 [25.76 months (95%CI: 14.11-37.41), p=0.041]. Miller Payne (M-P) grade and ypTNM stage were also significantly associated with DFS in univariate analysis and in the multivariate cox regression model after adjusting for molecular subtypes. The 5-year OS were 87.0% for patients who reached pCR and 52.0% for patients who didn’t (p=0.009). Conclusions: The pCR was significantly associated with molecular subtypes. HR negativity and overexpression of Her2 were significantly associated with higher pCR rate. Patients reached pCR had longer DFS and OS. DFS was significantly associated with cT stage (T1 vs T2 vs T 3-4), ypTNM stage and M-P grade.

IAM1363-01: A phase 1/1b study of a selective and brain-penetrant HER2 inhibitor for HER2-driven solid tumors.

TPS3186 Background: HER2 activation promotes carcinogenesis, prompting the development of HER2-directed therapies in cancers with HER2 alterations. There is a critical need for novel agents to treat HER2-driven cancers, as current inhibitors display significant toxicity and lack efficacy against certain mutations. IAM1363 (formerly IAM-H1 and ENT-H1) is an irreversible and brain-penetrant small molecule inhibitor targeting both wildtype HER2 and oncogenic HER2 mutants, including the recalcitrant exon 20 mutations. IAM1363, discovered through Iambic Therapeutics' AI-driven discovery platform, represents the only example of a Type II HER2 inhibitor. It was designed to avoid off-target toxicities from EGFR inhibition thus expanding the therapeutic index over existing HER2 inhibitors. In preclinical studies, IAM1363 shows preferential tumor enrichment, a unique feature observed across tumor types and anatomic sites. The promising target specificity and pharmacokinetic profile of IAM1363 offers the potential to bridge gaps left by current standard of care HER2 targeted treatments. Methods: IAM1363-01 is a first-in-human, multicenter, open-label, Phase 1/1b dose escalation and expansion trial evaluating IAM1363 as monotherapy and in combination with trastuzumab. The study will enroll patients with relapsed/refractory malignancies that have documented HER2 gene alterations (amplification or tyrosine kinase domain mutations) or protein overexpression. Prior treatment with HER2 directed therapies is allowed after a washout period. Part 1, dose escalation, will enroll patients with any tumor type. Part 2 will optimize IAM1363 dosing as monotherapy and in combination with trastuzumab. Part 3 consists of a Simon 2-Stage evaluation of IAM1363 as monotherapy in patients with colorectal, non-small cell lung, and bladder cancer with or without brain metastases and in combination with trastuzumab in breast cancer patients with brain metastases. Key objectives are to establish the safety and tolerability of IAM1363, characterize PK/PD, and determine the recommended Phase 2 dose. Exploratory analysis will correlate HER2 expression level/mutation status with tumor response and tolerability. IAM1363 will be given orally once daily at a starting dose of 120 mg/day in up to 4 planned dose levels. Dose escalation employs an accelerated titration design that transitions to a standard 3 + 3 design based on protocol-specific criteria. Up to 287 patients will be enrolled at approximately 20 sites and treated until disease progression or unacceptable toxicity. The trial is designed to establish the safety profile of IAM1363 as a single agent and in combination with trastuzumab and to provide initial proof of antitumor activity in malignancies with HER2 overexpression, gene amplification, or tyrosine kinase mutations, including in patients with brain metastases. Clinical trial information: NCT06253871 .

A phase 2, single arm, European multi-center trial evaluating the efficacy of afatinib as first line or later line treatment in advanced chordoma.

11517 Background: EGFR and Her2 overexpression in chordoma is well known, and chordoma cell-lines and mouse models were proven to be sensitive to EGFR inhibitor afatinib. This phase 2, single arm, European multi-center trial was designed to evaluate the efficacy of afatinib as first- or later-line tyrosine kinase inhibitor (TKI) treatment in advanced chordoma. Here we report efficacy and safety data. Methods: Eligible patients (pts) had locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies, with confirmed measurable and progressive lesions according to RECIST1.1. Pts were treated with afatinib 40mg/day in a 4 week cycle until disease progression (PD), unacceptable toxicity or withdrawal. Radiological tumor response assessment was performed every 3 cycles. The primary endpoint was response defined as progression free survival (PFS) rate ≥12 months (mos) for first-line cohort 1 and ≥ 9 mos for further-line treatment cohort 2, and change from baseline in EORTC QLQ- C30 and Brief pain inventory (BPI) questionnaires. Pts were enrolled using a Simon’s two-stage design, enrolling 13 patients in stage one, ≥3 patients with a PFS ≥ 12 or 9 mos were needed to enter stage two, where 43 pts total were to be enrolled, and ≥13 free from progression at 9 or 12 mos were required to meet the primary endpoint for success. Results: From Jun 2018 to Oct 2022, 47 pts were included. Four were ineligible for efficacy analysis (1 withdrawal, 3 stopped due to toxicity before first radiological evaluation). 34 entered cohort 1, 13 cohort 2. 31 (66.0%) were men, median age was 53 (range 28-85) years. 16 (34.0%) pts received prior systemic therapy (3 chemotherapy, 13 TKI, 2 immunotherapy, 2 other). The PFS rate at 12 mos was 40.0% in cohort 1 (12/30 pts), and 38.5% in cohort 2 (5/13 pts). Overall median PFS was 8.6 mos (95% CI 5.6-13.6); 9.1 mos (95% CI 5.8-16.6) in cohort 1 and 7.1 mos (95% CI 2.8-16.5) in cohort 2. Two pts remained on treatment at time of analysis. Best objective response by RECIST 1.1 was partial response in 4 pts (9.3%), stable disease in 33 (76.7%), PD in 5 pts (11.6%) and 1 (2.3%) unknown due to clinical progression. Median follow-up time was 23.7 mos (interquartile range 11.0-21.2). 16/47 pts (30.4%) experienced grade ≥3 adverse events (AEs). No grade 5 AEs related to afatinib were reported. Most common grade 3-4 afatinib-related AEs were skin toxicity (10.6% of pts), diarrhea (10.6%), mucositis (6.4%), hypertension (4.3%). Dose reduction was needed in 20/47 (42.6%) pts, and at least one dose interruption was needed in 31/47 (66.0%) pts. Conclusions: With a PFS rate at 12 mos of 40.0% in the first-line cohort and 38.5% at 9 mos in the further-line cohort, this phase 2 study met the PFS endpoint. QoLQ data will be provided at the conference . Partial response by RECIST was seen in 4/43 pts. Toxicity and dose reductions were relevant but manageable in most pts. Clinical trial information: NCT03083678 .