HER2-positive Gastric Cancer Patients Research Articles

498TiP Adjuvant trastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: The TRINITY trial

498TiP Adjuvant trastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: The TRINITY trial

YAP inhibition overcomes adaptive resistance in HER2-positive gastric cancer treated with trastuzumab via the AKT/mTOR and ERK/mTOR axis

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice.MethodsIn this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs.ResultsWe revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways.ConclusionThese findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab.

Clinicopathologic features and prognosis of HER2- positive gastric cancer

Abstract Background The role of human epidermal growth factor receptor 2 (HER2) overexpression has been well established in breast cancer, with corresponding targeted therapies. In contrast, the clinicopathological features and prognosis of HER2 overexpression in gastric cancer remain inconclusive. Methods In this study, 334 patients with gastric cancer who received surgical resection between May 2017 and June 2021 were enrolled at a single medical center in Taiwan. HER2 status was determined by immunohistochemistry (IHC) staining or fluorescence in situ hybridization (FISH). The clinicopathological features and survival curves of the HER2-positive and HER2-negative gastric cancer patients were analyzed. Results The HER2-positive ratio was 7.2%. HER2-positive gastric cancer was associated with more differentiated tumors (P=0.016), more Lauren’s intestinal type (P=0.010) and a higher portion of Ming’s expanding type (P=0.033) in the univariate analysis, but only Lauren’s intestinal type was an independent factor in the logistic regression model (P=0.015). The overall survival and disease-free survival between the HER2-positive and HER2-negative groups were not significantly different. Patients with HER2-positive gastric cancer were more likely to have distant lymphatic recurrence than those with HER2-negative gastric cancer (P=0.026). Conclusions HER2-positive gastric cancer is associated with intestinal histological type and distant lymphatic recurrence, but HER2 is not an independent prognostic factor.

Metabolic heterogeneity affects trastuzumab response and survival in HER2-positive advanced gastric cancer

BackgroundTrastuzumab is the only first-line treatment targeted against the human epidermal growth factor receptor 2 (HER2) approved for patients with HER2-positive advanced gastric cancer. The impact of metabolic heterogeneity on trastuzumab treatment efficacy remains unclear.MethodsSpatial metabolomics via high mass resolution imaging mass spectrometry was performed in pretherapeutic biopsies of patients with HER2-positive advanced gastric cancer in a prospective multicentre observational study. The mass spectra, representing the metabolic heterogeneity within tumour areas, were grouped by K-means clustering algorithm. Simpson’s diversity index was applied to compare the metabolic heterogeneity level of individual patients.ResultsClustering analysis revealed metabolic heterogeneity in HER2-positive gastric cancer patients and uncovered nine tumour subpopulations. High metabolic heterogeneity was shown as a factor indicating sensitivity to trastuzumab (p = 0.008) and favourable prognosis at trend level. Two of the nine tumour subpopulations associated with favourable prognosis and trastuzumab sensitivity, and one subpopulation associated with poor prognosis and trastuzumab resistance.ConclusionsThis work revealed that tumour metabolic heterogeneity associated with prognosis and trastuzumab response based on tissue metabolomics of HER2-positive gastric cancer. Tumour metabolic subpopulations may provide an association with trastuzumab therapy efficacy.Clinical trial registrationThe patient cohort was conducted from a multicentre observational study (VARIANZ;NCT02305043).

Targeting RNA N6-methyladenosine modification-- a novel therapeutic target for HER2- positive gastric cancer.

Gastric cancer is one of the most common cancers and is considered the 5th most frequent occurring cancer worldwide. It has gained great attention from the clinicians and researchers because of high mortality rate. It is generally treated with chemotherapy, radiotherapy, and surgery. Recently, additional treatment options including immunotherapy and targeted therapy and immunotherapy have been developed. However, poor prognosis, limited survival rate of patients, and drug resistance to treatment remain critical problems. To improve treatment options or to overcome the bottleneck of treatment, identification of diagnostic and prognostic markers, determining the most effective therapeutic options, and uncovering the molecular regulations associated with treatment strategies are required. In this regard n6-methyladenosine (m6A) regulation is considered important. This reversible modification plays a crucial role in progression, development and treatment of HER2-positive gastric cancer. Here, we discuss the role of m6A modification in HER2-positive gastric cancer progression through collecting related studies at present. We further discuss the association of m6A modification with therapeutic efficacy in HER2-positive gastric cancer and list some examples. We conclude that modification of m6A can be a new strategy for improving the prognosis and survival rate of HER2-positive gastric cancer patients.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study

BackgroundNovel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients.MethodsThis was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities.Results45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3–4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively.ConclusionCompared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis.

Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.

1561P APC mutation (mt.), MYC, and GATA6 amplifications (amp.) were associated with worse survival in HER2-positive advanced gastric cancer patients treated with S-1/capecitabine plus oxaliplatin combined with trastuzumab (T-mab) and nivolumab (N-mab)

1561P APC mutation (mt.), MYC, and GATA6 amplifications (amp.) were associated with worse survival in HER2-positive advanced gastric cancer patients treated with S-1/capecitabine plus oxaliplatin combined with trastuzumab (T-mab) and nivolumab (N-mab)

The relationship between brain metastasis and HER2 expression status in gastric cancer.

Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white,of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30months vs.16.13months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.

Genomic characterization between HER2-positive and negative gastric cancer patients in a prospective trial.

We aimed to clarify the genomic characteristics of HER2-positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial. We collected 80 formalin-fixed paraffin-embedded (FFPE) samples (49 HER2+ and 31 HER2-) from gastric cancer patients who participated in the TROX-A1 trial (UMIN000036865). We queried a 435-gene panel (CANCERPLEX-JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2- gastric cancer patients were analyzed. Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2-negative patients. The number of total mutations in HER2-negative patients with ARID1A mutation was remarkably higher than that in HER2-positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2-positive cases was significantly higher than that in HER2-negative cases. Moreover, PTEN deletion was more common in HER2-positive cases. Finally, we found that, compared with HER2-positive patients, HER2-negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune-related pathways in HER2-negative patients. According to the genomic profiling of HER2-positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2-positive gastric cancer, HER2-negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy

HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

Trastuzumab in combination with chemotherapy for HER2-positive metastatic gastric cancer patients underwent conversion therapy.

BackgroundConversion surgery is a treatment that aims for R0 resection of primary advanced gastric cancers (GCs) that have responded well to systemic chemotherapy. We investigated the role of conversion therapy in initially unresectable metastatic cancer with positive HER2 status that responded to chemotherapy plus trastuzumab.MethodsA total of 32 metastatic GC patients who underwent systemic chemotherapy plus trastuzumab sequenced by conversion surgery at Zhejiang Cancer Hospital between 2015 and 2020 were retrospectively reviewed.ResultsThe observed overall survival (OS) and progression-free survival (PFS) for all the patients were 30.2 and 25.1 months, respectively. The 1-year survival rate was 81.25%, and the 1-year PFS rate was 78.13%. Univariate and multivariate analyses demonstrated that liver metastasis (P=0.021), peritoneal metastasis (P=0.047), para-aortic lymph node metastasis (16a1/b2) (P=0.048), macroscopic type 4 (P=0.027), number of noncurative factors (P=0.011), Yoshida et al. category (P=0.021), and inductive chemotherapy cycles (P=0.025) were independent prognostic factors for OS.ConclusionsHER2-positive patients with potentially resectable disease had a remarkably good prognosis after conversion gastrectomy following trastuzumab treatment. Adequate selection of metastatic GC patients for conversion surgery is recommended.

Abstract 5336: Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients

Abstract Introduction: The effect of trastuzumab in targeted therapy for HER2-positive gastric cancer (GC) is limited by the eventual development of resistance within patients. Although numerous studies have been published on this topic, both the mechanism of innate and acquired trastuzumab resistance are still not fully understood. In this study, we compare the mutational landscape of paired solid tumor samples before and after treatment in an effort to identify acquired events associated with resistance. Methods: We performed whole-exome sequencing on 46 tumor and 23 whole blood samples from patients with stage IV gastric cancer were obtained from before treatment (n = 23) and at disease progression (PD) (n = 23). HER2 status was checked using immunohistochemistry and validated with florescence in situ hybridization (FISH). Correlation analysis was then conducted between the mutational profile and clinical data of patients. Results: Comparisons between innate resistance samples and acquired resistance samples at baseline revealed three copy number variation events (CDK12 amplification, ERBB2 amplification, MECOM amplification) that occurs in significantly different proportions (p < 0.05). In addition, for baseline samples, MECOM was shown to be associated with poor progression-free survival (PFS) (Hazard Ratio (HR), 12; 95% CI, 1.6 - 85; p = 0.027). Commonly acquired events (i.e., lacking in before treatment samples and present at PD) within patients include TP53 mutation, MYC amplification, MCL1 amplification, CDKN2A/2B deletion, and CCNE1 amplification. Of these, patients with MCL1 gene amplification had worse survival (HR, 4.8; 95% CI, 1.2 - 20; p = 0.050) than patients with wild-type MCL1. In addition, the NOTCH pathway acquired mutations in 4 of 23 patients and was found to be correlated with a worse PFS (HR, 5.1; 95% CI, 1.4 - 19; p = 0.023), indicating that this pathway is possibly involved with trastuzumab resistance to some degree. Conclusion: Overall, our results show that comparisons of samples obtained before treatment and at PD can give insight about innate and acquired resistance mechanisms to trastuzumab in stage IV, HER2-positive GC patients. Citation Format: Qi Xu, Jingjing Li, Haimeng Tang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Jianying Jin, Cong Luo, Haimin Weng, Jieer Ying. Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5336.

P-139 Trastuzumab deruxtecan showed similar clinical benefit for frail HER2 positive gastric cancer patients: Retrospective observational study

Trastuzumab deruxtecan(T-DXd) showed promising effect for HER2 positive advanced gastric cancer (AGC) patients who previously received two or more chemotherapy in DESTINY-Gastric01 trial. Few HER2-positive AGC patients can receive T-DXd after third-line or later line treatment. In addition, although there are many frail cases in AGC patients receiving third-line treatment, the effectiveness and safety of T-DXd for frail cases is not yet clear. In this multicenter retrospective study, we collected clinical data of HER2 positive AGC patients received T-DXd from Electronic medical record system. Frail is defined as 75 years or older with any PS. 19 AGC patients were received T-DXd after two or more prior chemotherapy. Frail patients were 6 patients (32%). There is no significant difference between frail and non-frail group in patients background. In all patients, response rate (RR) was 42%, disease control rate was 78%, median progression free survival (PFS) was 4 months (95% CI: 2.6-6.5) and median overall survival (OS) was 6.1 months (95%CI:3.7-9.4). There were no significantly difference in RR, DCR, PFS, OS between frail group and non-frail group. There was no significant difference in safety between frail and non-frail patients. However, dose reduction was required at 47% in all population and frail group tended to have more dose reductions (67% vs 38%). In the frail group, 3 cases of dose reduction from the initial administration were observed. No patients in the frail group could receive post therapy after T-DXd failure. T-DXd showed clinical benefit for AGC patients in clinical setting including frail patients. However, dose reduction was necessary in about 50% of all population, and there was a tendency that dose reduction was more often required in frail patients. Further large study including frail patients is needed.

Significance of tumor heterogeneity of p-Smad2 and c-Met in HER2-positive gastric carcinoma with lymph node metastasis

BackgroundTumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients’ clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC.Materials and methodsWe retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients’ and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis.ResultsImmunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly (p = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2-positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression.Conclusionp-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC.

Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab.

The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity represents HER2 heterogeneity, we aimed to investigate this in a larger cohort with longer follow-up duration. Data of 153 HER2-positive advanced GC patients who received first-line trastuzumab-based chemotherapy were analyzed. Repeat endoscopic biopsy was performed in patients with initially HER2-negative GC. Survival outcomes were analyzed according to the immunohistochemistry (IHC) score (IHC 2+ /in situ hybridization [ISH] + vs IHC 3+), HER2 status (initially vs rescued HER2 positive), and H-score. IHC 2+ /ISH + patients showed worse progression-free survival (PFS) and overall survival (OS) than those with IHC 3+ (p < 0.05). Rescued HER2-positive patients showed worse PFS and OS than initially HER2-positive patients (p < 0.05). Although survival outcomes were comparable according to HER2 status in IHC 2+ /ISH + patients, initially HER2-positive patients showed more favorable PFS and OS than rescued HER2-positive patients (p < 0.05) among those with IHC 3+ . Among the subgroups determined by HER2 status and IHC score, the initially IHC 3+ subgroup had the highest H-score. The low H-score group (H-score ≤ 210) had significantly worse survival outcomes than the high H-score group (H-score > 210) (p < 0.05). An H-score of ≤ 210 was independently associated with shorter OS (HR = 1.54, 95% CI 1.02-2.31, p = 0.04). Rescued HER2-positive patients showed worse clinical outcomes than initially HER2-positive patients, especially those with IHC 3+ . This finding highlights the impact of HER2 heterogeneity, which can be quantified indirectly as an H-score.

Intra-tumoral FGFR2 Expression Predicts Prognosis and Chemotherapy Response in Advanced HER2-positive Gastric Cancer Patients.

This study aimed to evaluate the relationship between clinical outcomes and intra-tumoral fibroblast growth factor receptor 2 (FGFR2) expression in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients who had undergone HER2-targeted chemotherapy. A retrospective analysis was performed in 22 patients with HER2-positive GC, who had undergone systemic chemotherapy. We performed immunohistochemistry staining of FGFR2 expression using surgically resected specimens or biopsied samples and evaluated clinicopathological characteristic and overall survival (OS) in the FGFR2-negative and -positive GC groups. A total of 8 and 14 patients were placed in the FGFR2-negative and -positive group, respectively. The median OS rates were 56.2 and 16.0 months in the FGFR2-negative and -positive groups, respectively. The FGFR2-negative group had a significantly better prognosis after HER2-targeted chemotherapy [p=0.027 (log-rank test)]. The univariate analysis revealed that performing gastrectomy, response to combination chemotherapy with trastuzumab, and FGFR2 positivity were significantly correlated with OS. In a multivariate analysis, the response to combination chemotherapy with trastuzumab (p=0.008) was significantly correlated with OS. In addition, the proportions of patients who showed CR or PR in response to chemotherapy were 87.5 and 42.9% in the FGFR2-negative and -positive groups, respectively (p=0.031). HER2-positive GC patients, without overexpression of FGFR2, exhibited an improved prognosis and response rate to trastuzumab combination chemotherapy. Assessment of intra-tumoral FGFR2 expression could be helpful in predicting the prognosis and response to trastuzumab in HER2-positive GC patients.

Prognostic Factors in Patients with Advanced HER2-Positive Gastric Cancer Treated with Trastuzumab-Based Chemotherapy: a Cohort Study.

Prognostic factors for the survival of patients with advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy remain controversial. The aim of this study was to identify the clinical factors that predict prognosis in patients with advanced HER2-positive gastric cancer. We retrospectively reviewed the medical records of HER2-positive gastric cancer patients treated with trastuzumab-based chemotherapy at our institution. Clinical features and laboratory test results that considered prognostic factors were re-examined. Overall survival (OS) was estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test and multivariate analysis was performed using Cox's proportional hazard regression model. A total of 133 patients with advanced HER2-positive gastric cancer were enrolled. The median OS in this cohort was 18.7months. Four prognostic factors: visceral metastasis (lung or liver), levels of hemoglobin (Hb) (< 11.6g/dl), lactate dehydrogenase (LDH) (> 222mg/dl), and C-reactive protein (CRP) (> 0.14mg/dl), were identified as independent prognostic factors. The patients were placed into three groups according to their number of prognostic factors. These included low (0, 1), moderate (2, 3), and high (4) risk factors. The OS was separated into three categories with a median OS of 32.0, 18.7, and 10.1months, respectively. Compared to the low-risk group, hazard ratios for the moderate- and high-risk groups were 1.75 and 3.49, respectively. Visceral metastasis and abnormal Hb, LDH, and CRP levels were associated with unfavorable OS. These findings may be beneficial for the management of advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy.

Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer

Phosphoproteomic analysis expands our understanding of cancer biology. However, the feasibility of phosphoproteomic analysis using endoscopically collected tumor samples, especially with regards to dynamic changes upon drug treatment, remains unknown in stage IV gastric cancer. Here, we conducted a phosphoproteomic analysis using paired endoscopic biopsy specimens of pre- and post-treatment tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from 4 HER2-positive gastric cancer patients who received trastuzumab-based treatment and from pre-treatment Ts and NATs of 4 HER2-negative gastric cancer patients. Our analysis identified 14,622 class 1 phosphosites with 12,749 quantified phosphosites and revealed molecular changes by HER2 positivity and treatment. An inhibitory signature of the ErbB signaling was observed in the post-treatment HER2-positive T group compared with the pre-treatment HER2-positive T group. Phosphoproteomic profiles obtained by a case-by-case review using paired pre- and post-treatment HER2-positive T could be utilized to discover predictive or resistant biomarkers. Furthermore, these data nominated therapeutic kinase targets which were exclusively activated in the patient unresponded to the treatment. The present study suggests that a phosphoproteomic analysis of endoscopic biopsy specimens provides information on dynamic molecular changes which can individually characterize biologic features upon drug treatment and identify therapeutic targets in stage IV gastric cancer.

A randomized phase II trial of preoperative chemotherapy of S-1/CDDP with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

285 Background: The efficacy of trastuzumab has been established for HER2-positive advanced gastric cancer patients with metastatic disease. However, it remains unclear if the addition of trastuzumab to preoperative chemotherapy is effective for treatment of HER2-positive locally advanced gastric cancer. Methods: Eligible patients with HER2-positive gastric cancer with extensive lymph node metastasis were randomized to preoperative S-1/cisplatin (SP) (group A) or SP plus trastuzumab (group B). In both groups, patients received S-1, 80–120 mg/body, on days 1–14 and cisplatin, 60 mg/m2, on day 1, q21, 3-4 courses. Additionally, in group B, patients received infusions of trastuzumab (first course 8 mg/kg followed by 6 mg/kg, day 1). After gastrectomy, adjuvant chemotherapy with S-1 was performed for 1 year in both groups. The primary endpoint was overall survival, and the sample size was planned to be 130 patients in total, expecting a 10% increase in the 3-year overall survival (70% vs 80%) with a 1-sided alpha of 0.2, a power of 0.75. Results: The study was terminated in March 2021 due to slow patient accrual. In total, 46 patients were randomized to either group A (22 patients) or group B (24 patients). Patient characteristics were well balanced between the groups. Planned preoperative chemotherapy was completed in 20 patients (90.9%) in group A and in 23 patients (95.8%) in group B, and R0 resection was achieved in 20 patients (90.9%) in group A and 22 patients (91.7%) in group B. The incidences of grade 3 or 4 hematological/non-hematological adverse events during preoperative chemotherapy were 27.3/18.2% in group A and 4.2/8.3% in group B. Objective response rate (CR/PR) tended to be higher in group B (66.7% [16/24]) than in group A (36.4% [8/22], p = 0.08). Pathological response rate (&gt; grade 1b in Japanese classification, 22.7% [5/22] vs. 50.0% [12/24], p = 0.07) and the proportion of patients achieving downstage to ypStage 0/I/II (22.7% [5/22] vs. 50.0% [12/24], p = 0.07) were also higher in group B than in group A. Conclusions: Preoperative chemotherapy with SP plus trastuzumab was feasible, and tended to show better radiological and pathological response rates. Better survival outcomes are expected by adding trastuzumab to preoperative chemotherapy with SP for locally advanced gastric cancer with extensive nodal metastasis. Clinical trial information: UMIN000016920.