HER2 Inhibition in Gastric Cancer—Novel Therapeutic Approaches for an Established Target

Fong, Caroline; Chau, Ian

doi:10.3390/cancers14153824

Cited by 8 publications

(3 citation statements)

References 103 publications

(109 reference statements)

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“…HER2 is an epithelial cell-expressed ligand-independent receptor tyrosine kinase involved in cell differentiation. HER2 has been documented to be amplified and overexpressed in a variety of human cancers, which is correlated with a worse prognosis, higher recurrence rates and shorter OS ( 27 ). A number of studies established that HER2 controls the abnormal expression of PD-L1 in the stomach and the combination of anti-HER2 and anti-PD-1 has proven synergistic anticancer effects in animal models ( 16 , 28 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

Zou,

Wang,

Zhang

et al. 2023

Oncol Lett

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The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.

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Section: Discussionmentioning

confidence: 99%

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

Zou,

Wang,

Zhang

et al. 2023

Oncol Lett

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“…HER2 is overexpressed in over 20% of all gastric cancers and is a valid therapeutic target in this setting ( 44 , 45 ). HER2-TTC was associated with potent target-mediated cytotoxicity in various cancer cell lines, including gastric cancer cell lines, expressing different levels of HER2 ( 46 ).…”

Section: Ttcs In Cancermentioning

confidence: 99%

Targeted thorium-227 conjugates as treatment options in oncology

et al. 2023

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Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer therapy, including high linear energy transfer (LET), penetration range of 2–10 cell layers, induction of complex double-stranded DNA breaks, and immune-stimulatory effects. Several alpha radionuclides, including radium-223 (223Ra), actinium-225 (225Ac), and thorium-227 (227Th), have been investigated. Conjugation of tumor targeting modalities, such as antibodies and small molecules, with a chelator moiety and subsequent radiolabeling with α-emitters enables specific delivery of cytotoxic payloads to different tumor types. 223Ra dichloride, approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-metastatic disease and no visceral metastasis, is the only approved and commercialized alpha therapy. However, 223Ra dichloride cannot currently be complexed to targeting moieties. In contrast to 223Ra, 227Th may be readily chelated, which allows radiolabeling of tumor targeting moieties to produce targeted thorium conjugates (TTCs), facilitating delivery to a broad range of tumors. TTCs have shown promise in pre-clinical studies across a range of tumor-cell expressing antigens. A clinical study in hematological malignancy targeting CD22 has demonstrated early signs of activity. Furthermore, pre-clinical studies show additive or synergistic effects when TTCs are combined with established anti-cancer therapies, for example androgen receptor inhibitors (ARI), DNA damage response inhibitors such as poly (ADP)-ribose polymerase inhibitors or ataxia telangiectasia and Rad3-related kinase inhibitors, as well as immune checkpoint inhibitors.

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“…Recently, immune checkpoint inhibitors were found to be efficacious in various tumor types, including gastric cancers ( 10 ). Previous studies have confirmed that trastuzumab inHER2-positive gastric cancer patients can modulate the tumor microenvironment (TME), via upregulating PD-1 and PD-L1 expression, expansion of tumor-specific CD4 and CD8 T cells, and enhancing the antitumor effects of immune checkpoint inhibitors ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and survival of anti-PD-1 antibody in combination with trastuzumab and chemotherapy versus trastuzumab and chemotherapy as first-line treatment of HER2-positive metastasis gastric adenocarcinoma: a retrospective study

Deng

Yang

et al. 2023

Front. Oncol.

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BackgroundThe KEYNOTE-811 study exhibited promising preliminary results for HER2-positive metastasis gastric adenocarcinoma; however, long-term survival benefit remains to be determined.MethodsIn this single-center, controlled, retrospective study, patients with histologically confirmed HER2-positive unresectable or metastatic gastric/gastroesophageal adenocarcinoma received either anti-PD-1 antibody combined with trastuzumab and chemotherapy (cohort A) or trastuzumab and chemotherapy treatment (cohort B). The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary end points were objective response rate (ORR), disease control rate (DCR), and duration of response (DoR).ResultsA total of 56 patients were eligible to join the study, with 30 patients in cohort A and 26 patients in cohort B. The median PFS (mPFS) was 16.2 months (95% CI, 15.093–17.307) in cohort A versus 14.5 months (95% CI, 9.491–19.509) in cohort B (p = 0.58). The median OS in cohort A was 28.1 months (95% CI, 17.625–38.575) versus 31.6 months (95% CI, 13.757–49.443) in cohort B (p = 0.534). ORRs were 66.7% and 50% in the two groups, respectively. DCRs were 90% and 84.6% in the two groups. Median DoR was not reached in cohort A and it was 16.3 (95% CI, 8.453–24.207) months in cohort B (p = 0.141). The most common irAEs were grade 1 hypothyroidism (33.3%) in cohort A. No treatment-related deaths occurred in this study.ConclusionsThis retrospective cohort study provided a preliminary picture on the long-term follow-up of combining anti-PD-1 antibody with trastuzumab and chemotherapy in HER2-positive GC, and a trend with longer DoR and ORR was identified. Further studies with larger sample sizes and more in-depth molecular investigation are needed.

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HER2 Inhibition in Gastric Cancer—Novel Therapeutic Approaches for an Established Target

Cited by 8 publications

References 103 publications

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

Targeted thorium-227 conjugates as treatment options in oncology

Efficacy and survival of anti-PD-1 antibody in combination with trastuzumab and chemotherapy versus trastuzumab and chemotherapy as first-line treatment of HER2-positive metastasis gastric adenocarcinoma: a retrospective study

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