Esophageal and gastric malignancies are associated with poor prognosis, in part due to development of recurrences or metastases after curative treatment. The transforming growth factor β (TGF-β) pathway might play a role in the development of treatment resistance. In this systematic review, we provide an overview of preclinical studies investigating the role of TGF-β in esophageal and gastric malignancies. We systematically searched MEDLINE/PubMed and EMBASE for eligible preclinical studies describing the effect of TGF-β or TGF-β inhibition on hallmarks of cancer, such as proliferation, migration, invasion, angiogenesis and immune evasion. In total, 2107 records were screened and 45 articles were included, using mouse models and 45 different cell lines. TGF-β failed to induce apoptosis in twelve of sixteen tested cell lines. TGF-β could either decrease (five cell lines) or increase proliferation (seven cell lines) in gastric cancer cells, but had no effect in esophageal cancer cells. In all esophageal and all but two gastric cancer cell lines, TGF-β increased migratory, adhesive and invasive capacities. In vivo studies showed increased metastasis in response to TGF-β treatment. Additionally, TGF-β was shown to induce vascular endothelial growth factor production and differentiation of cancer-associated fibroblasts and regulatory T-cells. In conclusion, we found that TGF-β enhances hallmarks of cancer in most gastric and esophageal cancer cell lines, but not in all. Therefore, targeting the TGF-β pathway could be an attractive strategy in patients with gastric or esophageal cancer, but additional clinical trials are needed to define patient groups who would benefit most.

TPS4154 Background: Esophageal cancer is the 6th leading cause of mortality worldwide, with an overall 5-year survival rate of 10%. This is in part due to more than 50% of patients presenting with irresectable or metastatic disease. With the introduction of definitive chemoradiation, 3-year survival rates of patients with irresectable tumors have risen to up to 40% (Hulshof et al., ASCO GI Oral Presentation, 2020). However, treatment still fails in the majority of patients due to locoregional recurrences or development of metastatic disease. Recently, it has been shown that addition of TGF-β inhibition to chemoradiation may improve treatment efficacy (Steins et al., Int J Cancer, 2019). Additionally, PD-L1 inhibition has emerged as a relevant therapeutic strategy in specific patient subgroups, such as squamous cell carcinoma (Kato et al., The Lancet Oncology, 2019). In this phase II study, we will investigate the feasibility of addition of bintrafusp alfa, a bifunctional fusion protein blocking TGF-β and PD-L1, to definitive chemoradiation in patients with esophageal squamous cell carcinoma. Methods: To assess feasibility, 52 patients will receive definitive chemoradiation combined with three doses of bintrafusp alfa at week 1, 4 and 7 (Table). Feasibility is defined as ≥80% of patients completing 2 cycles of bintrafusp alfa and will be tested with a one-sample test for a binomial proportion, comparing the observed percentage to the fixed reference value of unfeasibility (62%). Secondary endpoints are toxicity, progression-free survival, overall survival and quality of life. Additionally, exploratory endpoints include development of biomarkers to predict treatment response. Eligible for inclusion are patients with surgically irresectable (T1-4a N+ M0) squamous cell carcinoma of the esophagus or gastro-esophageal junction, or patients with resectable tumors refraining from radical surgery. Patients with M1 disease solely on the basis of supraclavicular metastasis are eligible. Patients with locoregional recurrences are eligible, provided that full dose of radiation can be safely delivered. Currently, 2 of planned 52 patients have been enrolled. Clinical trial information: NCT04595149. [Table: see text]

PurposeInsight into emotional distress of cancer survivors from ethnic minority groups in Europe is scarce. We aimed to compare distress levels of survivors from ethnic minorities to that of the majority population, determine whether the association between having cancer (yes vs. no) and distress differs among ethnic groups and investigate sociocultural correlates of distress.MethodsCross‐sectional data were derived from HELIUS, a multi‐ethnic cohort study conducted in the Netherlands. Of 19,147 participants, 351 were diagnosed with cancer (n = 130 Dutch, n = 75 African Surinamese, n = 53 South‐Asian Surinamese, n = 43 Moroccan, n = 28 Turkish, n = 22 Ghanaian). Distress (PHQ‐9, MCS‐12) and correlates were assessed by self‐report. Cancer‐related variables were derived from the Netherlands Cancer Registry.ResultsSurvivors were on average 7 years post‐diagnosis. Survivors from South‐Asian Surinamese, Moroccan, Turkish and Ghanaian origin reported more distress than survivors from Dutch origin (effect sizerange: 0.44–1.17; adjusted models). The association between having cancer or not with distress differed in direction between Dutch and the non‐Dutch ethnic groups: Non‐Dutch cancer patients tended to have more distress than their cancer‐free peers, whereas Dutch cancer patients tended to have less distress than their cancer‐free peers. For Moroccan and Turkish patients, the acculturation style of separation/marginalization, compared to integration/assimilation, was associated with higher depressive symptoms. In analyses pooling data from all ethnic minorities, lower health literacy, lower emotional support satisfaction and younger age at the time of migration were associated with higher depressive symptoms. Lower health literacy, fewer emotional support transactions, and more frequent attendance at religious services were associated with worse mental health.ConclusionCancer survivors from ethnic minorities experience more distress than those from the majority population. Culturally sensitive supportive care should be considered.