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Gastric and esophageal adenocarcinomas represent a biologically heterogeneous disease. The identification, in early eighties, of human epidermal growth factor receptor 2 (HER2) overexpression, being present in 12 to 20% of the cases, marked a major milestone in the efforts of unraveling the molecular complexity of this disease. This led to the development of anti-HER2-therapies, trastuzumab being the first to demonstrate, in combination with cisplatin and 5FU/capecitabine chemotherapy, an improvement in response rate and survival in the first-line setting of patients with metastatic, HER2-positive gastroesophageal adenocarcinomas. Afterwards, during a decade, several studies have tried new strategies either to block HER2 pathway differently or to combine different anti-HER2, without efficacy. Everything changed with studies demonstrating additive effect between anti-HER2 and immune checkpoint inhibitors and leading to phase III clinical trials combining anti-HER2 and anti-PD-L1/PD1 therapies. Pembrolizumab, a PD-1 inhibitor, was recently granted by FDA an accelerated approval, in patients with HER2-positive gastro-oesophageal adenocarcinomas, in combination with trastuzumab and platinum-based chemotherapy following meaningful improvement in overall response rate over standard treatment. Progression-free and overall-survival results are still awaited to change our first-line standard treatment. Furthermore, new HER2 inhibitors have been developed, blocking HER2-mediated pathway signaling via different mechanisms from pan-HER inhibition to anti-HER2 antibody drug conjugates with promising results in pretreated patients. Trastuzumab-deruxtecan has in particular showed interesting results in pretreated patients. We present here a review of the recent data and perspectives in HER2-positive metastatic gastroesophageal adenocarcinomas.

Gastric cancer is the 6th most common cancer in the world. Gastric adenocarcinomas can be divided into two groups: gastroesophageal junction adenocarcinomas and distal gastric adenocarcinomas, with different risk factors and potentially different therapeutic strategies. Therapeutic strategy for esogastric adenocarcinoma is multimodal. Gastric adenocarcinomas are managed with surgery and peri-operative chemotherapy. Gastroesophageal junction adenocarcinomas can either be treated surgically after neoadjuvant chemoradiotherapy or in the same way than gastric adenocarcinomas. There is currently no evidence of superiority of either treatment strategy. Recently, nivolumab has been validated as an adjuvant therapy for patients with esophageal cancer who received preoperative chemoradiotherapy and had residual tumor on the surgical specimen. In the absence of preoperative treatment, adjuvant chemoradiotherapy or chemotherapy should be discussed on a patient-by-patient basis. Currently, there is not indication for targeted therapies, nor for adapting postoperative treatment according to the response to preoperative treatment. The only validated indication for immunotherapy is as adjuvant treatment of esophageal cancer, but many studies are ongoing and may change practices in the future. The objective of this review is to synthesize the literature concerning the management of localized esogastric adenocarcinoma.

Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting.

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