The evolving therapeutic landscape of trastuzumab-drug conjugates: Future perspectives beyond HER2-positive breast cancer

: A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates (T-DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-Dxd) are the two approved T-DCs. T-Dxd along with other five T-DCs represents "second generation ADCs" that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T-DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates (T-DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T-DCs biological characteristics that underly the differences in T-DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T-DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T-DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed

Shifting from a Biological-Agnostic Approach to a Molecular-Driven Strategy in Rare Cancers: Ewing Sarcoma Archetype

: Sarcomas of the thoracic cavity are rare entities that predominantly affect children and young adults. They can be very heterogeneous encompassing several different histological entities. Ewing Sarcoma (ES) can potentially arise from every bone, soft tissue, or visceral site in the body. However, it represents an extremely rare finding when it affects the thoracic cavity. It represents the second most frequent type of thoracic sarcoma, after chondrosarcoma. ES arises more frequently in sites that differ from the thoracic cavity, but it displays the same biological features and behavior of extra-thoracic ones. Current management of ES often requires a multidisciplinary treatment approach including surgery, radiotherapy, and systemic therapy, as it can guarantee local and distant disease control, at least transiently, although the long-term outcome remains poor. Unfortunately, due to the paucity of clinical trials purposely designed for this rare malignancy, there are no optimal strategies that can be used for disease recurrence. As a result of its complex biological features, ES might be suitable for emerging biology-based therapeutic strategies. However, a deeper understanding of the molecular mechanisms driving tumor growth and treatment resistance, including those related to oncogenic pathways, epigenetic landscape, and immune microenvironment, is necessary in order to develop new valid therapeutic opportunities. Here, we provide an overview of the most recent therapeutic advances for ES in both the preclinical and clinical settings. We performed a review of the current available literature and of the ongoing clinical trials focusing on new treatment strategies, after failure of conventional multimodal treatments

Extraskeletal Ewing's sarcoma of the mediastinum: Case report

Background: Ewing sarcoma (ES) represents the second most common malignant bone tumor in children and young adults. ES is not a frequent finding in sites different from the skeletal. Common sites of appearance of ES are lower extremities, the pelvis, paravertebral spaces and head and neck. Primary extraskeletal ES located in the anterior mediastinum are very rare. These neoplasms should be discussed in specialized contests with a high volume of patients treated. Here, we present an uncommon mediastinal mass challenging in its characterization and management. Case description: A thirty-year-old woman performed a thoracic CT scan for dyspnea and persistent cough. Imaging showed a solid mass of 14 x 11 cm involving the left thorax with mediastinal deviation to the right side. Patient underwent an en bloc resection of the mass. Initial histological examination was suggestive for B3 thymoma/thymic carcinoma. Patient was then referred to our rare tumor reference center where a histological review excluded the diagnosis of thymic/thymoma neoplasms meanwhile a third revision assessed a diagnosis of ES. Patient refused adjuvant chemotherapy due to her desire of maternity and radiation therapy was not indicated because surgery was performed too many months earlier. A close follow-up was considered. After a few months the patient relapsed and first line chemotherapy was proposed. She reached a complete response at the first evaluation maintained also at the end of the protocol. In order to consolidate the obtained response, high dose chemotherapy followed by autologous stem cell transplantation (HDCT/ASCT) was suggested and the patient agreed. Conclusions: This case underlined that, potentially, ES can arise from any soft tissue site in the body, even in rare sites such as mediastinum. The evaluation of expert centers was critical to establish a correct diagnosis and therapeutic approach in this complex case. Taking into account the time lasting from the diagnosis and the aggressiveness of this kind of neoplasm, frequently relapsing, the patient after a multidisciplinary discussion was a candidate for a multimodal treatment

Impaired Seroconversion After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine in Patients With Thymic Epithelial Tumors

Introduction: Thymic epithelial tumors (TETs) are rare malignancies associated with dysregulation of the immune system and humoral- and cell-mediated immunity abnormalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is effective in preventing coronavirus disease 2019 morbidity and mortality. The aim of this study was to evaluate the seroconversion in patients with TET after two doses of mRNA vaccine. Methods: This is a prospective study in which consecutive patients with TET were enrolled before receiving the first dose of SARS-CoV-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding immunoglobulin (Ig)G antibody serologic levels were analyzed at different time points, including before first vaccine dose (T0), 1 month after the second dose (T2), and 3 months after the second dose (T3). Results: Overall, 39 patients were included in the analysis. All patients had negative antibody titer results at T0. There were 19 patients (48.7%) in the follow-up with no residual tumor lesion/s (referred as no evidence of disease), and 20 (51.3%) had evidence of disease (ED) and were receiving systemic treatment. Dysregulations of the immune system were diagnosed in 29 patients (74.4%) with Good syndrome (GS) being the most frequent immune disorder (48.7%). At univariate analysis, lack of seroconversion at T2 was significantly associated with ED (p < 0.001) and with GS (p = 0.043). A significant association with impaired seroconversion was confirmed at multivariate analysis for ED (p = 0.00101) but not for GS (p = 0.625). Conclusions: Our data revealed that patients with TET with ED had substantially higher probability of impaired seroconversion after SARS-CoV-2 mRNA vaccine as compared with patients with no evidence of disease