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As a developing region, Latin America faces unique cancer control and prevention challenges, which are intensified when considering rare cancers, including sarcomas. Sarcomas are a group of malignancies that arise in the connective tissues of the body-such as muscle, fat, nerves, blood vessels, and bones-accounting for a diverse range of tumours that, although rare, require specialized attention. Sarcoma care and research in Latin America require a comprehensive approach that includes deeper epidemiologic knowledge, diagnostic capacity building, access to innovative treatments, increased patient advocacy, and strengthening of clinical research capacity. This article will review current challenges and opportunities for treating patients with sarcoma in Latin America and outline a pathway toward improvement for regional collaborative groups.

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ABSTRACT: Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed across a broad range of histologies to allow the use of ADC biomarker-driven therapy irrespective of the primary tumor site. This suggests that the future efficacy of ADCs in multiple histologies may be similar to other classes of drugs that are considered histology-agnostic therapies nowadays. This review focuses on novel ADCs for the treatment of solid tumors, including topics such as their structure and mechanism of action, the latest indications of already US Food and Drug Administration-approved ADCs, and the outlook for new promising ADCs under development for the treatment of tumors of various histologies.

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Although a relatively uncommon tumor, cholangiocarcinoma is on the rise globally. Of note, most patients are diagnosed with metastatic disease, and the prognosis is poor with cytotoxic chemotherapy. Strategies targeting specific genomic alterations have demonstrated promising activity in recent years and could represent a new therapeutic avenue for these patients. In this review, we will address the biology and clinical results of FGFR inhibition in intrahepatic cholangiocarcinoma, highlighting limitations associated with treatment and discussing the use of circulating tumor DNA to detect mechanisms of resistance.

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Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause of cancer-related death worldwide. Single-agent anti-PD-1 immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in early-phase trials, a finding that was not confirmed in phase III studies. The combination of atezolizumab (an anti-PD-L1 ICI) with bevacizumab (an anti-VEGF antibody) was approved as first-line therapy in 2020, however, with significant improvement in response rate, progression-free survival, and overall survival in comparison with the previous standard of care, sorafenib. Numerous ongoing clinical trials are assessing ICIs in combination with each other or with targeted agents, and also in earlier stages with local therapies. This review summarizes the latest concepts in the use of ICIs for the management of HCC.

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Background: The development of novel therapies for patients with sarcoma is challenging due to the rarity and diversity of these mesenchymal neoplasms. Hence, histology-agnostic approvals can be of particular interest for the treatment of patients with soft tissue and bone sarcoma. Methods: We queried the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database Cohort v12.0-Public to investigate the prevalence of currently Food and Drug Administration (FDA)-approved and other potentially actionable histology-agnostic alterations in patients with soft tissue and bone sarcoma. Targets were identified by a literature review by the authors. Results are presented for each cohort identified in the GENIE database, namely: (1) soft tissue sarcoma (STS), (2) gastrointestinal stromal tumor (GIST), (3) bone sarcoma, (4) uterine sarcoma, and (5) breast sarcoma. Results: We identified 7,512 samples of 6,955 patients with sarcoma in the AAACR GENIE database v12.0-Public. Molecular alterations that could lead to the clinical use of a currently approved histology-agnostic therapy were identified in 2.1% of sarcomas (2.6% STS, 1.3% GIST, 1.4% bone, 2.7% uterine, and 0% breast). In addition, 2.9% of patients could be eligible for future histology-agnostic approvals. These specific mutations, fusions, and amplifications occurred in multiple histotypes in all cohorts. Discussion: Exploring a public large-scale genomic database, we identified that 5% of patients with sarcoma could be eligible for current histology-agnostic FDA-approved drugs or future potential histology-agnostic indications. These actionable alterations were present in a wide variety of histologies in soft tissue and bone sarcomas, highlighting that next-generation sequencing can be considered for patients with advanced sarcoma to guide treatment strategies.

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Recent failure of phase 3 trials and paucity of druggable oncogenic drivers hamper developmental therapeutics in sarcomas. Antibody-based therapeutics, like antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-based therapeutics, have emerged as promising strategies for anticancer drug delivery. The efficacy of these novel therapies is highly dependent on expression of the antibody target. We used RNA sequencing data from Cancer Genome Atlas (TCGA) to analyze expression of target antigens in sarcoma subtypes including dedifferentiated liposarcoma (DDLPS; n = 50), uterine leiomyosarcoma (ULMS; n = 27), leiomyosarcoma (STLMS; n = 53), undifferentiated pleomorphic sarcoma (UPS; n = 44), myxofibrosarcoma (MFS; n = 17), synovial sarcoma (SS; n = 10), and malignant peripheral nerve sheath tumor (MPNST; n = 5). We searched published literature and clinicaltrial.gov for ADC targets, bispecific antibodies, immunotoxins, radioimmunoconjugates, SPEAR T-cells, and CAR's that are in clinical trials. CD70 expression was significantly higher in DDLPS, UPS, and MFS than SS and STLMS. CDH3 expression was greater in LMS and ULMS than UPS (P < 0.001), MFS (P < 0.001), and DDLPS (P < 0.001). ERBB2 expression was low; however, it was overexpressed in MPNST when compared with UPS (P < 0.001), and MFS (P < 0.01). GPNMB was highly expressed in most sarcomas, with the exception of SS. LRRC15 also appeared to be a relevant target, especially in UPS. MSLN expression was relatively low except in SS and MPNST. PDGFRA was also highly expressed in most sarcomas with the exception of ULMS and STLMS. TNFRSF8 seems to be most appropriate in DDLPS, as well as MFS. AXL was expressed especially in MFS and STLMS. Sarcoma subtypes express multiple target genes relevant for ADCs, SPEAR T-cells and CAR's, warranting further clinical validation and evaluation.

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A case of diagnostic difficulty facing the patient with colonic polyposis secondary to Peutz-Jeghers syndrome, but without family history and pathognomonic clinical features of the disease, is illustrated. The exams, including biopsy, led to diagnostic uncertainty and the definitive diagnosis was characterized in therapeutic of exception. (AU)

Ilustra-se um caso de dificuldade diagnóstica frente à paciente com polipose colônica secundária a Síndrome de Peutz-Jeghers, sem história familiar e sem características clínicas patognomônicas da doença. Os exames, incluindo biópsia, geraram dúvida diagnóstica, sendo o diagnóstico definitivo caracterizado em terapêutica de exceção. (AU)

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