MET alterations as resistance mechanisms of dabrafenib-trametinib in BRAF p.V600E mutated non-small cell lung cancer patient.

The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1 > 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18 months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.

Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies.

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.

Takotsubo syndrome in a patient with metastatic renal cell carcinoma treated with pembrolizumab plus axitinib.

We report the case of a patient with metastatic renal cell carcinoma who developed Takotsubo syndrome (TTS) 6 days after starting pembrolizumab plus axitinib as first-line treatment. Coronary angiogram was negative for obstructive coronary artery disease and echocardiogram revealed a depressed left ventricular ejection fraction with apical akinesis. Axitinib was discontinued and myocardial contractile function fully recovered 23 days after the initial presentation. The treatment was safely resumed and granted a partial response of disease. A literature review regarding TTS in patients receiving VEGFR tyrosine kinase inhibitors and/or immune checkpoint inhibitors was performed. TTS is reported as a rare adverse event and the possible causal relationship between TTS and antineoplastic therapy is still unclear. Further research is warranted to better understand cardiotoxicity mechanisms and their management.

We report the case of a patient with metastatic renal cell carcinoma who developed a rare cardiac adverse event called Takotsubo syndrome 6 days after starting antineoplastic therapy with pembrolizumab plus axitinib. Axitinib was discontinued and cardiac function fully recovered 23 days after the initial presentation. The treatment was safely resumed and granted a partial response of disease. Takotsubo syndrome is reported as a rare adverse event and the possible causal relationship with antineoplastic therapy is still unclear. Further research is warranted to better understand cardiotoxicity mechanisms and their management.

Small cell lung cancer: Novel treatments beyond immunotherapy.

Small cell lung cancer (SCLC) arises in peribronchial locations and infiltrates the bronchial submucosa, including about 15% of lung cancer cases. Despite decades of research, the prognosis for SCLC patients remains poor because this tumor is characterized by an exceptionally high proliferative rate, strong tendency for early widespread metastasis and acquired chemoresistance. Omics profiling revealed that SCLC harbor extensive chromosomal rearrangements and a very high mutation burden. This led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy, which however resulted in a prolonged benefit only for a small subset of patients. Thus, the present review discusses the rationale and limitations of immunotherapeutic approaches, presenting the current biological understanding of aberrant signaling pathways that might be exploited with new potential treatments. In particular, new agents targeting DNA damage repair, cell cycle checkpoint, and apoptosis pathways showed several promising results in different preclinical models. Epigenetic alterations, gene amplifications and mutations can act as biomarkers in this context. Future research and improved clinical outcome for SCLC patients will depend on the integration between these omics and pharmacological studies with clinical translational research, in order to identify specific predictive biomarkers that will be hopefully validated using clinical trials with biomarker-selected targeted treatments.