Therapeutic strategies for HER2-positive breast cancer with central nervous system involvement: a literature review and future perspectives.

Background and Objective: Brain metastases (BMs) are present in approximately 55% of patients with HER2-positive breast cancer (HER2+ BC). The introduction of anti-HER2 agents has radically changed the prognosis of these patients by prolonging overall survival. Methods: In this review, we describe the biology of central nervous system (CNS) spreading in patients with HER2+ BC. We also provide a literature review of current treatment strategies of brain metastatic BC, focusing on HER2+ disease, and future perspectives. Key Content and Findings: Treatment of symptomatic BMs includes traditionally neurosurgery and/or radiotherapy, depending on the number of metastases, performance status and systemic disease control. Local treatments, such as surgical excision of BM and stereotactic radiosurgery (SRS), when feasible, are preferred over whole-brain radiotherapy, because of related cognitive impairment. These treatments can lead to a local control of the disease, however, systemic relapses can affect the prognosis of these patients. Recently, new anti-HER2 agents have demonstrated to be effective on BMs, thereby leading to improved survival outcomes with an acceptable quality of life. Despite the clinical benefit of these approaches, BMs still represent a cause of death and effective therapeutic strategies are needed. Conclusions: Different targeted agents have demonstrated significant efficacy with tolerable safety profiles in HER2+ BC patients with BM, and have already been approved for clinical use in this setting. A better understanding of the molecular mechanisms underlying the onset of BMs could suggest novel targeted approaches in order to prevent CNS localization or delay progression to CNS in HER-2 metastatic patients.

Immunotherapy in Early-Stage Non-Small Cell Lung Cancer (NSCLC): Current Evidence and Perspectives.

Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.

Enfortumab Vedotin in metastatic bladder cancer: a case report of durable clinical efficacy in a pretreated patient.

Metastatic urothelial bladder cancer is associated with high mortality rates. The advent of immunocheckpoint inhibitors (ICIs), with the approval of pembrolizumab in second line treatment, has changed the treatment landscape and improved clinical outcomes of patients. Until recently, subsequent lines of therapy have been limited to single-agents chemotherapy, poor efficacy and relevant toxicities. Recent studies in pretreated urothelial bladder cancer have led to the approval in clinical practice of enfortumab vedotin, demonstrating better clinical efficacy compared with the standard of care. Herein we report a case of a 57-year-old male patient with metastatic bladder cancer, who had unsatisfactory responses to first-line chemotherapy and subsequent second-line immunotherapy. Based on robust data of efficacy and safety from clinical trials, we treated the patient with enfortumab vedotin as third-line therapy. An initial adverse event, probably not strictly related to the drug, led to temporarily discontinuation of enfortumab vedotin and subsequent administration with a dose reduction. Despite this, the drug induced a first partial response on most of the metastatic sites and a complete response on lung and pelvic metastases was subsequently observed. Of note, responses were durable, with good tolerability and improvement in cancer-associated symptoms, such as pain.

Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review.

Background and Objective: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. Methods: In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. Key Content and Findings: KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. Conclusions: The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.

Evolving treatment landscape of immunotherapy in breast cancer: current issues and future perspectives.

Immune checkpoint inhibitors (ICIs) deeply changed the treatment landscape of breast cancer (BC). In particular, anti-programmed-death (ligand) 1 antibodies were approved for the treatment of triple-negative breast cancer (TNBC), both in first line for metastatic disease and in neoadjuvant setting, on the basis of a demonstrated improvement of the survival outcomes. In light of these results, current clinical trials aim at improving this benefit investigating novel combinations and strategies, at exploring the role of ICIs beyond TNBC, and at better selecting the patients in order to spare non-responders from avoidable toxicities. This narrative review aims at summarizing and discussing the evolving landscape of immunotherapeutic treatments for BC, highlighting the current challenges and the future perspectives.

'Why is survival with triple negative breast cancer so low? insights and talking points from preclinical and clinical research'.

INTRODUCTION: Triple negative breast cancer is typically related to poor prognosis, early metastasis, and high recurrence rate. Intrinsic and extrinsic biological features of TNBC and resistance mechanisms to conventional therapies can support its aggressive behavior, characterizing TNBC how extremely heterogeneous. Novel combination strategies are under investigation, including immunotherapeutic agents, anti-drug conjugates, PARP inhibitors, and various targeting agents, exploring, in the meanwhile, possible predictive biomarkers to correctly select patients for the optimal treatment for their specific subtype. AREAS COVERED: This article examines the main malignity characteristics across different subtype, both histological and molecular, and the resistance mechanisms, both primary and acquired, to different drugs explored in the landscape of TNBC treatment, that lead TNBC to still has high mortality rate. EXPERT OPINION: The complexity of TNBC is not only the main reason of its aggressivity, but its heterogeneity should be exploited in terms of therapeutics opportunities, combining agents with different mechanism of action, after a correct selection by biologic or molecular biomarkers. The main goal is to understand what TNBC really is and to act selectively on its characteristics, with a personalized anticancer treatment.

Immunotherapeutic Advances for NSCLC.

Immunotherapy with antibodies against PD-1 or PD-L1, either alone or in combination with chemotherapy, has revolutionized treatment paradigms of non-small cell lung cancer (NSCLC) patients without oncogenic driver alterations. These agents, namely immune checkpoint inhibitors (ICIs), have also widely demonstrated a remarkable efficacy in locally advanced as well as in early-stage NSCLC. Assessment of tumor PD-L1 expression by immunohistochemistry has entered into routine clinical practice to select patients for immunotherapy, even though its predictive role has long been debated. Despite improved survival outcomes over standard chemotherapy, treatment with ICIs is associated with initial low response rate, with a significant proportion of patients not responding to these agents. Hence, novel appealing predictive biomarkers, such as those related to tumor cell signaling pathways, metabolism or the tumor microenvironment, have emerged as potentially useful to select those patients most likely to benefit from immunotherapy. Moreover, most patients ultimately develop acquired resistance to ICI treatment over time and novel therapeutic strategies are urgently needed to overcome or delay resistance. Herein, we provide an overview on recent advances in immunotherapy in NSCLC, focusing on updated results from studies on ICIs in different disease settings and at different lines of treatment. We further describe currently emerging predictive biomarkers, beyond PD-L1, to optimize patient selection and novel strategies to improve clinical outcomes.

Capillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer.

Capillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with Cisplatin and Gemcitabine. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.