The Role of Histology-Agnostic Drugs in the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since 2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab (both for tumors with the mismatch-repair deficiency (dMMR)/high microsatellite instability (MSI-H) phenotype and for those with the high tumor mutational burden (TMB-H) phenotype), dostarlimab (for dMMR tumors), larotrectinib and entrectinib (for tumors harboring neurotrophic tyrosine receptor kinase (NTRK) fusions), and the combination of dabrafenib plus trametinib (for BRAF V600E-mutated tumors). The genomic alterations targeted by these antineoplastic agents are rare in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, only a small number of mCRPC patients were enrolled in the clinical trials that led to the approval of the above-mentioned drugs. Therefore, we critically reviewed the literature on the efficacy of histology-agnostic drugs in mCRPC patients. Although the available evidence derives from retrospective studies and case reports, our results confirmed the efficacy of pembrolizumab in dMMR/MSI-H mCRPC. In contrast, few data are available for dostarlimab, larotrectinib, entrectinib, and dabrafenib-trametinib in this subset of patients. Large, multi-institutional registries aimed at collecting real-world data are needed to better comprehend the role of tissue-agnostic drugs in mCRPC patients.

Effectiveness of Immunotherapy in Non-Small Cell Lung Cancer Patients with a Diagnosis of COPD: Is This a Hidden Prognosticator for Survival and a Risk Factor for Immune-Related Adverse Events?

The interplay between the immune system and chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) is complex and multifaceted. In COPD, chronic inflammation and oxidative stress can lead to immune dysfunction that can exacerbate lung damage, further worsening the respiratory symptoms. In NSCLC, immune cells can recognise and attack the cancer cells, which, however, can evade or suppress the immune response by various mechanisms, such as expressing immune checkpoint proteins or secreting immunosuppressive cytokines, thus creating an immunosuppressive tumour microenvironment that promotes cancer progression and metastasis. The interaction between COPD and NSCLC further complicates the immune response. In patients with both diseases, COPD can impair the immune response against cancer cells by reducing or suppressing the activity of immune cells, or altering their cytokine profile. Moreover, anti-cancer treatments can also affect the immune system and worsen COPD symptoms by causing lung inflammation and fibrosis. Immunotherapy itself can also cause immune-related adverse events that could worsen the respiratory symptoms in patients with COPD-compromised lungs. In the present review, we tried to understand the interplay between the two pathologies and how the efficacy of immunotherapy in NSCLC patients with COPD is affected in these patients.

Antibody-Drug Conjugates for the Treatment of Renal Cancer: A Scoping Review on Current Evidence and Clinical Perspectives.

Antibody-drug conjugates (ADCs) are complex chemical structures composed of a monoclonal antibody, serving as a link to target cells, which is conjugated with a potent cytotoxic drug (i.e., payload) through a chemical linker. Inspired by Paul Ehrlich's concept of the ideal anticancer drug as a "magic bullet", ADCs are also highly specific anticancer agents, as they have been demonstrated to recognize, bind, and neutralize cancer cells, limiting injuries to normal cells. ADCs are among the newest pharmacologic breakthroughs in treating solid and hematologic malignancies. Indeed, in recent years, various ADCs have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of several cancers, resulting in a "practice-changing" approach. However, despite these successes, no ADC is approved for treating patients affected by renal cell carcinoma (RCC). In the present paper, we thoroughly reviewed the current literature and summarized preclinical studies and clinical trials that evaluated the activity and toxicity profile of ADCs in RCC patients. Moreover, we scrutinized the potential causes that, until now, hampered the therapeutical success of ADCs in those patients. Finally, we discussed novel strategies that would improve the development of ADCs and their efficacy in treating RCC patients.

Prevalence of Cardiovascular Risk Factors and Coronary Angiographic Findings in High-Risk Immigrant Communities in Italy.

BACKGROUND: The prevalence of coronary artery disease (CAD) considerably varies by ethnicity. High-risk populations include patients from Eastern Europe (EEP), the Middle East and North Africa (MENAP) and South Asia (SAP). METHODS: This retrospective study aims to highlight cardiovascular risk factors and specific coronary findings in high-risk immigrant groups. We examined the medical records and coronary angiographies of 220 patients from the above-mentioned high-risk ethnic groups referred for Acute Coronary Syndrome (ACS) and compared them with 90 Italian patients (IP) from 2016 to 2021. In the context of high-risk immigrant populations, this retrospective study aims to shed light on cardiovascular risk factors and particular coronary findings. We analyzed the medical records of 220 patients from the high-risk ethnic groups described above referred for ACS and compared them with 90 IPs between 2016 and 2021. In addition, we assessed coronary angiographies with a focus on the culprit lesion, mainly evaluating multi-vessel and left main disease. RESULTS: The mean age at the first event was 65.4 ± 10.2 years for IP, 49.8 ± 8.5 years for SAP (Relative Reduction (ReR) 30.7%), 51.9 ± 10.2 years for EEP (ReR 26%) and 56.7 ± 11.4 years for MENAP (ReR 15.3%); p < 0.0001. The IP group had a significantly higher prevalence of hypertension. EEP and MENAP had a lower prevalence of diabetes. EEP and MENAP had a higher prevalence of STEMI events; SAP showed a significant prevalence of left main artery disease (p = 0.026) and left anterior descending artery disease (p = 0.033) compared with other groups. In SAP, we detected a higher prevalence of three-vessel coronary artery disease in the age group 40-50. CONCLUSIONS: Our data suggest the existence of a potential coronary phenotype in several ethnicities, especially SAP, and understate the frequency of CV risk factors in other high-risk groups, supporting the role of a genetic influence in these communities.

Quantification of Extracellular Volume in CT in Neoadjuvant Chemotherapy in Breast Cancer: New Frontiers in Assessing the Cardiotoxicity of Anthracyclines and Trastuzumab.

Breast cancer patients undergoing neoadjuvant chemotherapy with anthracyclines or trastuzumab can suffer cardiotoxic issues. Nowadays, the markers of cardiac damage are still not reliable, and extracellular volume (ECV) calculated from CT could be a promising cardiotoxic marker. Eighty-two patients, treated with two different chemotherapy regimens based on doxorubicin (DOX) or epirubicin-trastuzumab (EPI-TRAS), were retrospectively selected and the variations in extracellular volume (ECV) values were measured and analyzed. Whole Body CT (WB-CT) scans were acquired after 1 min, in the portal phase (PP), and after 5 min, in the delayed phases (DP), at the baseline (T0), after one year (T1) and after five years (T5) from the end of chemotherapies. The values measured by two radiologists with different levels of experience were evaluated in order to assess the inter-reader reproducibility assessment (ICC = 0.52 for PP and DP). Further, we performed a population-based analysis and a drug-oriented subgroup analysis in 54 DOX-treated and 28 EPI-TRAS-treated patients. In the general cohort of women treated with any of the two drugs, we observed in the lapse T0-T1 a relative increase (RI) of 25% vs. 20% (PP vs. DP, p < 0.001) as well as in the lapse T0-T5 an RI of 17% vs. 15% (PP vs. DP, p < 0.01). The DOX-treated patients reported in the lapse T0-T1 an RI of 22% (p < 0.0001) in PP and an RI of 16% (p = 0.018) in the DP, with ECV values remaining stably high at T5 both in PP (RI 14.0%, p < 0.0001) and in DP (RI 17%, p = 0.005) highlighting a possible hallmark of a persisting CTX sub-damage. On the other hand, ECV measured in EPI-TRAS-treated women showed an RI in T0-T1 of 18% (p = 0.001) and 29% (p = 0.006) in PP and DP, respectively, but the values returned to basal levels in T5 both in the PP (p = 0.12) and in DP setting (p = 0.13), suggesting damage in the first-year post-treatment and a possible recovery over time. For the 82 patients, an echocardiography was performed at T0, T1= 12 m + 3 m and T5 = 60 m + 6 m with LVEF values at T0 (64% ± 5%), T1 (54% ± 6%) and T5 (53% ± 8%). WB-CT-derived ECV values could provide a valid imaging marker for the early diagnosis of cardiotoxic damage in BC patients undergoing oncological treatments. We detected different patterns during the follow-up, with stably high values for DOX, whereas EPI-TRAS showed a peak within the first year, suggesting different mechanisms of cardiac damage.

MiRNAs and circRNAs for the Diagnosis of Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients: A Narrative Review.

Breast cancer (BC) is the most frequent type of female cancer with increasing incidence in recent years. Doxorubicin (DOX) is an important backbone chemotherapy in BC, responsible for cardiotoxicity (CTX) in about 9% of treated women within the first year. Biomarkers of early CTX diagnosis are essential to avoid complicated DOX-related cardiac diseases. Traditional serum biomarkers are either poorly sensitive with transient elevation, and even absent if investigated outside their diagnostic window, or arise only in late-stage CTX. Emerging biomarkers such as non-coding RNA (ncRNA) have been recently investigated in DOX-related CTX. In our review, we revised the role of microRNAs, the most studied type of ncRNA, both in animal and human models, highlighting the interesting but often contrasting results. Moreover, we reviewed a novel class of ncRNA, circular RNA (circRNA), focusing on their modulatory mechanisms also involving microRNAs. MicroRNA and circRNA are players in a wide homeostatic balance with their perturbation representing a possible compensation for DOX damage. Further studies are required to assess the modalities of early detection of their variation in BC patients suffering from heart disease induced by DOX treatment.

NTRK Gene Fusions in Solid Tumors and TRK Inhibitors: A Systematic Review of Case Reports and Case Series.

The approval of larotrectinib and entrectinib for cancer patients harboring an NTRK gene fusion has represented a milestone in the era of "histology-agnostic" drugs. Among the clinical trials that led to the approval of these two drugs, most of the enrolled patients were affected by soft tissue sarcomas, lung, and salivary gland cancer. However, as next-generation sequencing assays are increasingly available in the clinical setting, health care professionals may be able to detect NTRK gene fusions in patients affected by tumor types under or not represented in the clinical trials. To this aim, we systematically reviewed MEDLINE from its inception to 31 August 2022 for case reports and case series on patients with NTRK gene fusion-positive tumors treated with TRK inhibitors. A virtual cohort of 43 patients was created, excluding those enrolled in the above-mentioned clinical trials. Although our results align with those existing in the literature, various cases of central nervous system tumors were registered in our cohort, confirming the benefit of these agents in this subgroup of patients. Large, multi-institutional registries are needed to provide more information about the efficacy of TRK inhibitors in cancer patients affected by tumor types under or not represented in the clinical trials.