Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, ...as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.
Melanoma is an immunogenic tumor whose relationship with immune cells resident in the microenvironment significantly influences cancer cell proliferation, progression, and metastasis. During ...melanomagenesis, both immune and melanoma cells undergo the immunoediting process that includes interconnected phases as elimination, equilibrium, and escape or immune evasion. In this context, dendritic cells (DCs) are active players that indirectly counteract the proliferation of melanoma cells. Moreover, DC maturation, migration, and cross-priming as well as their functional interplay with cytotoxic T-cells through ligands of immune checkpoint receptors result impaired. A number of signals propagated by highly proliferating melanoma cells and accessory cells as T-cells, natural killer cells (NKs), tumor-associated macrophages (TAMs), T-regulatory cells (T-regs), myeloid-derived suppressor cells (MDSCs), and endothelial cells participate to create an immunosuppressive milieu that results engulfed of tolerogenic factors and interleukins (IL) as IL-6 and IL-10. To underline the role of the immune infiltrate in blocking the melanoma progression, it has been described that the composition, density, and distribution of cytotoxic T-cells in the surrounding stroma is predictive of responsiveness to immunotherapy. Here, we review the major mechanisms implicated in melanoma progression, focusing on the role of DCs.
Renal cell carcinoma (RCC) is one of primary cancers that frequently metastasize to the brain. Brain metastasis derived from RCC has the propensity of intratumoral hemorrhage and relatively massive ...surrounding edema. Moreover, it confers a grim prognosis in a great percentage of cases with a median overall survical (mOS) around 10 months. The well-recognized prognostic factors for brain metastatic renal cell carcinoma (BMRCC) are Karnofsky Performance Status (KPS), the number of brain metastasis (BM), the presence of a sarcomatoid component and the presence of extracranial metastasis. Therapeutic strategies are multimodal and include surgical resection, radiotherapy, such as stereotactic radiosurgery due to the radioresistance of RCC and systemic strategies with tyrosin kinase inhibitors (TKI) or Immune checkpoint inhibitors (ICI) whose efficacy is not well-established in this setting of patients due to their exclusion from most clinical trials. To date, in case of positive prognostic factors and after performing local radical therapies, such as complete resection of BM or stereotactic radiosurgery (SRS), the outcome of these patients significantly improves, up to 33 months in some patients. As a consequence, tailored clinical trials designed for BMRCC are needed to define the correct treatment strategy even in this poor prognostic subgroup of patients.
Immunotherapy is effective in metastatic melanoma (MM) but most studies failed in discovering a biomarker predictive of clinical response. Exosomes (Exo) from melanoma cells are detectable in sera of ...MM patients similarly to those produced by immune cells that control the tumor progression. Here, we investigated by flow-cytometry the levels of Exo from both T-cells and dendritic cells (DCs) in 59 patients with MM treated with IPI and the relative expression of PD-1, CD28 and ICOS as well as CD80 and CD86. We found a significant increment of PD-1 and CD28 expression in patients achieving a clinical response reflected by improvement of both PFS and OS. Furthermore, MM patients receiving IPI who showed extended PFS underwent increased expression of CD80 and CD86 on DC-derived Exo at the end of treatment. These results suggest a possible association of both PD-1 and CD28 up-regulation on immune cell-derived Exo in patients with better clinical response to IPI.
As for all types of cancer, the incidence of melanoma increases with age. However, naevus counts (the principal risk factor for melanoma) decrease with age; hence the relationship between ageing and ...melanoma is complex. Subjects who maintain a high naevus count after the age of 50 years are more likely to be affected by melanoma, as their lesions do not senesce. Longer telomere length, which is strongly related to age, is linked to high naevus counts/melanoma risk; thus melanoma biology is influenced by factors that slow down ageing. Age is also an important prognostic factor in melanoma. Increasing age leads to worse survival in stages I, II and III. Sentinel lymph node (SLN) status, which is a strong predictor of melanoma survival, is also affected by age, as SLN positivity decreases with age. However, the prognostic predictive value of SLN status on survival increases with age, so, again, these relationships are complex. In patients with stage IV melanoma, age impacts on survival because it affects responses to treatment. This review examines the effects of age on melanoma risk, prognostic factors and responses to treatment.
BackgroundConcomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.MethodsWe conducted a multicenter ...observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids.ResultsFrom June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death.ConclusionWe confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.
Background Innovative therapies have improved the overall survival in melanoma, although a high number of patients still experience disease progression or recurrence. Ex-vivo culture of circulating ...tumour cells (CTCs) represents a valuable laboratory resource for in-depth characterization of rare cell populations responsible for disease progression. Methods CTCs from patients with metastatic melanoma were in-vitro established. Their stemness was demonstrated by both phenotypic and genotypic assays, as well as by functional studies. Xenograft experiments in NOD.CB17 mice injected with CTCs from a single patient were completed. Data were analysed by Student's test and results expressed as mean + or - SEM. Results CTCs share the mutational profile with primary cells, an intermediate epithelial-mesenchymal transition (EMT) phenotype and high expression of the immunosuppressive factors. A subclonal CTC population exhibited stem cell properties as high aldehyde dehydrogenase 1 activity, melanosphere-forming ability, and expression of major stemness transcription factors. Xenograft experiments confirmed the CTC ability to generate melanoma in-vivo and revealed enhanced metastatic propensity. Conclusions CTCs play a relevant role in melanoma and may actively contribute to drive the disease progression and metastasis. Thus, they are a unique potential tool for pharmacogenomic studies to guide treatment strategies in advanced disease. Keywords: Melanoma, Circulating tumor cells, Phenotypic plasticity, Stemness, Metastases; NOD.CB17 mice
Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated ...(ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.
Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and ...malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.
Here, we describe a patient with bilateral breast cancer and melanoma, and with a concomitant double variant, namely p.Gln563Ter in
and p.Lys3326Ter in
. The
p.Lys3326Ter (K3326X) (rs11571833) ...mutation identified in our patient is a debated substitution of thymidine for adenine which is currently regarded as benign polymorphism in main gene databases. Recent studies, however, describe this variant as associated with breast and ovarian tumors. Based on the observation of the cancer's earliest age of onset in this subject, our purpose was to reevaluate this variant according to recent papers indicating a role of powerful modifier of the genetic penetrance. Genetic testing was performed in all consenting patient's relatives, and in the collection of the clinical data particular attention was paid to the age of onset of the neoplasia. Following our observation that the our patient with double heterozygosis had an early age of onset for cancer similar to a few rare cases of double mutation for
and
, we also performed an extensive review of the literature relative to patients carrying a double heterozygosity for both genes. In line with previous studies relative to the rare double heterozygosity in both
/
genes, we found the earlier onset of breast cancer in our patient with both
/
mutations with respect to other relatives carrying the single
mutation. The presence of the second K3326X variant in our case induces a phenotype characterized by early onset of the neoplasia in a manner similar to the other cases of double heterozygosity previously described. Therefore, we suggest that during the genetic counseling, it should be recommendable to evaluate the presence of the K3326X variant in association with other pathogenic mutations.
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