The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and ...better define the role of candidate genes. We characterized 273
and
negative probands through a custom-designed targeted gene panel that included
and
Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (
and
), including two novel variants in
and 4 in
. We also found four deleterious and five likely deleterious variants in
(3.3%). Thus, including potentially deleterious variants in
increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative
deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.
Due to the high mutational somatic burden of Cutaneous Malignant Melanoma (CMM) a thorough profiling of the driver mutations and their interplay is necessary to explain the timing of tumorigenesis or ...for the identification of actionable genetic events. The aim of this study was to establish the mutation rate of some of the key drivers in melanoma tumorigenesis combining molecular analyses and/or immunohistochemistry in 93 primary CMMs from an Italian cohort also characterized for germline status, and to investigate an interplay between germline and somatic variants.
mutations were present in 68% of cases, while
germline mutations were found in 16 % and p16 loss in tissue was found in 63%.
promoter somatic mutations were detected in 38% of cases while the
-245T>C polymorphism was found in 51% of cases.
mutations were found in 39% of
negative or undetermined cases. NF1 was expressed in all cases analysed. MC1R variations were both considered as a dichotomous variable or scored. While a positive, although not significant association between
germline mutations, but not
variants, and
somatic mutation was found, we did not observe other associations between germline and somatic events. A yet undescribed inverse correlation between
-245T>C polymorphism and the presence of
mutation was found. It is possible to hypothesize that -245T>C polymorphism could be included in those genotypes which may influence the occurrence of BRAF mutations. Further studies are needed to investigate the role of -245T>C polymorphism as a germline predictor of
somatic mutation status.
BackgroundNeoantigens derived from cancer-specific mutations are currently being utilized as targets in personalized cancer vaccine treatments. Here, we characterize the neoantigen-specific ...reactivity and clinical response in five patients treated with an AI generated personalized therapeutic cancer vaccine (EVX-01)1 in the ongoing melanoma single-arm open-label multi-center phase II trial (NCT05309421).MethodsThe proprietary PIONEERTM AI platform for the identification and selection of tumour-specific neoantigens was used to design a personalized peptide cancer vaccine (EVX-01) for each patient. Patients initiated treatment with anti-PD1 therapy (pembrolizumab) prior to EVX-01 and will receive up to 18 cycles. EVX-01 neoantigen vaccine (IM) was initiated at week 12; 6 priming immunizations 2-weekly and 4 booster immunizations at later time points. Blood samples were collected before, during and after EVX-01. Peripheral blood mononuclear cells (PBMCs) were isolated to assess for T-cell immunogenicity after in vitro stimulation with the vaccine neoantigens (IFNγ ELISpot and intracellular cytokine staining). Serum circulating tumor (ct) DNA will be monitored longitudinally (Illumina NovaSeq).ResultsFive patients were included in this trial update. Immune analysis demonstrated EVX-01 induced neoantigen specific T-cell responses in all patients and that the responses were mediated by activated CD4+ and CD8+ T cells. Prior to EVX-01 dosing and following 12 weeks of pembrolizumab, one patients (#4) presented with Progressive Disease (RECISTI.1 criteria). Following EVX-01 administration, patient #4 had a reduction in tumor size starting at week 24 and with further reduction at subsequent visits. Immune analysis revealed neoantigen-specific immune responses being induced 2 weeks after 3 immunizations and a further increase in response magnitude after all 6 immunizations. RECIST response data for the remaining patients will be available at the time of presentation.The combination of EVX-01 and anti-PD1 appeared safe and well tolerated with only grade 1 ADRs related to EVX-01.Trial RegistrationNCT05309421ReferenceMork, et al, Final results: Dose escalation study of a personalized peptide-based neoantigen vaccine in patients with metastatic melanoma. Journal of Clinical Oncology, June 01, 2023;41(16_suppl):9551–9551.Ethics ApprovalThe study obtained ethics approval from Bellberry Human Research Ethics Committee (Application No. 2022-03-183-A-8). All patients gave informed consent before taking part in the study.
Cutaneous melanoma is the most dangerous skin cancer, with high death rates in advanced stages. To assess the impact of each treatment on patient outcomes, most studies use relapse-free survival ...(RFS) as a primary endpoint and distant metastasis-free survival (DMFS) as a secondary endpoint. The aim of this narrative review of the main adjuvant studies for resected stage III/IV melanoma, with a specific focus on DMFS, is to evaluate DMFS trends and their potential association with RFS, identify which treatments are possibly associated with better outcomes in terms of DMFS and their potential predictive factors, and discuss DMFS trends in terms of patient management in daily practice. We outline the impact of each available treatment option on DMFS and RFS according to the years of follow-up and compare data from different studies. Overall, the trends of DMFS closely follow those of RFS, with most patients relapsing at visceral rather than regional sites. As it captures the burden of patients who develop distant relapse, DMFS could be considered a primary endpoint, in addition to RFS, in adjuvant trials, identifying patients whose relapse is associated with a worse prognosis and who may need further systemic treatment.
Since the end of 2019, global healthcare systems have been dealing with the COVID-19 pandemic.
In oncology, the biggest questions concern interaction of COVID-19 with pre-existing cancer disease and ...with systemic anticancer treatments. With regards to immunotherapy, there is uncertainty about its effect in the context of COVID-19 in terms of probability and course of viral infection.
Herein, we retrospectively report data of patients with advanced cutaneous squamous cell carcinoma (cSCC) treated with immunotherapy at five Italian referral cancer centers during the pandemic. cSCC is a disease poorly represented in the literature, typically affecting fragile, elderly patients, with multiple comorbidities and often immunosuppressed. Overall, 54 patients were identified, most of them coming from Lombardy and Piedmont, the two regions hit hardest by COVID in Italy. In most cases, our choice was to continue treatment, reserving temporary interruptions only to patients considered particularly at risk for age and comorbidity. A total of 9% of patients developed new-onset symptoms or had chest radiological assessment potentially related to COVID-19. Nasopharyngeal swabs were collected in all suspicious cases and two hospitalized patients were found to be positive. In conclusion, the outbreak of COVID-19 is a major worldwide health concern. Our data indicate that COVID-19 mortality in patients with cancer may be principally driven by advancing age, the presence of other comorbidities, and other cancer-related conditions (i.e. hospitalization). Our data further suggests the safety of continued use of PD-1 blockade during the COVID-19 pandemic (obviously implementing all the safety measures in the hospital environment) also considering the possible negative effects of a prolonged suspension on the course of the tumor evolution. We think it is useful to collect and report case studies coming from reference centers, because they can represent helpful examples for the scientific community of clinical management of patients affected by cancer in this difficult period and guide further research.
To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, ...MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients.
Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed.
No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559+ and 703+ days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders.
Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.
Melanoma has always been described as an immunogenic tumor. Despite that, until 2011 the standard of care in metastatic melanoma was chemotherapy, with low response rates and no clear impact on ...overall survival. Melanoma was the first cancer type to drive the use of immune-checkpoint inhibitors into clinical practice, which revolutionized the therapeutic paradigm not only in melanoma, but also in an increasing number of tumors. In this review, the preclinical bases and the main clinical studies that led to the approval of immune-checkpoint inhibitors in advanced melanoma will be described with insights on novel combinations of treatments and on prognostic and predictive biomarkers.
Nodular melanoma (NM) accounts for most thick melanomas and because of their frequent association with ulceration, fast growth rate and high mitotic rate, contribute substantially to melanoma-related ...mortality. In a multicentric series of 214 primary melanomas including 96 NM and 118 superficial spreading melanoma (SSM), histopathological features were examined with the aim to identify clinicopathological predictors of recurrence.
All consecutive cases of histopathologically diagnosed primary invasive SSM and NM during the period 2005-2010, were retrieved from the 12 participating Italian Melanoma Intergroup (IMI) centers. Each center provided clinico-pathological data such as gender, age at diagnosis, anatomical site, histopathological conventional parameters, date of excision and first melanoma recurrence.
Results showed that NM subtype was significantly associated with Breslow thickness (BT) at multivariate analysis: BT 1.01-2 mm (OR 7.22; 95% CI 2.73-19.05), BT 2.01-4 mm (OR 7.04; 95% CI 2.54-19.56), and BT > 4 mm (OR 51.78; 95% CI 5.65-474.86) (p < 0.0001). Furthermore, mitotic rate (MR) was significantly correlated with NM histotype: (MR 3-5 mitoses/mm
(OR 2.62; 95% CI 1.01-6.83) and MR > 5 mitoses/mm
(OR 4.87; 95% CI 1.77-13.40) (p = 0.002). The risk of recurrence was not significantly associated with NM histotype while BT BT 1.01-2.00 mm (HR 1.55; 95% CI 0.51-4.71), BT 2.01-4.00 mm (HR 2.42; 95% CI 0.89-6.54), BT > 4.00 mm. (HR 3.13; 95% CI 0.95-10.28) (p = 0.05), mitotic rate MR > 2 mitoses/mm
(HR 2.34; 95% CI, 1.11-4.97) (p = 0.03) and the positivity of lymph node sentinel biopsy (SNLB) (HR 2.60; 95% CI 1.19-5.68) (p = 0.007) were significantly associated with an increased risk of recurrence at multivariate analysis.
We found that NM subtype was significantly associated with higher BT and MR but it was not a prognostic factor since it did not significantly correlate with melanoma recurrence rate. Conversely, increased BT and MR as well as SNLB positivity were significantly associated with a higher risk of melanoma recurrence.
Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). ...We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.
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