Assessing the genetic risk of nodular melanoma using a candidate gene approach.

BACKGROUND: Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality. OBJECTIVES: Our study aim was to perform a rare-variant allele (RVA) analysis of whole-exome sequencing of patients with NM and non-NM (minor allele frequency ≤ 1% non-Finnish European) for a set of 500 candidate genes potentially implicated in melanoma. METHODS: This study recruited 131 participants with NM and 194 with non-NM from South-east Queensland and patients with NM from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts. RESULTS: Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores was similar in patients with NM and non-NM, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high-penetrant melanoma gene and loss-of-function variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared with non-NM cases. The genes with RVAs of greatest frequency in NM included PTCH1, ARID2 and GHR. Rare variants in the SMO gene, which interacts with PTCH1 as ligand and receptor, were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM-associated genes. A 14.8-fold increased ratio for NM compared with non-NM was seen when two RVAs of the 39 genes were carried by a patient. CONCLUSIONS: This study highlights the importance of considering frequency of RVA to identify those at risk of NM in addition to known high penetrance genes.

Study protocol for a randomised controlled trial to evaluate the use of melanoma surveillance photography to the Improve early detection of MelanomA in ultra-hiGh and high-risk patiEnts (the IMAGE trial).

INTRODUCTION: Melanoma surveillance photography (MSP) is a comprehensive surveillance method that comprises two- or three-dimensional total body photography with tagged digital dermoscopy, performed at prescribed intervals. It has the potential to reduce unnecessary biopsies and enhance early detection of melanoma, but it is not yet standard care for all high-risk patients in Australia. This protocol describes a randomised controlled trial (RCT) designed to evaluate the clinical impact and cost-effectiveness of using MSP for the surveillance of individuals at ultra-high or high risk of melanoma from a health system perspective. METHODS AND DESIGN: This is a registry-based, unblinded, multi-site, parallel-arm RCT that will be conducted over 3 years. We aim to recruit 580 participants from three Australian states: Victoria, New South Wales and Queensland, via state cancer registries or direct referral from clinicians. Eligible participants within 24 months of a primary cutaneous melanoma diagnosis will be randomised 1:1 to receive either MSP in addition to their routine clinical surveillance (intervention group) or routine clinical surveillance without MSP (control group). Most participants will continue surveillance with their usual care provider, and the frequency of follow-up visits in both groups will depend on the stage of their primary melanoma and risk factors. The primary outcome measure of the study is the number of unnecessary biopsies (i.e. false positives, being cases where a lesion is biopsied due to suspected melanoma on clinical examination, either with or without MSP, but the resulting histopathology finding is negative for melanoma). Secondary outcomes include the evaluation of health economic outcomes, quality of life and patient acceptability. Two sub-studies will explore the benefit of MSP in high-risk patients prior to a melanoma diagnosis and the diagnostic performance of MSP in the teledermatology setting compared to the en face clinical setting. DISCUSSION: This trial will determine the clinical efficacy, cost-effectiveness and affordability of MSP to facilitate policy decision-making at the national and local levels, across primary and specialist care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385732 . Registered on May 13, 2020.

Cancer Treatment Patterns and Factors Affecting Receipt of Treatment in Older Adults: Results from the ASPREE Cancer Treatment Substudy (ACTS).

INTRODUCTION: Cancer treatment planning in older adults is complex and requires careful balancing of survival, quality of life benefits, and risk of treatment-related morbidity and toxicity. As a result, treatment selection in this cohort tends to differ from that for younger patients. However, there are very few studies describing cancer treatment patterns in older cohorts. METHODS: We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Cancer Treatment Substudy (ACTS) to describe cancer treatment patterns in older adults. We used a multivariate logistic regression model to identify factors affecting receipt of treatment. RESULTS: Of 1893 eligible Australian and United States (US) participants with incident cancer, 1569 (81%) received some form of cancer treatment. Non-metastatic breast cancers most frequently received treatment (98%), while haematological malignancy received the lowest rates of treatment (60%). Factors associated with not receiving treatment were older age (OR 0.94, 95% CI 0.91-0.96), residence in the US (OR 0.34, 95% CI 0.22-0.54), smoking (OR 0.57, 95% CI 0.40-0.81), and diabetes (OR 0.56, 95% CI 0.39-0.80). After adjustment for treatment patterns in sex-specific cancers, sex did not impact receipt of treatment. CONCLUSIONS: This study is one of the first describing cancer treatment patterns and factors affecting receipt of treatment across common cancer types in older adults. We found that most older adults with cancer received some form of cancer treatment, typically surgery or systemic therapy, although this varied by factors such as cancer type, age, sex, and country of residence.

The role of surveillance imaging for resected high-risk melanoma.

BACKGROUND: Recommendations for surveillance imaging for resected melanoma vary considerably. This study examined the utility of imaging in patients with a high-risk primary melanoma undergoing a protocolized imaging schedule. METHODS: This retrospective study involved data collection regarding imaging, recurrence, and outcome characteristics for patients referred to the Victorian Melanoma Service from January 2016-April 2020 and managed for resected stage IIC or III melanoma. Patients with a T4b tumor who did not undergo a sentinel lymph node biopsy were included (T4bNX). Recurrences were "clinically detected" if they were primarily detected by patient symptoms or physical examination, or 'imaging-detected' if the patient was asymptomatic. Cox regression models including time-varying co-variates were used to assess the impact of imaging-detected versus clinically-detected recurrence on overall survival. RESULTS: Over a median follow-up time of 2.7 years, 199 patients underwent surveillance imaging (T4bNX:22, IIC:33, IIIA:22, IIIB:60, IIIC:61, IIID:1), and 44% (n = 88) experienced disease recurrence. Imaging detected over half (53%) of all recurrences. In adjusted analyses, mortality risk was reduced after an imaging-detected compared to clinically-detected recurrence at any given time from the start of surveillance (hazard ratio 0.25, 95% confidence interval 0.10-0.66, p = .005). CONCLUSION: Our study indicates that routine imaging in the early follow-up period of resected T4bNX, stage IIC and III melanoma plays an important role in the detection of asymptomatic recurrences. Imaging-detected recurrence may be associated with a survival benefit and studies with more prolonged follow-up are required to confirm these findings.

Association Between Low-Dose Methotrexate Exposure and Melanoma: A Systematic Review and Meta-analysis.

Importance: Methotrexate is widely used for the treatment of inflammatory disorders, including rheumatoid arthritis. Studies suggest that methotrexate may be associated with an increased risk of melanoma. Objective: To determine whether methotrexate exposure is associated with an increased risk of cutaneous melanoma. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to May 12, 2022, for eligible studies. Study Selection: Case-control studies, cohort studies, or randomized clinical trials (RCTs) were included if they examined the odds or risk of cutaneous melanoma in individuals exposed to low-dose methotrexate in comparison with individuals unexposed. No language limitations were applied. Data Extraction and Synthesis: Two independent reviewers extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed. To assess study quality, the Cochrane risk of bias tool was used for RCTs, and the Joanna Briggs Institute Checklist was used for cohort and case-control studies. Odds ratio from case-control studies and relative risk or hazard ratio from cohort studies or RCTs were pooled, and a random-effects model meta-analysis was conducted. Main Outcomes and Measures: Prespecified outcome was the odds ratio, hazard ratio, or risk ratio of cutaneous melanoma comparing low-dose methotrexate exposure with nonexposure. Results: Seventeen studies (8 RCTs, 5 cohort studies, 4 case-control studies) were eligible for inclusion, and of these, 12 studies with 16 642 cases of melanoma were pooled in the primary analysis. Indications for methotrexate included rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease and were unknown in 5 studies. Compared with unexposed individuals, study participants with methotrexate exposure had a small increased risk of melanoma (pooled relative risk, 1.15; 95% CI, 1.08-1.22), but this did not persist in a sensitivity analysis excluding the largest study (pooled relative risk, 1.11; 95% CI, 1.00-1.24). Subgroup analyses according to comparator group (comparing methotrexate exposure with either immunomodulator alone vs immunomodulator and methotrexate) or the indication for methotrexate being rheumatoid arthritis provided similar risk estimates. Using geographical population melanoma incidence rates, a number needed to harm of 18 630 was calculated in Australia, and 41 425 in North America. Conclusions and Relevance: In this systematic review and meta-analysis, low-dose methotrexate exposure was associated with an increased melanoma risk, but the absolute risk increase could be considered negligible.

Association between hypertension and cutaneous melanoma, and the effect of aspirin: extended follow-up of a large randomised controlled trial.

BACKGROUND: The association between hypertension and melanoma is unclear, and previous analyses of data from the ASPirin in Reducing Events in the Elderly (ASPREE) study demonstrated a reduced number of invasive melanoma events amongst aspirin-exposed hypertensive individuals. METHODS: Data from the ASPREE study which included (1) the intervention period with a median follow-up of 4.7 years, and (2) the observational period with an additional 2 years follow-up, were combined for this analysis. Logistic regression analyses examined the association between baseline hypertension and treatment status and past melanoma history. Survival analyses examined the association between hypertension and melanoma risk, and the effect of aspirin across hypertension groups. Cox proportional hazards models were used to compare incidence across groups. RESULTS: 19,114 participants (median age of 74 years) were randomised to daily 100 mg aspirin or placebo. At baseline, hypertension and past melanoma history were recorded in 14,195 and 685 individuals, respectively. After adjustment for confounders, hypertension was significantly associated with past melanoma history (OR=1.34, 95%CI: 1.11-1.62). In a prospective analysis, baseline hypertension was not associated with melanoma risk. However, aspirin was associated with a reduced risk of incident melanoma amongst individuals with uncontrolled hypertension (blood pressure ≥140/90 mmHg; HR=0.63, 95%CI 0.44-0.89), but not in those with controlled hypertension (HR=1.04, 95%CI 0.74-1.46). CONCLUSION: Our results support a reduced melanoma incidence amongst individuals with uncontrolled hypertension exposed to aspirin. Additional studies are required to confirm these findings.

Effect of Aspirin on Melanoma Incidence in Older Persons: Extended Follow-up of a Large Randomized Double-blind Placebo-controlled Trial.

The effects of aspirin on melanoma are unclear, with studies reporting conflicting results. Data from two periods of the ASPirin in Reducing Events in the Elderly (ASPREE) study; the randomized placebo-controlled trial period examining daily 100 mg aspirin in older adults with a median follow-up of 4.7 years, and the second period, an additional 2 years of observational follow-up, were utilized in this secondary analysis to examine whether aspirin exposure is associated with a reduced cutaneous melanoma incidence. All melanoma cases were adjudicated and Cox proportional hazards models were used to compare incidence between randomized treatment groups. ASPREE recruited 19,114 participants with a median age of 74 years. During the trial period, 170 individuals (76 aspirin, 94 placebo) developed an invasive melanoma, and no significant effect of aspirin was observed on incident melanoma [HR = 0.81; 95% confidence interval (CI), 0.60-1.10]. Including the additional 2 years of observational follow-up (median follow-up of 6.3 years), 268 individuals (119 aspirin, 149 placebo) developed an invasive melanoma, and similar results were observed (HR = 0.81; 95% CI, 0.63-1.03). A reduced number of events was observed with aspirin among females in a subgroup analysis (HR = 0.65; 95% CI, 0.44-0.92); however, the interaction effect with males (HR = 0.92; 95% CI, 0.68-1.25) was nonsignificant (P = 0.17). Our findings from this randomized trial do not provide strong support that aspirin is associated with a reduced risk of invasive melanoma in older individuals. Additional studies are required to further explore this relationship. PREVENTION RELEVANCE: Melanoma prevention is an important strategy to improve outcomes and while preventive efforts have largely focused on sun protection, the role of potential chemopreventive agents such as aspirin warrants investigation.

Yield of baseline imaging for distant metastases in high-risk primary melanoma.

BACKGROUND: The yield of baseline imaging in patients presenting with higher risk primary tumours, at least American Joint Committee on Cancer 8th edition stage IIC or III melanoma, is unclear. METHODS: This retrospective study included patients referred to the Victorian Melanoma Service from January 2017 to April 2020, diagnosed with at least stage IIC or stage III melanoma. Patients with a T4b tumour and no sentinel lymph node biopsy were included as 'T4bNX'. RESULTS: One hundred and sixty-four patients (median age 65 years) with baseline imaging (T4bNX: 19, IIC: 30, IIIA: 21, IIIB: 43, IIIC: 50, IIID: 1) were included. The majority were male (73%), and those with T4bNX melanoma tended to be older (median age 79 years). Distant metastases were detected in 21% (4/19) of T4bNX, 3% (1/30) of stage IIC, 0% (0/21) of stage IIIA, and 6% (6/94) of stages IIIB-D melanoma patients. All stage III patients with distant metastases had palpable lymphadenopathy a presentation. Two patients had brain metastases, both of whom had T4bNX melanoma and synchronous extra-cranial metastases. CONCLUSIONS: Compared to stage IIC, baseline imaging detects higher rates of extra-cranial distant disease in stages IIIB-D and T4bNX melanoma. Intracranial imaging has greater yield in patients with distant extra-cranial disease.

Opportunities and barriers for the use of Australian cancer registries as platforms for randomized clinical trials.

It is well recognized that randomized controlled trials (RCTs) are a powerful tool to investigate causal relationships, and are considered the gold standard level of research evidence. However, RCTs can be expensive and time-consuming, and when they employ strict eligibility criteria, it results in an unrepresentative population and limited external validity. Recently, the registry-based randomized clinical trial (RRCT) has emerged as an alternative trial design. Utilizing registries to underpin such studies, RRCTs can have advantages including rapid recruitment, and enhanced generalizability. In Australia, legislated mandatory reporting of cancer diagnoses means that jurisdictional cancer registries are a rich source of systematically collected patient details, representing sound platforms for comprehensive data capture that can serve as a key tool for further research. We review the roles of cancer registries in Australia, discuss important considerations relevant to the design of RRCTs, and outline the opportunities provided by cancer registries to strengthen cancer research.

The impact of incomplete clinical information and initial biopsy technique on the histopathological diagnosis of cutaneous melanoma.

BACKGROUND/OBJECTIVES: Increased rates of histopathological misdiagnosis of melanoma have been associated with incisional punch more so than shave biopsy when compared with complete excisional biopsy. It is unknown how the increasing utilisation of shave biopsy may impact melanoma diagnosis. The extent to which the provision of clinical information to the pathologist may improve diagnostic accuracy remains unclear. This study assessed the impact of both initial biopsy technique and provision of adequate clinical information to pathologists on the accuracy of histopathological diagnosis of melanoma and disease progression. METHODS: We conducted a retrospective cohort with nested case-control study of all histopathological false-negative and false-positive melanoma diagnoses from January 2014 to May 2019 from the Victorian Melanoma Service electronic database. Cases were assessed for the initial biopsy type, provision of clinical information on pathology request forms and disease progression associated with false-negative diagnosis. RESULTS: Partial shave biopsy had higher odds of false-negative (OR 5.19, 95% CI 2.89-9.32; P < 0.001) and false-positive diagnoses (OR 1.95, 95% CI 1.45-2.63; P < 0.001) of melanoma when compared with elliptical excisional biopsy. These odds ratios were comparable with those found with incisional punch biopsy. Providing the suspected clinical diagnosis to pathologists also reduced the odds of false-negative diagnosis with melanoma progression by 3.8-fold (P = 0.02). CONCLUSION: The choice of initial biopsy technique and providing the suspected clinical diagnosis to pathologists are important for correct histopathological diagnosis of cutaneous melanoma and prevention of further disease progression.

Genomic Risk Score for Melanoma in a Prospective Study of Older Individuals.

BACKGROUND: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest. METHODS: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma. RESULTS: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma. CONCLUSIONS: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance.

Reduced melanoma referrals during COVID-19 lockdown.

As the COVID-19 pandemic has reduced face-to-face medical consultations, reduced diagnoses of thin melanomas and delayed presentations of thick melanomas were anticipated.

The Importance of Incorporating Human Factors in the Design and Implementation of Artificial Intelligence for Skin Cancer Diagnosis in the Real World.

Artificial intelligence (AI) algorithms have been shown to diagnose skin lesions with impressive accuracy in experimental settings. The majority of the literature to date has compared AI and dermatologists as opponents in skin cancer diagnosis. However, in the real-world clinical setting, the clinician will work in collaboration with AI. Existing evidence regarding the integration of such AI diagnostic tools into clinical practice is limited. Human factors, such as cognitive style, personality, experience, preferences, and attitudes may influence clinicians' use of AI. In this review, we consider these human factors and the potential cognitive errors, biases, and unintended consequences that could arise when using an AI skin cancer diagnostic tool in the real world. Integrating this knowledge in the design and implementation of AI technology will assist in ensuring that the end product can be used effectively. Dermatologist leadership in the development of these tools will further improve their clinical relevance and safety.

Knowledge and attitudes of Australian dermatologists towards sentinel lymph node biopsy for melanoma: a mixed methods study.

BACKGROUND/OBJECTIVES: In melanoma management, sentinel lymph node biopsy (SLNB) is used to stage patients and to indicate prognosis. More recently, it has been used to select patients for adjuvant therapy. This study aimed to report knowledge of and attitudes towards SLNB for patients with melanoma among Australian dermatologists. METHODS: Mixed methods study using cross-sectional questionnaires (n = 88) and semi-structured interviews (n = 13), May-September 2019. RESULTS: Of the dermatologists surveyed, 56% thought SLNB had an important role in melanoma management, 26% were unsure and 18% thought SLNB unimportant. Of the 92% who would discuss SLNB with their patients, the main stated value of SLNB was for assessing eligibility for adjuvant therapies (79%); only 60% indicated SLNB was of value for providing prognostic information, and just over half (53%) thought it could improve staging. Interview data indicated that attitudes towards SLNB are shifting among dermatologists, driven by data from landmark clinical trials and the influence of professional networks. Accordingly, interviewees adopted one of three positions in relation to SLNB: (a) believed in utility of SLNB and adhered to the guidelines; (b) were unconvinced about utility of SLNB but adhered to the guidelines; and (c) were unconvinced about utility of SLNB and did not adhere to the guidelines. CONCLUSION: Although most of the dermatologists surveyed were familiar with and follow the SLNB recommendations, some disagreement with and distrust of the recommendations was evident. Greater acceptance of the SLNB recommendations appeared to be driven by the improved outcomes demonstrated in stage III patients receiving adjuvant systemic therapy.

Diagnosis and management of cutaneous melanoma.

BACKGROUND: In the field of melanoma, clinical trials evaluating the impact of sentinel node biopsy, completion lymph node dissection and adjuvant medical therapies on patient outcomes have provided evidence that has changed practice significantly over the past five years. OBJECTIVE: The aim of this article is to discuss key evidence that has informed new Cancer Council Australia melanoma management guidelines. DISCUSSION: General practitioners play a critical role in melanoma diagnosis and follow-up. Complete excisional biopsy to achieve accurate tumour microstaging is essential for obtaining reliable prognostic information, planning further management and accessing adjuvant medical therapies. The management of patients with Stage III disease has changed dramatically over the past few years. Less surgery is now recommended, and patients may be offered potentially life-prolonging systemic therapies. Multidisciplinary discussion of management is recommended. Rapid advances in therapeutic options for patients with advanced melanoma have placed new emphasis on the importance of accurate staging and early management. Accordingly, the Australian national melanoma management guidelines have recently been updated. These evidence-based guidelines are now readily available on Cancer Council Australia's electronic Wiki platform, which facilitates regular further updating.