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While psoriasis and atopic dermatitis (AD) are two common dermatological conditions, their diagnosis and therapeutic decision-making pathways are often complex. As a result, there has been increased focus on the development of precision medicine approaches for psoriasis and AD. Two companies at the forefront of dermatology precision medicine research are Mindera Health and Castle Biosciences. Here, we review the technologies developed by these two companies using a dermal diagnostic patch and superficial skin scrapings, respectively, their research published to date, and their future research goals. Research from both companies shows promise in predicting the response of inflammatory skin disease to biologics using minimally invasive techniques. However, challenges to adoption include insurance coverage and patient trust in the technologies. While there are several differences between Mindera Health and Castle Biosciences, they have a shared goal of utilizing minimally invasive technologies to sample skin and predict response to biologic treatments using a panel of optimized biomarkers.
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Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response.
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Anilidas , Antineoplásicos , Carcinoma Basocelular , Proteínas Hedgehog , Piridinas , Neoplasias Cutâneas , Humanos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Anilidas/efeitos adversos , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Disgeusia/induzido quimicamente , Alopecia/induzido quimicamenteRESUMO
Background: Empirical decisions to select therapies for psoriasis (PSO) and atopic dermatitis (AD) can lead to delays in disease control and increased health care costs. However, routine molecular testing for AD and PSO are lacking. Objective: To examine (1) how clinicians choose systemic therapies for patients with PSO and AD without molecular testing and (2) to determine how often the current approach leads to patients switching medications. Methods: A 20-question survey designed to assess clinician strategies for systemic treatment of AD and PSO was made available to attendees of a national dermatology conference in 2022. Results: Clinicians participating in the survey (265/414, 64% response rate) ranked "reported efficacy" as the most important factor governing treatment choice (P < .001). However, 62% (165/265) of clinicians estimated that 2 or more systemic medications were typically required to achieve efficacy. Over 90% (239/265) of respondents would or would likely find a molecular test to guide therapeutic selection useful. Limitations: To facilitate ease of recall, questions focused on systemic therapies as a whole and not individual therapies. Conclusion: Clinicians want a molecular test to help determine the most efficacious drug for individual patients.
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BACKGROUND: The use of ointments can be beneficial for dry, chapped, or cracked skin and also for supporting wound healing. We describe the results of 2 studies with an over-the-counter healing ointment (HO) to evaluate the effects on skin hydration and in the setting of wound healing after dermatologic procedures. Methods: Study 1 was a single-center, in-use study using HO on qualified areas at least once daily for 4 weeks in subjects with dry, cracked body skin and self-perceived sensitive skin. Study 2 was a multi-center study of wound healing in subjects using HO on a daily basis after having dermatologic surgical procedures. Results: In Study 1, there was a significant reduction in skin dryness after 1 and 4 weeks of HO use (P<0.05). Image analysis of the skin revealed a significant increase in skin smoothness after the first application of HO in 100% of subjects (P<0.05). Tolerability and safety were excellent, and HO was well-perceived by subjects throughout the study. In Study 2, HO improved clinical assessments at all time points compared with baseline with a decrease in erythema, edema, scabbing/crusting, and an improvement in overall wound appearance (P<0.05). There was no worsening or significant increase in measures for tolerability parameters at any study visits. Additionally, HO achieved a favorable perception by study subjects. Conclusions: HO has a well-established safety profile and has been shown to improve both skin hydration and the overall wound healing process after dermatologic surgical procedures. J Drugs Dermatol. 2024;23(5):360-365. doi:10.36849/JDD.8224.
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Medicamentos sem Prescrição , Pomadas , Cicatrização , Humanos , Cicatrização/efeitos dos fármacos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Medicamentos sem Prescrição/administração & dosagem , Idoso , Resultado do Tratamento , Dermatopatias/tratamento farmacológico , Pele/efeitos dos fármacos , Pele/patologia , Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Adulto Jovem , Administração CutâneaRESUMO
Aim: Cutaneous melanocytic neoplasms with diagnostic and/or clinical ambiguity pose patient management challenges. Methods: Six randomized case scenarios with diagnostic/clinical uncertainty were described with/without a benign or malignant diagnostic gene expression profile (GEP) result. Results: Clinical impact was assessed by reporting the mean increase/decrease of management changes normalized to baseline (n = 32 dermatologists). Benign GEP results prompted clinicians to decrease surgical margins (84.2%). Malignant GEP results escalated surgical excision recommendations (100%). A majority (72.2%) reduced and nearly all (98.9%) increased follow-up frequency for benign or malignant GEP results, respectively. There was an overall increase in management plan confidence with GEP results. Conclusion: Diagnostic GEP tests help guide clinical decision-making in a variety of diagnostically ambiguous or clinicopathologically discordant scenarios.
Dermatologists' use of diagnostic gene expression profiles for personalized patient care. When your doctor takes a piece of a mole, that mole is looked at under the microscope by a pathologist. The pathologist is responsible for figuring out if the mole is dangerous or not. Dangerous moles are removed with surgery to make sure all the dangerous tissue is gone. Moles without a health threat are left alone. Sometimes figuring out how dangerous a mole is is difficult. The pathologist may not provide the doctor with enough information for them to know how to treat your mole. There is a test that can provide information on whether your mole is unsafe. This test is called diagnostic gene expression profiling or GEP. In this study, GEP is used to help doctors figure out how to treat a mole and how often the patient should be seen in the office for skin checks. With GEP, important changes in patient treatment were identified. These include the need for an additional surgery, how much healthy tissue should be removed during surgery and how often the patient should be seen in the office. For suspicious moles where the pathology report is unclear, GEP can provide information that leads to more appropriate and personalized patient care.
Ancillary diagnostic gene expression profile testing for ambiguous cutaneous melanocytic lesions helps optimize dermatologist recommendations for excision margin and follow-up.
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INTRODUCTION: National Comprehensive Cancer Network (NCCN) recommendations for adjuvant radiation therapy (ART) use are similar for High Risk and Very High Risk cutaneous squamous cell carcinoma (cSCC) with negative post-surgical margins. Although studies report reductions in disease progression following ART treatment, ART use is likely inconsistent when guided by available risk factors. This study evaluated the association of ART with clinical risk factors in ART-treated and untreated patients and showed the clinical utility of the 40-gene expression profile (40-GEP) for guiding ART. METHODS: A multicenter study of 954 patients was conducted with institutional review board (IRB) approval. The 40-GEP test was performed using primary tumor tissue from patients with either a minimum of 3 years of follow-up or a documented regional or distant metastasis. Unsupervised hierarchical cluster analysis identified patterns of clinical risk factors for ART-treated patients, then identified untreated patients with matching risk factor profiles. Results were cross-referenced to 40-GEP test results to determine utility of the test to guide ART. RESULTS: Analysis demonstrated inconsistent implementation of ART for eligible patients. Cluster analysis identified four patient profiles based on clusters of risk factors and, notably, matching profiles in ART-treated and untreated patients. Further, the analysis identified patients who received but could have deferred ART on the basis of 40-GEP test result and biologically low risk of metastasis, and untreated patients who likely would have benefitted from ART on the basis of their 40-GEP test result. CONCLUSIONS: ART guidance is not determined by the presence of specific clinicopathologic factors, with treated and untreated patients sharing the same risk factor profiles. cSCC risk determination based on NCCN recommendations for clinical factor assessment results in inconsistent use of ART. Including tumor biology-based prognostic information from the 40-GEP refines risk and identifies patients who are most appropriate and likely to benefit from ART, and those that can consider deferring ART.
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Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening disease. There is limited understanding of patient characteristics in GPP and their correlation with disease progression or healthcare resource utilization. Our review aims to examine real-world evidence on these characteristics and the associated disease burden as related to economic and quality of life factors. Results showed that most patients with GPP experienced flares once a year, lasting from 2 weeks to 3 months, with > 80% of patients having residual disease post-flare, with/without treatment, indicating the long-term nature of GPP. The impact of GPP on patients' daily activities was significant, even in the absence of a flare. GPP adversely affected mental health, and anxiety and depression were reported regularly. Patients with GPP had more comorbidities, were prescribed more medication, and had more inpatient and outpatient visits than in matched plaque psoriasis or general population cohorts. Improving the education of healthcare providers in diagnosing GPP, defining disease flares, and managing the disease, as well as making globally accepted clinical guidelines for GPP treatment available, could help to reduce the burden on patients with GPP. Effective therapies that control and prevent GPP flares and manage chronic disease are needed.
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Objective: Adjuvant radiation therapy (ART) is often recommended for high-risk cSCC patients but carries significant costs and risks. This study aims to determine if utilizing the 40-GEP test to guide ART can reduce healthcare costs in cSCC management. Methods: Medical claims data with new diagnoses of cSCC for the 12 months ending June 2022 in the Medicare (≥65 years) population (source: IQVIA claims database) were obtained and normalized to the general population for missingness. CPT codes associated with radiation therapy within one-year post diagnosis were used to establish adjuvant RT use (defined as 'ART'). Average weighted direct costs for four major ART modalities were calculated from published studies and (IQVIA). Sensitivity analysis was used to assess the financial impact of ART treatment using varying distributions of 40-GEP Class results. Results: Normalized medical claims data identified 22,917 Medicare-eligible cSCC patients who received ART within the United States. The weighted average direct cost for ART, which includes the four most used CPT code-defined modalities (IGRT, IMRT, IMPT, and XRT), was $60,693 per patient, amounting to an annual projected ART cost of $1.4 billion. Using the distribution of 40-GEP results from published studies, utilization of a 40-GEP test result to avoid ART in these patients could save up to $972 million in Medicare-eligible population. Sensitivity analysis shows, depending upon the distribution of the 40-GEP results, that for every 10% of Class 2A test results omitting ART, an extra $38-66 million in annual savings is expected. Limitations: Potential limitations include a need for more comprehensive patient information and the cost of ART-related complications. Conclusion: Utilizing the 40-GEP test results to guide ART decision-making would result in material savings to Medicare.
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INTRODUCTION: The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old. METHODS: This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP. RESULTS: Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women's Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models). CONCLUSION: The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions.
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Necrobiosis lipoidica (NL) is a chronic granulomatous disorder of the skin which usually presents with red papules and plaques on the lower extremities. Diabetes mellitus has been found to be associated with NL, but the pathophysiology of the disease is unknown. Based on a Doppler flowmetry study showing increased blood flow at NL lesions and the macrophage upregulation of granulomatous disorders, it is reasonable to conclude that there is an inflammatory component to it. NL is extremely challenging to manage. The initial treatment of choice is usually topical or intralesional corticosteroids, and if this fails to work, many dermatologists depend on the small number of case reports for more treatment options. We present a pre-diabetic patient with nonulcerative NL who was successfully treated with the first-in-class therapeutic aryl hydrocarbon receptor (AHR)-modulating agent tapinarof cream (VTAMA, Dermavant). Following the case presentation is a discussion of this topical novel agent and its unique anti-inflammatory mechanism of action. Tapinarof specifically binds to and activates AHR leading to downregulation of TNF-α/IL-23/IL-17 and inhibition of IL-4/IL-13 mediated STAT6 activation. Anti-TNF-α agents and JAK-inhibitors have also been found to be beneficial in treating NL; tapinarof seems to target both these pathways without the risk of their serious adverse reactions.
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Objectives: Some melanocytic neoplasms suspicious for melanoma require additional workup to arrive at a final diagnosis. Within the last eight years, gene expression profiling (GEP) has become an important ancillary tool to aid in the diagnosis of melanocytic neoplasms with uncertain malignant potential. As the usage of two commercially available tests (23-GEP and 35-GEP) evolves, it is important to answer key questions about optimal utilization and their impact on patient care. Methods: Recent and relevant articles answering the following questions were included in the review. First, how do dermatopathologists synthesize the available literature, the latest guidelines, and their clinical experience to determine which cases would be most likely to benefit from GEP testing? Second, how best can a dermatologist convey to their dermatopathologist that the use of GEP in the diagnostic process could provide a more clearly defined result and thereby help empower the dermatologist to provide higher-quality patient care when making specific patient management decisions for otherwise pathologically ambiguous lesions? Results: When interpreted in the context of the clinical, pathologic, and laboratory information, GEP results can facilitate the rendering of timely, accurate, and definitive diagnoses for melanocytic lesions with otherwise uncertain malignant potential to inform personalized treatment and management plans. Limitations: This was a narrative review focused on clinical use of GEP compared to other ancillary diagnostic tests performed postbiopsy. Conclusion: Open communication between dermatopathologists and dermatologists, especially regarding GEP testing, can be a vital component to achieve appropriate clinicopathologic correlation for otherwise ambiguous melanocytic lesions.
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Cutaneous squamous cell carcinoma (cSCC) has become a significant public health issue due to its rapidly rising incidence and an estimated 1.8 million newly diagnosed cases annually. As with other cancers, treatment decisions for patients with cSCC are based primarily on a patient's risk for poor outcomes. There has been improvement in clinicopathologic factor-based risk assessment approaches, either through informal methods or ever evolving staging approaches. However, these approaches misidentify patients who will eventually have disease progression as low-risk and conversely, over classify patients as high-risk who do not experience relapse. To improve the accuracy of risk assessment for patients with cSCC, the 40-gene expression profile (40-GEP) test has been validated to show statistically significant stratification of a high-risk cSCC patient's risk of nodal or distant metastasis, independent of currently available risk-assessment methods. The 40-GEP test allows for a more accurate classification of metastatic risk for high-risk cSCC patients, with the aim to influence appropriate allocation of clinician time and therapeutic resources to those patients who will most benefit. The objective of this article is to present a treatment algorithm in which clinicians can easily integrate the results of the 40-GEP test into their current treatment approaches to tailor patient care based on individual tumor biology. The following modalities were considered: surveillance imaging, sentinel lymph node biopsy (SLNB), adjuvant radiation therapy (ART), and clinical follow-up. The authors have contributed their own cases for discussion as to how they have seen the beneficial impact of 40-GEP test results in their own practice. Overall, clinicians can identify risk-aligned treatment pathway improvements with the use of the 40-GEP test for challenging to manage, high-risk cSCC patients.
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Photodynamic therapy (PDT) with photosensitization using 5-aminolevulinic acid (ALA) [including a nanoemulsion (BF-200 ALA)] is approved in the USA for the treatment of actinic keratoses (AKs); another derivative, methyl aminolevulinate, is not approved in the USA but is used in Europe. For AK treatment, the photosensitizer may be applied to individual AK lesions or, depending on treatment regimen, to broader areas of sun-damaged skin to manage field cancerization, although not all products are approved for field treatment. ALA-PDT and photosensitizers have also been used off-label for the treatment of nonmelanoma skin cancers, primarily basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (cSCC). Advantages of PDT include potentially improved cosmesis and patient satisfaction; disadvantages include pain and duration of treatment. Alternative illumination approaches, including intense pulsed light as well as pulsed-dye lasers, have also been used successfully. Pretreating the affected tissue or warming during incubation can help to increase photosensitizer absorption and improve therapeutic efficacy. Combinations of multiple treatments are also under exploration. Reducing incubation time between photosensitizer application and illumination may significantly reduce pain scores without affecting treatment efficacy. Substituting daylight PDT for a conventional illumination source can also reduce pain without compromising efficacy. The objective of this narrative review is to describe current and ongoing research in the use of topical photosensitizers and modified light delivery regimens to achieve improved therapeutic outcomes with less toxicity in patients with AK, cSCC, BCC, and field cancerization.
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Treatment decisions for patients with cutaneous squamous cell carcinoma (cSCC) are traditionally based upon clinicopathologic risk factors and staging systems. Due to the accuracy limitations of these resources in predicting poor outcomes, there is a clinically significant need for more accurate methods of risk assessment. The 40-gene expression profile (40-GEP) test was developed to augment metastatic risk prediction of high-risk cSCC patients and has been validated in two independent, multi-center studies involving over 1,000 patients. This study substantiates that the 40-GEP is appropriately utilized by clinicians and that the personalized risk-stratification results are impactful in guiding risk-aligned patient management.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Prognóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Estadiamento de Neoplasias , TranscriptomaRESUMO
BACKGROUND: Prognostic assessment of cutaneous melanoma relies on historical, clinicopathological, and phenotypic risk factors according to American Joint Committee on Cancer(AJCC) and National Comprehensive Cancer Network (NCCN) guidelines but may not account for a patient's individual additional genetic risk factors. OBJECTIVE: To review the available literature regarding commercially available gene expression profile (GEP) tests and their use in the management of cutaneous melanoma. METHODS: A literature search was conducted for original, English-language studies or meta-analyses published between 2010 and 2021 on commercially available GEP tests in cutaneous melanoma prognosis, clinical decision-making regarding sentinel lymph node biopsy, and real-world efficacy. After the literature review, the Skin Cancer Prevention Working Group, an expert panel of dermatologists with specialized training in melanoma and non-melanoma skin cancer diagnosis and management, utilized a modified Delphi technique to develop consensus statements regarding prognostic gene expression profile tests. Statements were only adopted with a supermajority vote of > 80%. RESULTS: The initial search identified 1064 studies/meta-analyses that met the search criteria. Of these, we included 21 original articles and meta-analyses that studied the 31-GEP test (DecisionDx-Melanoma; Castle Biosciences, Inc.), five original articles that studied the 11-GEP test (Melagenix; NeraCare GmbH), and four original articles that studied the 8-GEP test with clinicopathological factors (Merlin; 8-GEP + CP; SkylineDx B.V.) in this review. Six statements received supermajority approval and were adopted by the panel. CONCLUSION: GEP tests provide additional, reproducible information for dermatologists to consider within the larger framework of the eighth edition of the AJCC and NCCN cutaneous melanoma guidelines when counseling regarding prognosis and when considering a sentinel lymph node biopsy.
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BACKGROUND: To improve identification of patients with cutaneous squamous cell carcinoma (SCC) at high risk for metastatic disease, the DecisionDx-SCC assay, a prognostic 40-gene expression profile (40-GEP) test, was developed and validated. The 40-GEP assay utilizes RT-PCR gene expression analysis on primary tumor biopsy tissue to evaluate the expression of 34 signature gene targets and 6 normalization genes. The test provides classifications of low risk (Class 1), moderate risk (Class 2A), and high risk (Class 2B) of metastasis within 3 years of diagnosis. The primary objective of this study was to validate the analytical performance of the 40-gene expression signature. METHODS: The repeatability and reproducibility of the 40-GEP test was evaluated by performance of inter-assay, intra-assay, and inter-operator precision experiments along with monitoring the reliability of sample and reagent stability for class call concordance. The technical performance of clinical orders from September 2020 through July 2021 for the 40-GEP test was assessed. RESULTS: Patient hematoxylin and eosin (H&E) stained slides were reviewed by a board-certified pathologist to assess minimum acceptable tumor content. Class specific controls (Class 1 and Class 2B) were evaluated with Levey-Jennings analysis and demonstrated consistent and reproducible results. Inter-assay, inter-operator and intra-assay concordance were all ≥90%, with short-term and long-term RNA stability also meeting minimum concordance requirements. Of the 2586 orders received, 93.5% remained eligible for testing, with 97.1% of all tested samples demonstrating actionable class call results. CONCLUSION: DecisionDx-SCC demonstrates a high degree of analytical precision, yielding high concordance rates across multiple performance experiments, along with exhibiting robust technical reliability on clinical samples.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Perfilação da Expressão Gênica/métodos , Humanos , Prognóstico , Reprodutibilidade dos Testes , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , TranscriptomaRESUMO
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, and the number of deaths due to cSCC is estimated to be greater than the number attributed to melanoma. While the majority of cSCC tumors are resectable with clear margins by standard excision practices, some lesions exhibit high-risk factors for which there is evidence of their association with recurrence, metastasis, and disease-specific death. The most commonly used staging systems and guidelines in the USA for cSCC are based on these clinical and pathologic high-risk factors; however, these are limited in their ability to predict adverse events, thus posing a challenge for implementing risk-directed patient management. Since the development of local recurrence and/or metastasis has a profound impact on the survival of patients with cSCC, accurate identification of patients at high risk for poor outcomes is critical, potentially allowing for early and appropriate adjuvant therapy. This review summarizes the current cSCC literature with a focus on how differing clinical assessments within each of the five selected risk factors (perineural invasion, differentiation, depth of invasion, size, and location) can influence the evaluation of patient outcomes, along with summarizing the utility of staging and guidelines, and highlighting the potential for molecular tools to improve upon cSCC risk assessment.
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Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n = 420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan-Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for class 1 and ≥50% for class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies.
Plain language summary Cutaneous squamous cell carcinoma is a common skin cancer, with approximately 2 million cases diagnosed each year in the USA. Because substantial numbers of patients experience metastasis, which can result in death, accurate metastatic risk assessment is important. Clinicians use clinicopathologic factors to determine risk for disease progression. However, traditional methods miss pinpointing many patients who experience metastasis and sometimes categorize patients as at risk who do not develop metastasis, indicating that additional tools are needed. A molecular test, the 40-gene expression profile (40-GEP), was developed to predict metastatic risk based on the biology of the tumor. This study demonstrates that the 40-GEP, either as an independent tool or together with traditional methods, accurately identifies patients' risk of metastasis. Using the 40-GEP could improve patient management to improve patient outcomes.
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Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica/métodos , Medição de Risco/métodos , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Neoplasias Cutâneas/patologiaRESUMO
INTRODUCTION: Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. METHODS: BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. RESULTS: The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). CONCLUSION: Dose reductions and interruptions were practical and did not impact the efficacy of sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01327053.