Hedgehog Pathway Inhibition.

The hedgehog (Hh) signaling pathway is aberrantly activated in a majority of basal cell carcinomas (BCC). Vismodegib and sonidegib are targeted inhibitors of Smoothened (SMO). Both drugs are approved for use in locally advanced BCC (laBCC), with vismodegib also approved for metastatic BCC (mBCC).

NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Quality of life in cemiplimab-treated patients with locally advanced basal cell carcinoma in a Phase II clinical trial.

Aim: To evaluate health-related quality of life (HRQoL) in cemiplimab-treated patients with locally advanced basal cell carcinoma (laBCC).Materials & methods: Eighty-four patients with laBCC received cemiplimab 350 mg every 3 weeks (up to 9 cycles). HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and each cycle. Mixed-effects repeated-measures models evaluated change from baseline across cycles.Results: Clinically meaningful improvement or maintenance was reported by 62-90% of patients on QLQ-C30 scales and by approximately 80% on Skindex-16 scales at Cycle 2, with consistent results at Cycle 9 except fatigue.Conclusion: Most cemiplimab-treated patients with laBCC reported improvement or maintenance of HRQoL with low symptom burden except fatigue.Clinical Trial Registration: ClinicalTrials.gov identifier NCT03132636, registered 28 April 2017.

Locally advanced basal cell carcinoma (laBCC) is a type of skin cancer that has the potential to invade surrounding tissues including bone, cartilage, nerve and muscle. Cemiplimab-rwlc is approved in the US for patients with laBCC following a therapy called hedgehog inhibitor (HHI) treatment or for whom HHIs are not appropriate. In a Phase II clinical trial, intravenous (in the vein) cemiplimab 350 mg every 3 weeks for up to nine treatment cycles resulted in clinically meaningful antitumor activity in patients with laBCC who progressed on or were intolerant to HHIs.This analysis evaluated health-related quality of life, symptom burden, emotions and functional status in these patients using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (QLQ-C30) and Skindex-16 questionnaires. Baseline scores (scores at the start of the clinical trial) showed moderate to high levels of functioning and low symptom burden that, except for fatigue, were maintained or improved over the course of cemiplimab treatment. These results show that despite the presence of fatigue, health-related quality of life and functional status were maintained with cemiplimab across the study duration.

Basal Cell Skin Cancer, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Somatic selection distinguishes oncogenes and tumor suppressor genes.

MOTIVATION: Functions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes, oncogenes (OGs) and tumor-suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putative cancer driver genes, resources for context-aware classifications of OGs and TSGs are limited. RESULTS: We show that the direction and magnitude of somatic selection of protein-coding mutations are significantly different for passenger genes, OGs and TSGs. Based on these patterns, we develop a new method (genes under selection in tumors) to discover OGs and TSGs in a cancer-type specific manner. Genes under selection in tumors shows a high accuracy (92%) when evaluated via strict cross-validations. Its application to 10 172 tumor exomes found known and novel cancer drivers with high tissue-specificities. In 11 out of 13 OGs shared among multiple cancer types, we found functional domains selectively engaged in different cancers, suggesting differences in disease mechanisms. AVAILABILITY AND IMPLEMENTATION: An R implementation of the GUST algorithm is available at https://github.com/liliulab/gust. A database with pre-computed results is available at https://liliulab.shinyapps.io/gust. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

NCCN Guidelines® Insights: Squamous Cell Skin Cancer, Version 1.2022.

The NCCN Guidelines for Squamous Cell Skin Cancer provide recommendations for diagnostic workup, clinical stage, and treatment options for patients with cutaneous squamous cell carcinoma. The NCCN panel meets annually to discuss updates to the guidelines based on comments from panel members and the Institutional Review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new surgical recommendation terminology (peripheral and deep en face margin assessment), as well as recent updates on topical prophylaxis, immunotherapy for regional and metastatic disease, and radiation therapy.

Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma.

Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.

Prognostic value of inositol polyphosphate-5-phosphatase expression in recurrent and metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. OBJECTIVE: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. METHODS: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. RESULTS: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). LIMITATIONS: This is a multicenter but single institution study of a white population. CONCLUSION: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study.

Following publication of the original article [1], it was reported that the legend for Fig. 1 was incomplete. The complete figure legend is.

The prognostic value of inositol polyphosphate 5-phosphatase in cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate 5-phosphatase (INPP5A) has been shown to play a role in development and progression of cutaneous squamous cell carcinoma (cSCC). The goal of the current study was to explore the prognostic value of INPP5A expression in cSCC. METHODS: A total of 189 cases of actinic keratosis and SCC in 174 patients were identified; clinical and outcome data were abstracted, histopathology was rereviewed, and immunohistochemical staining and interpretation was performed for INPP5A. RESULTS: The majority of tumors (89.4%) had an INPP5A score of 2 or 3. No patients had complete loss of INPP5A. Tumors with an INPP5A score of 1 were more likely to be intermediate- to high-risk tumors (Brigham and Women's Hospital stage ≥T2a 85.0% vs 23.7% [P < .0001]) characterized by a larger diameter (2.4 cm vs 1.3 cm [P = .0004]), moderate-to-poor differentiation (86.7% vs 17.6% [P < .0001]), and perineural invasion (37.5% vs 5.3%, [P < .0001]). An INPP5A score of 1 was associated with a worse 3-year survival (a rate of 42.3% [hazard ratio, 2.81, P = .0006]) and a local metastasis rate of 48.0% (hazard ratio, 4.71; P < .0001). CONCLUSIONS: Low INPP5A scores are predictive of aggressive tumors and may be a useful adjunct to guide clinical management of cSCC.

Clinical and histopathologic features of paraneoplastic granuloma annulare in association with solid organ malignancies: A case-control study.

BACKGROUND: Granuloma annulare (GA) is a granulomatous skin eruption rarely associated with cancer. We report seven cases of paraneoplastic GA in association with solid organ malignancy. OBJECTIVE: To compare the clinical and histopathological features of paraneoplastic GA to case-matched controls of classic GA. METHODS: Retrospective chart and histopathological review of 7 individuals and 13 age- and sex-matched controls. Paraneoplastic GA was defined as GA occurring within 6 months of the diagnosis of solid organ malignancy and/or persistent GA that resolved with cancer treatment. RESULTS: Most cases of paraneoplastic GA were associated with lung cancer (4/7). The clinical and histopathological features of paraneoplastic and classic GA were similar. Compared to classic GA, paraneoplastic GA cases were more often generalized disease (6/7 vs 6/13), refractory to treatment, and had a perivascular inflammatory cell infiltrate (5/7 vs 2/13). All cases of paraneoplastic GA that underwent definitive treatment of their cancer improved. LIMITATIONS: Single-institution, retrospective review with a small sample size. CONCLUSION: Paraneoplastic GA is rare, similar to classic GA, and refractory to treatment. We advocate for age-appropriate screening in individuals with GA that is nonresponsive to multiple lines of systemic treatment and evaluating patients with concerning signs or symptoms for an underlying neoplasm.

Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study.

BACKGROUND: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC. METHODS: One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety. RESULTS: At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib. CONCLUSIONS: This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC. TRIAL REGISTRATION: This study was registered prospectively with Clinicaltrials.gov , number NCT00833417 on January 30, 2009.

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters.

Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here, we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing. We show that promoter mutations exert a detrimental effect on the folding of one of these G-quadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression produces cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and induction of senescence by decreasing telomerase activity and telomere length. We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma.

Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy. IMPLICATIONS FOR PRACTICE: The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients.

Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) of the skin is the most common cancer, with a higher incidence than all other malignancies combined. Although it is rare to metastasize, patients with multiple or frequently recurring BCC can suffer substantial comorbidity and be difficult to manage. Assessment of risk is a key element of management needed to inform treatment selection. The overall management of BCC primarily consists of surgical approaches, with radiation therapy as an alternate or adjuvant option. Many superficial therapies for BCC have been explored and continue to be developed, including topicals, cryosurgery, and photodynamic therapy. Two hedgehog pathway inhibitors were recently approved by the FDA for systemic treatment of advanced and metastatic BCC, and others are in development. The NCCN Guidelines for Basal Cell Skin Cancer, published in full herein, include recommendations for selecting among the various surgical approaches based on patient-, lesion-, and disease-specific factors, as well as guidance on when to use radiation therapy, superficial therapies, and hedgehog pathway inhibitors.

Risk Factors Predicting Positive Margins at Primary Wide Local Excision of Cutaneous Melanoma.

BACKGROUND: A small percentage of patients will have positive histological margins after primary wide local excision (WLE) of cutaneous melanoma (CM). Risk factors that predict marginal involvement at WLE remain unclear. OBJECTIVE: To identify risk factors associated with positive margins after WLE of CM. MATERIALS AND METHODS: A retrospective review of patients treated at a single institution for CM with sentinel lymph node biopsy from 1997 to 2011 was conducted. RESULTS: Positive margins occurred in 6% of patients. Patients with positive margins were older (72.4 vs 60.7, p < .001), had thicker tumors (3.6 vs 1.9 mm, p < .001), and often involved the head and neck region (p < .001). Patients with positive margins at WLE had positive margins on initial biopsy (p = .012) and a higher rate of a melanoma in situ component on initial biopsy (24% vs 11%, p = .02). The 5-year local recurrence rate was significantly different between those with positive and negative margins at WLE (16.0% vs 6.9%; p = .047). CONCLUSION: Positive margins after WLE are uncommon. When a patient has multiple risk factors for positive margins at WLE, histologically clear margins should be obtained through mapped serial excision or Mohs micrographic surgery.