Incidence Of Cutaneous Squamous Cell Carcinoma Research Articles

Abstract 5256: Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL)

Abstract MBL is a common pre-malignant condition characterized by circulating clonal B-cells with an absolute B-cell count <5x109/L and no lymphadenopathy, organomegaly, or cytopenias. MBL is the precursor to CLL. The incidence of cutaneous SCC in CLL is significantly higher compared to controls. The incidence of SCC in MBLs has not yet been determined. Study participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, and were Olmsted County residents completed a health questionnaire and provided blood samples between 7/2009 and 12/2020. Stored peripheral blood mononuclear cells were screened for MBL using flow cytometry. We defined three MBL immunophenotypes: CLL-like MBL (CD5+, CD20dim), atypical MBL (CD5+, CD20+), and non-CLL-like MBL (CD5-, CD20+). MBL individuals were also classified by cell count into low-count MBL (LC-MBL) and high-count MBL (HC-MBL), with HC-MBL having a percent clonal B-cell count ≥85%. Data on newly diagnosed SCC was abstracted from the medical records, and prior history of skin cancer before sample collection was ascertained from patient questionnaires. Individuals were followed from sample date to the earliest of SCC, death, loss to follow-up, progression, or 12/31/2020. Cumulative SCC incidence was adjusted for competing risk of death. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age and sex. A total of 5,470 participants were screened for MBL and included 949 (17%) with LC-MBL, 63 (1%) with HC-MBL, and 4,458 (81%) controls (negative for MBL). Individuals with HC-MBL (median age 75 years) or LC-MBL (median age 73 years) were significantly older (P<0.001) than controls (median age 66 years). There were 41 (65%) males among HC-MBL, 447 (47%) among LC-MBL, and 1,551 (35%) among controls. Prior skin cancer history was highest among HC-MBLs (N=17, 27%) or LC-MBLs (N=236, 25%) compared to controls (N=767, 17%). After a median follow-up of 18 months (range 0-138), 154 of the 5,470 individuals were identified to have incident SCC following MBL screening. At least one SCC was observed in 3 individuals with HC-MBL, 33 individuals with LC-MBL, and 118 controls. The 5- and 10-year cumulative incidence of SCC in individuals with MBLs was 7% and 16%, respectively; control estimates were 4% and 8%, respectively. However, after adjusting for age and sex, we observed no evidence of an association between MBL and risk of incident SCC (HR=0.95, CI=0.65-1.40, P=0.80), nor when we stratified individuals by age or by sex (all P>0.05). In the largest MBL screening cohort to date, individuals with MBL do not have an increased risk of incident SCC compared to controls. In contrast to individuals with CLL, these individuals with screening MBL do not need increased dermatologic examination for skin cancer, which is important given the high prevalence of MBL (18% of the population above age 40). Citation Format: Ahmed Nadeem Ansari, Sara J. Achenbach, Sameer A. Parikh, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Connie E. Lesnick, Timothy G. Call, Janet E. Olson, James R. Cerhan, Neil E. Kay, Celine M. Vachon, Esteban Braggio, Curtis A. Hanson, Tait D. Shanafelt, Christian L. Baum, Susan L. Slager. Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5256.

Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis

Altered fibroblast GF receptor (FGFR) signaling has been shown to play a role in a number of cancers. However, the role of FGFR signaling in the development and progression of UVB-induced cutaneous squamous cell carcinoma remains unclear. In this study, the effect of UVB radiation on FGFR activation and its downstream signaling in mouse skin epidermis was examined. In addition, the impact of FGFR inhibition on UVB-induced signaling and skin carcinogenesis was also investigated. Exposure of mouse dorsal skin to UVB significantly increased the phosphorylation of FGFRs in the epidermis as well as the activation of downstream signaling pathways, including protein kinase B/mTOR, signal transducers and activators of transcription, and MAPK. Topical application of the pan-FGFR inhibitor AZD4547 to mouse skin before exposure to UVB significantly inhibited FGFR phosphorylation as well as mTORC1, signal transducer and activator of transcription 3, and MAPK activation (i.e., phosphorylation). Moreover, AZD4547 pretreatment significantly inhibited UVB-induced epidermal hyperplasia and hyperproliferation and reduced the infiltration of mast cells and macrophages into the dermis. AZD4547 treatment also significantly inhibited mRNA expression of inflammatory genes in the epidermis. Finally, mice treated topically with AZD4547 before UVB exposure showed decreased cutaneous squamous cell carcinoma incidence and increased survival rate. Collectively, the current data support the hypothesis that inhibition of FGFR in the epidermis may provide a new strategy to prevent and/or treat UVB-induced cutaneous squamous cell carcinoma.

Underestimation of Cutaneous Squamous Cell Carcinoma Incidence, Even in Cancer Registries

Despite cutaneous squamous cell carcinoma (cSCC) being the second most common skin cancer,1 our knowledge of the epidemiologic characteristics of cSCC is suboptimal. Dermatologists see patients with cSCC regularly in clinic, but we do not have high-quality information on the basic cancer statistics that are the bread and butter of oncology research and clinical care. For example, the publicly accessible Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review2 contains 30 tables and 7 figures on incidence and mortality for lung cancer in the United States, with age and sex breakdowns, going back to 1975. However, cSCC is nowhere to be found. In many countries, such as the US, cSCC is not included in cancer registries, which has long been recognized as a barrier to understanding this malignant neoplasm.

376 Estimation of cutaneous squamous cell carcinoma incidence attributable to arsenic in U.S. water supplies

Arsenic in water supplies potentially exposes millions of people to increased disease risk worldwide. Despite strengthened regulation, arsenic concentrations commonly found in U.S. water supplies may increase the incidence of cutaneous squamous cell carcinoma (cSCC). We estimated cSCC incidence attributable to arsenic in water supplies among U.S. non-Hispanic whites, a demographic with disproportionately high skin cancer incidence. We determined the number of people exposed to various concentrations of arsenic in water supplies by analyzing three datasets: urine samples from the National Health and Nutrition Examination Survey (2015–2016), public water supply data from the Environmental Protection Agency (EPA) Six-Year Review 3 (2006–2011), and private well user data from Ayotte et al. (2017). Among 743 representative patients, total arsenic concentrations in urine had a median (interquartile range) of 3.00 μg/l (2.25–4.02). Public water supplies serving 10 million out of 151 million non-Hispanic white users had detectable levels of arsenic. An estimated 1.6 million out of 33 million non-Hispanic white private well users had water arsenic concentrations above 10 μg/l (EPA limit for public water). These data were combined with published odds ratios for cSCC incidence with arsenic exposure, assuming that total arsenic concentrations in urine less than 4.76 μg/l do not affect cSCC risk. Based on urinary arsenic data, 32,512 out of 2,548,845 cSCCs annually in the U.S. are attributable to arsenic in water supplies. This estimate includes 26,228 cSCCs among public water users and 6,284 among private well users. Separately, water supply data suggest that at least 10,361 and 4,380 cSCCs are attributable to arsenic in public water supplies and in private wells, respectively. Overall, up to 1.3% of cSCC incidence in the U.S. may be attributed to arsenic in current water supplies. Thousands of cSCCs may be prevented by further restricting arsenic in U.S. water supplies.

Unlocking the Potential of Immuno-Oncology in Advanced Cutaneous Squamous Cell Carcinoma: Role of Checkpoint Blockade

Dr Robert welcomed the delegates to the symposium and outlined the agenda for the meeting, before presenting the first session on understanding cutaneous squamous cell carcinoma (CSCC). The rising incidence of CSCC presents a major challenge for healthcare systems and the frequency and impact of progression to advanced disease is underestimated. The diverse range and potential complications of CSCC lesions require a multidisciplinary approach, in which dermatologists play an important role. The message that CSCC remains a disease of high unmet need was echoed by Dr Peris, who presented on existing treatment approaches for the management of advanced CSCC. In the absence of an established management pathway for patients with locally advanced or metastatic disease, clinicians must rely on limited or anecdotal evidence to inform treatment decisions. Conventional chemotherapy and targeted therapies produce variable responses that are often short-lived, demonstrating a need for more effective and tolerable systemic treatments. Guidelines recognise these limitations and do not make any firm recommendations for the treatment of advanced CSCC. The importance of a multidisciplinary approach was underlined by Dr Migden’s presentation on future novel therapeutic strategies in CSCC. Immunotherapy is an exciting frontier that is becoming increasingly relevant to many specialists, including dermatologists, with several ongoing trials of immune checkpoint inhibitors in patients with advanced CSCC. A strong rationale exists for immunotherapy in these patients and the current evidence base supports the use of immune checkpoint blockade as an alternative to cytotoxic chemotherapy and targeted agents. Dr Migden concluded the symposium with an interactive presentation of five case studies of successful checkpoint inhibitor treatment of locally advanced CSCC, emphasising the key role of dermatologists in a multidisciplinary team approach.

Unlocking the Potential of Immuno-Oncology in Advanced Cutaneous Squamous Cell Carcinoma: Role of Checkpoint Blockade

Dr Robert welcomed the delegates to the symposium and outlined the agenda for the meeting, before presenting the first session on understanding cutaneous squamous cell carcinoma (CSCC). The rising incidence of CSCC presents a major challenge for healthcare systems and the frequency and impact of progression to advanced disease is underestimated. The diverse range and potential complications of CSCC lesions require a multidisciplinary approach, in which dermatologists play an important role. The message that CSCC remains a disease of high unmet need was echoed by Dr Peris, who presented on existing treatment approaches for the management of advanced CSCC. In the absence of an established management pathway for patients with locally advanced or metastatic disease, clinicians must rely on limited or anecdotal evidence to inform treatment decisions. Conventional chemotherapy and targeted therapies produce variable responses that are often short-lived, demonstrating a need for more effective and tolerable systemic treatments. Guidelines recognise these limitations and do not make any firm recommendations for the treatment of advanced CSCC. The importance of a multidisciplinary approach was underlined by Dr Migden’s presentation on future novel therapeutic strategies in CSCC. Immunotherapy is an exciting frontier that is becoming increasingly relevant to many specialists, including dermatologists, with several ongoing trials of immune checkpoint inhibitors in patients with advanced CSCC. A strong rationale exists for immunotherapy in these patients and the current evidence base supports the use of immune checkpoint blockade as an alternative to cytotoxic chemotherapy and targeted agents. Dr Migden concluded the symposium with an interactive presentation of five case studies of successful checkpoint inhibitor treatment of locally advanced CSCC, emphasising the key role of dermatologists in a multidisciplinary team approach.

Combined BRAF and MEK Inhibition with Vemurafenib and Cobimetinib for Patients with Advanced Melanoma

Acquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma, treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related to BRAF inhibitor-induced activation of the MAPK-pathway. Combined BRAF and MEK inhibition is the standard of care in patients with advanced BRAF-mutant melanoma.

Invasive cutaneous squamous cell carcinoma incidence in US health care workers.

Little data on cutaneous squamous cell carcinoma (SCC) epidemiology within the United States are currently available. Prior studies have focused on populations outside of the United States or been limited to regions within the US. In this study, prospective data were collected via biennial questionnaires from a total of 261,609 participants, which included women in the Nurses' Health Study (NHS, 1976-2008) and Nurses' Health Study II (NHS II, 1989-2009), and men in the Health Professionals Follow-Up Study (HPFS, 1986-2008). History of physician-diagnosed invasive SCC was confirmed by pathology record review. Over the entire follow-up period for each cohort, there were 1,265 invasive SCC cases per 100,000 persons in the NHS cohort, 389 cases per 100,000 persons in NHS II, and 2,154 cases per 100,000 persons in HPFS. An 18-year follow-up of participants in these cohorts revealed increasing invasive SCC incidence rates over time, with rates for men being consistently higher than those for women. In women, a larger proportion of invasive SCC lesions occurred on the lower extremities as compared to men (21 % in NHS vs. 6 % in HPFS, p < 0.0001; 14 % in NHS II vs. 6 % in HPFS, p < 0.0001), while in men, a larger proportion occurred on the head/neck (43 % in NHS vs. 60 % in HPFS, p < 0.0001; 48 % in NHS II vs. 60 % in HPFS, p < 0.0001). In summary, invasive SCC incidence rates among US men have been greater than those for women with distinct sites of common occurrence between men and women.

Cutaneous squamous cell carcinoma: Estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012

It is estimated that over 700,000 new cases of cutaneous squamous cell carcinoma (CSCC) are diagnosed annually in the United States. However, CSCC has been excluded from national cancer registries. Thus the precise incidence of CSCC, along with metastases and deaths resulting from it, is unknown. We sought to estimate the 2012 incidence of invasive (non-in situ) CSCC and the number of nodal metastases and deaths arising from it in the US white population. US studies reporting incidence of CSCC, or the number of nodal metastases or deaths arising from it, were reviewed. Linear regression was used to estimate current CSCC incidence based on available incidence data adjusting for higher reported incidences in southern versus northern/central United States. Reported risks of nodal metastases and death from CSCC were averaged. Averages were used to estimate current metastasis and death rates based on incidence estimates. The number of estimated CSCC deaths was compared against deaths from other cancers. It is estimated that 186,157 to 419,543 whites were given a diagnosis of CSCC, 5604 to 12,572 developed nodal metastasis, and 3932 to 8791 died from CSCC in the United States in 2012. The estimates of the 2012 incidence, nodal metastasis, and death from invasive CSCC are based on previous estimates of incidence and outcomes of CSCC. CSCC is an underrecognized health issue. In the central and southern United States, deaths from CSCC may be as common as deaths from renal and oropharyngeal carcinomas, and melanoma. Population-based studies reporting CSCC incidence and outcomes are required to verify these estimates.

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.)

Eruptive Keratoacanthoma-Type Squamous Cell Carcinomas in Patients Taking Sorafenib for the Treatment of Solid Tumors

Protein kinases (PKs) are indispensable for most cellular processes, and deregulation of PKs can lead to activation of oncogenic and anti-apoptotic pathways and immune dysregulation. To report the development of keratoacanthoma (KA)-type squamous cell carcinomas (SCCs) in patients treated with the multikinase inhibitor sorafenib for the treatment of solid tumors, to present the possible mechanisms for induction of these SCCs, and to discuss the implications for discontinuation of therapy and possible cotherapies to decrease this side effect. Fifteen patients taking the multikinase inhibitor sorafenib for the treatment of solid tumors who developed multiple KA-type SCCs, which continued to develop while the patients were undergoing therapy but stopped with discontinuation of sorafenib. This report is limited because it is a retrospective study that included only patients who developed multiple KA-type SCCs. Development of cutaneous SCCs appears to be a side effect limited to sorafenib, a multikinase inhibitor that inhibits not only multiple tyrosine kinases (TKs), but also the serine-threonine kinase Raf. The incidence of cutaneous SCCs does not appear greater with multikinase inhibitors that inhibit only TKs.

No Evidence for Increased Risk of Cutaneous Squamous Cell Carcinoma in Patients With Rheumatoid Arthritis Receiving Etanercept for Up to 5 Years

To determine the incidence of cutaneous squamous cell carcinoma (SCC) in patients with rheumatoid arthritis receiving etanercept, a tumor necrosis factor antagonist, for up to 5 years. An etanercept clinical trials' database and an etanercept postmarketing surveillance database were retrospectively analyzed for the incidence of SCC. Patients enrolled in clinical trials of etanercept were from private and institutional practices. The postmarketing database comprised reports from postmarketing trials and solicited and spontaneous reports. Patients A total of 1442 patients with rheumatoid arthritis with 4257 patient-years of etanercept exposure (median exposure, 3.7 years) are included in the clinical trials' database. More than 125,000 patients with more than 250,000 patient-years of etanercept exposure are included in the etanercept postmarketing database. Interventions Most patients enrolled in clinical trials of etanercept received a dosage of 25 mg of etanercept subcutaneously twice weekly for most of the time they received etanercept therapy. Only 4 cases of SCC were observed in the etanercept clinical trials' database, an incidence that compares favorably with the expected incidences based on general population data from Arizona (13.1) and Minnesota (5.9). Similarly, few cases of SCC (1 per 10,000 patient-years) have been reported during postmarketing surveillance of etanercept therapy. In patients with rheumatoid arthritis, etanercept use of up to 5 years does not seem to be associated with an increase in the incidence of cutaneous SCC.

PUVA and cancer risk: the Swedish follow-up study.

There is concern about the long-term carcinogenic effects of psoralen and ultraviolet A radiation (PUVA) for treatment of skin disorders. Many authors have found an increased risk for cutaneous squamous cell carcinoma (SCC). Except in anecdotal reports, malignant melanoma had not been observed in patients treated with PUVA until recently. In the U.S.A., a 16-centre prospective study of 1380 patients showed for the first time that there might also be an increased risk for malignant melanoma in patients treated with high cumulative dosages of PUVA. We have therefore followed up the Swedish PUVA cohort until 1994. This cohort had previously been followed up until 1985. Information from 4799 Swedish patients (2343 men, 2456 women) who had received PUVA between 1974 and 1985 was linked to the compulsory Swedish Cancer Registry in order to identify individuals with cancer. The average follow-up period was 15.9 years for men and 16.2 for women. We did not find any increased risk for malignant melanoma in our total cohort of 4799 patients treated with PUVA or in a subcohort comprising 1867 patients followed for 15-21 years. For cutaneous SCC there was an increase in the risk: the relative risk was 5.6 (95% confidence interval, CI 4. 4-7.1) for men and 3.6 (95% CI 2.1-5.8) for women. Significant (P < 0.05) increases were also found in the incidence of respiratory cancer in men and women and of kidney cancer in women. In conclusion, we did not find any increased risk for malignant melanoma in our patients treated with high doses of PUVA and followed up for a long time. We confirm previous reports of an increase in the incidence of cutaneous SCC in patients treated with PUVA, and recommend that patients should be carefully selected for PUVA and rigorously followed up.