JAMA Dermatology

<jats:sec id="ab-doi240070-4"><jats:title>Importance</jats:title><jats:p>Therapies for individual keratinocyte carcinomas (KCs) do not prevent the onset of new KCs in a field of sun damage, and therefore the KC burden remains unchanged.</jats:p></jats:sec><jats:sec id="ab-doi240070-5"><jats:title>Objective</jats:title><jats:p>To investigate the association of immune checkpoint inhibitors (ICIs) with changes in field cancerization evaluated by the number of actinic keratoses (AKs) and KCs at baseline compared with 12 months after starting ICI therapy.</jats:p></jats:sec><jats:sec id="ab-doi240070-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This prospective cohort study was performed at the outpatient oncology clinic of a single tertiary public hospital in Brisbane, Australia, from April 1, 2022, to November 30, 2023. Consecutive immunocompetent adults starting therapy with an inhibitor for programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PDL-1) for any active cancer, with a planned treatment duration of at least 6 months, and who exhibited clinical AKs on their forearms were eligible. Those with immunosuppression, concurrent chemotherapy or radiotherapy, or recent topical fluorouracil use were excluded.</jats:p></jats:sec><jats:sec id="ab-doi240070-7"><jats:title>Exposures</jats:title><jats:p>Intravenous ICI therapy, either PD-1 or PDL-1 inhibitors with or without a cytotoxic T-lymphocyte–associated protein 4 inhibitor, with therapy duration determined by the treating oncologist.</jats:p></jats:sec><jats:sec id="ab-doi240070-8"><jats:title>Main Outcomes and Measures</jats:title><jats:p>Clinical AKs were counted and photographed before and 3, 6, and 12 months after starting ICI therapy. KC numbers were evaluated based on histopathology reports of all skin lesions excised 12 months before and after starting ICI therapy. Participants’ medical history, primary cancer tumor response using Response Evaluation Criteria in Solid Tumors, and adverse events were recorded.</jats:p></jats:sec><jats:sec id="ab-doi240070-9"><jats:title>Results</jats:title><jats:p>A total of 23 participants were recruited, of whom 17 (73.9%) were male, with a mean (SD) age of 69.7 (9.6) years. No participants withdrew; however, 4 died during the study due to disease progression. The mean (SD) AK number significantly decreased from 47.2 (33.8) at baseline to 14.3 (12.0) at 12 months (<jats:italic>P</jats:italic> &amp;amp;lt; .001). Younger patients (8 of 12 [66.7%] vs 4 of 12 [33.3%]; <jats:italic>P</jats:italic> = .007) and those with a history of blistering sunburn (12 of 12 [100%] vs 0; <jats:italic>P</jats:italic> = .005) were more likely to reduce their AK numbers by 65% or greater. KC total numbers decreased from 42 in the 12 months before starting ICI therapy to 17 in the 12 months after. The number of cutaneous squamous cell carcinomas decreased from 16 to 5 in the same period.</jats:p></jats:sec><jats:sec id="ab-doi240070-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>This pilot cohort study found that ICIs used for any cancer were associated with a significant reduction of AKs, suggesting potential as an immunopreventive strategy for high-risk individuals. Given the known effects of other chemopreventive agents on KCs, further investigation into ICIs managing field cancerization is required, especially considering toxicity and cost.</jats:p></jats:sec>

The incidence and multiplicity rates of keratinocyte cancers in Australia.

Med J Aust

The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma.

Dermatol Surg

The risk of progression to invasive disease.

J Am Acad Dermatol

From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma.

J Clin Invest

Field cancerization: definition, epidemiology, risk factors, and outcomes.

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

J Eur Acad Dermatol Venereol

Epidermal mutation accumulation in photodamaged skin is associated with skin cancer burden and can be targeted through ablative therapy.

Sci Adv

Comparative genomics provides etiologic and biological insight into melanoma subtypes.

Cancer Discov

Actinic keratosis with atypical basal cells (AK I) is the most common lesion associated with invasive squamous cell carcinoma of the skin.

Immune checkpoint inhibitors in cancer therapy.

Curr Oncol

Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma.

N Engl J Med

Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study.

Lancet Oncol

PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma.

Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial.

Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing.

J Immunother Cancer

Immune checkpoint inhibitor therapy for advanced cutaneous squamous cell carcinoma in Australia: a retrospective real world cohort study.

Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629).

J Clin Oncol

New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1).

Eur J Cancer

Chemoprevention of cutaneous squamous cell carcinoma and its precursors in solid organ transplant recipients using topical sirolimus: a randomized, double-blind, placebo-controlled pilot trial.

Risk of invasive cutaneous squamous cell carcinoma after different treatments for actinic keratosis: a secondary analysis of a randomized clinical trial.

JAMA Dermatol

Randomized trial of four treatment approaches for actinic keratosis.

Randomized controlled trial of acitretin versus placebo in patients at high-risk for basal cell or squamous cell carcinoma of the skin (North Central Cancer Treatment Group Study 969251).

Cancer

A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention.

Evaluation of the use of capecitabine for the treatment and prevention of actinic keratoses, squamous cell carcinoma, and basal cell carcinoma: a systematic review.

Multinational analysis of estimated health care costs related to extended-interval fixed dosing of checkpoint inhibitors.

JAMA Netw Open

Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin—a case-control study.

BMC Cancer

JCO Precis Oncol

Immune-checkpoint inhibitors: long-term implications of toxicity.

Nat Rev Clin Oncol

Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy.

Am J Clin Dermatol

Cutaneous manifestations associated with immune checkpoint inhibitors.

Front Immunol

Artificial white light vs daylight photodynamic therapy for actinic keratoses: a randomized clinical trial.

Therapies for individual keratinocyte carcinomas (KCs) do not prevent the onset of new KCs in a field of sun damage, and therefore the KC burden remains unchanged.
To investigate the association of immune checkpoint inhibitors (ICIs) with changes in field cancerization evaluated by the number of actinic keratoses (AKs) and KCs at baseline compared with 12 months after starting ICI therapy.
This prospective cohort study was performed at the outpatient oncology clinic of a single tertiary public hospital in Brisbane, Australia, from April 1, 2022, to November 30, 2023. Consecutive immunocompetent adults starting therapy with an inhibitor for programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PDL-1) for any active cancer, with a planned treatment duration of at least 6 months, and who exhibited clinical AKs on their forearms were eligible. Those with immunosuppression, concurrent chemotherapy or radiotherapy, or recent topical fluorouracil use were excluded.
Intravenous ICI therapy, either PD-1 or PDL-1 inhibitors with or without a cytotoxic T-lymphocyte-associated protein 4 inhibitor, with therapy duration determined by the treating oncologist.
Clinical AKs were counted and photographed before and 3, 6, and 12 months after starting ICI therapy. KC numbers were evaluated based on histopathology reports of all skin lesions excised 12 months before and after starting ICI therapy. Participants' medical history, primary cancer tumor response using Response Evaluation Criteria in Solid Tumors, and adverse events were recorded.
A total of 23 participants were recruited, of whom 17 (73.9%) were male, with a mean (SD) age of 69.7 (9.6) years. No participants withdrew; however, 4 died during the study due to disease progression. The mean (SD) AK number significantly decreased from 47.2 (33.8) at baseline to 14.3 (12.0) at 12 months (P < .001). Younger patients (8 of 12 [66.7%] vs 4 of 12 [33.3%]; P = .007) and those with a history of blistering sunburn (12 of 12 [100%] vs 0; P = .005) were more likely to reduce their AK numbers by 65% or greater. KC total numbers decreased from 42 in the 12 months before starting ICI therapy to 17 in the 12 months after. The number of cutaneous squamous cell carcinomas decreased from 16 to 5 in the same period.
This pilot cohort study found that ICIs used for any cancer were associated with a significant reduction of AKs, suggesting potential as an immunopreventive strategy for high-risk individuals. Given the known effects of other chemopreventive agents on KCs, further investigation into ICIs managing field cancerization is required, especially considering toxicity and cost.

Immune Checkpoint Inhibitors in Field Cancerization and Keratinocyte Cancer Prevention.

Immune Checkpoint Inhibitors in Field Cancerization and Keratinocyte Cancer Prevention

Papers