Genetic Profiling Identifies High-Risk Cutaneous SCC Tumors

A distinct gene expression was identified in T2a cutaneous squamous cell carcinoma (cSCC) associated with poor outcomes, according to new findings.

Researchers found that 12 genes were significantly upregulated in tumors with poor outcomes, and four novel genes were downregulated in patients with poor outcomes. Some of these same genes are upregulated or downregulated in other cancer types.

"We hope our findings will have implications in clinical practice, as elucidation of these prognostic biomarkers may identify higher-risk low-stage tumors and patients who may benefit from closer surveillance, modified workup, and more aggressive treatment," said lead author, Jaclyn R. Himeles, MD, a dermatology resident at New York University Grossman School of Medicine, New York. "Understanding gene expression profiling may help provide identification of novel therapeutic targets."

"While validation experiments are ongoing, the identification of biomarkers of poor prognosis has the potential for risk stratifying T2a tumors, allowing for closer surveillance of higher-risk tumors," she added.

The findings were presented at the 2023 annual meeting of the American College of Mohs Surgery.

SCCs are among the most prevalent human cancers, and cSCC is the second most common cancer in the US. Although most patients have good outcomes, a subset will do poorly, explained Himeles.

Tumors are classified on the basis of the number of high-risk factors, and although most poor outcomes occur in high-stage tumors, one quarter occur with low-stage tumors. About 26% of patients develop nodal metastases, and recognizing variations in genomic expression between T2a tumors with good and poor outcomes may help improve risk assessment and prognosis.

"However, our current understanding of immunophenotypic prognostic factors remains limited," said Himeles. "Thus, we sought to define differential gene expression among T2a cSCC with poor outcomes compared to those with good outcomes and normal skin."

Study Details

Himeles and colleagues conducted a translational study at a single center and used NanoString technology to define differential gene expression among different groups of patients with cSCC. They also used retrospective chart review to link patterns of differentially expressed genes with clinical outcome.

In NanoString, sequence-specific mRNA probes are used to directly detect gene expression and return counts of each target molecule. RNA expression of 774 genes was assessed with this technology, using formalin-fixed, paraffin-embedded primary tumors, which included primary T2a poor outcome tumors and T2a good outcome tumors, and normal skin. The investigators defined poor outcome as local recurrence, in-transit metastases, nodal metastases, distant metastases, or disease-specific death.

A total of 27 T2a tumors were assessed in 27 patients, along with five normal skin samples. The average age of the patients in the cohort was 76 years, and a majority of the tumors were located on the head and neck. Medium follow-up was 43 months.

Within this group, 14 T2a tumors with poor outcomes were identified, with most being located on the head and neck; 71% of the patients were immunosuppressed. All patients had a tumor diameter > 2 cm, and the medium follow-up was 44 months.

In the subgroup with poor outcomes, nine patients had local recurrences, one had nodal metastasis, one had in-transit metastasis, and three had distant metastases. The researchers identified 12 genes that were significantly upregulated (P < .05) among tumors with poor outcomes: STC1, CCL20, CXCL6, KLRB1, TRAT1, TNFAIP6, WNT11, PALMD, IL7R, VCAM1, TNFAIP3, and DAB2. Additionally, four novel genes were downregulated in patients with poor outcomes: LILRA3, SLC11A1, IL17RE, and DDB2.

After transplant patients were excluded from the analysis, 11 genes were found to be upregulated in poor outcome tumors (STC1, CCL20, CXCL6, TNFAIP6, LGR5, IL7R, KLRB1, ITGA2, TNFAIP3, CD45RB, and RIPK2), and 14 genes were downregulated (HRAS, LILRA3, TGFB1, MACRO, APLNR, HLA-F, APOL6, BNIP3, DDB2, PIK3R2, CHUK, GLS, GALNT2, and SGK1).

The researchers also compared good-outcome and poor-outcome tumors vs normal tissue and identified 61 upregulated genes in poor-outcome tumors and 33 upregulated genes in good-outcome tumors. They also found that 221 genes were downregulated in poor-outcome tumors and nine were downregulated in good-outcome tumors.

"This suggests that tumors with good outcomes are more closely related to normal skin, as opposed to tumors with poor outcomes," explained Himeles. "Understanding gene expression profiling may help provide identification of novel therapeutic targets."

Encouraging but Preliminary

Commenting on the abstract, Anthony J. Olszanski, RPh, MD, associate professor in the Department of Hematology/Oncology of Fox Chase Cancer Center, Philadelphia, Pennsylvania, noted that event though SCC of the skin is one of the most common cancers and patients with high-risk features more commonly develop recurrences, including lymph node metastasis and death due to disease, optimal stratification of patients is lacking.

"Gene expression profiling may be able to assist in determining which patients are more likely to have a poor outcome," he said. "The results presented by Dr Himeles are encouraging in preliminarily identifying gene expression patterns which may assist in prognostication."

"Ultimately, use of this technology requires validation and, ultimately, direct proof that early identification of at-risk patients provides improved clinical outcomes," he cautioned. "It should be noted that without evidence of direct patient benefit, indiscriminate use of genomic testing can be associated with increased anxiety for patients and increased cost-burden."

No external funding of the study was reported. Himeles had no disclosures. Olszanski has disclosed financial support from Merck and BMS for advisory boards. Merck makes pembrolizumab and BMS makes nivolumab, and these drugs have some role in these diseases.

American College of Mohs Surgery (ACMS) 2023 Annual Meeting. Presented May 5.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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Genetic Profiling Identifies High-Risk Tumors in Cutaneous Squamous Cell Carcinoma

Study Details

Encouraging but Preliminary

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