Driver Mutations, Tumor Diameter Prognostic in Tumors of the Eye

Along with gene expression signatures from a 15-loci panel, tumor diameter and specific driver mutations predict metastasis risk and survival among patients with uveal melanoma, according to a pair of studies published in JAMA Ophthalmology.

Uveal melanoma is the most common primary tumor of the eye and tends to metastasize to the liver. Brachytherapy is a common first-line treatment, but surgical removal of the eye is often performed after disease progression.

Melanomas of the eye are genetically distinct from cutaneous melanomas (skin cancers). In a cohort study of 81 patients, three tumor-driver mutations-BAP1, SF3B1, and EIF1AX-were associated with tumor progression and metastasis, the researchers reported.

The three mutations “are clearly associated with metastatic risk,” said J. William Harbour, MD, of the University of Miami’s Sylvester Comprehensive Cancer Center, in a news release.

The three mutations were “almost mutually exclusive with each other,” the authors reported.

BAP1 is a tumor suppressor gene. Loss-of-function mutations release the brakes on tumor growth. In multivariate analyses, BAP1 mutations were most strongly associated with metastasis (relative risk [RR], 10.6 [95% CI, 3.4-33.5]; P < .001) and melanoma-specific mortality (RR, 9.0 [95% CI, 2.8-29.2]; P < .001).

In addition to testing for these three driver mutations, the authors also determined mutation status for GNA11 and GNAQ genes, which are also common in uveal melanomas. Despite the fact that these mutations were common, with each occurring in 44% of study cohort patients, they were not prognostic, however.

The authors also employed a widely used 15-loci gene expression profile (GEP) classification test, which orders eye tumors as class 1 or class 2. Whereas BAP1 was “almost always” associated with class 2 eye tumors, SF3B1 and EIF1AX were associated with class 1 tumors, Dr. Harbour noted.

Unlike tumors carrying SF3B1 mutations, tumors with BAP1 mutations are not promising candidates for checkpoint-inhibitor immunotherapies, the team noted.

The size of eye tumors is also prognostic, the team reported in a separate study, which was also published in JAMA Ophthalmology. The association between tumor size and prognosis was modulated by results from the GEP panel.

Tumors 12 mm or larger were associated with a 70% five-year risk of metastasis, the researchers found-whereas tumors smaller than 12 mm carry only a 10% metastasis risk over the same period of time.

In their retrospective study, involving a primary cohort of 339 patients with uveal melanoma and a validation cohort of 241 patients, the researchers found that the largest basal tumor diameter (LBD) of tumors with a GEP classification of 2 exhibited a “modest but significant” association with progression-free survival (PFS; odds ratio [OR], 1.13 [95% CI, 1.04-1.24]; P = .005), they reported.

“Gene expression profile classification remains the strongest indicator of metastatic risk in uveal melanoma, but a smaller tumor diameter provides additional prognostic information that could have important implications for patient counseling, primary tumor treatment, clinical trial enrollment, metastatic surveillance, and adjuvant therapy,” the researchers concluded.

“The diameter study suggests we should treat class 2 tumors when they’re smaller,” said Dr. Harbour. “We’re gearing up to validate these findings in a large, prospective multicenter trial.”