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Sentinel Lymph Node Biopsy and Age-Related Mutations: Therapeutic and Predictive Implications in Melanoma


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Findings from a study among patients with melanoma randomly assigned to observation following removal of a positive sentinel lymph node “strongly support the therapeutic effect of the sentinel lymph node biopsy in providing long-term regional nodal disease control in the large majority of patients,” the study’s lead author, Jessica Crystal, MD, of Cedars-Sinai Medical Center, Los Angeles, reported at the 2020 Society of Surgical Oncology (SSO) International Conference on Surgical Cancer Care.1

Jessica Crystal, MD

Jessica Crystal, MD

The study involved 823 patients from the observation arm of the second Multicenter Selective Lymphadenectomy Trial (MSLT-II). The median age of patients was 54.6 years, and 58.2% were male. “Most tumors were of intermediate depth, with a mean Breslow depth of 2.81 mm,” Dr. Crystal said. “The majority of the patients had a small tumor burden,” Dr. Crystal noted.

“The majority of recurrences occurred by year 3,” when the recurrence-free survival rate was 83.2%, Dr. Crystal reported. “At 10 years, the recurrence-free survival only dropped to 82%. There were no additional recurrences after 7 years,” she added. The MSLT-II study “predated the approval of modern adjuvant therapies,” Dr. Crystal noted, so “rates of invasive nodal recurrence may be even lower now that those therapies are more commonly used.”

On multivariate analysis, factors independently associated with basin control were younger age (≥ 50), thinner primary, axillary basin, and smaller sentinel lymph node metastasis. These factors, “if validated, may help guide clinical care in the future,” Dr. Crystal predicted.

The authors concluded: “Sentinel lymph node biopsy provides long-term clearance of the affected node basin in most cases of metastatic melanoma, even with multiple risk factors for recurrence. The procedure should therefore be regarded as therapeutic, in addition to its value as a staging procedure.”

More Precise Risk Stratification

To maximize the therapeutic benefit of adjuvant therapies for melanoma, “we need more precise risk-stratification tools,” general surgery resident Norma Farrow, MD, MHS, of Duke University, Durham, North Carolina, told participants of the melanoma forum.2 “One potential way to do this is to look more closely at the sentinel nodes themselves. As the interface between the tumor and the immune system, immune-mediated processes in the sentinel nodes determine whether disease is controlled or continues to spread.”

Norma Farrow, MD, MHS

Norma Farrow, MD, MHS

Dr. Farrow was lead investigator of a study to characterize sentinel lymph node immune signatures in patients with melanoma and to use those signatures to develop a risk-stratification model for recurrence. The investigators identified a cohort of patients with melanoma treated at Duke with excision and sentinel lymph node biopsy between 2001 and 2012. NanoString’s nCounter RNA-based technology and the nCounter Pancancer Immune Profiling Panel were used to analyze the expression of 730 genes known to be involved in immune and tumor signaling. They generated 60 gene-expression profiles, 31 for patients with positive lymph nodes and 29 for those with negative lymph nodes. These profiles were used to identify immune genes differentially expressed in the sentinel lymph nodes of patients who later had recurrences, and to develop a multivariate Cox regression model predictive of recurrence.

Patients with positive lymph nodes had a thicker Breslow tumor depth, median 2.5 mm vs 1.4 mm, than did those with negative lymph nodes; of those with positive lymph nodes, 67.7% had a single positive lymph node and 90.3% underwent immediate completion lymph node dissection. “The time period of this study was prior to the introduction of modern adjuvant therapies, and the majority of these patients who had positive sentinel nodes underwent complete lymph node dissection without receiving adjuvant therapy,” Dr. Farrow pointed out.

“At a median follow-up of 6.5 years, almost half of the patients with positive nodes developed recurrence, and approximately one-third had died. In contrast, 20% of those with negative nodes went on to develop recurrence, and 10% had died,” Dr. Farrow reported.

The final model developed by the investigators incorporated the expression of 12 genes, some with increased and some with decreased expression. Independent of sentinel node status, individual patient risk scores calculated using the model were able to accurately stratify patients into cohorts at high or low risk for disease recurrence. “None of the patients characterized as having a low-risk score by our model developed recurrence during our follow-up period.”

“It appears that an immune-suppressive sentinel lymph node microenvironment may be associated with a higher risk of recurrence,” Dr. Farrow concluded. The model “will need to be validated prior to any clinical use,” she noted, but “in the future, gene-expression profiling may be used to better predict patients at high risk for recurrence.”

Targetable Mutations

Younger patients with melanoma are more likely to have BRAF mutations and older patients are more likely to have NRAS mutations, and these age-related variations in mutational frequencies “demonstrate targetable alterations for potential personalized therapy,” reported Juan Santamaria-Barria, MD, of the John Wayne Cancer Institute, Los Angeles.3

The investigators analyzed samples from the Genomics Evidence Neoplasia Information Exchange Database (GENIE) maintained by the American Association for Cancer Research. In a cohort of 1,194 patients, “we found a common set of 30 genes sequenced in full across all their exons,” Dr. Santamaria-Barria said. “The mutational load for these 30 genes increased with age,” he added, with a mean 2.39 mutations per sample in patients younger than 40 vs 3.67 in patients older than 60.

Juan Santamaria-Barria, MD

Juan Santamaria-Barria, MD

“The top five mutations were BRAF, NRAS, TP53, APC, and KDR,” Dr. Santamaria-Barria said. Adolescents and adults younger than 40 had the highest frequency of BRAF mutations, 59% vs 38% for those older than 60, who had the highest level of NRAS mutations, 33% vs 17% for those younger than 40. “BRAF and NRAS were mostly mutually exclusive,” Dr. Santamaria-Barria said. “However, this mutual exclusivity appeared to decrease with age.”

The investigators used the Precision Oncology Knowledge Base, and “BRAF was the only mutated gene with category 1 level of evidence for targeted therapies in melanoma. The U.S. Food and Drug Administration (FDA) has recognized it as a biomarker predictive of response to an FDA-approved drug,” added Dr. Santamaria-Barria. “NRAS was the only gene with category 3A level of evidence, which is compelling clinical evidence predictive of a response.” 

DISCLOSURE: Drs. Crystal, Farrow, and Santamaria-Barria reported no conflicts of interest.

REFERENCES

1. Crystal J, Cochran J, Elashoff DE, et al: Sentinel lymph node biopsy in melanoma is therapeutic. 2020 SSO International Conference on Surgical Cancer Care. Abstract 76. Presented August 17, 2020.

2. Farrow N, Holl EK, Gao J, et al: An immune tolerant sentinel node microenvironment predicts recurrence in melanoma. 2020 SSO International Conference on Surgical Cancer Care. Abstract 77. Presented August 17, 2020.

3. Santamaria-Barria JA, Salomon MP, Matsuba C, et al: Age-related mutational differences in melanoma. 2020 SSO International Conference on Surgical Cancer Care. Abstract 81. Presented August 17, 2020.


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