Assessment of Frailty Can Guide Decision Making for Utilization of Sentinel Lymph Node Biopsy in Patients with Thick Melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is often omitted in selected patients with advanced primary melanoma, although the justification/criteria for omission have been debated. OBJECTIVE: We sought to determine whether assessment of frailty could serve as an objective marker to guide selection for SLNB in patients with advanced primary melanoma. METHODS: Patients presenting with clinical stage IIC (ulcerated, > 4 mm Breslow thickness) cutaneous melanoma from January 1999 through June 2019 were included. Frailty was assessed using the Memorial Sloan Kettering Frailty Index (MSK FI), a composite score of functional status and medical comorbidities. Five-year melanoma-specific survival (MSS) and overall survival (OS) were estimated using Cox regression, and predictors of OS were identified using competing risk models. RESULTS: MSS did not differ between patients who did (n = 451) or did not undergo SLNB (n = 179) [63.2% vs. 65.0%, p = 0.14]; however, omission of SLNB was associated with decreased 5-year OS (29% vs. 44%, p < 0.001). In a multivariable competing risk model, selection for SLNB omission was an independent predictor of death from non-melanoma causes (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.3, p < 0.001). After incorporation of the MSK FI score into the multivariable model in this subset, MSK FI (HR 2.4, 95% CI 1.5-4.1, p < 0.001), but not SLNB omission, was an independent predictor of poorer OS. CONCLUSION: We observed worse OS in patients with thick melanoma selected not to undergo SLNB, which was attributed to death due to non-melanoma causes. Formal assessment of frailty may provide an objective prognostic measure to guide selective use of SLNB in these patients.

Adjuvant immunotherapy for melanoma.

Surgical resection is the treatment for early cutaneous melanoma and is often curative. Some patients, however, will subsequently relapse. High-risk features in the primary tumor and regional lymph node metastasis highlight patient subsets that are at increased risk for recurrent disease. Immunotherapy in the form of checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have been shown to improve recurrence-free survival for node-positive melanoma in the adjuvant setting and will be the focus of this review.

The Landmark Series: MSLT-1, MSLT-2 and DeCOG (Management of Lymph Nodes).

Management of regional lymph nodes in patients with melanoma has evolved significantly in recent years. The value of nodal intervention, long utilized for its perceived therapeutic benefit, has now shifted to that of a critical prognostic procedure used to guide clinical decision making. This review focuses on the three landmark, randomized controlled trials evaluating the role of surgery for regional lymph nodes in melanoma: Multicenter Selective Lymphadenectomy Trial I (MSLT-I), German Dermatologic Cooperative Oncology Group-Selective Lymphadenectomy Trial (DeCOG-SLT), and Multicenter Selective Lymphadenectomy Trial II (MSLT-II).

Survival Outcomes After Metastasectomy in Melanoma Patients Categorized by Response to Checkpoint Blockade.

INTRODUCTION: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear. METHODS: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions. RESULTS: Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001). CONCLUSIONS: Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

Indications for the surgical resection of stage IV disease.

Tumor biology and careful patient selection weigh heavily in determining the appropriate role of surgical resection in stage IV melanoma. Historically, surgical resection for highly selected patients with metastatic melanoma was the only treatment modality associated with improved long-term survival and the ability to provide palliation. With the new age of effective systemic therapies, the treatment of metastatic melanoma has become more intricate and future work is needed to better define the role for surgery within the current treatment paradigm.

Correction to: Lymph Node Status in Breast Cancer Does Not Predict Tumor Biology.

In the "Results" section third paragraph, second sentence, there is an error. The corrected sentence is as follows.

Lymph Node Status in Breast Cancer Does Not Predict Tumor Biology.

BACKGROUND/OBJECTIVE: The 21-gene Oncotype DX® Breast Recurrence Score® (RS) assay has been prospectively validated as prognostic and predictive in node-negative, estrogen receptor-positive (ER+)/HER2- breast cancer patients. Less is known about its prognostic role in node-positive breast cancer. We compared RS results among patients with lymph node-negative (N0), micrometastatic (N1mi), and macrometastatic (N+) breast cancer to determine if nodal metastases are associated with more aggressive biology, as determined by RS. METHODS: Overall, 610,350 tumor specimens examined by the Genomic Health laboratory from February 2004 to August 2017 were studied. Histology was classified centrally, while lymph node status was determined locally. RS distribution (low: < 18; intermediate: 18-30; high: ≥ 31) was compared by nodal status. RESULTS: Eighty percent (n = 486,013) of patients were N0, 4% (n = 24,325) were N1mi, 9% (n = 56,100) were N+, and 7% (n = 43,912) had unknown nodal status. Mean RS result was 18, 16.7, 17.3 and 18.9 in the N0, N1mi, N+, and unknown groups, respectively. An RS ≥ 31 was seen in 10% of N0 patients, 7% of N1mi patients, and 8.0% of N+ patients. The likelihood of an RS ≥ 31 in N1mi and N+ patients varied with tumor histology, with only 2% of patients with classic infiltrating lobular cancer having an RS ≥ 31, versus 7-9% of those with ductal carcinoma. CONCLUSIONS: RS distribution among N0, N1mi, and N+ patients is similar, suggesting a spectrum of biology and potential chemotherapy benefit exists among node-negative and node-positive ER+/HER2- breast cancer patients. If RxPONDER does not show a chemotherapy benefit in N+ patients with a low RS result, our findings indicate that substantial numbers of patients could be spared the burden of chemotherapy.

The Prognostic Significance of Sentinel Lymph Node Status for Patients with Thick Melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is recommended for patients with intermediate-thickness melanoma, but the use of SLNB for patients with thick melanoma is debated. This report presents a single-institution study investigating factors predictive of sentinel lymph node (SLN) metastasis and outcome for thick-melanoma patients . METHODS: A retrospective review of a single-institution database from 1997 to 2012 identified 147 patients with thick primary cutaneous melanoma (≥4 mm) who had an SLNB. Clinicopathologic characteristics were correlated with nodal status and outcome. RESULTS: The median age of the patients was 67 years, and 61.9 % of the patients were men. The median tumor thickness was 5.5 mm, and 54 patients (36.7 %) had a positive SLN. Multivariable analysis showed that only tumor thickness significantly predicted SLN metastasis (odds ratio 1.14; 95 % confidence interval (CI) 1.02-1.28; P = 0.02). The overall median follow-up period was 34.6 months. Overall survival (OS) and melanoma-specific survival (MSS) were significantly worse for the positive versus negative-SLN patients. Multivariable analysis showed that age [hazard ratio (HR) 1.04; 95 % CI 1.01-1.07; P = 0.02] and SLN status (HR 2.24; 95 % CI 1.03-4.88; P = 0.04) significantly predicted OS, whereas only SLN status (HR 3.85; 95 % CI 2.13-6.97; P < 0.01) significantly predicted MSS. CONCLUSIONS: Tumor thickness predicts SLN status in thick melanomas. Furthermore, SLN status is prognostic for OS and MSS in thick-melanoma patients, with positive-SLN patients having significantly worse OS and MSS. These findings show that SLNB should be recommended for thick-melanoma patients, particularly because detection of SLN metastasis can identify patients for potential systemic therapy and treatment of nodal disease at a microscopic stage.

The GIST of targeted therapy for malignant melanoma.

The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF(V600E) melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.

Clinical Utility of Melanoma Sentinel Lymph Node Biopsy Nomograms.

BACKGROUND: For patients with melanoma, the decision to perform sentinel lymph node biopsy (SLNB) is based on the estimated risk of lymph node metastasis. We assessed 3 melanoma SLNB risk-prediction models' statistical performance and their ability to improve clinical decision making (clinical utility) on a cohort of melanoma SLNB cases. STUDY DESIGN: Melanoma patients undergoing SLNB at a single center from 2003 to 2021 were identified. The predicted probabilities of sentinel lymph node positivity using the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center (MSK), and Friedman nomograms were calculated. Receiver operating characteristic and calibration curves were generated. Clinical utility was assessed via decision curve analysis, calculating the net SLNBs that could have been avoided had a given model guided selection at different risk thresholds. RESULTS: Of 2,464 melanoma cases that underwent SLNB, 567 (23.0%) had a positive sentinel lymph node. The areas under the receiver operating characteristic curves for the Melanoma Institute of Australia, MSK, and Friedman models were 0.726 (95% CI, 0.702 to 0.750), 0.720 (95% CI, 0.697 to 0.744), and 0.721 (95% CI, 0.699 to 0.744), respectively. For all models, calibration was best at predicted positivity rates below 30%. The MSK model underpredicted risk. At a 10% risk threshold, only the Friedman model would correctly avoid a net of 6.2 SLNBs per 100 patients. The other models did not reduce net avoidable SLNBs at risk thresholds of ≤10%. CONCLUSIONS: The tested nomograms had comparable performance in our cohort. The only model that achieved clinical utility at risk thresholds of ≤10% was the Friedman model.

Prognosis of acral melanoma: a series of 281 patients.

BACKGROUND: Acral melanoma (AM) is an unusual malignancy with poor survival. This study defines a cohort of patients, treated at a single institution, and the factors associated with survival and comparison with nonacral cutaneous melanoma (NACM). METHODS: All patients with AM presenting from 1995 to 2010 were identified from a prospectively maintained database. Analysis of clinicopathologic features of AM associated with disease-specific survival (DSS) was performed. A stratified, stage-matched survival analysis compared the outcome of 281 acral to 843 extremity NACM patients. RESULTS: A total of 281 AM patients (170 volar, 111 subungual) were identified. Pathologic stage (p < 0.001), ulceration (p < 0.001), Breslow thickness (p < 0.001), and a positive sentinel lymph node (p < 0.001) were found to be poor prognostic indicators associated with DSS. In stage-matched analysis, AM had a worse DSS compared with NACM (hazard ratio 1.8; 95 % CI 1.2-2.7; p < 0.01). CONCLUSIONS: This study represents the largest, single-institution series describing the characteristics and outcomes of AM. AM tumors exhibit aggressive histopathologic features associated with a poorer survival outcome. AM patients have an inferior survival than extremity NACM when matched for stage, perhaps reflecting inherent alterations in tumor biology. This warrants further investigation into the differences between acral and cutaneous melanoma.

Melanoma mutagenesis and aberrant cell signaling.

BACKGROUND: Malignant melanoma is the most fatal type of skin cancer. Traditional melanoma classification has been based on histological subtype or anatomical location. However, recent evidence suggests that melanoma comprises a group of diseases characterized by distinct molecular mutations. These mutations affect disease behavior but provide unique opportunities for targeted therapy. METHODS: In this review, several signaling pathways in melanoma are described as well as how mutations of BRAF, NRAS, KIT, GNAQ, and GNA11 genes cause aberrant signaling and malignant transformation. RESULTS: Multiple genes affecting both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway are mutated in melanoma. Melanomas harboring the BRAF V600E mutation have demonstrated sensitivity to both RAF and MAPK/extracellular signal regulated kinase (ERK) inhibitors in vitro and in vivo. In addition, KIT-mutant melanomas, often arising from mucosal, acral, and chronically sun-damaged skin surfaces, have shown clinical response to several inhibitors of the type III transmembrane receptor tyrosine kinase KIT. Uveal melanoma, which often harbors GNAQ or GNA11 mutations, may also be sensitive to MAPK/ERK or protein kinase C/PI3K pathway inhibition. CONCLUSIONS: Emerging knowledge of these molecular alterations has led to clinical advances in patients with melanoma. The study of known mutations and identification of new potential targets must continue in an effort to develop more effective therapies for this disease.

Anal versus rectal melanoma: does site of origin predict outcome?

BACKGROUND: Anatomic site is a predictive factor in subtypes of cutaneous and mucosal melanoma. OBJECTIVE: The aim of this study was to examine the clinical relevance of location of origin of anorectal melanoma as a prognostic factor. DESIGN: With the use of a prospectively maintained database, clinical characteristics, management, and outcomes were compared according to the site of origin. SETTINGS, PATIENTS, INTERVENTIONS: A retrospective review was conducted of patients diagnosed with anorectal melanoma from 1994 to 2010. Tumors were defined as anal, anorectal, or rectal melanoma according to their anatomic relationship to the dentate line. MAIN OUTCOME MEASURES: Clinicopathologic factors were compared by χ2 test. Time-to-event analysis was performed by Kaplan-Meier analysis. RESULTS: Of the 96 patients included (41 with anal melanoma, 32 with anorectal melanoma, 23 with rectal melanoma), patients with rectal and anorectal mucosal melanoma had advanced primary tumors (median Breslow thickness, 12 mm and 8 mm, p = 0.002), whereas anal lesions could be found at earlier depths (median thickness, 6.5 mm). Patients with anal tumors more commonly underwent transanal excision (p < 0.02) and sentinel lymph node biopsy (p = 0.004) versus anorectal and rectal tumors. Patterns of recurrence were also distinct; nearly two-thirds of anorectal and rectal tumors recurred systemically, whereas anal melanoma more often recurred within the lymph nodes first (63%; p < 0.02). Recurrence occurred in 24 (59%) patients with anal tumors, 23 (72%) patients with anorectal tumors, and 16 (70%) patients with rectal tumors. Median overall survival was 22 months for anal melanoma, 28 months for anorectal melanoma, and 27 months for rectal melanoma. Recurrence and survival were not statistically different between the groups. LIMITATIONS: This study is limited by small sample size and its retrospective nature. CONCLUSIONS: This study represents the only series describing the outcomes of anorectal melanoma by anatomic location. Lesions at or proximal to the dentate line present with more advanced disease, possibly related to a delay in diagnosis. Lesions distal to the dentate line more commonly recur within lymph nodes, which may represent differences in nodal drainage. Irrespective of location, the long-term prognosis remains poor for all cases of anorectal melanoma.

Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade.

Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy. Cancer Immunol Res; 6(2); 189-200. ©2018 AACR.