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October 2024
Prospective multicenter evaluation (MERLIN_001 trial) of a clinicopathologic and gene expression profile test to predict sentinel node status in T1-T3 cN0 melanoma
Introduction
Guidelines recommend staging melanoma patients (pts) with sentinel lymph node biopsy (SLNB) for a predicted risk of SLN metastasis ≥10% and considering SLNB for 5-10% risk. A gene expression profile (GEP)-based test that accurately identifies pts with a low risk of SLN metastasis would help refine pt selection for SLNB, but current guidelines advise against using GEP for SLN risk prediction absent prospective trial data. This blinded prospective multicenter study evaluated the performance of a test combining clinicopathologic factors (age, Breslow thickness) with an 8-gene GEP (CP-GEP test) for predicting SLN status in pT1-T3 cN0M0 cutaneous melanoma pts undergoing clinically indicated SLN biopsy.
Methods
The CP-GEP was performed on formalin-fixed, paraffin-embedded tissue from the primary tumor biopsy and results recorded in binary fashion as Low or High Risk. The primary endpoint was negative predictive value (NPV) in Low Risk pts. Preplanned analyses included NPV assessment by T substage and age.
Results
The GEP was successfully performed in 97.4% of samples. 1,686 pts with a successful GEP underwent SLNB (17.6% SLN-positive); 37% were classified as Low Risk by CP-GEP. Among all pts classified as Low Risk, the SLN was positive in 7.1% for an NPV of 92.9% (95% CI 90.6-94.8%). High Risk pts were SLN positive in 23.8%. Most T1b pts (66.6%) were Low Risk, with an NPV of 94.9% (95% CI 91.8%-97.0%); fewer T2a pts were Low Risk (37.6%), with an NPV of 92.7% (95% CI 87.9-95.2%). Test performance was consistent across age subgroups.
Conclusion
In the first prospective multicenter blinded trial of a GEP prediction tool for SLN status, the CP-GEP test reliably identified pts with <10% risk of SLN metastasis, suggesting its potential to more precisely estimate individual pt risk of a SLN metastasis and inform shared decision-making for SLNB.
W. Yu et al. 2024. SMR Conference.
October 2024
CP-GEP Identifies T1a Melanoma Patients At Risk of Sentinel Lymph Node Metastasis
Introduction:
- In melanoma, accurate identification of T1a patients who should consider sentinel lymph node biopsy (SLNB) is important.
NCCN guidelines recommended consideration of SLNB for T1a melanoma patients with adverse features such as age <40 years, lymphovascular invasion, and/or ≥2 mitoses/mm². - This study evaluates the clinical utility of the Merlin Assay (CP-GEP model that uses clinicopathologic and gene expression variables) in stratifying T1a melanoma patients for SLNB referral, including those without adverse features.
Methods:
- This is a retrospective analysis of a cohort of 153 T1a melanoma patients from 11 centers diagnosed between 2007 and 2021 who underwent SLNB at the discretion of the treating surgeon.
- CP-GEP performance was assessed by comparing the SLN positivity rate (pre-test SLN+ rate) in the entire cohort to the post-test SLN+ rates for CP-GEP Low Risk and High Risk patients.
Results:
- For 153 T1a melanoma patients, the overall SLN positivity rate was 3.3%.
- CP-GEP identified 134 patients as Low Risk (88%) with a post-test SLN+ rate of 1.5%. In contrast, CP-GEP identified 19 patients as High Risk (12%) with a post-test SLN+ rate of 15.8%.
- In T1a melanoma patients, CP-GEP achieved an SLNB reduction rate of 87.6% at a NPV of 98.5%.
- In 49 patients with a least one adverse feature, CP-GEP identifies 37 Low Risk patients with a post-test SLN+ rate of 0% (Figure 1).
- In 104 patients without any adverse feature, CP-GEP identifies 7 High Risk patients with a post-test SLN+ rate of 14.3% (Figure 1).
Conclusions:
- Merlin Assay may support in risk stratifying cutaneous melanoma patients with T1a tumors.
- CP-GEP can support referral of T1a for SLNB surgery independent of traditional adverse features.
- CP-GEP can identify patients with T1a melanoma who are at high risk of SLN metastases who otherwise would not be offered an SLNB based on lack of adverse features. On the other hand, CP-GEP may deselect thin melanoma patients with adverse features who are at low risk for nodal metastases.
- In melanoma, accurate identification of T1a patients who should consider sentinel lymph node biopsy (SLNB) is important.
June 2024
9574 -Identification of patients at high risk for relapse using the Merlin Assay (CP-GEP) in an independent cohort of 432 patients with stage I/II melanoma who did not undergo sentinel lymph node biopsy
Background:
Sentinel lymph node biopsy (SLNB) is
the gold standard for nodal assessment in staging
cutaneous melanoma (CM) according to AJCC v8.
80-85% of patients (pts) do not have nodal metastasis,
but most pts who relapse or die from melanoma are
initially diagnosed as ‘low risk’ early-stage. We
showed that the clinicopathological-gene expression
profiling (CP-GEP) model can stratify pts with negative
SLNB for their risk of recurrence.Aim:
To demonstrate the ability of CPGEP
to stratify pts who did not undergo
SLNB for their risk of recurrence in an
expanded cohort.Methods:
formalin-fixed paraffin-embedded
primary tumor samples of pts with CM diagnosed
between 2000-2020 who did not undergo SLNB
were analyzed. The CP-GEP model used combines
the expression of 8 genes (SERPINE2, GDF15,
ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA)
by qPCR with age and Breslow thickness to obtain
a binary output: CP-GEP Low-Risk or High-Risk.
Relapse-free survival (RFS), distant metastasis free
survival (DMFS) and Melanoma Specific Survival
(MSS) were evaluated using Kaplan-Meier curves.
Median follow-up time was 5 years.Thao et al. 2022. International Journal of Dermatology.
December 2022
Cost evaluation of the Merlin assay for predicting melanoma sentinel lymph node biopsy metastasis.
Background
The Merlin assay for melanoma-risk assessment has become commercially available to reduce the rate of unnecessary sentinel lymph node biopsies (SLNB) in SLNB-eligible patients with cutaneous melanoma. Merlin low-risk patients are recommended to undergo wide local excision (WLE) of the primary tumor, whereas Merlin high-risk patients are recommended to undergo both SLNB and WLE. Here, we compared the cost of a Merlin testing strategy to that of a no-testing strategy (usual care) before prescribing SLNB.
Methods
We identified T1 and T2 patients who underwent WLE and SLNB but not completion lymph node dissection between 2007 and 2018. Controls were T1 patients who only underwent WLE. Costs for WLE and SLNB were calculated by converting institutional cost data to standardized Medicare reimbursement rates. We then developed a decision tree to compare the cost of Merlin testing to that of a no-testing strategy (usual care).
Results
The average standardized cost of WLE was $2066, whereas the cost of WLE and SLNB was $11,976 based on Medicare rates. At a cost below $7350 for T1b melanoma and $4600 for T1b to T2 melanoma, Merlin testing was cost-saving compared to a no-testing strategy (usual care), assuming Medicare reimbursement rates.
Conclusion
Merlin testing for T1b and T2 melanoma is potentially cost saving depending on the cost of the molecular assay and SLNB reimbursement rates. In addition to being cost saving, Merlin is expected to improve health-related quality of life.
Hieken et al. 2022. International Journal of Dermatology.
July 2022
Using the Merlin Assay for reducing sentinel lymph node biopsy complications in melanoma: a retrospective cohort study.
Background
The assessment of the sentinel lymph node is a cornerstone of melanoma staging. However, ~80% of sentinel lymph node biopsies (SLNB) are negative and nontherapeutic, and patients are unnecessarily exposed to surgery-related complications. Here, we gauged the potential of the Merlin assay to reduce SLNB-associated complications. The Merlin assay uses clinicopathologic variables and tumor gene expression profiling to identify low-risk patients who may forgo SLNB.
Methods
We utilized the Merlin test development cohort to determine SLNB complication rates for procedures performed between 2004 and 2018 at Mayo Clinic. Complications evaluated were lymphedema, seroma, infection/cellulitis, hematoma, and wound dehiscence. Patients who underwent a completion lymph node dissection were excluded.
Results
A total of 558 patients were included. The overall 90-day complication rate specific to SLNB (1 year for lymphedema) was 17.4%. The most common complications were seroma (9.3%), infection/cellulitis (4.8%), and lymphedema (4.3%). All three were more common in patients with a lower extremity primary tumor location versus other locations. With Merlin test results applied, SLNB-related complications would have decreased by 59%.
Conclusion
SLNB is a safe procedure but carries a significant complication rate. Merlin testing might reduce the need for SLNB and its associated complications.
June 2022
Use of Merlin Assay to identify patients with a low-risk for SN metastasis in a prospective multicenter Dutch study of a primary melanoma gene-signature (CP-GEP model) to predict sentinel node status during COVID-19.
Background:
Approximately 70%-85% of patients who undergo sentinel lymph node biopsy (SLNb) show no nodal metastasis in the sentinel node (SN). The clinicopathological and gene expression profile (CP-GEP) model (Merlin Assay) was developed and validated to identify patients that may forgo the SLNb surgery due to their low risk for for nodal metastasis This study was initiated during the first wave of Covid-19 pandemic to allow for surgical triage on SLNb and evaluate the implementation of the Merlin assay in clinical practice.
Methods:
This study was conducted in four designated melanoma centers in the Netherlands. Patients (age > 18y) with newly diagnosed melanoma of the skin, eligible to undergo SLNb were screened for study inclusion. Main exclusion criteria was prior history of primary melanoma ( > T1b) in the past 5 years. After enrollment, tissue sections of the primary melanoma were centrally reviewed at the Erasmus MC Cancer Institute to determine Breslow thickness at primary diagnosis. FFPE tumor tissue was dispatched for molecular analysis of eight target genes known to play a role in cancer development. In combination with age, Breslow thickness, and GEP outcome, risk of having nodal metastasis was calculated. Results were binary presented as ‘CP-GEP low risk’ and ‘CP-GEP high risk’. SLNb status was used as gold standard for comparison.
Results:
A total of 177 patients were analyzed using the CP-GEP model. Median age was 64 years (IQR 52-73) Median Breslow thickness was 1.4mm (IQR 1.0-2.4). Of all patients 28.2% was diagnosed with T1, 40.7% with T2 and 20.9% with T3 melanoma. Corresponding positivity rate was 7%, 14% and 29% respectively. A total of 24 out of 177 patients had a positive SLNb. Median turn-around time from inclusion to CP-GEP result was 15 days. Overall 37.1.% of patients had a CP-GEP low risk profile. The CP-GEP model had a NPV of 94.6%. Conclusions: This is the first prospective multicenter implementation study for the Merlin assay. Results are in line with previous validation studies. The CP-GEP model could accurately identify patients at low risk for SN metastasis. Implementation in clinical practice is feasible based on current turn-around time. In the future, using the Merlin assay to deselect patients for SLNB may allow for a reduction of surgery in patients with melanoma.
June 2022
MERLIN_001: A prospective registry study of a primary melanoma gene signature to predict sentinel node (SN) status and determine its prognostic value for more accurate staging of SN-negative melanoma patients.
Background:
For patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) provides important staging and prognostic information that guides surveillance and adjuvant systemic therapy decisions. At most centers, SLNB is indicated for patients with cutaneous melanoma with at least a 5% risk of having nodal metastases, typically melanomas ≥ 0.8 mm in thickness or thinner lesions with high-risk features such as elevated mitotic rate and/or ulceration. SLNB, generally involving a separate incision, does carry a small but measurable risk of complications including seroma, infection and rarely lymphedema, and most patients have negative sentinel lymph nodes. Currently, there is an unmet clinical need to identify patients who may safely forgo SLNB due to a low (<5%) risk of nodal metastasis, who otherwise meet established criteria for SLNB. Previously, a model consisting of gene expression profile (GEP) of the primary tumor combined with clinicopathological features (CP) has been developed to identify melanoma patients with a low risk of having a positive SLNB. The model has also been validated in multiple retrospective studies. The aim of the MERLIN_001 registry study is to prospectively validate the CP-GEP model in an independent multicenter cohort of primary cutaneous melanoma patients who undergo SLNB for standard indications.
Methods:
In the next two years, a total of 10 centers across the US will enroll 2,340 patients with clinically node-negative cutaneous melanoma undergoing SLNB using current guideline indications and will follow these patients for 5 years (ClinicalTrials.gov identifier: NCT04759781). Enrollment of patients started in September 2021 and 242 patients have been enrolled as of February 1, 2022. FFPE material from the initial melanoma biopsy will be used to assess the GEP of the primary melanoma. The CP-GEP probability scores will be expressed as a binary classification (Low Risk or High Risk for nodal metastasis) and will be compared to SLN pathology. Performance metrics for CP-GEP will be evaluated and will include: Negative Predictive Value, Positive Predictive Value, Sensitivity and Specificity, and the corresponding 95% confidence intervals. Risk for nodal metastasis will be calculated for Low Risk and High Risk CP-GEP patients. Finally, the performance of CP-GEP to stratify patients according to risk of recurrence (local, regional, distant, death) will also be studied, since data will be collected for up to 5 yrs. Clinical trial information: NCT04759781.
April 2022
Use of CP-GEP to identify primary cutaneous melanoma patients with low risk for SN metastasis in a prospective multicenter Dutch study during COVID-19.
Introduction
Approximately 70%-85% of patients who undergo sentinel lymph node biopsy (SLNB) show no nodal metastasis in the sentinel node (SN). CP-GEP, a model that combines clinicopathologic and gene expression variables from the primary tumor was developed and validated to identify patients that may forgo the SLNB surgery due to their low risk for SN-metastasis. This study was initiated during the first wave of COVID-19 pandemic to allow for surgical triage on SLNB and evaluate the implementation of the CP-GEP model in clinical practice.
Methods
This study was conducted in four designated melanoma centers in the Netherlands. Patients (age>18y) with newly diagnosed melanoma of the skin, eligible to undergo SLNB were screened for study inclusion. Main exclusion criteria was prior history of primary melanoma (>T1b) in the past 5 years. After enrollment, tissue sections of the primary melanoma were evaluated to determine Breslow thickness at primary diagnosis. FFPE tumor tissue was dispatched for molecular analysis of eight target genes known to play a role in cancer development. In combination with age, Breslow thickness, and GEP outcome, risk of having SN-metastasis was calculated. Results were binary presented as ‘CP-GEP Low Risk’ and ‘CP-GEP High Risk’. SLNB status was used as gold standard for comparison.
Results
A total of 177 patients were analyzed using the CP-GEP model. Median age was 64 years (IQR 52-73) Median Breslow thickness was 1.4mm (IQR 1.0-2.4). Of all patients 28.2% was diagnosed with T1, 40.7% with T2 and 20.9% with T3 melanoma. Corresponding positivity rate was 7%, 14% and 29% respectively. A total of 24 out of 177 patients had a positive SLNB (13.6%). Median turn-around time from inclusion to CP-GEP result was 15 days. Overall 37.1.% of patients had a CP-GEP Low Risk outcome. The CP-GEP model had a NPV of 94.6%.
Conclusion
This is the first prospective multicenter implementation study for the CP-GEP model. Results are in line with previous validation studies. The CP-GEP model could accurately identify patients at low risk for SN metastasis. Implementation in clinical practice is feasible based on current turn-around time. In the future, using the CP-GEP model to deselect patients for SLNB may allow for a reduction of surgery in patients with melanoma.
Tjien-Fooh et al. 2022. AAD Conference.
March 2022
Cutaneous melanoma patients with minimal SN tumor burden: CP-GEP (Merlin Assay) may guide decision-making beyond nodal assessment.
Abstract
Nodal pathological assessment via sentinel lymph node biopsy (SLNB) is important for primary cutaneous melanoma risk-stratification. The prognosis of patients with minimal sentinel node (SN) tumor burden – defined by the Rotterdam Criteria as a tumor burden of 0.1 mm or less – can be diverse. Therefore, optimal treatment of patients with minimal SN tumor burden is subject of an ongoing debate. CP-GEP assesses the risk of SLNB metastasis at diagnosis. Specifically, CP-GEP considers patient age at diagnosis, Breslow thickness and expression of eight genes in the primary tumor. Combination of these variables results in either of two risk labels: CP-GEP Low Risk or High Risk. Previously, we also investigated prognostic performance of CP-GEP in four independent cohorts from the US, the Netherlands, and Sweden totaling 1684 patients, 79 of whom had minimal SN tumor burden. The proportion of patients with minimal SN tumor burden was comparable between cohorts, 3-5%. We found that patients with minimal SN tumor burden from Sweden had a relapse risk comparable to SLNB positive patients, whereas Dutch and American patients had a relapse risk comparable to SLNB negative patients. We speculate that this discrepancy is caused by differences in histopathologic workup of SN. Of the 79 patients with minimal SN tumor burden, we observed recurrences in 2/17 (11.8%) CP-GEP Low Risk patients versus 19/62 (30.6%) recurrences in CP-GEP High Risk patients at a median follow-up time of 5.6 years. Further analysis of CP-GEP in larger cohorts is required to confirm observed trends.
Johansson et al. 2021. European Journal of Surgical Oncology.
February 2022
Validation of a clinicopathological and gene expression profile model to identify patients with cutaneous melanoma where sentinel lymph node biopsy is unnecessary.
Background
In patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) serves as an important technique to asses disease stage and to guide adjuvant systemic therapy. A model using clinicopathologic and gene expression variables (CP-GEP; Merlin Assay) has recently been introduced to identify patients that may safely forgo SLNB. Herein we present data from an independent validation cohort of the CP-GEP model in Swedish patients.
Methods
Archival histological material (primary melanoma tissue) from a prospectively collected cohort of 421 consecutive patients with pT1-T4 melanoma undergoing SLNB between 2006 and 2014 was analyzed using the CP-GEP model. CP-GEP combines Breslow thickness and patient age with the expression levels of eight genes from the primary melanoma. Stratification is based on their risk for nodal metastasis: CP-GEP Low Risk or CP-GEP High Risk.
Results
The SLNB positivity rate was 13%. Of 421 primary melanomas, the CP-GEP model identified 86 patients as having a low risk for nodal metastasis. In patients with pT1-2 melanomas, the SLNB reduction rate was 35.4% (95% CI: 29.4–41.8) with a negative predictive value (NPV) of 96.5% (95% CI: 90.0–99.3). Among patients with pT1-3 melanomas, CP-GEP suggested a SLNB reduction rate of 24.0% (95% CI: 19.7–28.8) and a NPV of 96.5% (95% CI: 90.1–99.3). Only one of 118 pT3 tumors was classified as CP-GEP Low Risk, and all pT4 tumors were classified as being high risk for nodal metastasis.
Conclusion
This study demonstrates that CP-GEP can identify patients with a low risk for nodal metastasis. Patients with pT1-2 melanomas have the highest clinical benefit from using the test, where 35% of the patients could forgo a SLNB procedure.
Mulder et al. 2020. British Journal of Dermatology.
May 2021
Validation of a clinicopathological and gene expression profile model for sentinel lymph node metastasis in primary cutaneous melanoma.
Background
The Clinicopathological and Gene Expression Profile (CP-GEP) model was developed to accurately identify patients with T1–T3 primary cutaneous melanoma at low risk for nodal metastasis.
Objectives
To validate the CP-GEP model in an independent Dutch cohort of patients with melanoma.
Methods
Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible. The CP-GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA). Using the pathology result of SLNB as the gold standard, performance measures of the CP-GEP model were calculated, resulting in CP-GEP high risk or low risk for nodal metastasis.
Results
In total, 210 patients were included in the study. Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma. Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively. Overall, the CP-GEP model had a negative predictive value (NPV) of 90·5% [95% confidence interval (CI) 77·9–96.2], with an NPV of 100% (95% CI 72·2–100) in T1, 89·3% (95% CI 72·8–96·3) in T2 and 75·0% (95% CI 30·1–95·4) in T3 melanomas. The CP-GEP indicated high risk in all T4 melanomas.
Conclusions
The CP-GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis. In this validation cohort, the CP-GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.
Yousaf et al. 2021. International Journal of Dermatology.
April 2021
Validation of CP-GEP (Merlin Assay) for predicting sentinel lymph node metastasis in primary cutaneous melanoma patients: a U.S. cohort study.
Background
Approximately 85% of melanoma patients who undergo a sentinel lymph node biopsy (SLNB) are node-negative. Melanoma incidence is highest in patients ≥65 years, but their SLNB positivity rate is lower than in younger patients. CP-GEP, a model combining clinicopathologic and gene expression variables, identifies primary cutaneous melanoma (CM) patients who may safely forgo SLNB due to their low risk for nodal metastasis. Here, we validate CP-GEP in a U.S. melanoma patient cohort.
Methods
A cohort of 208 adult patients with primary CM from the Mayo Clinic and West Virginia University was used. Patients were stratified according to their risk for nodal metastasis: CP-GEP High Risk and CP-GEP Low Risk. The main performance measures were SLNB reduction rate (RR) and negative predictive value (NPV).
Results
SLNB positivity rate for the entire cohort was 21%. Most patients had a T1b (34%) or T2a (31%) melanoma. In the T1-T2 group (153 patients), CP-GEP achieved an SLNB
RR of 41.8% (95% CI: 33.9-50.1) at an NPV of 93.8% (95% CI: 84.8-98.3). Subgroup analysis showed similar performance in T1-T2 patients ≥65 years of age (51 patients;
SLNB positivity rate, 9.8%): SLNB RR of 43.1% (95% CI: 29.3-57.8) at an NPV of 95.5% (95% CI: 77.2-99.9).
Conclusion
We confirmed the potential of CP-GEP to reduce negative SLNB in all relevant age groups. Our findings are especially relevant to patients ≥65 years, where surgery is often elective. CP-GEP may guide SLNB decision-making in clinical practice.
Johansson et al. 2021. EADO Conference.
April 2021
Independent validation study of CP-GEP model (Merlin Assay) to identify patients who can safely forgo sentinel lymph node biopsy.
Background
For patients with primary cutaneous melanoma, sentinel lymph node biopsy (SLNB) is an important technique to assess disease stage and to guide adjuvant systemic therapy1. Around 80-85% of all SLNB procedures do not detect nodal metastasis. A model using clinicopathologic and gene expression variables (CP-GEP; Merlin Assay) has been introduced to identify patients that may safely forgo SLNB2 due to their low risk for nodal metastasis. CP-GEP combines Breslow thickness and patient age with the expression of eight genes to classify patients as High Risk or Low Risk for nodal metastasis.
Purpose
The aim was to independently validate the Merlin Assay in a population-based retrospective cohort.
Method
421 FFPE primary melanomas were analyzed for CPGEP which classified patients into Low risk and High risk for nodal metastasis. CP-GEP risk labels were compared to the known SLNB status.
Results
The median age was 60 years and 49% of the patients were females. Of the 421 patients, 335 patients (80%) were classified as CP-GEP High Risk and 86 (20%) as CP-GEP Low Risk for nodal metastasis. The overall SLNB positivity was 13%. Of the 86 CP-GEP Low Risk patients, CP-GEP could correctly identify 83 (96.5%) patients who were SLNB negative. For patients with T1-T2 tumors, the negative predictive value (NPV) was 96.5% and the SLNB reduction rate was 35.4%. For patients with T1-T3 tumors, the NPV was 96.5% and the SLNB reduction rate was 24.0%. All T4 tumors were classified as CP-GEP High Risk for nodal metastasis.
Conclusion
The CP-GEP model has been independently validated in a European retrospective patient cohort, and can be used to identify patients who may safely forgo SLNB procedure due to their low risk for nodal metastasis.
April 2021
Using the clinicopathologic and gene expression (CP-GEP) model to predict sentinel node status in patients with primary melanoma: a prospective cohort study during the COVID-19 pandemic.
Background
In light of the current COVID-19 pandemic, avoiding unnecessary interventions and keeping patients out of the hospital becomes increasingly important. The CP-GEP model (Merlin Assay) has been developed and validated to identify patients with primary melanoma (pT1 b-pT3) that can safely forgo the sentinel lymph node biopsy (SLNB) due to their low risk for nodal metastasis. During the current pandemic, a prospective trial was conducted to assess the accuracy of using the CPGEP model to identify patients that have a low risk for nodal metastasis and therefore could forgo the SLNB.
Methods
During the COVID-19 pandemic, from July 2020 to February 2021, all newly diagnosed cutaneous melanoma (pT1 b-pT3) patients elected to undergo SLNB at the Erasmus MC Cancer Institute were included. Formalin-fixed paraffin embedded tissue (FFPE) from the primary melanoma tissue was analyzed using CP-GEP. The CP-GEP model combines patient age and Breslow thickness with the expression of eight target genes. Patients were classified as CP-GEP High Risk or CP-GEP Low Risk for having nodal metastasis.
Results
From all eligible patients (n=19), consent was obtained and FFPEs could be retrieved for further analysis. Patients had a median age of 53 years (interquartile range [IQR] 37 – 67) and median Breslow thickness was 2.0 mm (IQR 1,4-2.8). In two out of 19 patients, the surgeon determined preoperatively not to proceed with SLNB (as a result of locally advanced melanoma). Of the remaining 17 patients, five had a positive SLNB (e.g. nodal metastasis, 29.4% ). All SLNB positive patients (n=5) were identified by CP-GEP as being High Risk for nodal metastasis. Of all SLNB negative patients (n=12), CP-GEP identified five patients (41. 7%) as being Low Risk for nodal metastasis. Overall, the potential SLNB reduction rate in this cohort was 29.4% while having a negative predictive value of 100%.
Conclusions
The CP-GEP (Merlin Assay) model is a non-invasive and validated tool that can be used to identify patients with a primary cutaneous melanoma (pT1 b-pT3) who are at low risk for nodal metastasis and therefore could safely forgo SLNB. Also, during the current COVID-19 pandemic, the CP-GEP model could be a promising tool to deselect patients for elective surgery (Figure).
November 2020
The use of a clinicopathologic and gene expression model (Merlin Assay) to risk stratify cutaneous melanoma patients in clinical practice: A pilot study.
Abstract
The management of primary cutaneous melanoma (PCM) faces new challenges during the COVID-19 pandemic. National guidelines aiming to optimize medical resource usage have led to delays in elective surgical procedures such as the sentinel lymph node (SLN) biopsy, which causes stress and anxiety in patients. We recently reported on the development of a model which combines clinicopathologic variables and a gene expression profile (CP-GEP) to identify patients who may safely forgo SLN biopsy due to their low risk of nodal metastasis. The CP-GEP model combines Breslow thickness and patient age with the expression of eight genes in diagnostic biopsy tissue. Here, we report on the feasibility of running the CP-GEP model – which we refer to as the Merlin Assay – in an independent Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory accredited by the College of American Pathologists (CAP). 50 micron recuts of T1 to T3 diagnostic biopsy tissue were requested from 50 PCM patients who were seen in the fall of 2019. Turnaround time from sample receipt at the laboratory to test reporting was within five working days. 3/50 samples (6%) did not contain sufficient RNA for molecular analysis; 47/50 samples (94%) were tested successfully. Of the 47 patients with Merlin test results, 34/47 (72.3%) underwent SLN biopsy. Of the 34 patients with known SLN status, 13/34 (38.2%) were T1, 13/34 (38.2%) were T2 and 8/34 (23.6%) were T3 patients. 1 of 13 (7.7%) T1, 4 of 13 (30.1%) T2 and 1 of 8 (12.5%) T3 patients were SLN positive. All SLN positive patients were correctly classified as high risk by the Merlin Assay. We conclude that the implementation of the Merlin Assay in clinical practice is feasible as a send-out test and may be used for deselecting low risk PCM patients for SLN biopsy during the ongoing COVID-19 pandemic.
Arias-Mejias et al. 2020. International Journal of Dermatology.
November 2020
Primary cutaneous melanoma risk stratification using a clinicopathologic and gene expression model: a pilot study.
Meves & Eggermont 2020. Mayo Clin Proc Inn Qual Out.
October 2020
Deselecting melanoma patients for sentinel lymph node biopsy during COVID-19: clinical utility of tumor molecular profiling.
September 2020
Validation of a Model Combining Clinicopathologic Risk Factors and a Gene Expression Profile to Identify Primary Melanoma Patients Who Can Safely Forgo Sentinel Lymph Node Biopsy.
Background:
The sentinel lymph node biopsy (SLNB) procedure has gained importance now that primary cutaneous melanoma (PCM) patients with a positive sentinel lymph node are considered candidates for adjuvant systemic therapy. However, SLNB is an invasive procedure, and approximately 80% of patients lack nodal metastasis. Many SLNB negative patients are exposed to invasive surgery but enjoy no discernible therapeutic benefit. Therefore, there is a need for a non-invasive test to accurately identify PCM patients who may forgo the SLNB procedure due to low risk of nodal metastasis. Previously, a clinicopathological and gene expression profile model (CPGEP model) has been developed to identify PCM patients who can safely forgo SLNB. Moreover, a validation of the CP-GEP model in a European cohort has been reported. Here, we describe the validation of the CP-GEP model in a US cohort.
Methods:
We identified 162 patients who underwent SLNB at the Mayo Clinic or West Virginia University within 90 days of PCM diagnosis. Formalin-fixed paraffin embedded diagnostic PCM biopsy tissue from all patients were analyzed using the CPGEP model. The CP-GEP model combines Breslow thickness and patient age with the expression of eight genes to classify patients as CP-GEP High Risk or CP-GEP Low Risk for nodal metastasis.
Results:
At diagnosis, the median patient age was 56 years (IQR, 41 to 69 years) and the median Breslow thickness was 1.9 mm (IQR, 0.9 to 2.1 mm). 62 of 162 patients {38.2%) presented with Tl melanoma while 58 of 162 patients (35.8%) presented with T2 melanoma. Overall, 19.8% of patients had a positive sentinel lymph node. In patients with stage Tl to T2 melanoma, the CP-GEP model achieved an SLNB reduction rate of 44.2% at a negative predictive value of 98.1%.
Conclusions:
The CP-GEP model is a non-invasive and validated tool that is able to predict nodal metastasis in an US cohort that can be used to identify PCM patients who can safely forego SLNB. The CP-GEP model is a promising tool for patient care, preventing unnecessary surgery in a large group of patients.
Bellomo et al. 2020. JCO Precision Oncology.
April 2020
Model combining tumor molecular and clinicopathologic risk factors predicts sentinel lymph node metastasis in primary cutaneous melanoma.
Purpose
More than 80% of patients who undergo sentinel lymph node (SLN) biopsy have no nodal metastasis. Here, we describe a model that combines clinicopathologic and molecular variables to identify patients with thin- and intermediate-thickness melanomas who may forgo the SLN biopsy procedure because of their low risk of nodal metastasis.Patients and Methods
Genes with functional roles in melanoma metastasis were discovered by analysis of next-generation sequencing data and case-control studies. We then used polymerase chain reaction to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 754 consecutive thin- and intermediate-thickness primary cutaneous melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. A penalized maximum likelihood estimation algorithm was used to train logistic regression models in a repeated cross-validation scheme to predict the presence of SLN metastasis from molecular, clinical, and histologic variables.
Results
Expression of genes with roles in epithelial-to-mesenchymal transition (glia-derived nexin, growth differentiation factor 15, integrin-β3, interleukin 8, lysyl oxidase homolog 4, transforming growth factor-β receptor type 1, and tissue-type plasminogen activator) and melanosome function (melanoma antigen recognized by T cells 1) were associated with SLN metastasis. The predictive ability of a model that only considered clinicopathologic or gene expression variables was outperformed by a model that included molecular variables in combination with the clinicopathologic predictors Breslow thickness and patient age (area under the receiver operating characteristic curve, 0.82; 95% CI, 0.78 to 0.86; SLN biopsy reduction rate, 42%; negative predictive value, 96%).
Conclusion
A combined model that included clinicopathologic and gene expression variables improved the identification of patients with melanoma who may forgo the SLN biopsy procedure because of their low risk of nodal metastasis.March 2020
A combined clinicopathologic and gene expression model (CP-GEP) identifies primary cutaneous melanoma patients who can safely forgo sentinel lymph node biopsy.
More than 80% of patients undergoing sentinel lymph node (SLN) biopsy have no nodal metastasis, and are unnecessarily exposed to procedure-induced morbidity such as lymphedema. Our objective was to develop a model combining clinicopathologic and gene expression (CP-GEP) to discriminate high-risk patients from patients who can safely forego SLN biopsy, thus reducing procedure-associated morbidity, and prioritizing care for high risk patients. A panel of 108 candidate biomarkers was identified, and the expression of these genes was quantified in FFPE diagnostic biopsy tissue across a cohort of 754 patients; 128/754 (17%) SLN positive patients. All patients underwent SLN biopsy at Mayo Clinic within 90 days of diagnosis between 2004 and 2018. We trained logistic regression models, using a penalized maximum likelihood estimation algorithm, in a repeated cross-validation scheme. The CP-GEP model, combining age and Breslow depth with genes involved in extracellular matrix remodeling (glia-derived nexin, growth differentiation factor 15, integrin β3, interleukin 8, lysyl oxidase homolog 4, TGFβ receptor type 1 and tissue-type plasminogen activator), and melanosome function (antigen recognized by T-cells), outperformed models based on only clinicopathologic variables, or only on gene expression, in discriminating SLN positive and negative patients (AUC, 0.82, 95% CI 0.78-0.86). The CP-GEP model achieved a SLN biopsy reduction rate of 42% at a negative predictive value of 96%. The 5-year relapse-free survival for CP-GEP negative patients was 88% compared with 50% for CP-GEP positive and SLN positive patients, confirming the value of the CP-GEP model as a tool to inform SLN biopsy decisions.Mulder et al. 2019. ESMO Conference.
September 2019
Validation of a ClinicoPathological and Gene Expression Profile (CP-GEP) model for sentinel lymph node metastasis in primary cutaneous melanoma.
Background
As primary cutaneous melanoma patients with a positive sentinel lymph node (SLN, stage III) are now considered candidates for adjuvant systemic therapy, a SLN biopsy (SLNB) is indicated in more patients. However, SLNB is an invasive procedure and is negative in approximately 80% of patients. Therefore, there is a need for a non-invasive test to accurately identify patients with primary cutaneous melanoma without nodal metastases. Here we describe the first independent validation of a recently developed CP-GEP model to predict nodal metastasis. This risk model combines Breslow thickness, age, and gene expression variables from the primary melanoma.
Methods
This study focused on all patients >18 years who underwent a SLNB at the Erasmus Medical Center (between January 2007 and December 2017), within 90 days after diagnosis of primary cutaneous melanoma. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary cutaneous melanomas, reversed transcribed into cDNA and subsequently analyzed for the expression of 8 target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, IL8, MLANA) using an optimized qPCR protocol.
Results
FFPE tissue samples from 211 patients were analyzed using the CP-GEP model. At diagnosis, the median age was 55 years (interquartile range [IQR] 45-65), and the median Breslow thickness was 2.1mm (IQR 1.4-3.4). Most patients presented with a T2 or T3 melanoma, accounting for 94 and 70 patients, respectively. Overall, 27.5% of patients had a positive SLN. The CP-GEP model had a negative predictive value (NPV) of 89.4%. In patients with stage T1-T2 melanoma, the model was able to achieve an SLNB reduction rate of 40.1% with an NPV of 90.7%.
Conclusions
The CP-GEP model is a non-invasive and validated tool that is able to predict nodal metastasis in an independent Dutch population. Consequently, this risk model is able to accurately identify patients with primary cutaneous melanoma that can safely forego SLNB. Therefore, the CP-GEP model is a promising tool for patient care, preventing unnecessary surgery in the majority of patients.
Sominidi-Damodaran et al. 2019. EADO conference.
April 2019
Stromal gene expression predicts sentinel lymph node metastasis of primary cutaneous melanoma Sominidi-Damodaran et al. 2019. EADO conference.
Bellomo et al. 2019. CIM Conference.
April 2019
A molecular model to identify patients who can safely forgo sentinel lymph node biopsy in primary cutaneous melanoma.
Purpose
Greater than 80% of melanoma patients who undergo sentinel lymph node (SLN) biopsy are SLN negative. Our objective was to use molecular markers crucial in the reciprocal and bidirectional interaction between integrins and the tumor microenvironment to distinguish between high-risk patients and patients who can safely forego SLN biopsy.
Patients and Methods
Genes with functional roles in melanoma metastasis were discovered by analysis of next-generation sequencing data, case-control studies, analysis of publicly available genomic datasets and a review of the cancer literature. Of 192 candidate biomarkers discovered, 108 were quantified by quantitative PCR in a cohort of 754 consecutive thin and intermediate-thickness melanomas. Outcome of interest was SLN metastasis within 90 days of melanoma diagnosis. Logistic regression with LASSO regularization was applied to clinicopathologic variables and molecular data in a cross-validation training-validation scheme. Three models were built using: only clinicopathologic features (CP); only gene expression profiling (GEP); and both clinicopathologic and gene expression profiling (CP-GEP).
Results
128/754 patients (17%) were SLN positive. Expression of genes with roles in extracellular matrix remodeling (glia-derived nexin, growth differentiation factor 15, integrin β3, interleukin 8, lysyl oxidase homolog 4, TGFβ receptor type 1 and tissue-type plasminogen activator) and melanosome function (antigen recognized by T-cells) were associated with SLN metastasis. The predictive ability of a model that only considered CP or GEP variables was outperformed by a model which included molecular variables in combination with the clinicopathologic predictors Breslow depth and patient age. CP-GEP achieved a SLN biopsy reduction rate of 80% for clinical stage T1b melanoma with an NPV >95% across all T stages.
Conclusion
A combined model including clinicopathologic and gene expression variables improved the identification of melanoma patients who can safely forgo SLN biopsy due to their less than 5% risk of nodal metastasis.