or AJCC stage as a sole determinant to guide the use of baseline ultrasonography or SLNB, a 40-GEP Class 2A or 2B result may provide additional evidence that a CSCC tumor has a high risk for metastasis.
Adjuvant Radiation Therapy
Another CSCC management decision-making point is whether or not to use ART for treatment. Using ART for cancer treatment involves balancing the potential to provide local cure against the potential to cause harm and illustrates an unmet need for personalized medicine in CSCC management. Knowledge of an individual tumor’s biological potential could help with patient selection, allowing clinicians to reserve ART for patients with the greatest risk for metastasis and reduce the risk of overtreatment for a majority of patients. Existing guidelines recommend ART for any CSCC with AJCC T4 staging, extensive perineural involvement, positive tissue margins after definitive surgery, or after therapeutic lymphadenectomy in patients whose CSCC has metastasized to regional lymph nodes.14,16,18 While randomized trials are lacking in this setting, several retrospective studies indicate that ART significantly reduced the risk of local recurrence.26-28 However, the absolute benefit of ART depends on the risk of recurrence, which is difficult to quantify in many cases.
Importantly, the 40-GEP test was developed to specifically predict nodal or distant metastasis and may not apply to ART directly, which, historically, has focused on reducing loco-regional recurrence. However, there may be potential applications of the 40-GEP test in informing decision making about the use of ART. Tumors with BWH T2b/T3 or AJCC T3/T4 staging and a Class 2A GEP result were 4.6 to 5.8 times more likely to metastasize with a 35% risk of metastasis. Tumors with a Class 2B GEP result had an even higher risk of metastasis (≥50%) and were 15 times more likely to metastasize.12 Patients with these 40-GEP test results could be considered for referral to a radiation oncologist for a multidisciplinary discussion. Conversely, radiation oncologists may reconsider the use of ART in patients with BWH T2b/T3 disease with a Class 1 GEP test result as their recurrence rates are low and the morbidities of treatment may outweigh the benefits.
Follow-up and Surveillance
With 75% of CSCC recurrences occurring within two years of the initial diagnosis, follow-up and surveillance are a critical part of the CSCC management plan.3 Overall, the frequency of clinical follow-up should align with patient risk. Current recommendations propose that follow-up intervals be based on tumor risk classification with patients with high-risk CSCC receiving more extensive follow-up (Table 3).19,20,22 The risk thresholds for metastasis from these recommendations align with 40-GEP test results. Clinicians may consider annual radiologic or ultrasound nodal surveillance with more frequent clinic visits for patients with a Class 2A GEP test result. For patients with a Class 2B GEP test result, clinicians may consider biannual radiologic/ultrasound surveillance with more frequent clinical visits. Patients with a Class 1 GEP test result may not require radiologic/ultrasound nodal surveillance.
Adjuvant Radiation Therapy
Another CSCC management decision-making point is whether or not to use ART for treatment. Using ART for cancer treatment involves balancing the potential to provide local cure against the potential to cause harm and illustrates an unmet need for personalized medicine in CSCC management. Knowledge of an individual tumor’s biological potential could help with patient selection, allowing clinicians to reserve ART for patients with the greatest risk for metastasis and reduce the risk of overtreatment for a majority of patients. Existing guidelines recommend ART for any CSCC with AJCC T4 staging, extensive perineural involvement, positive tissue margins after definitive surgery, or after therapeutic lymphadenectomy in patients whose CSCC has metastasized to regional lymph nodes.14,16,18 While randomized trials are lacking in this setting, several retrospective studies indicate that ART significantly reduced the risk of local recurrence.26-28 However, the absolute benefit of ART depends on the risk of recurrence, which is difficult to quantify in many cases.
Importantly, the 40-GEP test was developed to specifically predict nodal or distant metastasis and may not apply to ART directly, which, historically, has focused on reducing loco-regional recurrence. However, there may be potential applications of the 40-GEP test in informing decision making about the use of ART. Tumors with BWH T2b/T3 or AJCC T3/T4 staging and a Class 2A GEP result were 4.6 to 5.8 times more likely to metastasize with a 35% risk of metastasis. Tumors with a Class 2B GEP result had an even higher risk of metastasis (≥50%) and were 15 times more likely to metastasize.12 Patients with these 40-GEP test results could be considered for referral to a radiation oncologist for a multidisciplinary discussion. Conversely, radiation oncologists may reconsider the use of ART in patients with BWH T2b/T3 disease with a Class 1 GEP test result as their recurrence rates are low and the morbidities of treatment may outweigh the benefits.
Follow-up and Surveillance
With 75% of CSCC recurrences occurring within two years of the initial diagnosis, follow-up and surveillance are a critical part of the CSCC management plan.3 Overall, the frequency of clinical follow-up should align with patient risk. Current recommendations propose that follow-up intervals be based on tumor risk classification with patients with high-risk CSCC receiving more extensive follow-up (Table 3).19,20,22 The risk thresholds for metastasis from these recommendations align with 40-GEP test results. Clinicians may consider annual radiologic or ultrasound nodal surveillance with more frequent clinic visits for patients with a Class 2A GEP test result. For patients with a Class 2B GEP test result, clinicians may consider biannual radiologic/ultrasound surveillance with more frequent clinical visits. Patients with a Class 1 GEP test result may not require radiologic/ultrasound nodal surveillance.
SUMMARY
In this article, an expert panel has presented and reviewed
situations where information from GEP testing could aid
decision making in CSCC management. GEP testing has the
potential to improve current high-risk CSCC assessment
practices and allow clinicians to provide personalized care
for patients. Further insight into tumor characteristics could
help avoid unnecessary treatment and surveillance (eg,
overtreatment with ART, radiologic surveillance in lowrisk
tumors) while allowing healthcare providers to add
management modalities or increase treatment intensity or
follow-up as needed. The additional information that can be
gained from GEP testing could also be used to inform if and
when to refer a patient for medical, surgical, or radiation
oncology. There is also the potential in the future that GEP test
results could be used to determine whether to consider SLNB
or enroll a patient in an adjuvant immunotherapy clinical trial;
however, additional studies are needed.
DISCLOSURES
S. Arron is employed by Rakuten Medical and is a consultant
for Castle Biosciences and Enspectra Health. T. Blalock is the
principal investigator on a research study funded by Castle
Biosciences. J.M. Guenther is on the speaker bureau for
Castle Biosciences. D. Hyams is on the speaker bureau for
Castle Biosciences. S. Ibrahim has received advisor fees
from Castle Biosciences, Regeneron Pharmaceuticals, and
Sun Pharmaceutical Industries, research funding from Castle
Biosciences, Galderma, and Regeneron Pharmaceuticals, and
speaker fees from Castle Biosciences, Galderma, Genentech,
Regeneron Pharmaceuticals, and Sun Pharmaceutical
Industries. S. Koyfman has received research support
from Merck and Bristol Myers Squibb, an honorarium from
UpToDate, and is on advisory boards for Merck and Regeneron
Pharmaceuticals. A. Wysong is a board member for the
American College of Mohs Surgery, Women’s Dermatologic
Society, and Dermatology Foundation and is the principal
investigator on an institutional research grant from Castle
Biosciences.