SAN FRANCISCO—Both population and genetic screening can have a positive impact on melanoma detection and treatment. That was the conclusion of those listening to a debate here at the American Academy of Dermatology Annual Meeting between Martin A. Weinstock, MD, PhD, Professor of Epidemiology and Dermatology at Brown University, and Sancy Leachman, MD, PhD, Professor and Chair of Dermatology at Oregon Health & Science University.
After the debate, the vast majority (90%) of the audience agreed that population screening was of primary importance, although new genetic tools show promise as well.
Martin Weinstock: Population Screening
Weinstock pointed to the benefits of full-body skin exams in improving the detection of melanoma. As melanoma becomes thicker, there is a greater risk of mortality, and the relative risk goes down with clinical skin exams.
A study from Queensland, Australia found a 40 percent reduction in mortality with use of a clinical skin exam within three years of noticing the problem, and a 23 percent reduction in deaths from melanoma within 10 years.
Skin self-exams also help reduce the risks of melanoma—“Skin awareness is associated with better prognosis,” he said. Population-based case-control studies show a one-third reduction in melanoma risk with monthly exams, and a two-third reduction in fatal or advanced melanoma. “Both a clinical skin exam and self-exams reduce the risk of death from melanoma.”
Weinstock cited a population-based screening program at Lawrence Livermore National Laboratory that showed that after the introduction of skin screening, there was a marked increase in diagnosis of in situ melanoma among employees. At the same time, there were reductions in the thickness of melanoma lesions and a statistically significant reduction in melanoma mortality.
A German study also shows the advantages of population screening, Weinstock continued. At baseline, the people of Schleswig-Holstein had a moderate mortality rate from melanoma before skin screening from 1998 to 2000. Ten years later, there was a 50 percent reduction in the population-based mortality rate from melanoma.
The negative consequences of screening for melanoma are overdiagnosis, morbidity, and costs due to follow-up workups, treatment, and distress, he noted, defining overdiagnosis as a diagnosis made that would not have caused morbidity or death if it had not been made. “Overdiagnosis is not a medical error or malpractice, but an outcome of a health system—not individual failings.”
He compared melanoma screening to screening for other cancers: “The reduction of prostate cancer mortality with PSA screening is weak or nonexistent. Prostate cancer screening has a false-positive rate of 12 to 13 percent, and there is significant morbidity from evaluation and treatment of prostate cancer. With little mortality gained, recommendations are against PSA screening for prostate cancer.”
Breast cancer is also overdiagnosed. For example, a recent Norwegian screening program found that about 20 percent of all diagnoses of invasive breast cancer were overdiagnoses. “This likely underestimates the U.S. rates—yet still, we screen for breast cancer because it saves lives.”
The recent National Lung Screening Trial found that using low-dose spiral computed tomography (CT) to screen for lung cancer led to a similar number of deaths as screening with chest x-rays. “In high-risk groups, overdiagnosis is common with low-dose CT, but there is a 15 to 20 percent lower mortality with low-dose CT,” he said.
Population screening does lead to increased diagnoses of melanoma. In the German study, invasive melanoma diagnoses increased to 53 percent of women in Schleswig-Holstein with screening, compared with 18 percent in another city, Saarland, which had no screening. More than twice as many men in Schleswig-Holstein (26%) were diagnosed with melanoma than in Saarland (10%).
Randomized trials of thorough skin self-exams show that people can learn to double their skin exams over one year, and those who do the exams have about twice the number of surgeries within six months, Weinstock said.
“The screening benefit is to cut melanoma deaths, which are now at 10,000 per year in the U.S. The harms from melanoma screening are relatively minor,” he said.
An updated United States Preventive Services Task Force report on skin cancer screening is expected to be released in mid-2016. In 2009, the Task Force concluded there is not enough evidence to recommend for or against routine screening (total body examination by a primary care physician or patient self-examination) for early detection of skin cancers in the adult general population.
Sancy Leachman: Genetic Screening
Leachman noted four types of genetic screening for melanoma:
- Genetic predisposition testing of the blood uses individual genes versus a panel of tests to assess the risk of melanoma;
- Genetic diagnostic testing of the tumor, a nevus, or melanoma, uses fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), or quantitative real-time polymerase chain reaction (PCR) to assess whether the biopsy is malignant or benign;
- Genetic prognostic testing of the primary tumor with polymerase chain reaction assesses the risk that melanoma will spread; and
- Genetic therapeutic eligibility testing of the primary or metastasized tumor uses DNA mutations in BRAF, NRAS, and KIT to assess whether targeted therapies are an option.
Genetic predisposition testing informs patients at high risk before melanoma and other associated cancers develop. “If photoprotection, self-skin screening, and surveillance increase, fewer life-threatening melanomas will develop, Leachman explained. “If appropriate associated cancer screening is implemented, fewer cancers will kill. Prevention of cancer reduces morbidity secondary to surgery and therapy, and increases quality of life.”
Mutations in the p16 gene are the most common known cause of hereditary melanoma syndrome. Following positive p16 testing results, unaffected carriers report improvements in the thoroughness of skin self-exams, adherence to annual total-body skin exams, daily routine sun protection, use of protective clothing, and a reduced number of sunburns. Data show that about two-thirds of patients maintain these gains after two years, she said.
Traditional dermatopathology is highly subjective, with substantial inter-rater variability in pigmented lesions. “There is a 38 percent discordance rate among experts reviewing ‘classic’ examples of melanocytic neoplasms.”
The premise is that molecular testing is more objective and reproducible and will improve management.
“The ideal would be to prove that sensitivity and specificity is better than gold-standard dermatopathology with respect to outcome. The caveat is that dermatopathology is poorly validated. Favorable outcome is accurately predicted in 47 percent of cases and unfavorable outcome predicted in 73 percent of cases.”
Sensitivity and specificity of diagnostic tests support their benefit. For melanoma, FISH has a sensitivity range of 43 to 100 percent and a specificity range of 29 to 80 percent; CGH has a sensitivity range of 92 to 96 percent and specificity of 87 to 100 percent; and PCR has a sensitivity of 90 percent and specificity of 91 percent, she said.
“Genetic diagnostic testing impacts melanoma by helping to ensure that malignant lesions are appropriately excised and treated at the time of diagnosis, improving survival by decreasing recurrences. It also helps to ensure that benign lesions are not overtreated, reducing unnecessary morbidity, and reduces uncertainty and psychological or emotional distress, improving quality of life.”
Predictions of five-year survival rates support the benefit of gene-expression profiling (GEP), which can be used to classify stage I or II melanomas as low risk (Class 1) or high risk (Class 2) for future metastasis. She cited a recent study using GEP showing five-year disease-free survival (DFS) rates of 100 percent in a development set and 97 percent in a validation set for Class 1 patients and 38 percent in the development set and 33 percent in the validation set for Class 2 patients.
“GEP was a more significant and better predictor of DFS, distant metastasis-free survival, and overall survival than sentinel lymph node biopsy, and improved prognostication in combination with SLN biopsy,” she said. In SLN biopsy-negative patients with Class 2 high-risk GEP, the five-year disease-free survival rate was 35 percent, distant metastasis-free survival was 49 percent, and overall survival was 54 percent.
In conclusion, Leachman said: “Predisposition genetic testing to assess the risk for development of melanoma empowers high-risk patients to comply with prevention behaviors likely to reduce life-threatening disease. Diagnostic genetic testing to assess the likelihood that a lesion is malignant reduces unnecessary treatment of benign disease and improves detection and treatment of malignant disease, likely to result in improved outcome from earlier removal from a subset.
Prognostic genetic testing to assess the likelihood that a malignant lesion will metastasize permits increased surveillance of highest-risk individuals, likely to result in improved outcome from earlier treatment.”
The post-debate survey showed that about two-thirds of the audience still believed in the benefits of population screening, but a substantial number did switch to genetic screening—making Sancy Leachman the debate champion.Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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