Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.1.0
• GENE/GENE PANEL: CDKN2A
• Condition: Pancreatic cancer/melanoma syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• CDKN2A ⇔ 606719: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Melanoma morbidity and/or mortality / Skin surveillance	2	3C	2B	3	10CB
Pancreatic cancer morbidity and/or mortality / Periodic pancreatic imaging	2	2C	1N	3	8CN
Pancreatic cancer morbidity and/or mortality / Smoking cessation and/or avoidance	2	2C	2B	3	9CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

An accurate estimate of the prevalence of Pancreatic Cancer/Melanoma Syndrome (PCMS; aka Familial Atypical Multiple Mole Melanoma-Pancreatic Cancer Syndrome) is difficult to make given the highly variable phenotype and limited data. [1]

Clinical Features

PCMS is a predisposition syndrome associated with an increased risk of developing malignant melanoma and/or pancreatic cancer. Individuals within families may develop either or both types of cancer. PCMS is classically characterized by cutaneous findings of a high total body nevi count (usually more than 50 and often into the hundreds; including some atypical nevi which may resemble early melanoma) and a family history of melanoma. Controversy surrounds the pathologic significance of atypical nevi seen in PCMS syndrome; atypical nevi often regress and melanomas often develop on normal skin. The clinical and histopathologic characteristics of melanoma in PCMS are not different from those seen in sporadic cases. Evidence is also mixed regarding whether there is a difference in location of melanomas between CDKN2A kindreds versus population-based controls. Pancreatic cancer is the second most frequent cancer diagnosed in PCMS kindreds. [2, 1]

Natural History

An earlier age of onset of melanoma is present in PCMS kindreds compared with the general population. A median age of melanoma diagnosis has been observed between 33 and 45 years old; however, there are several documented cases of melanoma occurring as early as the early teens and twenties. Controversy exists as to whether or not pancreatic cancer is diagnosed at an earlier age in PCMS kindreds compared to sporadic cases. [2, 1]

2. How effective are interventions for preventing harm?

Patient Management

Low fat diet should be recommended for the prevention of pancreatic cancer. (Tier 4) [3]

Fat consumption has been hypothesized to influence pancreatic cancer risk; however a recent meta-analysis of epidemiologic studies found no statistically significant association between fat intake and pancreatic cancer risk. (Tier 5) [4]

Surveillance

Screening recommendations for melanoma in PCMS kindreds are based on the PCMS clinical phenotype rather than the presence of a CDKN2A pathogenic variant. Screening should begin at age 10 with a baseline total body skin examination including scalp, oral mucosa, genital area, and nail, as family members may develop melanoma in their early teens. Patients should be examined every 6 months initially to ensure nevi stability. Once stability is established these visits can be conducted annually or as needed if the patient detects an abnormality on self-exam. Self-examination should be performed by the patient with assistance from a friend or family member every month. Nevi may become more unstable during puberty and pregnancy and may warrant increased frequency of physician examinations during these periods. (Tier 3) [1]

A retrospective case-control study compared the melanomas of 32 unscreened index patients with a CDKN2A pathogenic variant with those diagnosed in 92 relatives after entering an annual screening program. The surveillance detected melanomas were found to be thinner than those of the index patients indicating that they were detected in an earlier stage, except among patients who were not compliant with the surveillance protocol. However, the majority of screen-detected melanomas were diagnosed in patients that were under intensified surveillance because of a previous melanoma. (Tier 5) [5]

A systematic review addressing visual screening for skin cancer identified no trials addressing the effectiveness of skin cancer screening on morbidity and mortality in average-risk individuals. One ecological study found that after the implementation of a population based skin cancer screening program the population age- and sex-adjusted melanoma mortality decreased by 48% with an absolute mortality difference of 0.8 melanoma deaths per 100,000 persons. Eight observational studies examined the association between lesion thickness or stage at diagnosis and mortality. All studies demonstrated a consistent linear increase in the risk of melanoma mortality with increasing tumor thickness. Tumor thickness >4.0mm was associated with a hazard ratio of 3.1-32.6 in multivariate models, indicating increased risk of melanoma mortality compared with thinner lesions. (Tier 5) [6]

Consensus guidelines state that due to increased risk of pancreatic cancer, surveillance should be performed with endoscopic ultrasound and/or MRI of the pancreas. Guidelines differ regarding the frequency and age to start and stop surveillance. Due to variable penetrance, guidelines also differ on whether all individuals with a pathogenic variant in CDKN2A should be screened, or only those with a first degree relative with pancreatic cancer. Guidelines state that there is no proven effective screening tool to reduce pancreatic cancer mortality and that these screening recommendations are primarily based on evidence on increased risk, rather than a proven efficacy of screening. Therefore, surveillance is recommended to be performed in experienced centers utilizing a multidisciplinary approach and under research conditions. The most common findings in surveillance studies are cystic lesions in the pancreas. Management of these cysts is unclear as, similar to cysts in a nonhereditary setting, most are benign or just have low-grade dysplasia. (Tier 2) [3, 7]

178 patients with a pathogenic variant in CDKN2A were included in a screening program with annual MRI with or without ultrasound. Mean age at the start of the program was 56 years (range: 37-75 years) and mean follow up time was 53 months (range: 0-169 months). A total of 866 MRI and 106 ultrasounds were performed. Pancreatic ductal adenocarcinoma (PDAC) was detected in 13 (7.3%) patients. The mean age at diagnosis was 58 years. The cumulative incidence was 14% by age 70. The results showed increased rates in the identification of tumors in stages that allowed for treatment with resection. The resection rate of screen detected cancer (75%) was much higher than reported for sporadic cancer patients (15-20%) and compared to historical controls of with CDKN2A pathogenic variants with symptomatic PDAC (15%). The 5-year survival rate was substantially higher (24%) than the survival rate reported for patients with symptomatic sporadic cancer (4-7%). (Tier 5) [8]

Circumstances to Avoid

As smoking has been shown to be an independent risk factor for pancreatic cancer in families with familial pancreatic cancer (based on family history) (OR=3.7, 95% CI: 1.8-7.6) with smokers developing cancer one decade earlier than nonsmokers (59.6 vs. 69.1 years; p=0.01) , all high-risk individuals should be counseled against smoking. (Tier 2) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

No information on the prevalence of CDKN2A pathogenic variants in the general population were identified.

Penetrance

The penetrance for melanoma in kindreds with CDKN2A pathogenic variants is estimated at 58% to 92% by 80 years of age and varies with geography. (Tier 3) [1]

A study of 19 families with known CDKN2A pathogenic variants estimated penetrance for pancreatic cancer to be 17% in individuals with CDKN2A pathogenic variants by 75 years of age. (Tier 3) [2, 1]

Relative Risk

The risk for developing pancreatic cancer in PCMS families with a known pathogenic variant in CDKN2A is increased 13- to 22- fold with some sources reporting a risk as high as 39 fold. (Tier 3) [7, 1, 3]

Expressivity

PCMS has a highly variable phenotype both between and within kindreds. There is significant heterogeneity in the cutaneous phenotype, some family members will display only part of the phenotype or will show no cutaneous characteristics but may later develop melanoma or pancreatic cancer. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions include the use of full body skin exams and imaging to screen for pancreatic cancer. Incorrect diagnosis of lesions identified during surveillance for pancreatic cancer is a significant concern. Some cysts are found at resection to be benign or low grade pancreatic intraepithelial neoplasia. These results highlight the risk of overtreatment using surveillance. The risk of overtreatment for pancreatic screening is magnified by the risks of morbidity and mortality (∼1–2%) of pancreatic surgery. [7]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Some family members will display only part of the phenotype or will show no cutaneous characteristics but may later develop melanoma or pancreatic cancer. (Tier 3) [1]

Date of Search: 09.22.2016

Reference List

1. Eckerle Mize D, Bishop M, Resse E, Sluzevich J. Familial Atypical Multiple Mole Melanoma Syndrome. Cancer Syndromes. (2009)

2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MELANOMA-PANCREATIC CANCER SYNDROME. MIM: 606719: 2012 Aug 22. World Wide Web URL: http://omim.org.

3. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. (2015) 110(2):223-62; quiz 263.

4. Shen QW, Yao QY. Total fat consumption and pancreatic cancer risk: a meta-analysis of epidemiologic studies. Eur J Cancer Prev. (2015) 24(4):278-85.

5. van der Rhee JI, de Snoo FA, Vasen HF, Mooi WJ, Putter H, Gruis NA, Kukutsch NA, Bergman W. Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families. J Am Acad Dermatol. (2011) 65(2):289-96.

6. Wernli KJ, Henrikson NB, Morrison CC, Nguyen M, Pocobelli G, Blasi PR. Screening for Skin Cancer in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. (2016) 316(4):436-47.

7. Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, Nio Y, Schulick RS, Bassi C, Kluijt I, Levy MJ, Chak A, Fockens P, Goggins M, Bruno M. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. (2013) 62(3):339-47.

8. Vasen H, Ibrahim I, Ponce CG, Slater EP, Matthai E, Carrato A, Earl J, Robbers K, van Mil AM, Potjer T, Bonsing BA, de Vos Tot Nederveen Cappel WH, Bergman W, Wasser M, Morreau H, Kloppel G, Schicker C, Steinkamp M, Figiel J, Esposito I, Mocci E, Vazquez-Sequeiros E, Sanjuanbenito A, Munoz-Beltran M, Montans J, Langer P, Fendrich V, Bartsch DK. Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers. J Clin Oncol. (2016) 34(17):2010-9.