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 1.0.1
• GENE/GENE PANEL: STK11
• Condition: Peutz-Jeghers Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• STK11 ⇔ 175200: 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
Breast Cancer / Risk Reducing Surgery	2	3C	3B	1	9CB
Breast Cancer / Cancer-Specific Surveillance	2	3C	2A	3	10CA
Breast Cancer / Chemoprevention	2	3C	2A	2	9CA
Ovarian Cancer / Risk Reducing Surgery	2	2A	3B	1	8AB
Ovarian Cancer / Cancer-Specific Surveillance	2	2A	0B	3	7AB
Colorectal Cancer / Cancer-Specific Surveillance	2	3A	3B	3	11AB

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

Prevalence of the Genetic Condition

There are roughly 13,028,000 people, or 4.1% of the US population, currently living with cancer. PJS is a rare cancer syndrome, which likely represents a small proportion of cancer prevalence. Specifically for colorectal cancer (CRC), PJS accounts for less than 0.01% of cases. [1, 2, 3]

Clinical Features

PJS is associated with mucocutaneous pigmentation, gastrointestinal polyps, and increased cancer risk. The hamartomatous (benign, tumor-like) polyps are most common in the small intestine but can also occur in the stomach, colon, and extra-intestinal sites such as the bladder and bronchus. Patients are at an increased risk for a variety of epithelial cancers including CRC, gastric, pancreatic, breast, and ovarian cancers as the most common. Women are at risk of ovarian sex-cord tumors with annular tubules, a benign neoplasm, and adenoma malignum of the cervix, a rare aggressive cancer. Males are at risk of testicular tumors of sex cord and Sertoli-cell type. [3, 4, 5, 6]

Natural History

Roughly 45% of individuals with PJS have no family history. Mucocutaneous pigmentation is typically the first sign of PJS, presenting in childhood and typically fading in puberty or adulthood. Polyp-related symptoms (bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction) appear by age 10 in 33% of cases and by age 20 in 50% of cases. No differences in cancer risk by sex have been noted. The average age of a cancer diagnosis is estimated at 42, with 5% being diagnosed with any cancer by age 30, 31% by age 50, and 85% by age 70. [3, 4, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

Women should be 'breast aware' and alert their doctor to any changes. No evidence was identified for the effectiveness of either clinical or self-breast examination as the sole screening modality in women with a family history of breast cancer and/or BRCA1/2 mutations. (Tier 2) [7]

For chemoprevention of breast cancer, tamoxifen should be offered to premenopausal women and postmenopausal women without a uterus, and tamoxifen or raloxifene should be offered to postmenopausal women with a uterus. This recommendation for women with PJS was based on on evidence from randomized trials conducted in women considered 'high risk' for breast cancer based on factors such as age of onset and family history. Results indicated breast cancer incidence was lower in patients given tamoxifen compared to placebo (RR=0.65, 95% CI: 0.56-0.74). (Tier 1) [7]

Prophylactic mastectomy and bilateral salpingo-oophorectomy can be offered to reduce the risk of breast and ovarian cancers. This recommendation for women with PJS was based on evidence showing risk reductions of roughly 90% and 50-75%, respectively, for breast cancer and ovarian cancer among women with BRCA1/2 mutations after bilateral mastectomy and oophorectomy. (Tier 2) [7]

Surveillance

A baseline colonoscopy and gastro-duodenoscopy are recommended followed by colonoscopy and gastro-duodenoscopy every 2-5 years from age 20-25 and small bowel video capsule endoscopy (VCE) or MRI/enteroclysis are recommended every 2-4 years. However, the age to begin surveillance and its recommended frequency can vary across guidelines. PJS is rare, so evidence on the effectiveness of surveillance is limited to pooled case series and anecdotal case reports. However, the high risk of gastrointestinal malignancy provides substantial rationale for cancer surveillance. (Tier 2) [4, 5, 8, 9, 10]

For breast cancer surveillance, women can consider annual mammography at age 30, and are recommended to begin annual mammography by age 40. Women should not be offered MRI at any age. This recommendation for women with PJS was based on evidence that suggests a disease specific survival benefit with mammographic surveillance in women aged less than 50 years who were considered 'high risk' or medium risk' for breast cancer based on family history. (Tier 1) [7]

Patients should have annual physical exams (including testicular palpitation) and hemoglobin analysis as well as annual pancreatic MRI and endoscopic ultrasonography from age 30. Women should have annual pelvic exams, cervical smears, transvaginal ultrasonagraphy, and CA-125 monitoring started at age 25-30. (Tier 2) [5, 10]

Circumstances to Avoid

No agents that increase the risk for the development of polyps or cancer have been identified. (Tier 4) [3]

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

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The incidence of PJS is estimated to be between 1/50,000 and 1/200,000 live births. Between 80-95% of patients with PJS are estimated to have a mutation in STK11. (Tier 3) [4]

Penetrance

The cumulative cancer risk by ages 60-70 are estimated as 37-93% for any cancer and for the two most common types of cancer the risks are 38-66% for gastrointestinal cancer and 13-18% for gynecological cancer. (Tier 1) [5]

Lifetime risk for specific cancers are: 39% colon, 29% stomach, 13% small intestine, 11-36% pancreas, 45-50% breast, 18-21% ovary, 10% cervix, 9% uterus, and 15-17% lung. (Tier 4) [10]

Relative Risk

RR=9.9-18 for any type of cancer, RR=50.5 for gastrointestinal cancer, and RR=20.3 for gynecological/breast cancer. (Tier 1) [5]

Expressivity

Variable expressivity is common, with variability of the age at first polyp and some individuals developing only polyps or perioral pigmentation. (Tier 4) [3]

4. What is the Nature of the Intervention?

Nature of Intervention

The interventions identified in this report include prophylactic surgery to remove target organs, invasive screening tests, and medications with potential side effects [e.g. evidence of an increased incidence of endometrial cancer in patients given tamoxifen compared to placebo (RR=2.13, 95% CI: 1.36-3.32) and inconclusive evidence regarding the effect of raloxifene on endometrial cancer (RR= 1.14, 95% CI: 0.65-1.98].

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

Chance to Escape Clinical Detection

The average age of cancer diagnosis is 42, meaning that many patients would develop cancer well before the recommended age to start surveillance of breast and CRC cancer in the general population, making it likely that cancer in these patients would not be detected early. (Tier 1) [5, 6]

Patients are also encouraged to undergo surveillance for additional cancers, including ovarian and pancreatic, not typical of routine clinical monitoring or annual exams. (Tier 2) [5]

Date of Search: 01.30.2014 (updated 03.10.2015)

Reference List

1. Dunlop MG. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut. (2002) 51 Suppl 5:V21-7.

2. American Cancer Society. Other. (2014) Website: www.cancer.org

3. Peutz-Jeghers Syndrome. Gene Reviews. (2014) Website: http://www.ncbi.nlm.nih.gov/books/NBK1266/

4. Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Friedl W, Moller P, Hes FJ, Jarvinen H, Mecklin JP, Nagengast FM, Parc Y, Phillips RK, Hyer W, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen JT, Clark SK, Hodgson SV. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. (2010) 59(7):975-86.

5. van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. (2010) 105(6):1258-64; author reply 1265.

6. Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. (2000) 119(6):1447-53.

7. Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. NICE. (2013) Website: https://www.nice.org.uk/guidance/cg164/chapter/recommendations

8. Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP, Lucassen A, Jenkins P, Fairclough PD, Woodhouse CR. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. (2010) 59(5):666-89.

9. Diagnosis and management of colorectal cancer. A national clinical guideline. Edinburgh (Scotland) Scottish Intercollegiate Guidelines Network (SIGN). NCG. (2015) Website: https://www.guideline.gov/content.aspx?id=35211

10. Provenzale D, Jasperson K, Ahnen DJ, Cannon JA, David DS, Early DS, et al. Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2014. Publisher: National Comprehensive Cancer Network. (2014) Website: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf