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 1.0.0
• GENE/GENE PANEL: TP53
• Condition: Li-Fraumeni Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• TP53 ⇔ 151623: 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 / Cancer specific or general surveillance	2	3C	2B	3	10CB
Breast cancer / Risk reducing surgery	2	3C	3C	1	9CC
Breast cancer / Avoidance of radio therapy	2	3C	2C	3	10CC
Ovarian cancer / Cancer specific or general surveillance	2	3C	0C	3	8CC
Ovarian cancer / Risk reducing surgery	2	3C	3C	1	9CC
Ovarian cancer / Avoidance of radio therapy	2	3C	2C	3	10CC
Colorectal cancer / Cancer specific or general surveillance	2	3C	3C	2	10CC
Colorectal cancer / Risk reducing surgery	2	3C	3C	1	9CC
Colorectal cancer / Avoidance of radio therapy	2	3C	2C	3	10CC
Sarcomas / Surveillance	2	3C	2E	3	10CE
Sarcomas / Avoidance of radio therapy	2	3C	2C	3	10CC
CNS Tumors / Surveillance	2	3C	1C	3	9CC
CNS Tumors / Avoidance of radio therapy	2	3C	2C	3	10CC
Adrenocortical tumors / Surveillance	2	3C	2E	3	10CE
Adrenocortical tumors / Avoidance of radio therapy	2	3C	2C	3	10CC

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

Prevalence of the Genetic Condition

Currently in the US, there are an estimated 13,028,000 people living with cancer. LFS is a rare cancer syndrome, which likely represents a small proportion of cancer prevalence. It is estimated that approximately 400 families with LFS have been identified. [1, 2]

Clinical Features

LFS is associated with early onset of tumors, multiple tumors within an individual, and multiple affected family members. The most common types of tumors are soft tissue sarcomas, osteosarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, which account for about 70% of LFS-related tumors. [2, 3, 4]

Natural History

Of those with LFS, women have a higher risk (93%) of developing cancer by age 50 compared to men (68%), and women have a younger average age of onset (29 years) compared to men (40 years). Roughly 50% of tumors develop by age 30 and 90% by age 60. Individuals with LFS often develop additional malignancies, with an estimated 57% developing a second cancer, and 38% developing a third. Besides an earlier age of onset, the characteristics of LFS-associated tumors compared to non-LFS are unclear, though there is some evidence that breast cancers in LFS are more likely to be HER2-positive compared to other cases. They are also predominantly estrogen and/or progesterone hormone receptor-positive. The overall prognosis is unknown for LFS. [2, 3, 4]

2. How effective are interventions for preventing harm?

Patient Management

Information on effectiveness was not provided for any of the patient management recommendations below unless otherwise stated.

Women should be 'breast aware' and alert their doctor to any changes. However, there is a lack of evidence for a high risk population that either clinical breast examination or self-examination is useful as the sole surveillance modality. (Tier 2) [3, 5]

For chemoprevention, Tamoxifen should be offered to pre and post-menopausal women without a uterus, and Tamoxifen or Raloxifene should be offered to postmenopausal women with a uterus. Results of randomized trials suggest that breast cancer incidence is lower in patients given Tamoxifen compared to the placebo (RR=0.65, 95% CI: 0.56-0.74). However, evidence for the effectiveness of chemoprevention specific to TP53 carriers was not provided. (Tier 1) [5]

Prophylactic bilateral mastectomy and oophorectomy should be offered as a risk-reducing option. Risk reduction for breast cancer and ovarian cancer after bilateral mastectomy and oophorectomy is roughly 90% and 50-75%, respectively, among populations considered high risk. However, the effectiveness of these interventions was not provided specifically for TP53 carriers. (Tier 2) [5]

Both men and women should be educated regarding the signs and symptoms of cancer. (Tier 2) [3]

Patients should contact their physician for any lingering symptoms and illnesses, such as headaches, bone pain, or abdominal discomfort. (Tier 3) [2]

Surveillance

Annual surveillance with breast MRI should be offered to women aged 20-49 years, and should be considered for women aged 50-69. Ultrasound and mammogram breast surveillance for should not be offered, unless MRI is not suitable or when results of MRI are difficult to interpret. In general early detection using surveillance has been shown to confer a survival advantage in women aged less than 50 years with a family history of breast cancer. Although MRI has been shown to be more sensitivity at early detection of breast cancer in the high risk group there is no evidence that this modality in particular confers a survival benefit. The evidence on the effectiveness of MRI breast surveillance in TP53 carriers was not provided. (Tier 1) [5]

Both men and women should undergo comprehensive annual physicals, including skin and neurological exam, starting age 20-25 and should consider colonoscopy every 2-5 years beginning no later than age 25. Information on the effectiveness of these surveillance recommendations was not provided. (Tier 2) [3]

One prospective observational study implemented a surveillance protocol which included the surveillance recommendations listed above as well as additional recommendations. For breast cancer, surveillance included monthly breast self-exams starting at age 18, clinical breast exams twice yearly starting at age 20-25, annual mammography and breast MRI starting at age 20-25, and the consideration of risk reducing mastectomy. For colorectal cancer, surveillance included colonoscopy every 2 years starting at age 40. For melanoma, surveillance included annual dermatological exams. Additional surveillance included annual brain MRI for brain tumors; annual rapid total body MRI and ultrasound of abdomen and pelvis every 6 months for soft tissue and bone sarcomas; and complete blood count, erythrocyte sedimentation rate, and lactate dehydrogenase every 4 months for leukemia or lymphoma. Among 18 patients undergoing surveillance, 10 asymptomatic tumors were detected in 7 patients, while cancers detected in non-surveillance patients were high grade and high stage. The 3-year overall survival was 100% in the surveillance group and 21% in the non-surveillance group. (Tier 5) [6]

Circumstances to Avoid

Information on the effectiveness of these interventions was not provided.

Therapeutic radiotherapy for cancer treatment should be used with caution. (Tier 2) [3]

Carriers of TP53 mutations are counseled to avoid sun exposure, tobacco use, and other known or suspected carcinogens. They are also encouraged to avoid or minimize exposure to diagnostic and therapeutic radiation when possible, including mammography for breast cancer screening. (Tier 3) [2]

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

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Germline mutations in the TP53 gene have been observed in over 50% of families meeting the classic definition of LFS. (Tier 2) [3]

The frequency of TP53 germline mutations in the general population is estimated between 1/5000 and 1/20,000. (Tier 3) [2]

Penetrance

Mutations in TP53 are highly penetrant, with estimated cancer risks of approximately 60% by age 45 and 95% by age 70. (Tier 2) [3]

For lifetime risk of developing cancer, women have a nearly 100% risk while men have a 73% risk. (Tier 3) [2]

Relative Risk

The relative risk of overall tumor development was not found, however tumor-specific relative risks and 95% confidence intervals are available: bone: 107 (49-203), connective tissue: 61 (33-102), brain: 35 (19-60), pancreas: 7.3 (2-19), breast: 6.4 (4.3-9.3), colon: 2.8 (1-6), liver: 1.8 (2.1-6.4). (Tier 3) [2]

Expressivity

LFS patients display high variability in age at onset, tumor locations, and number of types of tumors. (Tier 2) [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 setting of recommended care?

Chance to Escape Clinical Detection

The median age of breast cancer and colorectal cancer diagnosis in LFS is 33 years, younger than the recommended age to start surveillance, making it likely that these patients would escape detection. (Tier 3) [3]

Patients are also encouraged to undergo additional skin, neurological, and system-specific screenings that are not typical of routine clinical monitoring or annual exams. (Tier 2) [3]

Date of Search: 01.07.2014 (updated 11.01.2016)

Reference List

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

2. K Schneider, K Zelley, KE Nichols, J Garber. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2013 Apr 11]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1311

3. NCCN Guidelines® Genetic/Familial High-Risk Assessment Breast and Ovarian. (2019) Website: https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. LI-FRAUMENI SYNDROME 1; LFS1. MIM: 151623: 2016 Jun 24. World Wide Web URL: http://omim.org.

5. 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

6. Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, Malkin D. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. (2011) 12(6):559-67.