Learning Objectives and CME/Disclosure Information

Original Launch Date: 08.10.23

Expiration Date: 08.10.25

ACCME PARS: 102715

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Identify patients at risk for LFS based on personal and family cancer history
2. Describe which cancers are typically associated with LFS

Estimated time to complete activity: 0.5 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG President and CEO, The ObG Project

Disclosure of Financial Relationship

Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.

The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics.

Planners and Managers: PIM Planners have nothing to disclose

Method of Participation and Request for Credit

Participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the test and evaluation. Upon registering and successfully completing the test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.5 contact hours.

Read Disclaimer & Fine Print

SUMMARY:

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome. Individuals with this condition are at risk for many different types of cancers in childhood and in adulthood. Families with LFS are typically characterized by cancers diagnosed at particularly young ages and individuals with multiple primary cancers in the LFS spectrum

Cancer Risks

• Cancer risk by age 70 is nearly 100% among people with LFS
• Risk of a second malignancy is approximately 50%
• LFS increases the risk for the following cancer types
  • Breast (85% risk by age 60)
  • Soft-tissue sarcoma (15% to 22% risk)
  • Osteosarcoma (5% to 11% risk)
  • Central nervous system tumors (6% to 19% risk)
  • Adrenocortical carcinomas (6% to 12% risk)
  • Other associated cancers (risks are not well quantified, but observed in higher prevalence among individuals with LFS)
    • Leukemias and lymphomas
    • Gastrointestinal and colorectal cancers
    • Bronchoalveolar
    • Kidney
    • Melanoma

Genetics

• Autosomal dominant | 7% to 20% of cases are de novo
• Caused by pathogenic variants in TP53, which has many important functions for tumor suppression
• Acquired (somatic) variants in TP53 are commonly found in many tumor types, even among individuals without LFS

Diagnosis

• Clinical diagnostic criteria apply to patients with a sarcoma <45 years and additional family history
• Expert criteria for consideration of genetic testing (known as the Chompret criteria) include
  • Tumor from LFS spectrum <46 years and at least one first- or second-degree relative with either a tumor from the LFS spectrum <56 years or multiple primary cancers at any age
  • Multiple tumors from the LFS spectrum, one diagnosed <46 years
  • Adrenocortical carcinoma, choroid plexus sarcoma, or rhabdomyosarcoma of embryonal anaplastic subtype diagnosed at any age
  • Breast cancer <31 years
• Targeted genetic testing is appropriate when a family member has been diagnosed with LFS
• Testing for LFS may be indicated if a TP53 variant has been identified in a tumor sample

Management

• Referral to cancer genetics and oncology for counseling and management
• Follow-up generally includes
  • Surveillance for breast cancer including consideration of risk-reducing mastectomy
  • Neurologic exams, with a high index of suspicion for cancers
  • Intensive colorectal cancer screening
  • Dermatologic examinations
• Annual whole-body or brain MRIs may be considered
• Therapeutic and diagnostic radiation exposure should be avoided as much as possible
• Pediatricians should be aware of a familial LFS diagnosis and risks for childhood-onset cancers

Note: Because medical interventions can prevent severe morbidity and mortality, Li-Fraumeni syndrome is on the ACMG list of secondary findings | In summary, the ACMG document on reporting such findings makes the following recommendations

• In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
• Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge
• An individual can ‘opt out’ of receiving secondary findings

KEY POINTS:

• LFS is associated with a broad spectrum of cancer types, particularly
  • Breast cancers
  • Sarcomas
  • Central nervous system tumors
• Consider LFS and referral to genetics for patients who present with
  • A personal and family history of LFS-related cancers
  • Young age of onset (<46 years)
  • Multiple primary cancers in the same individual
• Management includes aggressive systematic screening for malignancies and risk-reducing mastectomy

Learn More – Primary Sources:

ACMG and NSGC Joint Practice Guidelines: Referral Indications for Cancer Predisposition Assessment

GeneReviews – Li-Fraumeni Syndrome

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort

OMIM: Li-Fraumeni Syndrome

NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic

Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing

ACOG Committee Opinion 793: Hereditary cancer syndromes and risk assessment

Locate a Genetic Counselor or Genetics Services: 

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC 

Genetic Services Locator-CAGC 

Related ObG Topics:

NCCN: New Genetic Risk Assessment Recommendations for Breast, Ovarian and Pancreatic Cancers

Consensus Guideline: Treatment Options for Hereditary Breast Cancer

ACMG Statement on Genetic Testing for All Breast Cancer Patients