What are the management and treatment options for individuals with an Ataxia-Telangiectasia Mutated (ATM) gene mutation?

Management and Treatment Options for Individuals with ATM Gene Mutations

Individuals with ATM gene mutations require personalized cancer surveillance protocols based on their specific variant type, with enhanced breast cancer screening for women, consideration of pancreatic cancer surveillance in those with family history, and annual PSA testing for men beginning at age 40. 1

Breast Cancer Management

Surveillance Recommendations

• Enhanced breast surveillance based on individualized risk assessment using models such as CanRisk 1, 2
• Annual breast MRI starting at ages 30-35 years 1
• Annual mammography starting at age 40 1
• For carriers of the high-risk c.7271T>G p.(Val2424Gly) variant, begin enhanced surveillance from age 25 due to significantly higher breast cancer risk (up to 60% lifetime risk) 2

Risk-Reducing Surgery

• Risk-reducing mastectomy is not routinely recommended for unaffected female ATM heterozygotes 1, 2
• For women diagnosed with unilateral breast cancer, decision for bilateral mastectomy should be based on:
  • Individual estimated risk
  • Tumor characteristics (age, size, stage, grade, receptor status)
  • Family history 1

Pancreatic Cancer Management

• Benefits of surveillance remain unclear with limited evidence 1
• Consider surveillance for ATM heterozygotes with a family history of pancreatic cancer in first- or second-degree relatives on the side of the family from which the ATM variant originates 1
• Surveillance methods include:
  • Annual endoscopic ultrasound
  • MRI/magnetic resonance cholangiopancreatography 1
• American Society of Gastroenterology guidelines suggest pancreatic cancer screening even without family history, though acknowledging low-quality evidence 1

Prostate Cancer Management

• Annual PSA testing beginning at age 40 is recommended 1, 2
• Digital rectal exam may be useful to guide interpretation of PSA findings 1

Ovarian Cancer Management

• Risk-reducing salpingo-oophorectomy (RRSO) is generally not recommended as female ATM heterozygotes typically don't meet the risk threshold 1
• Consider RRSO only in context of:
  • Strong family history of ovarian cancer
  • Age of cancer diagnosis in family members
  • Other hormonal risk factors 1

Radiation Therapy Considerations

• Current evidence supports offering radiation therapy when indicated, without modification based on ATM heterozygote status 2
• No evidence supports avoiding or modifying radiation therapy based on ATM mutation status 2

PARP Inhibitors and Targeted Therapies

• Limited evidence for effectiveness of PARP inhibitors in ATM-mutated cancers 2
• Olaparib as monotherapy and talazoparib with enzalutamide have FDA approval for HRR tumor gene mutations, including ATM 1
• No evidence of clinical benefit for targeted therapies in other tumor types 1

Genetic Counseling Considerations

• Cascade testing of adult family members is appropriate 2
• Consider partner testing before pregnancy planning, especially with family history of Ataxia-Telangiectasia 2
• Discuss preimplantation genetic testing and prenatal diagnosis options 2

Important Caveats and Pitfalls

1. Variant-specific risk: The c.7271T>G p.(Val2424Gly) variant confers significantly higher breast cancer risk (up to 60%) and requires more aggressive surveillance 1, 2

2. Variants of uncertain significance (VUS) should not guide clinical management or predictive testing 2

3. Radiation sensitivity: Despite theoretical concerns, current evidence does not support avoiding radiation therapy in ATM heterozygotes 1, 2

4. Heterogeneous cancer risks: ATM mutations confer variable risks for different cancer types, with strongest evidence for breast, pancreatic, and prostate cancers 1

5. Evolving evidence: Management recommendations may change as more prospective data becomes available on ATM-associated cancer risks and treatment responses 1, 2