Management and Treatment Options for Individuals with ATM Gene Mutations
Management of individuals with ATM gene mutations should be tailored based on whether they have biallelic mutations (causing Ataxia-Telangiectasia) or heterozygous mutations (carriers), with specific cancer surveillance and risk reduction strategies implemented according to the type of mutation and family history. 1
Biallelic ATM Mutations (Ataxia-Telangiectasia)
Clinical Management
- Neurological Support: For progressive cerebellar degeneration and ataxia
- Immunological Management: Treatment of recurrent sinopulmonary infections and bronchiectasis
- Cancer Surveillance: Heightened monitoring due to elevated malignancy risk
- Supportive Care: Median survival is between 19-30 years, with respiratory failure and malignancy being the main causes of death 1
Emerging Treatments
- Dexamethasone Administration: Positive effects on neurological features have been observed in phase II and III clinical trials using dexamethasone delivered through autologous erythrocytes (EryDex) 2
- Potential Gene Therapy: Research into ATM variants capable of restoring cellular functionality shows promise for future therapeutic approaches 2
Heterozygous ATM Mutations (Carriers)
Cancer Risk Management
Breast Cancer
- Risk Assessment: Use individualized risk assessment models like CanRisk to determine surveillance needs
- Enhanced Surveillance: Most ATM heterozygotes qualify for enhanced breast surveillance
- MRI Screening: Many carriers meet criteria for breast MRI based on country-specific guidelines 1
- Risk-Reducing Surgery:
- Bilateral risk-reducing mastectomy is not routinely recommended but may be considered based on individualized risk assessment and shared decision-making
- For women already diagnosed with breast cancer, contralateral risk-reducing mastectomy should be considered only after thorough risk assessment 1
Pancreatic Cancer
- Surveillance: Consider pancreatic cancer screening, ideally as part of a clinical trial
- Limited Evidence: Studies show limited detection of pancreatic cancers in ATM heterozygotes during surveillance programs 1
Prostate Cancer
- Screening: Annual PSA testing beginning at age 40 is reasonable
- Digital Rectal Exam: May be useful to guide interpretation of PSA findings 1
Ovarian Cancer
- Risk-Reducing Surgery: Routine risk-reducing salpingo-oophorectomy (RRSO) is not supported by current evidence
- Exceptions: Consider RRSO in the context of family history of ovarian cancer or if gynecological surgery is planned for other reasons 1
Special Considerations for Specific Variants
- Higher Risk Variants: Some specific missense variants like c.7271T>G p.(Val2424Gly) confer significantly higher breast cancer risk (up to 60% by age 80) compared to typical truncating variants 1
- Risk Assessment Tools: Note that standard risk assessment models like CanRisk may underestimate risks for these higher-risk variants 1
Family Planning and Genetic Counseling
- Partner Testing: Consider partner testing before pregnancy planning, especially with family history of AT or in consanguineous relationships 1
- Reproductive Options: Discuss preimplantation genetic testing and prenatal diagnosis options 1
- Cascade Testing: Offer genetic testing to adult family members to guide their management 1
Treatment Considerations for Cancer in ATM Mutation Carriers
- Radiation Therapy: Current consensus is to offer radiation therapy when indicated, without modification based on ATM heterozygote status 1
- PARP Inhibitors: Limited evidence for effectiveness in ATM-mutated cancers, with mixed responses observed in clinical trials 1
Important Caveats
- Variant Classification: Variants of uncertain significance (VUS) should not guide clinical management or predictive testing
- Variant Reclassification: ATM variants may be reclassified over time as new evidence emerges
- Research Gaps: Further studies are needed to fully define ATM-associated cancer risks and the effectiveness of early detection and risk-reducing interventions 1
- Mutational Heterogeneity: High incidence of new and individual mutations has been demonstrated in different populations 3