Prevalence and outcomes of cancer and treatment-associated toxicities for patients with Ataxia Telangiectasia.

Background: Ataxia Telangiectasia (A-T) is a DNA repair disorder with cancer predisposition.

Objective: Characterize the prevalence and outcomes of hematologic and solid cancers and treatment-associated toxicities in individuals with A-T.

Methods: Data was retrospectively analyzed from the Johns Hopkins Ataxia Telangiectasia Clinical Center cohort. Cumulative incidence and standardized incidence ratios of cancer, survival probability after cancer diagnosis, and standardized mortality ratios were calculated. Cox regression estimated risk of death based on chemotherapy (standard v reduced) dosing and multivariable logistic regression evaluated cancer risk associations with ATM exons and variants.

Results: Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, 62 (74%) were hematologic in origin and 22 (26%) were solid organ cancers. The cumulative incidence of cancer was 29% by age 35 years. Non-Hodgkin lymphoma occurred most frequently (n=39), while solid cancers disproportionately affected those ≥18 years old (n=22). The standardized mortality ratio was 24.6 (95% CI:21.1-28.4) overall and 232.9 (95% CI:178.1-299.2) among individuals with cancer. Risk of death was higher when treated with standard/unknown versus modified chemotherapy (HR 2.2, 95% CI:1.1-4.4, p=0.024). Chemotherapy-associated toxicities developed in 58% of individuals, predominantly neurologic (n=14) and gastrointestinal (n=10) systems. Three exons were enriched for cancer-associated variants.

Conclusion: Individuals with A-T experience a wide array of blood and solid organ malignancies, high mortality rates, and treatment related toxicities, highlighting need for targeted therapies to mitigate toxicity and optimize survival.

Clinical implication: A-T patients with cancer face elevated mortality rates, underscoring the urgency for tailored therapies to minimize toxicity and improve survival outcomes.