Nonhematologic neoplasia in biallelic BRCA2 mutated Fanconi anemia.

Abstract

10041 Background: Fanconi anemia (FA) is a cancer predisposition disorder. Affected individuals do not tolerate conventional doses of chemotherapy or radiation well. Biallelic BRCA2 mutations cause a rare (̃3%) form of FA. Most patients with this subtype have a family history of breast cancer and die in early childhood. Optimal management remains uncertain. Herein, we report the world’s largest single center cohort of biallelic BRCA2 patients, with a focus on non-hematologic malignancies. Methods: The University of Minnesota’s prospectively maintained FA database was analyzed for data on biallelic BRCA2 mutated FA patients. IRB-approved consent was obtained for all subjects. Results: Twenty patients with biallelic BRCA2 were identified. Median age of FA diagnosis was 1.5 years (range: 0-16.2 years). All patients had a significant history of cancer in the family with breast cancer being particularly frequent (65%). Eight (40%) patients developed non-hematologic neoplasia before 18 years of age. These included 10 malignant tumors and 4 benign neoplastic lesions; 3 patients had more than one solid tumor (see Table). Surgical resection was attempted in all malignant tumors, dose reduced adjuvant chemotherapy was utilized in 5 cases and radiation in one case. Thirteen (65%) patients developed hematologic malignancies (AML=6, ALL=3, MDS=4), all without preceding marrow failure. Fourteen patients underwent allogeneic HCT. Eleven patients have died, 3 from solid tumors and 5 from leukemias. Nine patients are currently alive, of whom 3 are post-HCT. Only 4 (age range: 6.5-16.3 years) patients in the cohort remain free of any oncologic diagnoses. Conclusions: Patients with FA due to biallelic BRCA2 mutations have a unique phenotype with an extraordinarily high risk of early-onset de-novo acute leukemia and solid tumors, often both diagnosed in the same patient. They require extensive, lifelong cancer surveillance from an early age to optimize outcomes. Therapy for malignant diagnoses should aim to minimise exposure to genotoxic / crosslinking agents and radiation. BRCA2 mutation testing in family members and appropriate genetic counselling is essential. Additionally, a family history of BRCA2 mutated cancers should prompt FA testing in offspring with any relevant FA-related clinical findings. Nonhematologic neoplasia and therapy.[Table: see text]