Cancer in Fanconi anemia

Three separate and complementary reports recently described the leukemia and solid tumor experience in cohorts of patients with Fanconi anemia (FA).1-3 Here we examine the similarities and differences of these reports (Table1) in order to synthesize the most current evidence for physicians and patients.

The literature review (LIT) encompasses 1300 cases reported worldwide from 1927 to 2001.3 The International Fanconi Anemia Registry (IFAR) includes 754 North American patients ascertained between 1982 and 2001.2 Our North American Survey (NAS) collected cross-sectional data from 145 patients during 2000.1 These cohorts are not mutually exclusive, and each study has potential biases. LIT cases are susceptible to publication bias, due to preferential reporting of patients with interesting outcomes. IFAR and NAS cases are subject to selection bias, since they studied volunteers. Some of the data were obtained by unverified self-report, although in the latter 2 studies, neoplasm diagnoses were confirmed objectively.

A strength of the IFAR report is the large number of subjects; a limitation of NAS is its small numbers. All of the cohorts have missing data, hindering some comparisons. Also, IFAR does not distinguish myelodysplastic syndromes (MDS) from leukemia patients, nor solid tumor patients vis-à-vis prior transplantation status. Therefore, the impact of MDS and transplantation on hazard rates cannot be assessed. It would be informative for IFAR to separately analyze MDS, acute myeloid leukemia (AML), and solid tumors prior to/after transplantation. Importantly, the competing risk end points differed between IFAR (any adverse outcome) and NAS (first adverse event).

IFAR also defined “hematologic abnormality” as hemoglobin level below 10 g/dL, absolute neutrophil count below 1 × 10⁹/L, or platelet count below 100 × 10⁹/L; LIT and NAS employed the consensus criteria for therapeutic intervention: hemoglobin level below 8 g/dL, absolute neutrophil count below 0.5 × 10⁹/L, or platelet count below 30 × 10⁹/L.4 

What general conclusions can be drawn by comparing these cohorts? The cumulative incidence of any hematologic finding in FA may be as high as 90%, although bone marrow failure that requires therapy appears to have a cumulative incidence of about 60%. The crude risk of leukemia (exclusive of MDS) is between 5% and 10%, while the cumulative incidence of leukemia (using competing risk analyses) is about 10% by age 25. The crude risk of MDS is about 5%, and the evolution from MDS to leukemia is not inevitable: it was estimated at 9% per year in NAS. It would be valuable to know what this risk was in IFAR.

The crude risk of solid tumors in FA patients who have not received a transplant is 5% to 10%, while the cumulative incidence in the presence of competing risks is about 30% by age 45. Removing competing risks, solid tumor incidence reaches 75% by age 45.1,3 

The impact of transplantation on the solid tumor hazard rate in FA is not well defined, although some suggest the crude risk reaches 42% by 12 years (3.5% per year) after transplantation.5 Among IFAR patients, solid tumors developed in 2.7% without and 13% with transplantation. A time-dependent analysis would be more informative, since the crude rates are biased by the short survival of patients receiving transplants. The crude rate for solid tumors in NAS was 0.7% per year versus 2% per year without or with transplantation (rate ratio 2.8; P = .07). These data suggest that the risk of solid tumors may be increased by transplantation.

Despite the differences in study design and analysis, the overall impressions are consistent: FA is a condition with very high risks of bone marrow failure, leukemia, and solid tumors. The first adverse event may be determined by each individual's unique combination of FA genotype, cancer susceptibility modifier genes, and environmental risk factors. Future studies are needed to quantify more precisely the individualized risk of each adverse event, elucidate their pathophysiology, and clarify the role of FA genes in the etiology of hematopoietic failure and cancer.