486P - The influence of NF1 germline and somatic mutations on breast cancer patient survival

Background

Somatic inactivation of the NF1 gene is frequent in breast cancer, particularly in advanced stages, and it has been suggested as a potential mechanism of resistance to endocrine therapy. Pathogenic germline variants of the NF1 gene cause neurofibromatosis 1 (NF1) syndrome that is associated with an increased risk for breast cancer and reduced estrogen receptor expression in breast cancer. The present study aims to explore the consequences of somatic and germline NF1 mutations in hormone receptor positive and negative breast cancer.

Methods

In order to study germline NF1 alterations, a Finnish cohort of 1,811 individuals with verified NF1 syndrome (926 women) and a ten-fold control cohort were cross-referenced with the Finnish Cancer Registry. The process identified 49 women with NF1 and 226 controls who had been diagnosed with breast cancer between 1996 and 2020. The analysis was limited to non-localized disease. Register-based information on endocrine therapy was used as a proxy for hormone receptor status. Survival after breast cancer with or without somatic NF1 deficiency was analyzed using the METABRIC dataset, which contained 582 breast cancers harboring somatic alterations of the NF1 gene, and 1,392 tumors where the NF1 gene was intact. Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CI).

Results

Somatic NF1 alterations were associated with worse prognosis compared to tumors with normal NF1 after estrogen receptor positive breast cancer (HR 1.53, 95% CI 1.16-2.02) while the NF1 alteration status had no effect on survival after the diagnosis of an estrogen receptor negative breast cancer (HR 1.10, 95% CI 0.80-1.52). In contrast, pathogenic germline variants of the NF1 gene were not associated with decreased survival in patients with or without endocrine therapy (HR 0.76, 95% CI 0.28-2.04; and HR 1.04, 95% CI 0.40-2.70, respectively).

Conclusions

Only somatic alterations of the NF1 gene modify endocrine therapy outcomes in breast cancer. This suggests that estrogen receptor-positive breast cancer employs a different pathway for estrogen receptor signaling in women with pathogenic germline NF1 variants than in the setting of somatic NF1 inactivation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cancer Foundation Finland, Turku University Hospital.

Disclosure

All authors have declared no conflicts of interest.