Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer

TY - JOUR

T1 - Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer

AU - Sønderstrup, I. M. H.

AU - Jensen, M. B.

AU - Ejlertsen, B.

AU - Eriksen, J. O.

AU - Gerdes, A. M.

AU - Kruse, T. A.

AU - Larsen, M. J.

AU - Thomassen, M.

AU - Lænkholm, A. V.

PY - 2019/3/4

Y1 - 2019/3/4

N2 - Background: Patients with a BRCA1 or BRCA2 mutation (BRCA-mutated breast cancer) are frequently diagnosed with low differentiated and highly proliferating breast cancer characterized by high amounts of tumor-infiltrating lymphocytes (Tils). Stromal Tils (sTils) are highly prognostic in sporadic triple-negative and HER2 positive breast cancer however, their prognostic importance in BRCA-mutated breast cancers is unknown. Material and methods: Formalin-fixed paraffin-embedded primary tumor tissue from 411 patients with a germline BRCA1 or BRCA2 mutation and diagnosed with early breast cancer was included. The percentage of sTils was quantified on full HE sections according to guidelines proposed by the Immuno-Oncology Biomarker in Breast Cancer Working Group. Distribution of sTils and associates with patient and tumor characteristics were assessed according to categorical sTils groups defined as low (<10%), intermediate (10–59%) and high (≥60%). Prognostic associations of sTils were evaluated as a continuous variable in univariate and multivariate models. Only follow-up time beyond date of BRCA mutation test was included. Results: A large proportion had high sTils (27% in the full cohort, 36% in BRCA1-mutated, and 44% in ER negative breast cancers). Higher sTils were associated with BRCA1, ER negative breast cancer, high histological grade and medullary histology. In combined analysis for BRCA1 and BRCA2-mutated breast cancers, increasing sTils in 10% intervals were significantly associated with OS (HR 0.92, 95% CI 0.84–1.00, p =.05). For each 10% increment of sTils in BRCA1 breast cancers, a 10% reduction of mortality (adjusted HR 0.90 95% CI 0.81–0.99, p =.03) and a 13% reduction in risk of DFS-event (HR 0.87 95% CI 0.76–1.00, p =.05) was observed even after adjustment for ER status. No significant association with survival was of observed in the BRCA2 subgroup. Test for interaction of sTils and BRCA status was not statistically significant (p =.3). Conclusions: Breast cancer patients with a germline BRCA mutation had higher sTils than previously reported in sporadic breast cancers, and sTils were associated with favorable survival among BRCA carriers.

AB - Background: Patients with a BRCA1 or BRCA2 mutation (BRCA-mutated breast cancer) are frequently diagnosed with low differentiated and highly proliferating breast cancer characterized by high amounts of tumor-infiltrating lymphocytes (Tils). Stromal Tils (sTils) are highly prognostic in sporadic triple-negative and HER2 positive breast cancer however, their prognostic importance in BRCA-mutated breast cancers is unknown. Material and methods: Formalin-fixed paraffin-embedded primary tumor tissue from 411 patients with a germline BRCA1 or BRCA2 mutation and diagnosed with early breast cancer was included. The percentage of sTils was quantified on full HE sections according to guidelines proposed by the Immuno-Oncology Biomarker in Breast Cancer Working Group. Distribution of sTils and associates with patient and tumor characteristics were assessed according to categorical sTils groups defined as low (<10%), intermediate (10–59%) and high (≥60%). Prognostic associations of sTils were evaluated as a continuous variable in univariate and multivariate models. Only follow-up time beyond date of BRCA mutation test was included. Results: A large proportion had high sTils (27% in the full cohort, 36% in BRCA1-mutated, and 44% in ER negative breast cancers). Higher sTils were associated with BRCA1, ER negative breast cancer, high histological grade and medullary histology. In combined analysis for BRCA1 and BRCA2-mutated breast cancers, increasing sTils in 10% intervals were significantly associated with OS (HR 0.92, 95% CI 0.84–1.00, p =.05). For each 10% increment of sTils in BRCA1 breast cancers, a 10% reduction of mortality (adjusted HR 0.90 95% CI 0.81–0.99, p =.03) and a 13% reduction in risk of DFS-event (HR 0.87 95% CI 0.76–1.00, p =.05) was observed even after adjustment for ER status. No significant association with survival was of observed in the BRCA2 subgroup. Test for interaction of sTils and BRCA status was not statistically significant (p =.3). Conclusions: Breast cancer patients with a germline BRCA mutation had higher sTils than previously reported in sporadic breast cancers, and sTils were associated with favorable survival among BRCA carriers.

KW - Adolescent

KW - Adult

KW - Aged

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Cohort Studies

KW - Disease-Free Survival

KW - Female

KW - Humans

KW - Lymphocytes, Tumor-Infiltrating/pathology

KW - Middle Aged

KW - Mutation

KW - Prognosis

U2 - 10.1080/0284186x.2018.1539239

DO - 10.1080/0284186x.2018.1539239

M3 - Journal article

C2 - 30614364

SN - 0284-186X

VL - 58

SP - 363

EP - 370

JO - Acta Oncologica

JF - Acta Oncologica

IS - 3

ER -