Lower mitotic activity in BRCA1/2-associated primary breast cancers occurring after risk-reducing salpingo-oophorectomy

Abstract

Risk-reducing salpingo-oophorectomy (RRSO) is associated with 50% reduction of BRCA1/2-associated breast cancer (BC) risk, possibly through decreased growth activity. In this pilot study, tumor characteristics and growth rates of BRCA1/2-associated primary BCs (PBCs) detected after RRSO were compared with those of PBCs originating without RRSO. From a cohort of 271 women with BRCA1/2-associated screen detected BC, we selected 20 patients with PBC detected ≥12 months after RRSO (RRSO group). Controls were 36 BRCA1/2 mutation carriers with PBC detected without RRSO (non-RRSO group) matched for age at diagnosis (± 2.5 y) and for BRCA1 or BRCA2 mutation. Pathology samples were revised for histological subtype, tumor differentiation grade, mitotic activity index (MAI), estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Tumor growth rates, expressed as tumor volume doubling times (DT), were calculated from revised magnetic resonance and mammographic images. Median age at PBC diagnosis was 52 y (range 35-67). PBCs after RRSO had lower MAIs (12 vs. 22 mitotic counts/2 mm, P = 0.02), were smaller (11 vs. 17 mm, P = 0.01), and tend to be PR-positive more often than PBCs without RRSO (38% vs. 13%, P = 0.07). Differentiation grade, ER, and HER2 status were not different. Median DT was 124 d (range 89-193) in the RRSO group and 93 days (range 54-253) in the non-RRSO group (P = 0.47). BC occurring after RRSO in BRCA mutation carriers features a lower MAI, suggesting a less aggressive biological phenotype. When confirmed in larger series, this may have consequences for BC screening protocols after RRSO.

Keywords: BRCA1/2; breast cancer; estrogen; mitotic activity; risk-reducing salpingo-oophorectomy; tumor characteristics; tumor growth.

Figure 1. Patient inclusion from the Rotterdam Family Cancer Clinic. ^aPBC, primary breast cancer; ^bRRSO, risk-reducing salpingo-oophorectomy.

Figure 2. (A) Tumor volumes over time and (B) tumor volume doubling times (DTs) for primary breast cancers occurring after risk-reducing salpingo-oophorectomy (RRSO) and without RRSO (non-RRSO). ln, natural logarithm; tumor volumes: V = 4/3π*1/2a*1/2b*1/2c, where a, b, and c are perpendicular tumor diameters on MRI or mammography; tumor volume doubling time (DT): DT = (ln2)/β; β = slope between natural logarithms of tumor volumes.