Secretory breast carcinoma: morphologic and molecular heterogeneity with indicators of aggressive potential in a cohort of 29 cases

Abstract Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6‐NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12–63 years (median 44). Twenty‐eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0–1/10 high‐power fields, HPF). A single patient with distant metastasis harboured a solid‐predominant tumour showing nuclear grade 2–3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan‐TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2–30% of tumour cells), and all were HER2 negative or low (0–1+). Ki‐67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6‐NTRK3 dual‐fusion; 3 NTRK3 break‐apart). In the metastatic case, RNA sequencing confirmed canonical ETV6‐NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) – RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow‐up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6‐NTRK3 rearrangement with diffuse pan‐TRK/S100 positivity. A solid‐predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK‐inhibitor therapy in advanced disease.