Breast cancer liver metastasis: Primary tumor predictors and histopathologic characteristics of metastatic lesions

Background: Breast cancer metastasis to the liver (BCLM) has poor outcomes because predicting patients at risk for liver metastasis remains elusive as does effective targeting of metastatic lesions. Known risk factors for BCLM include young patient age and primary breast cancer diagnoses of high grade, late stage and triple negative or HER2+ subtypes. Prognostic sensitivity is currently low. Further, lack of histopathologic characterization of BCLM tumors in the literature limits development of targeted therapeutics. Methods: We collected retrospective and prospective BCLM tissues from forty-seven breast cancer patients who underwent liver biopsy (87%) or surgical resection (13%) for clinical indications of BCLM at OHSU Portland, Oregon. Patients were enrolled regardless of age or breast cancer subtype. Patient clinicopathological characteristics at time of primary breast cancer diagnosis were used to identify breast cancer attributes associated with liver metastasis. Histological and immunohistology analyses of formalin fixed paraffin (FFPE) embedded BCLM tissues were employed to assess metastatic tumor and tumor niche characteristics within the liver. Results: At primary breast cancer diagnosis, 38% of cases were ≤45 years of age, with 72% of these young cases diagnosed within 10 years of childbirth. Regardless of patient age, 85% of the primary cancers were ER+, 60% luminal A, 57% low grade, and 73% early stage. The majority of the BCLM lesions were also ER+, while ~10% of the ER+ primary lesions converted to ER- in metastasis. Progesterone receptor switching from ER+PR+ primary to ER+PR- BCLM occurred in ~50% of ER+PR+ cases. High GATA3 staining was observed in 86% of the BCLM tumors, supporting luminal breast cell origin. Replacement growth pattern was dominant, observed in 87% of cases, with immunohistology and immunofluorescence evidence that breast tumor cells utilize existing sinusoidal architecture to establish and maintain metastatic outgrowth. Conclusions: In our single institution cohort, we find that recent pregnancy, young age and proximity to recent childbirth are associated with breast cancer metastasis to the liver. We found most primary cancers that progressed to liver metastasis were ER positive, luminal A, low-grade and early-stage, suggesting these classically-good prognostic indicators in breast cancer may not remain good indicators when accompanied by metastasis to the liver. Finally, improved understanding of the dominant replacement growth pattern and the relation between tumor cells and the liver sinusoids may lead to new drug targets and precision therapies.