Background Breast cancer patients generally have a worse prognosis in presence of liver metastasis. The purpose of this study was to evaluate the risk factors and prognosis of breast cancer patients with liver metastases (BCLM). Methods Data on 311,573 breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database diagnosed 2010 to 2016 and 1728 BCLM patients from Fudan University Shanghai Cancer Center (FUSCC) were analyzed for further exploration. We extracted the clinicopathological characteristics for analysis by two independent authors. Logistic regression was used to identify factors associated with the risk of liver metastases. Survival analysis was completed using Cox proportional hazards regression model and Kaplan-Meier analysis. Results Young age, invasive ductal carcinoma, higher pathological grade, and subtype of triple-negative and human epidermal growth factor receptor 2 positive (HER2+), were associated with increased risk of the liver metastases. The median overall survival (OS) after BCLM diagnosis was 20.0 months in the SEER database and 27.3 months in the FUSCC dataset. We observed that hormone receptor-positive (HR+)/HER2+ patients had the longest median OS 38.0 for SEER vs. 34.0months for FUSCC), whereas triple-negative breast cancer had the poorest OS (9.0 vs. 15.6 months) in both SEER and FUSCC. According to the results from the FUSCC, the subtype of HR+/HER2+ (hazard ratio (HR)=2.62; 95% confidence interval (CI)= 1.88-3.66; P<0.001) and HR-/HER2+ (HR=3.43; 95% CI=2.28-5.15; P<0.001) were associated with a significantly increased death risk in comparison with subtype of HR+/HER2-, if the patients did not receive HER2-targeted therapy. For BCLM patients who had received HER2-targeted therapy, however, HR+/HER2+ was an indicator for decreased death risk in comparison of the subtype of HR+/HER2- (HR=0.74; 95% CI=0.58-0.95; P<0.001). Conclusions BCLM is associated with poor survival, depending on HR/HER2-defined subtypes. Patients with HR+/HER2+ subtype displayed the longest median survival than HR+/HER2- and triple-negative BCLM patients. HER2-targeted therapy should be recommended for HER2+ BCLM patients.

Background: Liver metastasis is a significant adverse predictor of overall survival (OS) among breast cancer patients. The purpose of this study was to determine the risk and prognostic factors of breast cancer with liver metastases (BCLM). Methods: Data on 311,573 breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database and 1728 BCLM patients from Fudan University Shanghai Cancer Center (FUSCC) were included. Logistic regression was used to identify risk factors for liver metastasis. Cox proportional hazards regression model was adopted to determine independent prognostic factors in BCLM patients.Results: Young age, invasive ductal carcinoma, higher pathological grade, and subtype of triple-negative and human epidermal growth factor receptor 2 positive (HER2+) were risk factors for developing liver metastasis. The median OS after liver metastasis was 20.0 months in the SEER database and 27.3 months in the FUSCC dataset. Molecular subtypes also played a critical role in the survival of BCLM patients. We observed that hormone receptor-positive (HR+)/HER2+ patients had the longest median OS (38.0 for SEER vs. 34.0months for FUSCC), whereas triple-negative breast cancer had the shortest OS (9.0 vs. 15.6 months) in both SEER and FUSCC. According to the results from the FUSCC, the subtype of HR+/HER2+ (hazard ratio (HR)=2.62; 95% confidence interval (CI)= 1.88-3.66; P<0.001) and HR-/HER2+ (HR=3.43; 95% CI=2.28-5.15; P<0.001) were associated with a significantly increased death risk in comparison with HR+/HER2- patients if these patients did not receive HER2-targeted therapy. For those who underwent HER2-targeted therapy, however, HR+/HER2+ subtype reduced death risk compared with HR+/HER2- subtype (HR=0.74; 95% CI=0.58-0.95; P<0.001).Conclusions: Breast cancer patients at a high risk for developing liver metastasis deserve more attention during the follow-up. BCLM patients with HR+/HER2+ subtype displayed the longest median survival than HR+/HER2- and triple-negative patients due to the introduction of HER2-targeted therapy and therefore it should be recommended for HER2+ BCLM patients.

Background: PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of PARPi in TNBC can be improved with CDK4/6 inhibitors (CDK4/6i).Methods: We screened primary PARPi-sensitive and resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired PARPi resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically.Results: We demonstrated for the first time that the combination of PARPi and CDK4/6i has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In the PARPi-sensitive MB436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In the PARPi-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of PARPi and CDK4/6i greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumor growth. Inadequate DNA damage caused by PARPi activated the Wnt signaling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site activated the Wnt signaling pathway and mediated PARPi resistance, which could be strongly inhibited by the combined treatment with CDK4/6i.Conclusions: Our data provide a rationale for the clinical evaluation of the therapeutic synergy of PARPi and CDK4/6i in BRCAmut/TNBCs with high Wnt signaling activation, high MYC expression and do not respond to PARPi monotherapy.