Theresa Link

A Subpopulation of Stromal Cells Controls Cancer Cell Homing to the Bone Marrow

Breast and prostate cancer cells home to the bone marrow, where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSCs by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers, suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this MSC subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.Significance: These findings establish an inverse relationship between a subpopulation of mesenchymal stromal cells and cancer cells in the bone marrow. Cancer Res; 78(1); 129-42. ©2017 AACR.

Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression

BACKGROUND Prostate stem cell antigen (PSCA) has been suggested as biomarker and therapeutic target for prostate cancer. Recent advances showed that PSCA is up-regulated in other cancer entities, such as bladder or pancreatic cancer. However, the clinical relevance of PSCA-expression in breast cancer patients has not yet been established and is therefore addressed by the current study. METHODS PSCA-protein expression was assessed in 405 breast cancer patients, using immunohistochemistry (PSCA antibody MB1) and tissue microarrays. RESULTS PSCA-expression was detected in 94/405 patients (23%) and correlated with unfavorable histopathological grade (p=0.011) and increased Ki67 proliferation index (p=0.006). We observed a strong positive correlation between PSCA-protein expression and HER2/neu receptor status (p<0.001). PSCA did not provide prognostic information in the analyzed cohort. Interestingly, the distribution of PSCA-expression among triple negative patients was comparable to the total population. CONCLUSION We identified a subgroup of PSCA-positive breast cancer patients, which could be amenable for a PSCA-targeted therapy. Moreover, given that we found a strong positive correlation between PSCA- and HER/neu expression, targeting PSCA may provide an alternative therapeutic option in case of trastuzumab resistance.Background Prostate stem cell antigen (PSCA) has been suggested as biomarker and therapeutic target for prostate cancer. Recent advances showed that PSCA is up-regulated in other cancer entities, such as bladder or pancreatic cancer. However, the clinical relevance of PSCA-expression in breast cancer patients has not yet been established and is therefore addressed by the current study. Methods PSCA-protein expression was assessed in 405 breast cancer patients, using immunohistochemistry (PSCA antibody MB1) and tissue microarrays. Results PSCA-expression was detected in 94/405 patients (23%) and correlated with unfavorable histopathological grade (p=0.011) and increased Ki67 proliferation index (p=0.006). We observed a strong positive correlation between PSCA-protein expression and HER2/neu receptor status (p<0.001). PSCA did not provide prognostic information in the analyzed cohort. Interestingly, the distribution of PSCA-expression among triple negative patients was comparable to the total population. Conclusion We identified a subgroup of PSCA-positive breast cancer patients, which could be amenable for a PSCA-targeted therapy. Moreover, given that we found a strong positive correlation between PSCA- and HER/neu expression, targeting PSCA may provide an alternative therapeutic option in case of trastuzumab resistance.

Abstract P6-06-48: Breast cancer subtypes and metastatic pattern at the Regional Breast Center Dresden

Background: Breast cancer is classified into the subtypes luminal A, luminal B (HER2 positive or negative), HER2 enriched (not luminal) and triple negative (St. Gallen International Breast Cancer Conference 2011). These breast cancer subtypes show differences in response to therapies and prognosis. Amongst others prognosis is depended on hormone receptor positivity, extent and localization of metastases. Routine screening for metastatic disease is not part of the guidelines for breast cancer aftercare although in oligometastatic disease surgery or local ablative therapies can be used to improve outcome. We evaluated if tumor aftercare should be individualized due to different patterns of metastases of the breast cancer subtypes. Methods: Four hospitals incorporated into the Regional Breast Center Dresden as a certified center of excellence for treating breast cancer. We retrospectively evaluated sites and characteristics of metastases and survival data according to the intrinsic breast cancer subtypes from patients treated between 2006 and 2011. Immunohistochemical detection of estrogen and progesterone receptor, grading and overexpression of HER2 oncogene was used for identifying tumor subtypes. All data were collected at the Clinical Cancer Registry Dresden. Results: In 2006 routinely identification of overexpression of HER2 started. Since that time 2334 patients had therapy for breast cancer- 12,4% (290/2334) with metastatic disease (7.2%; 168/2334 primary and 5.2%; 122/2334 relapse). Mean duration of follow up was 38 months. Metastatic disease was more frequently found in HER2 enriched, 27.2%; 30/110, and triple negative, 19.7%; 44/223, than in the luminal subtypes: luminal A 8.3%; 107/1284, luminal B HER2 negative 12.2%; 23/188, luminal B HER2 positive 16%; 36/225. Luminal A and B HER2 negative subtypes showed a preference for solely bone metastases (43%; 56/130) which was rare in triple negative breast cancer (6.8% 3/44). If bone metastases occurred in triple negative breast cancer they mostly appeared together with visceral and/or brain metastatic disease (27%; 12/44). Solely visceral metastases were found in the HER2 enriched subtype (46.7%; 14/30), luminal B HER2 positive (38.9%; 14/36), and triple negative breast cancer (20.2%; 19/44). Brain metastases were more frequently observed in triple negative breast cancer (22.7%; 10/44). Overall survival rate at 5 years for metastatic disease was 38.5% (95%CI 28.2-52.5) for luminal A, 23.1% (95%CI 12.0-44.5) for luminal B (HER2 negative), 11.9% (95%CI 5.5-25.7) for luminal B (HER2 positive), 27.6% (95%CI 14.4-52.8) for HER2 enriched and 6.5% (95%CI 2.4-17.1) for triple negative subtype. Conclusion: Different patterns of metastatic disease were seen according to the subtypes of breast cancer. An individualized tumor aftercare that includes screening for visceral metastasis might improve prognosis of patients with luminal B HER positive, HER enriched and triple negative subtype. Further investigation on patients eligible for metastatic surgery should be performed with longer follow up and evaluated with respect to post-interventional survival. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-48.