A83-01 inhibits TGF-ß-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells.

PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-ß and Wnt/ß-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-ß on Wnt/ß-catenin signaling pathway was examined by using a human Wnt/ß-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay. RESULTS: HER2-overexpressing breast cancer cells treated with TGF-ß have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-ß-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and ß-catenin pathways. The TGF-ß-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-ß regulating Wnt3 during EMT. Subsequently, TGF-ß-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/ß-catenin signaling were repressed by the shRNA treatment. TGF-ßR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-ß-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-ß-induced cell invasion significantly in both trastuzumab responsive and resistant cells. CONCLUSIONS: Our data demonstrated an important interdependence between TGF-ß and Wnt/ß-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-ß-induced EMT. A83-01 could inhibit the TGF-ß-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment.

Are primary care providers prepared to care for survivors of breast cancer in the safety net?

BACKGROUND: With the growing number of survivors of breast cancer outpacing the capacity of oncology providers, there is pressure to transition patients back to primary care. Primary care providers (PCPs) working in safety-net settings may have less experience treating survivors, and little is known about their knowledge and views on survivorship care. The current study was performed to determine the knowledge, attitudes, and confidence of PCPs in the safety net at delivering care to survivors of breast cancer. METHODS: A modified version of the National Cancer Institute's Survey of Physician Attitudes Regarding Care of Cancer Survivors was given to providers at 2 county hospitals and 5 associated clinics (59 providers). Focus groups were held to understand barriers to survivorship care. RESULTS: Although the majority of providers believed PCPs have the skills necessary to provide cancer-related follow-up, the vast majority were not comfortable providing these services themselves. Providers were adherent to American Society of Clinical Oncology recommendations for mammography (98%) and physical examination (87%); less than one-third were guideline-concordant for laboratory testing and only 6 providers (10%) met all recommendations. PCPs universally requested additional training on clinical guidelines and the provision of written survivorship care plans before transfer. Concerns voiced in qualitative sessions included unfamiliarity with the management of endocrine therapy and confusion regarding who would be responsible for certain aspects of care. CONCLUSIONS: Safety-net providers currently lack knowledge of and confidence in providing survivorship care to patients with breast cancer. Opportunities exist for additional training in evidence-based guidelines and improved coordination of care between PCPs and oncology specialists.

Elevated Baseline Serum PD-L1 Level May Predict Poor Outcomes from Breast Cancer in African-American and Hispanic Women.

BACKGROUND: The therapeutic targeting of PD-1/PD-L1 has shown clinical efficacy in treating metastatic breast cancer. We investigated the clinical significance of measuring serum PD-L1 levels in African-American and Hispanic women with breast cancer. METHODS: PD-L1 levels were measured with the ELISA method from the serum samples of 244 African-Americans and Hispanics with breast cancer and 155 women without cancers. The levels of INFα2 and TNFα were measured with a Luminex multiplex assay. The protein levels of pAkt and CD44/CD24 in tumor cells were tested with immunohistochemistry analysis. Cox regression was used to assess the predicting role of serum PD-L1 for disease-free survival (DFS). RESULTS: PD-L1 levels were significantly elevated in breast cancer cases compared to non-cancer cases. The high PD-L1 levels were associated with HER2-positive and triple-negative breast cancer. PD-L1 level independently predicted DFS in both African-American and Hispanic women. The evaluated PD-L1 level was found to be associated with high IFNα2 and TNFα in breast cancer patients. CONCLUSIONS: PD-L1 serum levels can predict DFS in African American and Hispanic women with breast cancer. Furthermore, a high level of PD-L1 is more likely to be associated with tumor loss PTEN and the activation of Akt or with breast cancer cells expressing CD44high/CD24low. Further validation studies are needed to determine if PD-L1 could serve as a biomarker for patient selection for anti-PD-L1 therapy and assess treatment outcomes.

Association of Vitamin D3 Level with Breast Cancer Risk and Prognosis in African-American and Hispanic Women.

Background: This study investigated the association of vitamin D3 levels with breast cancer risk and progression in African-Americans and Hispanics. Methods: A total of 237 African-American (Cases = 119, Control = 118) and 423 Hispanic women (Cases = 124, Control = 299) were recruited in the study. Blood samples were collected at the time of breast cancer screening and prior to cancer treatment for 4 weeks on average for the cases. The serum 25-hydroxyvitamin D (25(OH)D3) was measured at a Quest-Diagnostics facility. Results: The results showed that 69.2% of African-Americans and 37.8% of Hispanics had 25(OH)D3 levels below 20 ng/mL. The 25(OH)D3 level below 20 ng/mL was significantly associated with breast cancer in both African-Americans (OR = 2.5, 95% CI = 1.3-4.8) and Hispanics (OR = 1.9, 95% CI = 1.1-3.0). However, the predicted probabilities of breast cancer in African-Americans were significantly higher than in Hispanics (p < 0.001). The 25(OH)D3 below 20 ng/mL was significantly associated with triple negative breast cancer (TNBC) in African-Americans (OR = 5.4, p = 0.02, 95% CI = 1.4-15), but not in Hispanics in our cohort of participants. Levels of 25(OH)D3 below 26 ng/mL predicts a decrease in disease-free survival, but it was not an independent predictor. Conclusions: Our data shows an association between 25(OH)D3 levels and the risk of breast cancer. Further studies on the relationship between 25(OH)D3 level and breast cancer risk are warranted.

Increasing minority patient participation in cancer clinical trials using oncology nurse navigation.

BACKGROUND: Residential distance from an academic or cancer center is a significant barrier to minority patient participation in cancer research. Most cancer clinical trials (CTs) are only accessible at academic and cancer centers, yet most cancer patients receive treatment in their home communities where access to CTs may be limited. Oncology nurse navigation is an innovative approach for increasing minority CT participation by facilitating access to cancer CTs in communities where minority patients live. The purpose of this study was to evaluate the impact of oncology nurse navigation on community-based recruitment of black patients to breast cancer CTs at a major cancer center. METHODS: We merged the roles of a traditional oncology research nurse and a professional patient navigator to create a novel health care provider role, the oncology nurse navigator. The primary duties of the oncology nurse navigator were to engage black cancer patients in the offices of their community physicians and to collaborate with community physicians to increase black patient participation in cancer research. The oncology nurse navigator played a key role in all phases of the CT participation process (e.g., screening for eligibility and completion of informed consent and clinical research forms) and guided each patient around barriers in the health care system. The accrual of eligible patients to breast cancer CTs was used to assess the impact of oncology nurse navigation on community-based recruitment of blacks to cancer CTs. RESULTS: Between January 2007 and December 2008, a total of 132 black breast cancer patients were screened by a single oncology nurse navigator for eligibility to University of Southern California-sponsored breast cancer CTs. Fifty-nine patients were eligible for CTs, and each was invited to participate in 1 or more CTs for which they were eligible. Fifty-one of 59 eligible black patients (86% of eligible patients) were enrolled to 1 or more research protocols. The estimated cost per enrolled patient was $5,677, nearly half the expected per patient cost of treating patients on CT at an academic or cancer center. CONCLUSIONS: Oncology nurse navigation is an effective outreach strategy for increasing black patient participation in cancer research and may be achieved at nearly half the cost of traditional methods of enrolling patients in CTs at cancer centers.