Circulating tumor cells (CTC), [18F]fluorodeoxyglucose positron emission tomography, and computed tomography (PET/CT) for treatment monitoring in patients with metastatic breast cancer (MBC)

e12007 Background: Use of [18F]-fluorodeoxyglucose PET /CT and/or CTC is being investigated to follow up response to treatment in patients with MBC. It is not clear if these tests can be a surrogate for one another. Methods: We retrospectively analyzed a database of female patients with MBC undergoing chemotherapy or hormonal therapy. Most of these patients received at least 2 lines of therapy. Standard CT scan tumor measurements were used to assess response to therapy. CTC were defined either low (0–5) or high (&gt;5). Maximum standard uptake values (max SUV) on PET scan were defined either low (&lt;3) or high (&gt;3). Correlation between the max SUV and CTC counts was statistically analyzed. Sensitivity, specificity, positive and negative predictive values were calculated from 2 x 2 table. Results: A total of 9 female patients with MBC were identified (mean age of 52 years). The receptor status of these patients includes 67 % positive for ER and 33 % positive for HER-2/neu. Median follow up was 9.8 months. There were 59 time points (&gt; or = 4 weeks apart) when either PET/CT or CTC were performed. The results of PET/CT scans were compared with CTC at 38 events. The sensitivity of CTC to detect metastatic disease shown on PET/CT was 32% and specificity of 100%. The positive and negative predictive values were 100% and 32% respectively. There was a positive correlation between the max SUV and CTC count (p = 0.001). However in three patients, despite of progression of disease per PET/CT, CTC were undetectable at three different time points. Interestingly, two out of these three patients were triple negative. Disease progression was confirmed by biopsy in two of these patients. Conclusions: Our data suggest positive correlation between PET/CT scan and CTC. However, CTC had poor sensitivity and negative predictive value to detect progressive metastatic disease. Normal CTC values have to be interpreted cautiously in patients with MBC. We are now planning to investigate the utility of these tests, prospectively, in a large cohort of MBC patients. No significant financial relationships to disclose. </jats:p

P5-01-19: Endothelin-1 Expression in Breast Cancer Tissue, Surrounding Stroma, Correlation with Tumor Microvessel Density and Clinical Outcome.

Abstract Background: Endothelin-1 (ET-1) is a peptide which regulates normal biological processes such as vascular tone. In addition, endothelin signaling pathway is dysregulated in pathophysiological conditions such as cancer and fibrosis. It has been shown that endothelin-1 is expressed in breast cancer tissue but little is known with regard to ET-1 expression in surrounding tumor stroma. In the present study, we investigated ET-1 expression in breast tumor cells, surrounding stroma, association with tumor microvessel density (MVD) and impact on clinical outcome. Materials and Methods: We conducted a retrospective, multicenter study. Patients from 3 medical centers with histologically documented stage I-III invasive breast cancer were included in the study. Paraffin embedded formalin fixed breast cancer tissue and surrounding stroma were evaluated for ET-1 and CD34 (marker for MVD) by IHC. ET-1 cytoplasmic expression was scored as positive (3+ by IHC) or negative (0, 1+, 2+). Stained vessels by CD34 were counted in five consecutive fields at 40 x magnification and their mean was recorded. Demographics, clinical data and recurrence free interval (RFI) in months were available for statistical analysis. Results: The study included 92 patients with average age of 55 years at diagnosis. Median follow up of patients at the time of analysis was 72 months. Total of 29 patients experienced disease progression ( 17 locoregional and 12 distant). Tumor ET-1 expression positively correlated with earlier stage: odds ratio (OR) = 22 for stage I and OR=20 for stage II as compared with stage III. Positive ET-1 staining in tumor was detected in 72.8 % of cases, while ET-1 positive expression in stroma was detected only in 6.5% of cases. Interestingly, all ET-1 stroma positive tumors were estrogen receptor (ER) positive. The means of CD34 were not different according to ET-1 expression either in the tumor or stroma. Triple negative breast cancer tumors exhibited higher MVD (p=0.0177). In the logistic regression model relating ET-1 expression in tumor to clinical variables, ET-1 positive tumors showed a trend for the association with higher relapse rate (p=0.058). Multivariate analysis suggested that there was no significant difference in the recurrence free interval (RFI) between the ET-1 positive and ET-1 negative groups (long-rank test p-value = 0.71). Survival analysis identified stage as a significant predictor of RFI in the Cox proportional hazard model that included ET-1 expression and other clinical variables. Conclusions: The significant predictor for ET-1 expression in the tumor was early stage. High tumor ET-1 expression was more common in patients who experienced breast cancer recurrence. No association was found between ET-1 expression and MVD, and between ET-1 expression and time to recurrence. Further studies with larger sample size are needed to better delineate a role of ET-1 as prognostic biomarker in early stage breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-19.</jats:p

P2-03-06: Endothelin-1/Endothelin A Receptor Signalling in Breast Cancer.

Abstract Background: Endothelin-1 (ET-1) and endothelin A receptor (ETAR) are implicated in breast cancer growth and progression. ET-1 is secreted by both tumor cells and stroma (macrophages, endothelial cells). The purpose of this study is to evaluate ET-1/ETAR role on cell proliferation and its effects on EGFR signaling pathway. Materials and Methods: Two breast cancer cell lines: MCF-7 and MDA-MB-231 were stimulated with ET-1. Proliferation of breast cancer cells was analyzed using MTT assay. Protein expression (EGFR, pEGFR, AKT, pAKT, ERK, pERK) was evaluated by Western blot. siRNA knockdown of endothelin A receptor (ETAR) was performed in MCF-7 and MDA-MB-231. Results: ET-1 stimulated proliferation in both cell lines. Interestingly, at higher ET-1 concentrations cell proliferation was more pronounced in MCF-7 when compared with MDA-MB-231. Stimulation with ET-1 activated EGFR and downstream signaling proteins (pAKT and pERK) in both cell lines. Incubation of breast cancer cells with ET-1 for 48 hours had different effect on total EGFR level: 3 fold increase of total EGFR was seen in MCF-7, while no change was detected in MDA-MB-231. siRNA against ETAR decreased ET-1 induced cell proliferation and reduced total EGFR level in MCF-7. Conclusions: These observations suggest that ET-1/ETAR plays an important role in survival and proliferation of breast cancer cells. However, those effects are diverse in different subtypes of breast cancer. Our results may represent an improved selective targeted treatment strategy, especially for estrogen receptor positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-06.</jats:p

Retrospective review of toxicities and response of two commonly used regimens (FOLFOX6 and XELOX) in stage IV colorectal cancer

13568 Background: Oxaliplatin and 5FU based regimens have become standard first line treatment for stage IV colorectal cancer. At our institution predominately the regimens FOLFOX6 (oxaliplatin/infusional 5FU via a central venous catheter) and XELOX (oxaliplatin/ capecitabine given orally) are used. We performed a retrospective review of 40 patients to see if any differences, primarily in toxicities, but also in response, emerged. Methods: . Twenty consecutive patients with Stage IV colorectal cancer who received FOLFOX6 as initial therapy and twenty consecutive patients who received initial XELOX, with the oxaliplatin given via a peripheral IV, were analyzed. The decision to administer FOLFOX6 or XELOX was not made for clinical reasons, but came about from logistical difficulties placing central venous catheters in our institution, due to cost and operating time. Comparisons were performed with a Mann Whitney test. The two groups were well matched in terms of sex, age, and performance status. Response evaluations were made based on RECIST criteria. Results: Toxicities compared in the two groups (FOLFOX6 v. XELOX) were gastrointestinal, &gt;Gr. II (5 v. 20%); dermatologic, &gt;Gr. III (0 v. 35%); bone marrow, &gt; Gr. II (15 v. 20%); neurologic, &gt;Gr. III peripheral neuropathy (10 v. 10%); and development of arm pain/discomfort (0 v. 30%). The two toxicities reaching a significant difference, with the higher incidence from XELOX, were &gt; Grade II dermatitis (p= 0.03) and development of arm pain (p=0.05). The response rate of FOLFOX6 was 75% and that for XELOX was 55% (p value of 0.144). Conclusions: Our conclusions from this analysis are that the two regimens are comparable in terms of response, but that FOLFOX6 may be preferable in order to avoid severe dermatitis and if XELOX is the treatment choice, serious consideration should given to administer the oxaliplatin via a central catheter. No significant financial relationships to disclose. </jats:p

Abstract OT3-05-10: A single arm phase II study of palbociclib in combination with tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Hormone receptor positive breast cancer is the most commonly diagnosed subset of breast cancer (60-65%). Endocrine therapy is effective for this subset of breast cancer, in both the adjuvant and metastatic settings. Despite advances in endocrine therapy, many patients relapse during or after completing adjuvant therapy and metastatic breast cancer remains incurable. Palbociclib is a reversible, oral, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). CDK4 and CDK6 together with cyclin D have important roles in regulation of the G1/S transition via regulation of the phosphorylation state of retinoblastomaprotein (Rb). Palbociclib showed significantly improved progression-free survival taken together with endocrine agents in treatment of metastatic breast cancer. Preclinical data showed that in combination with tamoxifen, palbociclib had synergistic growth inhibitory activity as well as efficacy in a model of acquired tamoxifen resistance. Combining palbociclib with tamoxifen in first line treatment of metastatic hormone receptor positive breast cancer may offers an appealing alternative to other endocrine combinations. Methods: This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in patients with hormone receptor positive/HER2 negative advanced breast cancer. The primary objective is to determine the objective response rate (complete or partial response) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease). Secondary objectives are: safety and tolerability, progression-free survival, clinical benefit rate, 2-year overall survival. Correlative objectives will explore alterations in circulating tumor DNA and changes in gene expression pattern at the time of progression. Eligibility criteria: women or men with diagnosis of hormone receptor positive/ HER2 negative locally advanced or metastatic breast cancer, not amenable to curative surgery; no prior systemic anti-cancer therapy for advanced hormone receptor positive breast cancer; adequate organ function; pre and post menopausal women are allowed. Drug administration: palbociclib dose will be 125 mg orally once daily on days 1-21 of each 28-day cycle; tamoxifen dose will be 20 mg orally once daily for every day of the 28-day cycle. As of June 2017, the study enrolled 10/71 patients and it is still open to enrollment. NCT 02668666; [email protected] Citation Format: Danciu OC, Hoskins K, Tamkus D, Truica C, Blaes A, Green L, Liu L, Toppmeyer D, Wisinski K. A single arm phase II study of palbociclib in combination with tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-10.</jats:p