Thehang Luu

CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells.

Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.

A Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) in Metastatic Breast Cancer: A California Cancer Consortium Study

Purpose: The primary goal of this trial was to determine the response rate of single-agent vorinostat in patients with metastatic breast cancer. The secondary goals included assessment of time to progression, evaluation of toxicities, and overall survival. Experimental Design: From June 2005 to March 2006, 14 patients received vorinostat, 200 mg p.o., twice daily for 14 days of each 21 day cycle. Response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: The median age for all patients was 60.5 years (range, 37-88). Eight patients were estrogen receptor and/or progesterone positive, four were Her-2 positive. Sites of metastatic disease included brain, liver, lungs, bones, pelvis, pleura, chest wall, and distant lymph nodes. Patients received a median of 1.5 prior (range, 0-2) chemotherapeutic regimens for metastatic disease. Fatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically significant adverse effects. The median number of cycles delivered was 2 (range, 1-20). There were no complete or partial responses, and the study was terminated after the first stage; however, 4 patients were observed with stable disease with time to progression of 4, 8, 9, and 14 months. The median number of months that patients received treatment on this study was 1.7 (range, 0.5-14). Conclusions: Although not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken.

The Effect of Aromatase Inhibition on the Cognitive Function of Older Patients With Breast Cancer

INTRODUCTION This study evaluated the association between aromatase inhibitor (AI) therapy and cognitive function (over a 6-month period) in a cohort of patients aged ≥ 60 years compared with an age-matched healthy control group, and it evaluated changes in regional cerebral metabolism as measured by positron emission tomography (PET) scans of the brain done in a subset of the patient cohort. PATIENTS AND METHODS Thirty-five patients (32 evaluable) and 35 healthy controls were recruited to this study. Patients with breast cancer completed a neuropsychological battery, self-reported memory questionnaire, and geriatric assessment before initiation of AI therapy and again 6 months later. Age-matched healthy control participants completed the same assessments at the same time points as the patient group. RESULTS No significant decline in cognitive function was seen among individuals receiving an AI from pretreatment to 6 months later compared with healthy controls. In the PET cohort over the same period, both standardized volume of interest and statistical parametric mapping analyses detected specific changes in metabolic activity between baseline and follow-up uniquely in the AI patients, most significantly in the medial temporal lobes. CONCLUSION Although patients undergoing AI treatment had few changes in neuropsychological performance compared with healthy controls over a 6-month period, regionally specific changes in cerebral metabolic activity were identified during this interval in the patient group. Additional longitudinal follow-up is needed to understand the potential clinical implications of these findings.

Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin.

The aim of this study is to investigate the efficacy of combining a histone deacetylase inhibitor (LBH589) and a breast cancer stem cells (BCSC)-targeting agent (salinomycin) as a novel combination therapy for triple-negative breast cancer (TNBC). We performed in vitro studies using the TNBC cell lines to examine the combined effect. We used the mammosphere and ALDEFLUOR assays to estimate BCSC self-renewal capacity and distribution of BCSCs, respectively. Synergistic analysis was performed using CalcuSyn software. For in vivo studies, aldehyde dehydrogenase 1 ALDH1-positive cells were injected into non-obese diabetic/severe combined immunodeficiency gamma (NSG) mice. After tumor formation, mice were treated with LBH589, salinomycin, or in combination. In a second mouse model, HCC1937 cells were first treated with each treatment and then injected into NSG mice. For mechanistic analysis, immunohistochemistry and Western blot analysis were performed using cell and tumor samples. HCC1937 cells displayed BCSC properties including self-renewal capacity, an ALDH1-positive cell population, and the ability to form tumors. Treatment of HCC1937 cells with LBH589 and salinomycin had a potent synergistic effect inhibiting TNBC cell proliferation, ALDH1-positive cells, and mammosphere growth. In xenograft mouse models treated with LBH589 and salinomycin, the drug combination effectively and synergistically inhibited tumor growth of ALDH1-positive cells. The drug combination exerted its effects by inducing apoptosis, arresting the cell cycle, and regulating epithelial–mesenchymal transition (EMT). Combination of LBH589 and salinomycin has a synergistic inhibitory effect on TNBC BCSCs by inducing apoptosis, arresting the cell cycle, and regulating EMT; with no apparent associated severe toxicity. This drug combination could therefore offer a new targeted therapeutic strategy for TNBC and warrants further clinical study in patients with TNBC.

Chemotherapy-induced nausea and vomiting in Asian women with breast cancer receiving anthracycline-based adjuvant chemotherapy.

BACKGROUND Chemotherapy-induced nausea and vomiting (CINV) remain among the most frequently reported distressing side effects associated with anthracycline-based chemotherapy despite significant advances in antiemetic management. The main risk factor for severity of CINV is the emetogenic potential of the chemotherapeutic agents. However, patient-related risk factors have been identified, including genetic makeup. Although studies have noted that ethnicity influences nausea and vomiting in other contexts, there is a paucity of research regarding the impact of ethnicity on CINV. This study was undertaken to evaluate whether Asian women receiving anthracycline-based chemotherapy experience more CINV than non-Asians. METHODS A retrospective, comparative, correlational chart review was performed to abstract the relevant variables. RESULTS Data from a convenience sample of 358 women with breast cancer who received chemotherapy with doxorubicin between 2004 and 2008 at City of Hope in Duarte, California, were evaluated. The sample consisted of Caucasians (45%), Hispanics (27.7%), Asians (19.8%), and African Americans (7.5%). The results indicate that Asian women with breast cancer undergoing anthracycline-based chemotherapy experienced statistically significantly more clinically important CINV than their non-Asian counterparts. LIMITATIONS The data were collected retrospectively, with a certain population distribution at a specific time. CONCLUSION This study provides interesting preliminary evidence that Asian ethnicity plays a role in the development of severe CINV. When managing chemotherapy toxicities in women with breast cancer, health-care providers should tailor therapy to individual risk profiles. Specifically, consideration of antiemetic therapy should accommodate patient characteristics, such as Asian descent.

Combining Emerging Agents in Advanced Breast Cancer

Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability.

Pathologic complete response rates in triple-negative, HER2-positive, and hormone receptor-positive breast cancers after anthracycline-free neoadjuvant chemotherapy with carboplatin and paclitaxel with or without trastuzumab

BACKGROUND Pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) is considered a surrogate for improved survival. Platinum-containing NCT, particularly in patients with HER2+ and triple-negative breast cancers (TNBC) may increase pCR rates. METHODS Tumor characteristics, pCR rates (no invasive disease in breast and lymph nodes), toxicities, and survival in patients who received carboplatin, a taxane, and trastuzumab (HER2+ disease) between April 2009 and December 2011, were reviewed. RESULTS Thirty eight patients (39 tumors) completed a median of 4 cycles of NCT. Eighteen of 39 (46%) tumors were HER2+, 8/18 (44%) responded with pCR; 13/18 HER2+ tumors were HR+ (72%) and 4/13 (31%) had a pCR. Ten of 39 (26%) tumors were TNBC; 6/10 (60%) had a pCR. At a median of 25-months no recurrences were observed in patients with pCR. CONCLUSIONS Prospective studies of anthracycline-free platinum-containing NCT are warranted in LABC patients with HER2+ and TNBC.

Safety and Efficacy of Neratinib (HKI-272) in Combination with Vinorelbine in ErbB2+ Metastatic Breast Cancer.

Background: The irreversible pan-ErbB tyrosine kinase inhibitor neratinib (HKI-272) potently blocks downstream signaling of the ErbB1, -2, and -4 receptors and has demonstrated antitumor activity in patients with ErbB2+ breast cancer (BC). Vinorelbine has shown synergistic antitumor activity in combination with the ErbB2-specific monoclonal antibody trastuzumab. The objective of this ongoing phase 1/2 study is to evaluate the safety and efficacy of neratinib in combination with vinorelbine in patients with solid tumors and ErbB2+ metastatic BC.Material and Methods: This open-label, 2-part, phase 1/2 study enrolled patients with solid tumors (part 1) to evaluate safety and determine the maximum tolerated dose (MTD) of neratinib administered as ascending multiple daily oral doses (160 mg, 240 mg) in combination with IV vinorelbine 25 mg/m2 (days 1 and 8 every 3 weeks). In part 2, the clinical activity, safety, and pharmacokinetics (PK) of the combination will be assessed in patients ≥18 years of age with ErbB2+ metastatic BC (Eastern Cooperative Oncology Group status of 0 to 2) who had received ≤2 prior treatments with a trastuzumab-containing regimen for ≥6 weeks, with or without prior lapatinib exposure. The primary endpoint is objective response rate. Tumor responses are assessed by modified RECIST criteria every 6 weeks.Results: In part 1 (n = 12), no dose-limiting toxicities were observed in the neratinib 240-mg–vinorelbine 25-mg/m2 cohort (full standard doses; defined as the MTD). Two patients withdrew from the study because of adverse events (1 case each of neuropathy and progression of non-small cell lung cancer). As of the 1 May 2009 data cutoff, 1 patient with gastric cancer had received treatment with neratinib 160 mg plus vinorelbine for 183 days and 1 patient with BC had received treatment with neratinib 240 mg plus vinorelbine for 259 days. In part 2, as of 1 May 2009, 14 patients with ErbB2+ metastatic BC were enrolled and treated at the MTD (including 11 in the no prior lapatinib exposure cohort and 3 in the prior lapatinib exposure cohort; 100% were female). The median duration of treatment with neratinib was 5.9 weeks (range, 0-26). The most common drug-related treatment-emergent adverse events (all grades, ≥10% of patients) included diarrhea (86%), vomiting (36%), nausea (29%), fatigue (29%), headache (14%), and neutropenia (14%). No cases of rash were observed. The most common adverse events leading to dose reductions were diarrhea (n = 2) and vomiting (n = 1). One patient withdrew from the study because of diarrhea. Six patients from part 2 are evaluable for efficacy, all in the no prior lapatinib cohort. Among these 6 patients, best overall responses (based on investigator-assessed radiographic and clinical data) included 1 partial response and 4 cases of stable disease Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5095.

Phase I/II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer

PURPOSE We investigated the efficacy and toxicity of sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in combination with vinorelbine therapy in a phase I/II trial in patients with metastatic breast cancer. PATIENTS AND METHODS We enrolled 11 patients in the phase I portion to determine the maximum tolerated dose (MTD) of the combination, followed by 35 extra patients treated at the MTD in phase II. The median age of patients was 54 years old (range, 31-72 years old). Tumors were estrogen receptor and progesterone receptor (ER/PR) positive in 54% (22/54) of patients, and triple negative (ER(-), PR(-), HER2(-)) in 41% (17/54) of patients. Of all patients, 22% received sorafenib and vinorelbine as first-line therapy, 37% as second-line therapy, and 41% as third-line therapy. RESULTS In total, 41 patients were treated at the MTD (6 during phase I; 35 in phase II). The observed 44% 4-month progression-free survival rate was similar to the estimated historical rate of 43% with vinorelbine treatment. The combination was tolerated with expected toxicities. Patients treated at the MTD who had received prior bevacizumab treatment received a median of 1.5 cycles (range, 1-10 cycles) compared with a median of 5 cycles (range, 2-12 cycles) for patients without prior bevacizumab treatment. CONCLUSION Further evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of interest if specific biomarkers guiding patient selection can be identified.

Age-Related Changes in Nanoparticle Albumin-Bound Paclitaxel Pharmacokinetics and Pharmacodynamics: Influence of Chronological Versus Functional Age

PURPOSE This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer. METHODS Forty patients received nab-paclitaxel (100 mg/m(2) weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥ 3 toxicity were examined post hoc. RESULTS Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30-81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041). CONCLUSION A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥ 3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.