Publications by authors named "Meghana Trivedi"

38 Publications

A novel role of ADGRF1 (GPR110) in promoting cellular quiescence and chemoresistance in human epidermal growth factor receptor 2-positive breast cancer.

FASEB J 2021 07;35(7):e21719

Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, USA.

While G protein-coupled receptors (GPCRs) are known to be excellent drug targets, the second largest family of adhesion-GPCRs is less explored for their role in health and disease. ADGRF1 (GPR110) is an adhesion-GPCR and has an important function in neurodevelopment and cancer. Despite serving as a poor predictor of survival, ADGRF1's coupling to G proteins and downstream pathways remain unknown in cancer. We evaluated the effects of ADGRF1 overexpression on tumorigenesis and signaling pathways using two human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC) cell-line models. We also interrogated publicly available clinical datasets to determine the expression of ADGRF1 in various BC subtypes and its impact on BC-specific survival (BCSS) and overall survival (OS) in patients. ADGRF1 overexpression in HER2+ BC cells increased secondary mammosphere formation, soft agar colony formation, and % of Aldefluor-positive tumorigenic population in vitro and promoted tumor growth in vivo. ADGRF1 co-immunoprecipitated with both Gαs and Gαq proteins and increased cAMP and IP1 when overexpressed. However, inhibition of only the Gαs pathway by SQ22536 reversed the pro-tumorigenic effects of ADGRF1 overexpression. RNA-sequencing and RPPA analysis revealed inhibition of cell cycle pathways with ADGRF1 overexpression, suggesting cellular quiescence, as also evidenced by cell cycle arrest at the G0/1 phase and resistance to chemotherapy in HER2+ BC. ADGRF1 was significantly overexpressed in the HER2-enriched BC compared to luminal A and B subtypes and predicted worse BCSS and OS in these patients. Therefore, ADGRF1 represents a novel drug target in HER2+ BC, warranting discovery of novel ADGRF1 antagonists.
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http://dx.doi.org/10.1096/fj.202100070RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218746PMC
July 2021

Oral Endocrine Therapy Agent, Race/Ethnicity, and Time on Therapy Predict Adherence in Breast Cancer Patients in a Large Academic Institution.

Clin Breast Cancer 2020 12 13;20(6):520-526. Epub 2020 Jun 13.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX. Electronic address:

Introduction: Adherence to oral endocrine therapy (OET) reduces recurrence risk for hormone receptor (HR)-positive breast cancer (BC). Refill data accessed through electronic health records may provide objective assessment of OET adherence. Our goal was to (1) determine the feasibility of reviewing electronic health records for assessing OET adherence, (2) evaluate 6 months' OET adherence in HR-positive BC patients, and (3) identify predictors of low adherence.

Patients And Methods: A single-center, retrospective study from May through December 2018 was conducted. Primary end point was adherance rate at 6 months. Chi-square and Student t tests were used to compare adherent and nonadherent groups. Multivariable logistic regression models were used to assess predictors of adherence.

Results: Of 492 patients, 338 patients were included in adherence analysis. Of 338 patients identified, 82% (n = 277) were adherent at 6 months. In the multivariable logistic model, race/ethnicity, type of endocrine therapy, and time on therapy were found to be significantly associated with adherence. Asian/non-Hispanic and white/Hispanic patients were less likely to be adherent compared to white/non-Hispanics (Asian/non-Hispanic: odds ratio [OR], 0.3; 95% confidence interval [CI], 0.11-0.82; white/Hispanic: OR, 0.27; 95% CI, 0.11-0.64). Patients prescribed aromatase inhibitors were more likely to be adherent compared to patients prescribed tamoxifen (OR, 2.06; 95% CI, 1.02-4.14). Last, patients prescribed OET for 3 to 5 years had lower adherence compared to patients given OET for 2 years or less (OR, 0.29; 95% CI, 0.09-0.91).

Conclusion: Accessing refill data through electronic health records was found to be feasible. Tamoxifen therapy, Asian/non-Hispanic and white/Hispanic origin, and longer time on therapy predicted nonadherence in our patients.
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http://dx.doi.org/10.1016/j.clbc.2020.06.004DOI Listing
December 2020

Metabolic syndrome and early stage breast cancer outcome: results from a prospective observational study.

Breast Cancer Res Treat 2020 Jul 4;182(2):401-409. Epub 2020 Jun 4.

Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.

Purpose: Obesity and insulin resistance have been associated with poor prognosis in breast cancer (BC). The present prospective study aimed to investigate the impact of metabolic syndrome (MetS) and its components on early BC (eBC) patients' outcome.

Methods: MetS was defined by the presence of 3 to 5 of the following components: waist circumference > 88 cm, blood pressure ≥ 130/≥ 85 mmHg, serum levels of triglycerides ≥ 150 mg/dL, high density lipoprotein < 50 mg/dL and fasting glucose ≥ 110 mg/dL. Seven hundred and seventeen patients with data on ≥ 4 MetS components at BC diagnosis were enrolled. Study population was divided into two groups: patients with < 3 (non-MetS) vs. ≥ 3 components (MetS). Categorical variables were analyzed by Chi-square test and survival data by log-rank test and Cox proportional hazards regression model.

Results: Overall, 544 (75.9%) and 173 (24.1%) women were categorized as non-MetS and MetS, respectively. MetS patients were more likely to be older, postmenopausal, and insulin-resistant compared to non-MetS patients (p < 0.05). In multivariate analysis, MetS patients had a numerically higher risk of relapse [disease-free survival (DFS), hazard ratio (HR) 1.51, p = 0.07] and a significantly higher risk of death compared to non-MetS patients [overall survival (OS), HR 3.01, p < 0.0001; breast cancer-specific survival (BCSS), HR 3.16, p = 0.001]. Additionally, patients with 1 to 2 components of MetS had an increased risk of dying compared to patients with 0 components (OS, HR 4.90, p = 0.01; BCSS, HR 6.07, p = 0.02).

Conclusions: MetS correlated with poor outcome in eBC patients. Among patients without full criteria for MetS diagnosis, the presence of 1 or 2 components of the syndrome may predict for worse survival.
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http://dx.doi.org/10.1007/s10549-020-05701-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297840PMC
July 2020

Evaluation of the Predictive Role of Tumor Immune Infiltrate in Patients with HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2 Therapy without Chemotherapy.

Clin Cancer Res 2020 02 25;26(3):738-745. Epub 2019 Oct 25.

Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.

Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with benefit to trastuzumab and chemotherapy in patients with early-stage HER2 breast cancer. The predictive value of TILs, TIL subsets, and other immune cells in patients receiving chemotherapy-sparing lapatinib plus trastuzumab treatment is unclear. Hematoxylin and eosin-stained slides ( = 59) were used to score stromal (s-)TILs from pretreatment biopsies of patients enrolled in the neoadjuvant TBCRC006 trial of 12-week lapatinib plus trastuzumab therapy (plus endocrine therapy for ER tumors). A 60% threshold was used to define lymphocyte-predominant breast cancer (LPBC). Multiplexed immunofluorescence (m-IF) staining (CD4, CD8, CD20, CD68, and FoxP3) and multispectral imaging were performed to characterize immune infiltrates in single formalin-fixed paraffin-embedded slides ( = 33).

Results: The pathologic complete response (pCR) rate was numerically higher in patients with LPBC compared with patients with non-LPBC (50% vs. 19%, = 0.057). Unsupervised hierarchical clustering of the five immune markers identified two patient clusters with different responses to lapatinib plus trastuzumab treatment (pCR = 7% vs. 50%, for cluster 1 vs. 2 respectively; = 0.01). In multivariable analysis, cluster 2, characterized by high CD4, CD8, CD20 s-TILs, and high CD20 intratumoral TILs, was independently associated with a higher pCR rate ( = 0.03). Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by s-CD4, intratumoral (i-) CD4, and i-CD20 TILs.

Conclusions: LPBC was marginally associated with higher pCR rate than non-LPBC in patients with lapatinib plus trastuzumab treated HER2 breast cancer. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002194PMC
February 2020

A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer.

J Clin Med 2019 10 24;8(11). Epub 2019 Oct 24.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA.

Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl-) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl- and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl- TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl- tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl- tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = -1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl- TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl- tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation.
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http://dx.doi.org/10.3390/jcm8111772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912280PMC
October 2019

Patient-reported outcomes in light of supportive medications in treatment-naïve lung cancer patients.

Support Care Cancer 2020 Apr 23;28(4):1809-1816. Epub 2019 Jul 23.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Health Building-2, 4849 Calhoun Rd., Houston, TX, 77204, USA.

Purpose: The impact of supportive medications on patient-reported outcomes (PROs) has not been systematically evaluated. We describe the supportive medications used by treatment-naïve lung cancer patients and assess their association with PROs from MD Anderson Symptom Inventory (MDASI).

Methods: Treatment-naïve lung cancer patients who completed PROs from MDASI at the initial visit to MD Anderson Cancer Center were included. Medications from the initial visit were abstracted from the electronic medical records system and categorized into therapeutic classes based on U.S. Pharmacopeia v7.0. A chi-square or Mann-Whitney U test was conducted as appropriate.

Results: Among 459 patients, ~ 50% took any analgesics and 25% were on opioids. One-third of patients with moderate-severe pain were not on any analgesics. Patients taking opioids had significantly worse median pain scores (6 vs. 0) compared with those not taking any analgesics (p < 0.0001). Higher proportion of patients with moderate-severe pain took opioids compared with those with mild pain (52% vs. 16%, p < 0.0001). Patients on opioids also reported significantly worse scores for five other cancer-specific core symptoms and all six symptoms rating interference with daily life. Only 15% of patients with higher composite score for depression-related symptoms were on antidepressants. However, patients taking antidepressants did not significantly differ in any individual MDASI symptom scores compared with those not on antidepressants (p = 0.4858).

Conclusions: Our results suggest a need for better screening for pain and depression and optimization of pain management in treatment-naïve lung cancer patients since their poor functional status may result in suboptimal cancer therapy.
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http://dx.doi.org/10.1007/s00520-019-05004-8DOI Listing
April 2020

Circulating tumor cell investigation in breast cancer patient-derived xenograft models by automated immunofluorescence staining, image acquisition, and single cell retrieval and analysis.

BMC Cancer 2019 Mar 12;19(1):220. Epub 2019 Mar 12.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA.

Background: Breast cancer patient-derived xenograft (BC-PDX) models represent a continuous and reproducible source of circulating tumor cells (CTCs) for studying their role in tumor biology and metastasis. We have previously shown the utility of BC-PDX models in the study of CTCs by immunohistochemistry (IHC) on serial paraffin sections and manual microscopic identification of cytokeratin-positive cells, a method that is both low-throughput and labor-intensive. We therefore aimed to identify and characterize CTCs from small volume mouse blood samples and examined its practical workflow in a study of BC-PDX mice treated with chemotherapy using an automated imaging platform, the AccuCyte®-CyteFinder® system.

Methods: CTC analysis was conducted using blood from non-tumor bearing SCID/Beige mice spiked with human breast cancer cells, BC-PDX-bearing mice, and BC-PDX mice treated with vehicle or chemotherapeutic agent(s). After red blood cell lysis, nucleated cells were mixed with transfer solution, processed onto microscope slides, and stained by immunofluorescence. The CyteFinder automated scanning microscope was used to identify CTCs, defined as nucleated cells that were human cytokeratin-positive, and mouse CD45-negative. Disaggregated primary BC-PDX tumors and lung metastatic nodules were processed using the same immunostaining protocol. Collective expression of breast cancer cell surface markers (EpCAM, EGFR, and HER2) using a cocktail of target-specific antibodies was assessed. CTCs and disaggregated tumor cells were individually retrieved from slides using the CytePicker® module for sequence analysis of a BC-PDX tumor-specific PIK3CA mutation.

Results: The recovery rate of human cancer cells spiked into murine blood was 83 ± 12%. CTC detection was not significantly different from the IHC method. One-third of CTCs did not stain positive for cell surface markers. A PIK3CA T1035A mutation present in a BC-PDX tumor was confirmed in isolated single CTCs and cells from dissociated metastatic nodules after whole genome amplification and sequencing. CTC evaluation could be simply implemented into a preclinical PDX therapeutic study setting with substantial improvements in workflow over the IHC method.

Conclusions: Analysis of small volume blood samples from BC-PDX-bearing mice using the AccuCyte-CyteFinder system allows investigation of the role of CTCs in tumor biology and metastasis independent of surface marker expression.
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http://dx.doi.org/10.1186/s12885-019-5382-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419430PMC
March 2019

Neratinib in HER2-Positive Breast Cancer Patients.

Ann Pharmacother 2019 06 4;53(6):612-620. Epub 2019 Jan 4.

1 University of Houston College of Pharmacy, Houston, TX, USA.

Objective: To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of neratinib in human epidermal growth factor receptor (HER2)+ breast cancer (BC).

Data Sources: A PubMed search was performed using the term neratinib between September 12, 2018, and November 21, 2018. References of published articles and reviews were also assessed for additional information.

Study Selection And Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of neratinib were evaluated.

Data Synthesis: Neratinib, an irreversible inhibitor of HER1, HER2, and HER4, is Food and Drug Administration approved for the extended adjuvant treatment of stage I-III HER2+ BC to follow trastuzumab-based therapy. A phase III study has demonstrated statistically significant improvement in 5-year disease-free survival rate (90.2 vs 87.7; hazard ratio = 0.73, 95% CI = 0.57-0.92, P = 0.0083). Its most common adverse effect is diarrhea, observed in more than 90% of patients. The incidence of grade 3/4 diarrhea (~40%) is reduced by half with loperamide prophylaxis, which is recommended for the first 8 weeks of neratinib therapy. Other common adverse reactions are nausea and fatigue. The patients need to be monitored for liver function tests and drug interactions with acid-reducing agents, CYP3A4 inhibitors/inducers, and P-glycoprotein substrates with narrow therapeutic window. Relevance to Patient Care and Clinical Practice: American Society of Clinical Oncology and National Comprehensive Cancer Network clinical guidelines suggest the use of neratinib for extended adjuvant therapy following 1-year trastuzumab in stage I to III HER2+ BC. Diarrhea remains a clinically significant but manageable adverse event.

Conclusion: Neratinib significantly improves treatment outcomes and has manageable toxicity in stage I to III HER2+ BC patients.
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http://dx.doi.org/10.1177/1060028018824088DOI Listing
June 2019

The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.

Br J Cancer 2019 02 17;120(3):331-339. Epub 2018 Dec 17.

Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Background: The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations.

Methods: Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models.

Results: In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance.

Conclusions: These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models.
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http://dx.doi.org/10.1038/s41416-018-0354-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353941PMC
February 2019

Identifying adherence barriers to oral endocrine therapy among breast cancer survivors.

Breast Cancer Res Treat 2019 Apr 6;174(2):297-305. Epub 2018 Dec 6.

Departments of Pharmaceutical Health Outcomes and Policy, University of Houston, College of Pharmacy, 4849 Calhoun Road, Houston, TX, 77204-5047, USA.

Purpose: Approximately 70-80% of breast cancers are hormone receptor-positive (HR+). OET, including tamoxifen and aromatase inhibitors, is considered standard adjuvant therapy for HR+ breast cancer. Despite demonstrated benefits, nearly half of patients are non-adherent and over two-thirds discontinue therapy before the recommended 5 years. Our objective was to identify and summarize literature-reported barriers associated with non-adherence/non-persistence to OET among breast cancer survivors.

Methods: A PUBMED literature search was conducted using the following terms: 'breast cancer,' 'oral endocrine therapy' or 'Tamoxifen' or 'Aromatase Inhibitors,' 'adherence,' or 'barriers.' The search was restricted to past six years. The abstracts of each result were reviewed and categorized as either patient-reported or physician-reported. All patient- and physician-reported factors that affected adherence and persistence were listed and grouped together into the three main categories: Socio-demographic and medical parameters, general psychosocial parameters, and psychosocial parameters related to OET.

Results: A total of 320 articles were identified, of which 19 met inclusion criteria. Adverse drug reactions were the most commonly reported barrier but were generally underreported among physicians. Among patient-reported barriers, common social-demographic and medical parameters were age, comorbidity, and financial status. General psychosocial variables were lack of patient-provider communication, depressive symptoms, and lack of perceived self-efficacy. Treatment toxicity was the most commonly reported psychosocial parameter related to OET.

Conclusion: The determinants of non-adherence and non-persistence are multi-dimensional and influenced by several factors. The three categories of adherence barriers should be evaluated and considered when designing future interventions to enhance OET adherence for a tailored approach.
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http://dx.doi.org/10.1007/s10549-018-05073-zDOI Listing
April 2019

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients.

Ann Pharmacother 2019 05 7;53(5):501-509. Epub 2018 Dec 7.

3 Houston Methodist Hospital, Houston, TX, USA.

Objective: To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib (LEE011, Kisqali) in hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) metastatic breast cancer.

Data Sources: A PubMed search was performed using the terms 'Ribociclib', 'Kisqali', and 'LEE011' between May 2018 and November 2018. References of published articles and reviews were also assessed for additional information.

Study Selection And Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib were evaluated.

Data Synthesis: Ribociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is Food and Drug Administration (FDA) approved in combination with endocrine therapy for treatment of HR+/HER2- advanced or metastatic breast cancer in premenopausal/perimenopausal and postmenopausal women. Three phase III trials have evaluated ribociclib in combination with endocrine therapy, including letrozole, anastrozole, tamoxifen, and fulvestrant. These studies found that ribociclib 600 mg/d, 21 days on, 7 days off, leads to a significantly greater median progression-free survival (PFS), ranging from 8 to 13 months. Ribociclib is well tolerated in elderly patients, maintains health-related quality of life, and significantly reduces pain scores. The dose-limiting toxicities found in phase I studies were neutropenia, thrombocytopenia, and QTc prolongation. Common adverse effects seen in phase III trials include neutropenia, leukopenia, nausea, diarrhea, vomiting, and fatigue. Relevance to Patient Care and Clinical Practice: Literature on the safety and efficacy of ribociclib as well as its place in therapy in comparison to other FDA-approved CDK4/6 inhibitors for breast cancer is discussed.

Conclusions: Ribociclib, when added to endocrine therapy, significantly improves PFS and has manageable toxicity in premenopausal/perimenopausal and postmenopausal women with HR+/HER2- advanced breast cancer.
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http://dx.doi.org/10.1177/1060028018817904DOI Listing
May 2019

Epigenetic Silencing of Tracks the Acquisition of the Notch1-EGFR Signaling in a Xenograft Model of CD44/CD24/CD90 Myoepithelial Cells.

Mol Cancer Res 2019 02 21;17(2):628-641. Epub 2018 Sep 21.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.

The surface glycoprotein THY is a marker of myoepithelial precursor cells, which are basal cells with epithelial-mesenchymal intermediate phenotype originating from the ectoderm. Myoepithelial precursor cells are lost during progression from to invasive carcinoma. To define the functional role of Thy1-positive cells within the myoepithelial population, we tracked Thy1 expression in human breast cancer samples, isolated THY1-positive myoepithelial progenitor cells (CD44/CD24/CD90), and established long-term cultures (parental cells). Parental cells were used to generate a xenograft model to examine Thy1 expression during tumor formation. Post-transplantation cell cultures lost 1 expression through methylation at the locus and this is associated with an increase in and transcript levels. Thy1-low cells are sensitive to the EGFR/HER2 dual inhibitor lapatinib. High expression is associated with poorer relapse-free survival in patients with breast cancer. methylation may track the shift of bipotent progenitors into differentiated cells. Thy1 is a good candidate biomarker in basal-like breast cancer. IMPLICATIONS: Our findings provide evidence that expression is lost in xenografts due to promoter methylation. Thy1-low cells with increased EGFR and Notch1 expression are responsive to target therapy. Because DNA methylation is often altered in early cancer development, candidate methylation markers may be exploited as biomarkers for basal-like breast cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0324DOI Listing
February 2019

GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer.

Breast Cancer Res Treat 2018 Jul 24;170(2):279-292. Epub 2018 Mar 24.

Department of Pharmacy Practice and Translational Research, University of Houston, 4849 Calhoun St, Houston, TX, 77204, USA.

Purpose: G protein-coupled receptors (GPCRs) represent the largest family of druggable targets in human genome. Although several GPCRs can cross-talk with the human epidermal growth factor receptors (HERs), the expression and function of most GPCRs remain unknown in HER2+ breast cancer (BC). In this study, we aimed to evaluate gene expression of GPCRs in tumorigenic or anti-HER2 drug-resistant cells and to understand the potential role of candidate GPCRs in HER2+ BC.

Methods: Gene expression of 352 GPCRs was profiled in Aldeflur+ tumorigenic versus Aldeflur- population and anti-HER2 therapy-resistant derivatives versus parental cells of HER2+ BT474 cells. The GPCR candidates were confirmed in 7 additional HER2+ BC cell line models and publicly available patient dataset. Anchorage-dependent and anchorage-independent cell growth, mammosphere formation, and migration/invasion were evaluated upon GPR110 knockdown by siRNA in BT474 and SKBR3 parental and lapatinib+ trastuzumab-resistant (LTR) cells.

Results: Adhesion and class A GPCRs were overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population of BT474 cells, respectively. GPR110 was the only GPCR overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population in BT474, SKBR3, HCC1569, MDA-MB-361, AU565, and/or HCC202 cells and in HER2+ BC subtype in patient tumors. Using BT474 and SKBR3 parental and LTR cells, we found that GPR110 knockdown significantly reduced anchorage-dependent/independent cell growth as well as migration/invasion of parental and LTR cells and mammosphere formation in LTR derivatives and not in parental cells.

Conclusion: Our data suggest a potential role of GPR110 in tumorigenicity and in tumor cell dissemination in HER2+ BC.
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http://dx.doi.org/10.1007/s10549-018-4751-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110614PMC
July 2018

Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize.

Cancer Res 2018 02 2;78(4):845-852. Epub 2018 Feb 2.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Circulating tumor cell (CTC) clusters may represent one of the key mechanisms initiating the metastasis process. However, the series of pathophysiologic events by which CTC clusters originate, enter the circulation, and reach the distant sites remain to be identified. The cellular and molecular mechanisms that provide survival advantage for CTC clusters during the transit in the blood stream are also still largely unknown. Understanding the biology of CTC clusters is critical to assess this unified scheme employed by cancer and to device strategies to overcome key pathways responsible for their improved metastatic potential. CTC clusters remain an underdeveloped area of research begging the attention of multidisciplinary cancer research teams. Here, we provide insight on existing preclinical evidence on the potential mechanisms leading to CTC cluster formation and dissemination and on processes that may offer survival advantage. We also offer our perspective on future directions to delineate the role of CTC clusters in metastatic cascade and discuss their clinical significance. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2748DOI Listing
February 2018

Interventions to improve endocrine therapy adherence in breast cancer survivors: what is the evidence?

J Cancer Surviv 2018 06 2;12(3):348-356. Epub 2018 Feb 2.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 4849 Calhoun Rd, Houston, TX, 77204, USA.

Purpose: Endocrine therapy reduces the risk of breast cancer recurrences and mortality in hormone receptor-positive (HR+) breast cancer survivors. However, non-adherence to treatment remains a significant problem. The aim of this study was to review current literature and ongoing trials to identify interventions employed to improve adherence to adjuvant endocrine therapy (AET) in breast cancer survivors.

Methods: We searched PubMed and the National Library of Medicine registry of clinical trials using the terms "breast cancer" and "adherence" or "compliance" and "intervention" and "medication" or "endocrine therapy" or "hormone therapy" to identify published studies as well as ongoing clinical trials.

Results: Three hundred and sixty-three studies were identified; five studies met the inclusion criteria. Most studies enrolled postmenopausal women diagnosed with early stage HR+ breast cancer. Providing educational materials was the most common intervention implemented to improve adherence to one or more aromatase inhibitors. None of the studies found a significant improvement in adherence with the intervention evaluated. Twelve clinical trials investigating various interventions, mostly based on technology, to improve AET adherence were also identified.

Conclusions: Improving adherence to AET in HR+ breast cancer survivors is an urgent medical need. While newer clinical trials are overcoming some of the limitations seen with published studies, tailored interventions led by clinicians need further investigation.

Implications For Cancer Survivors: Our study highlights the unmet clinical need to develop and test feasible interventions to improve AET adherence in HR+ breast cancer survivors to extend their long-term survival.
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http://dx.doi.org/10.1007/s11764-017-0674-4DOI Listing
June 2018

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom?

Breast Care (Basel) 2017 Oct 19;12(5):290-294. Epub 2017 Oct 19.

Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.

Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in luminal breast cancer (BC). Despite the efficacy of endocrine agents, many patients with luminal BC do not respond to endocrine therapy and many others develop endocrine resistance over time, due to the activation of escape pathways such as the PI3K/AKT/mTOR signaling. Several clinical trials have demonstrated the efficacy of mTOR and PI3K inhibitors in overcoming endocrine resistance in hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic BC (MBC) patients. Nevertheless, to date, everolimus is the only agent targeting the PI3K/mTOR pathway that has been approved for clinical use. Recently, the introduction of CDK 4/6 inhibitors into clinical practice has significantly changed the therapeutic scenarios in luminal MBC. In the absence of direct comparisons among the new treatment combinations and predictive biomarkers of response, the choice of optimal therapeutic algorithms is very challenging. Future trials should focus on identifying more effective and safe combination therapies and defining the best treatment sequences in luminal BC.
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http://dx.doi.org/10.1159/000481657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704698PMC
October 2017

Challenges of measuring accurate estradiol levels in aromatase inhibitor-treated postmenopausal breast cancer patients on vaginal estrogen therapy.

Pharmacol Res Perspect 2017 Aug;5(4)

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas.

Breast cancer patients who are taking adjuvant Aromatase Inhibitor (AI) therapy typically have extremely low estradiol levels, which are undetectable by routine clinical laboratories. Thus, it becomes difficult to assess the safety of interventions such as low-dose vaginal estrogen, which may increase estradiol levels. In this study, we aimed to assess the utility of enzyme-linked immunosorbent assay (ELISA) to measure low estradiol concentrations in breast cancer survivors on AI therapy treated with either vaginal estrogen or lubricant for atrophic vaginitis as a part of clinical trial. The samples were tested using two independent ELISA kits. Some of the samples were also evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for comparison. We found that while the results by ELISA were reproducible, they were not accurate when compared to LC-MS/MS. It is possible that medications or supplements may cross-react with the ELISA reagents and confound the assessment; however, those were often not the reason for the discrepancy. Our results highlight the need for developing novel, reliable, and clinically accessible assays to measure ultra-low estradiol levels to improve care of breast cancer survivors. At this stage, based on our findings, we recommend using MS-based assays for estradiol quantitation for breast cancer survivors, whenever necessary.
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http://dx.doi.org/10.1002/prp2.330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684855PMC
August 2017

FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer.

Proc Natl Acad Sci U S A 2016 10 6;113(43):E6600-E6609. Epub 2016 Oct 6.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030;

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.
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http://dx.doi.org/10.1073/pnas.1612835113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087040PMC
October 2016

Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

Breast Cancer Res Treat 2016 06 13;157(2):203-210. Epub 2016 May 13.

Lester and Sue Smith Breast Cancer, Baylor College of Medicine, Houston, TX, USA.

Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.
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http://dx.doi.org/10.1007/s10549-016-3827-7DOI Listing
June 2016

Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance.

Mol Cancer Res 2016 05 10;14(5):470-81. Epub 2016 Mar 10.

Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.

Unlabelled: The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.

Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.
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http://dx.doi.org/10.1158/1541-7786.MCR-15-0423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867274PMC
May 2016

Oral Glutamine in Preventing Treatment-Related Mucositis in Adult Patients With Cancer: A Systematic Review.

Nutr Clin Pract 2016 Apr 27;31(2):171-9. Epub 2015 Oct 27.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas

Background: Breakdown of the mucosal barrier resulting in mucositis is a common adverse event in patients with cancer receiving chemotherapy and radiation. Many studies have evaluated the use of oral glutamine to prevent mucositis in these settings, but current guidelines make no recommendations with regard to its use. Our objective was to systematically review the evidence for the use of oral glutamine in preventing mucositis in adult patients with cancer undergoing chemotherapy and/or radiation.

Materials And Methods: A systematic search of English-language literature was done via MEDLINE using the search terms glutamine, cancer, and mucositis or esophagitis or stomatitis. Fifteen studies conducted in adult patients with cancer receiving chemotherapy and/or radiation comparing single-agent oral glutamine with control were identified.

Results: Oral glutamine was shown to be effective in 11 of the 15 studies included in the systematic review. It significantly reduced the incidence of grade 2, 3, or 4 mucositis and/or reduced weight loss as well as the duration, time of onset, and/or maximum grade of mucositis. The most common dosing regimen was 30 g/d in 3 divided doses, with other regimens ranging from 7.5-24 g/d. Rates of nausea, vomiting, dry mouth, and anorexia were similar in the glutamine and control groups.

Conclusion: In summary, the favorable efficacy and low toxicity of oral glutamine observed in clinical trials we reviewed provide a strong rationale for large randomized placebo-controlled studies to further evaluate its efficacy in preventing mucositis in patients with cancer receiving chemotherapy and/or radiation.
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http://dx.doi.org/10.1177/0884533615611857DOI Listing
April 2016

The risk of febrile neutropenia and need for G-CSF primary prophylaxis with the docetaxel and cyclophosphamide regimen in early-stage breast cancer patients: a meta-analysis.

Breast Cancer Res Treat 2015 Oct 4;153(3):591-7. Epub 2015 Sep 4.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX, 77030, USA.

The febrile neutropenia (FN) rates reported with the docetaxel 75 mg/m(2) plus cyclophosphamide 600 mg/m(2) (TC) regimen given every 3 weeks vary from 4 to 69 % in early-stage breast cancer (ESBC) patients. This creates uncertainty as to whether patients receiving the TC regimen should also receive granulocyte colony-stimulating factor primary prophylaxis (G-CSFpp), which is recommended when chemotherapy regimens have ≥20 % FN rate. We conducted a meta-analysis of published studies to determine FN rate with the TC regimen, its dependence on patients' age, and the efficacy of G-CSFpp in reducing it in ESBC patients. We systematically searched the literature via PUBMED using the following terms: 'docetaxel', 'cyclophosphamide', 'febrile neutropenia', and 'breast cancer'. Inclusion criteria were full text peer-reviewed clinical studies in English reporting FN rates with TC regimen in relationship to G-CSFpp. Comprehensive meta-analysis software was used for all statistical analyses. Eight studies (N = 1542 patients) were included in our meta-analysis. The pooled mean FN rate was 23.2 % (95 % confidence interval (CI) 6.9-55.2 %; Q = 218.17, I (2) = 97.7). The FN risk in <65 years old patients was lower by 67.7 % compared to that in patients ≥65 years old (pooled odds ratio (OR) 0.323; 95 % CI 0.127-0.820; P = 0.017). The FN risk was reduced by 92.3 % with G-CSFpp (pooled OR 0.077; 95 % CI 0.013-0.460; P = 0.005). Our meta-analysis demonstrated that TC regimen was associated with ≥20 % FN risk, which was significantly higher in patients ≥65 years old and improved with G-CSFpp. G-CSFpp should be considered for all ESBC patients receiving TC regimen, especially those ≥65 years old.
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http://dx.doi.org/10.1007/s10549-015-3531-zDOI Listing
October 2015

The changing role of ER in endocrine resistance.

Breast 2015 Nov 10;24 Suppl 2:S60-6. Epub 2015 Aug 10.

Lester and Sue Smith Breast Center, Baylor College of Medicine, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, USA; Department of Medicine, Baylor College of Medicine, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, USA. Electronic address:

Estrogen receptor (ER) is expressed in approximately 70% of newly diagnosed breast tumors. Although endocrine therapy targeting ER is highly effective, intrinsic or acquired resistance is common, significantly jeopardizing treatment outcomes and minimizing overall survival. Even in the presence of endocrine resistance, a continued role of ER signaling is suggested by several lines of clinical and preclinical evidence. Indeed, inhibition or down-regulation of ER reduces tumor growth in preclinical models of acquired endocrine resistance, and many patients with recurrent ER+ breast tumors progressing on one type of ER-targeted treatment still benefit from sequential endocrine treatments that target ER by a different mechanism. New insights into the nature and biology of ER have revealed several mechanisms sustaining altered ER signaling in endocrine-resistant tumors, including deregulated growth factor receptor signaling that results in ligand-independent ER activation, unbalanced ER co-regulator activity, and genomic alterations involving the ER gene ESR1. Therefore, biopsies of recurrent lesions are needed to assess the changes in epi/genomics and signaling landscape of ER and associated pathways in order to tailor therapies to effectively overcome endocrine resistance. In addition, more completely abolishing the levels and activity of ER and its co-activators, in combination with selected signal transduction inhibitors or agents blocking the upstream or downstream targets of the ER pathway, may provide a better therapeutic strategy in combating endocrine resistance.
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http://dx.doi.org/10.1016/j.breast.2015.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666002PMC
November 2015

Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy.

Clin Cancer Res 2015 Sep 26;21(17):3995-4003. Epub 2015 May 26.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.

Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.

Experimental Design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.

Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER(-)) converted to ER(+) upon anti-HER2 therapy. In ER(-)/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001).

Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558260PMC
September 2015

Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis.

Breast Cancer Res 2015 Jan 9;17. Epub 2015 Jan 9.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.

Introduction: Real-time monitoring of biologic changes in tumors may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in cancer patients pose major hurdles. The goal of this study was to determine whether breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes.

Methods: CTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counterstaining of red blood cell-lysed blood and bone marrow fractions, respectively. The rate of lung metastases (LM) was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher's Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed by using the expression arrays of primary tumors from different PDX lines and subsequently overlapped to identify common genes.

Results: In total, 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present as either single cells or clusters, were detected in 83% (15 of 18) and 62.5% (10 to16) of the lines, respectively. A positive association was noted between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 of 18 (50%) lines, of which all nine had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the two genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified four genes (HLA-DP1A, GJA1, PEG3, and XIST). This four-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients.

Conclusion: This study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases.
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http://dx.doi.org/10.1186/s13058-014-0508-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318479PMC
January 2015

Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications.

Breast Care (Basel) 2013 Aug;8(4):256-62

Lester and Sue Smith Breast Center, Baylor College of Medicine, University of Houston, College of Pharmacy, Houston, TX, USA ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA ; Margaret M. and Albert B. Alkek Department of Medicine, Baylor College of Medicine, Houston, TX, USA ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

The estrogen receptor (ER) and/or the human epidermal growth factor receptor 2 (HER2) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. As a result, targeting these pathways provides the most effective therapies in appropriately selected patients. Nevertheless, resistance to both endocrine and anti-HER2 therapies occurs frequently and represents a major clinical challenge. Compelling preclinical and clinical evidence relates this treatment resistance to the presence of a complex bidirectional molecular crosstalk between the ER and HER2 pathways. As a consequence, treatment strategies targeting either pathway are associated with up-regulation of the other one, ultimately resulting in resistance to therapy. Therefore, a more promising strategy to prevent or overcome either endocrine or anti-HER2 resistance at least in some tumors is to combine targeted treatments that simultaneously block both signaling pathways. Many clinical trials exploring this strategy have shown positive results, and many more are currently ongoing. Future clinical trials with appropriate patient selection, based on biomarker evaluation of primary tumors and possibly of recurrent lesions, are warranted for the optimization of individualized therapeutic strategies.
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http://dx.doi.org/10.1159/000354253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808214PMC
August 2013

Metastasis dormancy in estrogen receptor-positive breast cancer.

Clin Cancer Res 2013 Dec;19(23):6389-97

Authors' Affiliations: Lester and Sue Smith Breast Center, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine; Department of Clinical Sciences and Administration, University of Houston, College of Pharmacy; McNair Medical Institute, Houston, Texas; and Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.

About 20% to 40% of patients with breast cancer eventually develop recurrences in distant organs, which are often not detected until years to decades after the primary tumor diagnosis. This phenomenon is especially pronounced in estrogen receptor-positive (ER(+)) breast cancer, suggesting that ER(+) cancer cells may stay dormant for a protracted period of time, despite adjuvant therapies. Multiple mechanisms have been proposed to explain how cancer cells survive and remain in dormancy, and how they become reactivated and exit dormancy. These mechanisms include angiogenic switch, immunosurveillance, and interaction with extracellular matrix and stromal cells. How to eradicate or suppress these dormant cancer cells remains a major clinical issue because of the lack of knowledge about the biologic and clinical nature of these cells. Herein, we review the clinical manifestation of metastasis dormancy in ER(+) tumors, the current biologic insights regarding tumor dormancy obtained from various experimental models, and the clinical challenges to predict, detect, and treat dormant metastases. We also discuss future research directions toward a better understanding of the biologic mechanisms and clinical management of ER(+) dormant metastasis.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878717PMC
December 2013

The incidence of tumor cell contamination of peripheral blood stem cells: a meta-analysis to evaluate the impact of mobilization regimens and the influence on outcomes in breast cancer patients.

Acta Haematol 2014 25;131(3):133-40. Epub 2013 Oct 25.

University of Houston College of Pharmacy, Houston, Tex., USA.

Tumor cell contamination (TCC) of peripheral blood stem cells (PBSCs) is a major risk in the autologous PBSC transplant setting. However, the effect of different mobilization regimens (cytokines only versus cytokines + chemotherapy) on TCC of PBSCs and its impact on treatment outcomes have not been systematically reviewed. In the present meta-analysis, we aimed to investigate this effect in breast cancer patients since multiple studies have been conducted in this setting. We systematically searched MEDLINE and Cochrane Library up to May 2012. Seventeen studies (1,819 patients) were assessed. There was no significant difference in the incidence of TCC of PBSCs between the two mobilization regimens. When the analysis was restricted to granulocyte colony-stimulating factor as a cytokine, this difference was again not significant. We also found that TCC of PBSCs was associated with a higher annual recurrence rate in these patients. This suggests that there may be a significant risk for reinfusion of tumor cell-positive PBSCs, and whether it can increase the risk of disease recurrence needs to be determined. This study also raises important questions regarding the causes of TCC of PBSCs. These issues should be investigated systematically in PBSC transplant patients.
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http://dx.doi.org/10.1159/000353478DOI Listing
June 2014

Transient severe hyperbilirubinemia after hepatic arterial infusion of oxaliplatin in patients with liver metastases.

Cancer Chemother Pharmacol 2013 Dec 8;72(6):1265-71. Epub 2013 Oct 8.

Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX, 77030, USA.

Purpose: We have observed severe, but rapidly reversible, hyperbilirubinemia in patients receiving hepatic arterial infusion (HAI) of oxaliplatin. We performed a retrospective analysis to characterize this unusual phenomenon.

Methods: We reviewed the electronic medical records of 113 consecutive patients receiving HAI oxaliplatin to describe the associated hyperbilirubinemia.

Results: Four of 113 patients (3.5 %) presented with transient, severe (grade 3/4) hyperbilirubinemia post-HAI oxaliplatin. Peak levels of total bilirubin within 10-16 h of starting HAI oxaliplatin were 4.6, 12.2, 12.8, and 21.2 mg/dL and declined rapidly (within 24 after stopping treatment). One out of four patients experienced severe abdominal pain, and another patient had an infusion reaction (hypertension and hypoxemia) that reversed after discontinuation of infusion. Total bilirubin was predominantly direct. No significant decline in hemoglobin or increase in alkaline phosphatase occurred. Increase in liver transaminases post-infusion was mild to moderate (grades 1-3) and was seen after HAI oxaliplatin regardless of the emerged hyperbilirubinemia.

Conclusions: Severe hyperbilirubinemia is a rare but rapidly reversible adverse effect of HAI oxaliplatin and may be accompanied by an abdominal pain syndrome or infusion reaction. Treating physicians should be aware for the potential of this reaction. The mechanism of this unusual reaction merits further investigation.
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http://dx.doi.org/10.1007/s00280-013-2302-yDOI Listing
December 2013

Development of acneiform rash does not predict response to lapatinib treatment in patients with breast cancer.

Pharmacotherapy 2013 Oct 6;33(10):1126-9. Epub 2013 Jun 6.

University of Houston College of Pharmacy, Houston, Texas.

Study Objective: To determine if development of acneiform rash is a predictor of objective response rate with lapatinib.

Design: Subanalysis of data from a prospective, phase II study.

Setting: Academic breast care clinic.

Patients: Forty-nine treatment-naïve patients with human epidermal growth factor receptor-2 (HER2)-positive locally advanced breast cancer, who were treated with neoadjuvant lapatinib monotherapy for 6 weeks; 47 patients were included in the final analysis.

Measurements And Main Results: Of the 49 patients enrolled, 33 (67%) developed a rash of any type, and 26 (55%) had acneiform rash. Of the 26 evaluable patients with acneiform rash (55%), 19 (73%) responded to lapatinib and 7 (27%) did not. Of the 21 evaluable patients without acneiform rash, 11 (67%) responded to treatment and 7 (33%) did not. Thus, no association was found between the occurrence of acneiform rash and response to lapatinib monotherapy.

Conclusion: This study does not support the development of the acneiform rash as a predictor of clinical efficacy of lapatinib in the treatment of breast cancer.
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http://dx.doi.org/10.1002/phar.1308DOI Listing
October 2013
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