Predictors of long-term durable response in de novo HER2-positive metastatic breast cancer and the real-world treatment experience at two institutions.

PURPOSE: HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR). Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Patient factors that predict DR continue to be elucidated. METHODS: This is a retrospective study of patients with de novo HER2 + MBC. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor, and initial treatment were analyzed. RESULTS: 96 patients with de novo HER2 + MBC, 28 with DR, and 68 with progression were identified. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p = 0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p < 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p = 0.002.) Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab. CONCLUSION: Nearly a third of patients with de novo HER2 + MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. Among patients with DR, indefinite trastuzumab administration is the norm.

Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

Optimizing the quality of breast cancer biomarker use at Duke Cancer Institute.

Advances in identifying biomarker profiles in patients with early-stage breast cancer have improved 5-year curative rates. Identification of the HER2 receptor provides valuable information that has been shown to extend survival in adjuvant and metastatic settings. Current clinical guidelines discuss when confirmatory testing may be inappropriate. Using a quality improvement approach, the team at Duke Cancer Institute determined HER2 ordering practices in a large academic cancer center. HER2 ordering using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) was abstracted from the charts of 314 patients with early-stage breast cancer. Qualitative responses to current clinical practices were obtained from clinicians. Of the patients included, duplicate IHC was performed for 36% and in triplicate for 6%; repeat testing resulted in clinically significant change in HER2 status for approximately 20%. Repeat biomarker testing on metastatic biopsy sites "all of the time" was favored by the surveyed physicians. FISH was ordered for each grade of IHC: 0+ (>20% of cases), 1+ (>20%), 2+ (99%), 3+ (54%). Most physicians "strongly" or "somewhat" favored solutions that integrate order sets and care pathways into the electronic medical record. This quality improvement project identified root causes and solutions to practice variance in breast cancer biomarker ordering and interpretation. Further investigations are planned to standardize best practices while appreciating the clinical challenges posed by discordant test results.

Self-efficacy for coping with symptoms moderates the relationship between physical symptoms and well-being in breast cancer survivors taking adjuvant endocrine therapy.

PURPOSE: This study examined the relationships between physical symptoms, self-efficacy for coping with symptoms, and functional, emotional, and social well-being in women who were taking adjuvant endocrine therapy for breast cancer. METHODS: One hundred and twelve women who were taking adjuvant endocrine therapy (tamoxifen or an aromatase inhibitor) for breast cancer completed measures of physical symptoms, self-efficacy for coping with symptoms, and functional, social, and emotional well-being at the time of routine medical follow-up (women were on average 3.4 years post-surgery; range 3 months to 11 years). RESULTS: Multiple linear regression analyses showed that higher self-efficacy for coping with symptoms was associated with greater functional, emotional, and social well-being after controlling for physical symptoms (p < 0.05). Self-efficacy for coping with symptoms moderated the relationship between physical symptoms and functional (B = 0.05, SE = 0.02, t = 2.67, p = 0.009) and emotional well-being (B = 0.03, SE = 0.01, t = 2.45, p = 0.02). As self-efficacy increased, the relationship between greater physical symptoms and lower well-being became weaker. Among women with high levels of self-efficacy, physical symptoms were not related to functional and emotional well-being. CONCLUSIONS: Self-efficacy for coping with symptoms may reduce the negative impact of physical symptoms and contribute to well-being in breast cancer survivors taking adjuvant endocrine therapy. Future studies could examine whether psychosocial interventions aimed at increasing self-efficacy for managing symptoms help women better cope with treatment side effects and improve quality of life.

Symptom communication in breast cancer: relationships of holding back and self-efficacy for communication to symptoms and adjustment.

Adjuvant endocrine therapy improves overall survival for women with breast cancer. However, side effects may compromise patients' quality of life (QOL). This study examined how two communication variables (self-efficacy for symptom communication [SE] and holding back from discussing cancer-related concerns [HB]) relate to QOL, pain and menopausal symptoms. Participants with breast cancer (N = 61) completed questionnaires regarding symptoms, communication, and QOL. SE was positively related to QOL and negatively related to pain interference. HB from discussing cancer-related concerns was related negatively to QOL and positively to pain interference. HB mediated the relationship between SE and QOL as well as between SE and pain interference. Increased SE is beneficial among women on endocrine therapy for breast cancer. Future research should determine if interventions to improve SE are feasible and can improve QOL and symptom tolerability.

Quantitative assessment of distant recurrence risk in early stage breast cancer using a nonlinear combination of pathological, clinical and imaging variables.

Use of genomic assays to determine distant recurrence risk in patients with early stage breast cancer has expanded and is now included in the American Joint Committee on Cancer staging manual. Algorithmic alternatives using standard clinical and pathology information may provide equivalent benefit in settings where genomic tests, such as OncotypeDx, are unavailable. We developed an artificial neural network (ANN) model to nonlinearly estimate risk of distant cancer recurrence. In addition to clinical and pathological variables, we enhanced our model using intraoperatively determined global mammographic breast density (MBD) and local breast density (LBD). LBD was measured with optical spectral imaging capable of sensing regional concentrations of tissue constituents. A cohort of 56 ER+ patients with an OncotypeDx score was evaluated. We demonstrated that combining MBD/LBD measurements with clinical and pathological variables improves distant recurrence risk prediction accuracy, with high correlation (r = 0.98) to the OncotypeDx recurrence score.

TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2. METHODS: Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS). RESULTS: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone. CONCLUSION: PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care.

Feasibility and reproducibility of microarray biomarkers in clinical settings are doubted because of reliance on fresh frozen tissue. We sought to develop and validate a paradigm of frozen tissue collection from early breast tumors to enable use of microarray in oncology practice. Frozen core needle biopsies (CNBx) were collected from 150 clinical stage I patients during image-guided diagnostic biopsy and/or surgery. Histology and tumor content from frozen cores were compared to diagnostic specimens. Twenty-eight patients had microarray analysis to examine accuracy and reproducibility of predictive gene signatures developed for estrogen receptor (ER) and HER2. One hundred twenty-seven (85%) of 150 patients had at least one frozen core containing cancer suitable for microarray analysis. Larger tumor size, ex vivo biopsy, and use of a new specimen device increased the likelihood of obtaining adequate specimens. Sufficient quality RNA was obtained from 90% of tumor cores. Microarray signatures predicting ER and HER2 expression were developed in training sets of up to 363 surgical samples and were applied to microarray data obtained from core samples collected in clinical settings. In these samples, prediction of ER and HER2 expression achieved a sensitivity/specificity of 94%/100%, and 82%/72%, respectively. Predictions were reproducible in 83-100% of paired samples. Frozen CNBx can be readily obtained from most breast cancers without interfering with pathologic evaluation in routine clinical settings. Collection of tumor tissue at diagnostic biopsy and/or at surgery from lumpectomy specimens using image guidance resulted in sufficient samples for array analysis from over 90% of patients. Sampling of breast cancer for microarray data is reproducible and feasible in clinical practice and can yield signatures predictive of multiple breast cancer phenotypes.

Detecting geriatric needs in older patients with breast cancer through use of a brief geriatric screening tool.

INTRODUCTION: Identification of geriatric syndromes is important for determining functional age and optimizing care for people with cancer. Based on administration of a geriatric screening tool, we aimed to describe needed resources for geriatric syndromes, including lack of social support, depressed mood, deficits in instrumental and activities of daily living (IADL/ADL), falls, nutritional issues, polypharmacy, ability to pay for medications, and memory deficits, in a population of patients with breast cancer. METHODS: Consecutive medical oncology patients with breast cancer age 65 years and older, seen at a tertiary care center, completed a screening tool, adapted from Overcash 2006, consisting of a nurse-administered memory assessment and a one-page, self-administered questionnaire. Responses identified geriatric syndromes. Demographics and clinical information were retrospectively gathered. Frequencies and means were used to describe data. RESULTS: From January 2012 through July 2014, patients (n = 429) completed the screening tool as part of routine care. Study group had mean age 76 years (range 65-89), mean time since diagnosis 6.5 years, 91% non-metastatic disease, mean Charlson Comorbidity score 1.8 (range 0-10). Treatment included partial mastectomy (49%), adjuvant radiation (43%), chemotherapy (25%), and endocrine therapy (61%). The screening tool identified need for social support (8%); depression (31%); mobility issues (20%); falls (28%); nutritional needs (33%); polypharmacy (83%); and memory deficit (19%). CONCLUSION: This screening tool identified geriatric syndromes requiring attention in many patients with breast cancer presenting for medical oncology appointments. In oncology practice, need for referral networks to address geriatric syndromes should be assessed.

Higher symptom burden is associated with lower function in women taking adjuvant endocrine therapy for breast cancer.

OBJECTIVE: To explore the impact of symptoms on physical function in women on adjuvant endocrine therapy for breast cancer. METHODS: Eligible women were postmenopausal, had hormone receptor positive, stage I-IIIA breast cancer, completed surgery, chemotherapy, radiation, and on adjuvant endocrine therapy. At a routine follow-up visit, women (N = 107) completed standardized symptom measures: Brief Fatigue Inventory, Brief Pain Inventory, Menopause Specific Quality of Life Questionnaire, Functional Assessment of Cancer Therapy Neurotoxicity scales. Two performance measures assessed function: grip strength (Jamar dynamometer; n = 71) and timed get-up-and-go (TUG; n = 103). Analyses were performed with an overall symptom composite score. Correlations and multiple linear regression analyses were performed to test adverse effects on physical function. RESULTS: The mean age was 64 years (range 45-84), 81% white, 84% on an aromatase inhibitor, and on endocrine therapy for mean 35 months (range 1-130 months). Dominant hand grip strength was inversely correlated with symptom composite scores (r = -0.29, p = .02). Slower TUG was positively correlated with higher Charlson comorbidity level (r = 0.36, p < .001) and higher symptom composite scores (r = 0.24, p = .01). In multivariate analyses, weaker dominant and non-dominant hand grip strength were significantly associated with greater symptom composite scores (ß = -0.27, t = 2.43, p = .02 and ß = -0.36, t = 3.15, p = .003, respectively) and slower TUG was associated with higher symptom composite scores (ß = 0.18, t = 1.97, p = .05). CONCLUSIONS: Higher symptom burden is associated with worse physical function, as measured by hand grip strength and TUG. Further study to determine the impact of endocrine therapy and its side effects on function is warranted.

Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.

PURPOSE: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). PATIENTS AND METHODS: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

A Phase I Trial of the PI3K Inhibitor Buparlisib Combined With Capecitabine in Patients With Metastatic Breast Cancer.

BACKGROUND: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m2) for 2 weeks with a 1-week break. Dose escalation used a traditional "3 + 3" design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose. RESULTS: Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m2 twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted. CONCLUSION: The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug-drug interactions and more accurate predictive biomarkers of response.

Hypermethylation of the breast cancer-associated gene 1 promoter does not predict cytologic atypia or correlate with surrogate end points of breast cancer risk.

Mutation of the breast cancer-associated gene 1 (BRCA1) plays an important role in familial breast cancer. Although hypermethylation of the BRCA1 promoter has been observed in sporadic breast cancer, its exact role in breast cancer initiation and association with breast cancer risk is unknown. The frequency of BRCA1 promoter hypermethylation was tested in (a) 14 primary breast cancer biopsies and (b) the initial random periareolar fine-needle aspiration (RPFNA) cytologic samples obtained from 61 asymptomatic women who were at increased risk for breast cancer. BRCA1 promoter hypermethylation was assessed from nucleotide -150 to nucleotide +32 relative to the transcription start site. RPFNA specimens were stratified for cytologic atypia using the Masood cytology index. BRCA1 promoter hypermethylation was observed at similar frequency in nonproliferative (normal; Masood

Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies.

PURPOSE: This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies. PATIENTS AND METHODS: Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks. RESULTS: Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders. CONCLUSION: Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.

Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.

PURPOSE: This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks. RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

Retinoic acid receptor-beta2 promoter methylation in random periareolar fine needle aspiration.

Methylation of the retinoic acid receptor-beta2 (RARbeta2) P2 promoter is hypothesized to be an important mechanism for loss of RARbeta2 function during early mammary carcinogenesis. The frequency of RARbeta2 P2 methylation was tested in (a) 16 early stage breast cancers and (b) 67 random periareolar fine needle aspiration (RPFNA) samples obtained from 38 asymptomatic women who were at increased risk for breast cancer. Risk was defined as either (a) 5-year Gail risk calculation > or = 1.7%; (b) prior biopsy exhibiting atypical hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ; or (c) known BRCA1/2 mutation carrier. RARbeta2 P2 promoter methylation was assessed at two regions, M3 (-51 to 162 bp) and M4 (104-251 bp). In early stage cancers, M4 methylation was observed in 11 of 16 (69%) cases; in RPFNA samples, methylation was present at M3 and M4 in 28 of 56 (50%) and 19 of 56 (38%) cases, respectively. RPFNAs were stratified for cytologic atypia using the Masood cytology index. The distribution of RARbeta2 P2 promoter methylation was reported as a function of increased cytologic abnormality. Methylation at both M3 and M4 was observed in (a) 0 of 10 (0%) of RPFNAs with Masood scores of < or = 10 (nonproliferative), (b) 3 of 20 (15%) with Masood scores of 11 to 12 (low-grade proliferative), (c) 3 of 10 (30%) with Masood scores of 13 (high-grade proliferative), and (d) 7 of 14 (50%) with Masood scores of 14 of 15 (atypia). Results from this study indicate that the RARbeta2 P2 promoter is frequently methylated (69%) in primary breast cancers and shows a positive association with increasing cytologic abnormality in RPFNA.

Medication taking behaviors among breast cancer patients on adjuvant endocrine therapy.

PURPOSE: To explore how symptoms and psychosocial factors are related to intentional and unintentional non-adherent medication taking behaviors. METHODS: Included were postmenopausal women with hormone receptor positive, stage I-IIIA breast cancer, who had completed surgery, chemotherapy, and radiation, and were taking endocrine therapy. Self-administered, standardized measures were completed during a routine clinic visit: Brief Fatigue Inventory, Brief Pain Inventory, Menopause Specific Quality of Life Questionnaire, Functional Assessment of Cancer Therapy General and Neurotoxicity scales, and Self-Efficacy for Appropriate Medication Use Scale. Regression analyses were performed to determine the degree to which demographic, medical, symptom, and psychosocial variables, explain intentional, such as changing one's doses or stopping medication, and unintentional, such as forgetting to take one's medication, non-adherent behaviors. RESULTS: Participants were 112 women: mean age 64 (SD = 9) years; 81% white; mean time from surgery 40 (SD = 28) months; 49% received chemotherapy (39% including a taxane); mean time on endocrine therapy, 35 (SD = 29.6) months; 82% taking an aromatase inhibitor. Intentional and unintentional non-adherent behaviors were described in 33.9% and 58.9% of participants, respectively. Multivariate analysis showed that higher self-efficacy for taking medication was associated with lower levels of unintentional (p = 0.002) and intentional (p = 0.004) non-adherent behaviors. The presence of symptoms (p = 0.03) and lower self-efficacy for physician communication (p = 0.009) were associated with higher levels of intentional non-adherent behaviors. CONCLUSIONS: These results suggest that women who report greater symptoms, lower self-efficacy for communicating with their physician, and lower self-efficacy for taking their medication are more likely to engage in both intentional and unintentional non-adherent behaviors.

Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.

PURPOSE: Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. PATIENTS AND METHODS: Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. RESULTS: Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). CONCLUSION: Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.