Adjustment to breast cancer: age‐related differences in coping and emotional distress

Women who are diagnosed with breast cancer are at high risk for experiencing affective distress; however, previous research suggests that older women may be less likely than younger women to experience extreme distress. Two issues remain unclear regarding age and affective distress: (a) the psychological processes that account for the association of age and distress, and (b) whether this association remains stable over the course of treatment and recovery from breast cancer. This study investigated symptoms of anxiety and depression in 80 women ages 36–80 years old with newly diagnosed breast cancer near the time of their diagnosis and at 3 and 6 months postdiagnosis. Disease severity and coping style were also examined. Symptoms of anxiety/depression and age were negatively correlated near the time of diagnosis. Path analysis controlling for disease severity revealed that coping involving the ventilation of emotion fully mediated the effect of age on symptoms of anxiety and depression. However, the association of age with symptoms of anxiety/depression was no longer significant at 3 and 6 months postdiagnosis, although emotional ventilation still predicted greater emotional distress at 6 months. These findings suggest that age is a salient factor to consider in the psychological adjustment of women with breast cancer near the time of initial diagnosis, with younger women exhibiting greater affective distress and a tendency to engage in less adaptive ways of coping. However, younger and older women do not differ in their adjustment over the subsequent course of their treatment and initial recovery. The use of emotional ventilation coping remains associated with poorer adjustment, independent of patients age.     

CD8⁺ cytotoxic T cell and FOXP3⁺ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes

The prognostic significance of tumor-associated FOXP3⁺ regulatory T cells (Tregs) and CD8⁺ cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas is studied. Tregs and CTLs were assessed by immunohistochemistry in 1270 cases of invasive breast carcinoma for their associations with patient survival, histopathologic features, and molecular subtypes. Infiltrates of Tregs and CTLs were observed within tumor bed and in the tissue surrounding tumor. Within tumor bed, increased infiltration of Tregs and CTLs was significantly more common in those with unfavorable histologic features, including high histologic grade and negative ER and PR status. In addition, high density Treg infiltration was also associated with tumor HER2 overexpression, decreased overall survival (OS) and progression-free survival (PFS). In tissue surrounding tumor, in contrast, high CTL/Treg ratio was found to be significantly associated with improved OS and PFS. These prognostic associations were confirmed by multivariate analysis. Furthermore, the density of Treg infiltrates within tumors was inversely correlated with the prognosis of the molecular subtypes of tumors. The ratio of CTL/Treg infiltrates in the surrounding tissue was also significantly higher in luminal than non-luminal subtypes of carcinoma. The prognostic significances of Tregs and CTLs in breast carcinoma depend on their relative density and location. The density of intratumoral Treg infiltrates and the peritumoral CTL/Treg ratio are independent prognostic factors and correlated with the prognosis of the molecular subtypes of breast carcinoma, which may serve as potential target for stratifying immunotherapy to battle against the aggressive subtypes of breast carcinoma.     

Suppression of parathyroid hormone‐related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues

Stromal-epithelial interactions modulate growth and development in normal and neoplastic mammary gland. The release of IGF binding proteins (IGFBPs) by the stromal compartment of the mammary gland may play a modulating role in the IGF-mediated proliferation of mammary epithelium. Therefore, the IGFBP-expression pattern of the canine mammary tumor cell line U335 (CMT-U335), which has a mesenchymal phenotype, was determined. In addition, the effects of IGFs and all trans retinoic acid (RA) on DNA synthesis, and IGFBP secretion and distribution were examined. The IGFBPs secreted by CMT-U335 were characterized as IGFBP-2, -4, -5, and -6. Moreover, CMT-U335 appeared to be a suitable mammary mesenchymal cell line for study of the regulatory factors of IGFBP expression and the mechanism(s) involved. IGFs and RA enhanced IGFBP concentrations in cell-conditioned medium with IGF-I and RA having an additive effect. The IGF-I-stimulated DNA synthesis, however, was inhibited by RA. The difference between IGF-I and RA was an enhanced IGFBP-5 binding to the extracellular matrix (ECM) by RA, whereas IGF-I reduced binding to the ECM. Because high doses of insulin had no significant effects on IGFBP concentrations in the medium, it is concluded that IGF-I-induced changes in IGFBP concentrations are not mediated by type-I IGF receptors and may be the consequence of IGFBP redistribution.     

Patients’ perceptions of gene expression profiling in breast cancer treatment decisions

Introduction

Determining the likely benefit of adjuvant chemotherapy for early-stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions.

Methods

We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques.

Results

Patients’ understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information.They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of “magical thinking” was derived from an amplified perception of the test’s validity and patients’ need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions.

Conclusions

Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions.     

The expression of β-catenin in different subtypes of breast cancer and its clinical significance

The Wnt/β-catenin signaling pathway is implicated in mammary oncogenesis. Reports of β-catenin expression and its association with outcome in breast cancer are controversial. This study was performed to address the distribution of β-catenin expression in invasive breast cancer and the correlation between β-catenin expression and survival of breast cancer patients, and to determine whether β-catenin was specifically activated in any molecular subtypes. Immunohistochemistry was performed on a tissue microarray containing 169 invasive breast cancers to detect expression of β-catenin. One hundred thirty one of the 169 patients were followed up. Correlation between β-catenin expression and different molecular subtypes was determined using chi-square analysis. Overall survival (OS) was analyzed by Kaplan-Meier method with log-rank test. The invasive breast cancer displayed the different patterns of β-catenin expression from normal tissues with significantly increased cytoplasmic and nuclear staining of β-catenin. Aberrant β-catenin expression was observed in 109 in the 169 cases (64.50 %), and there was no difference in β-catenin expression in the four molecular subtypes. Furthermore, aberrant β-catenin expression was significantly associated with adverse outcome not only in the entire cohort but also in each of the different molecular subtypes. β-catenin activation is preferentially found and is associated with a poor clinical outcome in invasive breast cancer independent of molecular subtype.     

Pathway‐based personalized analysis of breast cancer expression data

Introduction

Most analyses of high throughput cancer data represent tumors by “atomistic” single‐gene properties. Pathifier, a recently introduced method, characterizes a tumor in terms of “coarse grained” pathway‐based variables.

Methods

We applied Pathifier to study a very large dataset of 2000 breast cancer samples and 144 normal tissues. Pathifier uses known gene assignments to pathways and biological processes to calculate for each pathway and tumor a Pathway Deregulation Score (PDS). Individual samples are represented in terms of their PDSs calculated for several hundred pathways, and the samples of the data set are analyzed and stratified on the basis of their profiles over these “coarse grained”, biologically meaningful variables.

Results

We identified nine tumor subtypes; a new subclass (comprising about 7% of the samples) exhibits high deregulation in 38 PKA pathways, induced by overexpression of the gene PRKACB. Another interesting finding is that basal tumors break into two subclasses, with low and high deregulation of a cluster of immune system pathways. High deregulation corresponds to higher concentrations of Tumor Infiltrating Lymphocytes, and the patients of this basal subtype have better prognosis. The analysis used 1000 “discovery set” tumors; our results were highly reproducible on 1000 independent “validation” samples.

Conclusions

The coarse‐grained variables that represent pathway deregulation provide a basis for relevant, novel and robust findings for breast cancer. Our analysis indicates that in breast cancer reliable prognostic signatures are most likely to be obtained by treating separately different subgroups of the patients.     

Does emotional expression make a difference in reactions to breast cancer?

PURPOSE/OBJECTIVES: To examine the feasibility of using an emotional expression intervention with patients with cancer and test the hypothesis that emotional expression improves psychosocial adjustment. DESIGN: Sequentially randomized pretest/post-test design with repeated measures. SETTING: Two radiation therapy (RT) facilities. SAMPLE: Women completing RT for stage I or II breast cancer, who spoke and read English, were independent in self-care, and provided written consent. Subjects (N = 44) were middle-aged (mean = 53.6 years), Caucasian, married, and well educated. METHODS: Following a baseline interview, subjects were sequentially randomized to an attentional control group, a single dose, or a three-dose emotional expression writing group. Interventions were administered at the time of completion of RT. Follow-up telephone interviews were completed at 1, 4-6, 16, and 28 weeks post-RT. MAIN RESEARCH VARIABLES: Positive and negative affect, intrusiveness of thoughts, use of avoidant coping, side effect severity, trait negative affectivity, content of written essay, and themes derived from content analysis. FINDINGS: A high level of acceptance and completion of emotional expression existed, but no effect of the intervention on psychosocial adjustment was evident. Process measures in the three-dose group changed as expected. No relationship existed between content changes and outcome measures. CONCLUSIONS: Emotional expression is feasible for patients with cancer, but the efficacy of the intervention in improving mood and decreasing cognitive intrusion and avoidance was not supported. Emotional expression processes were consistent with those seen in other samples and may influence outcomes that were not addressed in this study. IMPLICATIONS FOR NURSING PRACTICE: More extensive testing is needed, including additional outcome variables. Essays reveal concerns around communication, recurrence, and health behavior changes that should be considered in practice.     

Immunohistochemical expression of internal and external ErbB‐2 domains in invasive breast cancer

We tested three ErbB2 monoclonal antibodies (MoAbs) specific to the intracytoplasmic internal domain (clone CB 11) and the extracellular glycosylated peptide domain (clones CBE1 and Tab250) in 351 primary invasive breast carcinomas. ErbB2 immunodetection allowed us to differentiate three main groups: group 1 (62.7%) lacked both MoAb ErbB2 domains (erb –/–); group 2 stained for both domains (erb +/+) (26.5%); group 3 stained for the internal domain only (erb +/–) (10.8%). The relationships among these groups and nodal status (N) were statistically significant, with N+ cases reaching the highest value (89.2%) in the erb +/– group. Lack of immunostaining in the external domain thus seems to be associated with increased metastatic spread. At variance analysis the difference in hormonal receptor content between groups 1 and 3 was not significant; while between groups 1 and 2 it was. The growth fraction of groups 2 and 3 was significantly higher than that of group 1. Our results showed that anti-ErbB-2 MoAb clone CB 11 was able to detect a higher number of ErbB-2 expressing cases than the two that are specific for the external domain (clones Tab 250 and CBE1). Due to the strong association between group 3 cases and the highest metastatic potential, this aggressive group could be identified only with the use of an internal-domain specific MoAb CB11, which thus seems to present a better discriminative power as a diagnostic marker in the biopathological characterization of breast carcinoma.     

Regulation of BAX and BCL‐2 expression in breast cancer cells by chemotherapy

Optimizing chemotherapeutic drug delivery strategies relies, in part, on identification of the most clinically effective sequence, dose, and duration of drug exposure. The combination of dose intensive etoposide (VP16) followed by cyclophosphamide has clinical efficacy in the treatment of advanced breast cancer. However, molecular mechanisms that underlie the effectiveness of this combination of chemotherapeutic agents have not been investigated. In this study we investigated regulation of BAX and BCL2 expression by VP16 and cyclophosphamide as a potential mechanism for the induction of breast cancer cell death induced by this regimen.There was a dose and time dependent increase in BAX expression in the breast cancer cell lines MCF7, MDAMB435S, and MDAMBA231 following in vitro treatment with 50–100M VP16. Elevation of BAX protein expression in the presence of VP16 alone did not correlate with reduced viability or induction of apoptosis in MCF7, MDAMB435S, or MDAMBA231. VP16 did effectively block the breast cancer cell lines evaluated (MCF7 and MDAMB435S) at G₂/M phase of the cell cycle, confirming activity of the drug in vitro. MCF7 and MDAMB435S cells that were pretreated with VP16 and subsequently exposed to 1.0–12.0g/m1 4hydroperoxycyclophosphamide (4HC), an active metabolite of cyclophosphamide, had markedly reduced viability when compared to matched controls treated with either VP16 or 4HC individually. Consistent with this loss of viability, exposure of all three cell lines to the combination of VP16 and 4HC resulted in higher BAX protein levels than those observed following treatment with either single agent. This combination of chemotherapeutic agents also resulted in reduced BCL2 expression.These observations suggest that combination chemotherapy may derive its efficacy, in part, through coordinated regulation of specific gene products associated with apoptosis. Characterization of molecular events that underlie susceptibility of specific tumor cells to combination chemotherapeutic regimens may lead to additional improvements in treatment strategies for this disease.     

TGF-β1 mRNA expression in clinical breast cancer and its relationship to ER mRNA expression

Eighty nine primary breast cancers were investigated forthe expression of TGF-1 and ER mRNA usingPCR of reverse transcribed RNA. PCR products werevalidated using Southern blots and hybridization with radiolabelledcDNA probes. TGF₁ mRNA was found to beexpressed in 56/89 (63%) of the breast cancerswhile ER mRNA was expressed in 23/89 (26%)of the tumours. Using chi-square analysis TGF- mRNAexpression was found to correlate significantly with ERmRNA expression (p < 0.001), in that virtuallyall tumours that expressed ER mRNA co-expressed TGF₁.In tumours that were ER mRNA negative, TGF₁expression was more variable. These results suggest thatduring tumour progression, ER expression is lost morefrequently than is growth factor expression.     

Is guideline adherence the key to increased survival in patients with breast cancer?

Recently, Varga et al. reported in an observational study that guideline adherence could prevent 56.3-78.9% of all deaths in patients with early onset breast cancer [Oncology 2010;78:189-195]. This would mean that nearly all deaths due to breast cancer can be avoided by guideline-adherent treatment. We argue that some methodological issues like immortal time bias or healthy adherer bias may have contributed to these implausible findings. However, the non-transparent reporting of the methods, especially regarding the operationalization of guideline adherence, hampers critical assessment of this study.