Good versus bad news consultations in advanced breast cancer: the role of empathy in information recall - an observational study.

OBJECTIVE: We explored, in advanced breast cancer, whether: (1) patients recall less information following bad versus good news consultations; (2) empathy has a greater effect on recalled information following bad versus good news consultations. METHODS: Observational study using audio-recorded consultations. Participants' recall of provided information about treatment options, aims/positive effects and side-effects was assessed. Clinician-expressed empathy and consultation type were determined. Regression analyses assessed associations between consultation type and recall, exploring moderating influences of clinician-expressed empathy. RESULTS: For 41 consultations (18 bad news, 23 good news), recall data were completed; total recall (47% vs 73%, p=0.03) and recall about treatment options (67% vs 85%, p=0.08, trend) were significantly worse following bad news compared with good news consultations. Recall about treatment aims/positive effects (53% vs 70%, p=0.30) and side-effects (28% vs 49%, p=0.20) was not significantly worse following bad news. Empathy moderated the relationship between consultation type and total recall (p<0.01), recall about treatment options (p=0.03) and about aims/positive effects (p<0.01) but not about side-effects (p=0.10). Only following good news consultations empathy influenced recall favourably. CONCLUSIONS: This explorative study suggests that in advanced cancer, information recall is especially impaired following bad news consultations, for which empathy does not improve remembered information.

The effect of trastuzumab on cardiac function in patients with HER2-positive metastatic breast cancer and reduced baseline left ventricular ejection fraction.

We investigated the effect of trastuzumab on cardiac function in a real-world historic cohort of patients with HER2-positive metastatic breast cancer (MBC) with reduced baseline left ventricular ejection fraction (LVEF). Thirty-seven patients with HER2-positive MBC and baseline LVEF of 40% to 49% were included. Median LVEF was 46% (interquartile range [IQR] 44%-48%) and median follow-up was 18 months (IQR 9-34 months). During this period, the LVEF did not worsen in 24/37 (65%) patients, while 13/37 (35%) patients developed severe cardiotoxicity defined as LVEF <40% with median time to severe cardiotoxicity of 7 months (IQR 4-10 months) after beginning trastuzumab. Severe cardiotoxicity was reversible (defined as LVEF increase to a value <5%-points below baseline value) in 7/13 (54%) patients, partly reversible (defined as absolute LVEF increase ≥10%-points from nadir to a value >5%-points below baseline) in 3/13 (23%) patients and irreversible (defined as absolute LVEF increase <10%-points from nadir and to a value >5%-points below baseline) in 3/13 (23%) patients. Likelihood of reversibility was numerically higher in patients who received cardio-protective medications (CPM), including ACE-inhibitors, beta-blockers and angiotensine-2 inhibitors, compared to those who did not receive any CPM (71% vs 13%, P = .091). Sixty-five percent of patients who received trastuzumab for HER2-positive MBC did not develop severe cardiotoxicity during a median follow-up of 18 months, despite having a compromised baseline LVEF. If severe cardiotoxicity occurred, it was at least partly reversible in more than two-thirds of the cases. Risks and benefits of trastuzumab use should be balanced carefully in this vulnerable population.

Baseline effector cells predict response and NKT cells predict pulmonary toxicity in advanced breast cancer patients treated with everolimus and exemestane.

BACKGROUND: The mTOR inhibitor everolimus used in cancer has immune-modulating effects, potentially contributing to an antitumor response but also leading to pulmonary toxicity. We studied the association of immunological cell subsets with antitumor response and pulmonary toxicity in breast cancer patients treated with everolimus plus exemestane. METHODS: In this exploratory analysis, peripheral blood mononuclear cells (PBMCs) were collected at baseline and 14, 35, 60, and 90 days after start of treatment, and at the moment of pulmonary toxicity. The percentage and absolute number of T-cells, B-cells, NK-cells, monocytes and numerous subtypes were measured in peripheral blood using flow cytometric analysis and were compared using a (paired) t-test. RESULTS: From 20 patients, a total of 89 samples were collected. At baseline, responders versus non-responders had 0.86% versus 0.32% CD4+ effector cells (CD45RA+CD27-) (p = 0.1266) and non-response could be predicted with 0.71 sensitivity and 0.82 specificity. Patients who developed pulmonary toxicity compared to patients without pulmonary toxicity had relatively more NKT-cells at baseline (6.0% versus 1.3%, p = 0.0068, 59 k versus 12 k * 109/l, p = 0.0081) and at the moment of toxicity (5.2% versus 1.2%, p = 0.0106 and 47 k versus 16 k * 109/l, p = 0.0466). Baseline percentage NKT cells predicted pulmonary toxicity with 0.78 sensitivity and 1.0 specificity. CONCLUSIONS: Our results suggest that baseline CD4+ effector cells may be predictive of antitumor responses and baseline NKT cells may be predictive of pulmonary toxicity. These results warrant further validation.

Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane.

BACKGROUND: Everolimus-related interstitial lung disease (ILD) (also: pneumonitis) poses a difficulty for physicians, as it is hard to discriminate ILD from other causes of respiratory symptoms and to decide on safe treatment continuation. OBJECTIVE: We investigated the capability of pulmonary function tests (PFT), plasma biomarkers, everolimus pharmacokinetics, and FDG-PET to discriminate between everolimus-related ILD and other causes of respiratory problems and to predict the severity of ILD. PATIENTS AND METHODS: Women starting treatment with everolimus plus exemestane for advanced breast cancer were included. At baseline and during the first 3 months, respiratory symptoms, PFT with diffusion capacity of the lungs for carbon monoxide corrected for hemoglobin (DLCOc) and forced vital capacity, serum plasma biomarkers (including SP-D and YKL-40), everolimus trough concentration, and 18F-FDG-PET were prospectively recorded. RESULTS: Twenty-seven (out of 29 included) patients were evaluable for analysis. Fifteen patients (56%) developed everolimus-related respiratory signs or symptoms and four patients (15%) needed everolimus discontinuation and received corticosteroids. Change in DLCOc differentiated ILD from alternative diagnoses with 0.91 sensitivity and 0.78 specificity. Decrease in DLCOc (non-significant) was greatest in patients who needed everolimus discontinuation. Serum SP-D and YKL-40 could differentiate ILD from alternative diagnoses with 0.83 and 0.83 sensitivity, and 0.85 and 0.62 specificity, respectively. 18F-FDG-PET abnormalities did not precede clinical symptoms. No relationship between ILD and everolimus trough concentration was found. CONCLUSIONS: This study shows that everolimus-related ILD occurs frequently. Prospective monitoring of DLCOc in combination with measurement of serum SP-D and YKL-40 appear useful to discriminate ILD from other causes of respiratory symptoms. Clinicaltrials.gov identifier: NCT01978171.

Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane.

BACKGROUND: Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. OBJECTIVE: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. PATIENTS AND METHODS: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). RESULTS: Among 44 evaluable patients, the geometric mean (GM) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 µg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 µg/L. GM Ctrough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 µg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SULpeak high) at day 14. Patients with <11% versus >11% decrease in SULpeak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. CONCLUSIONS: Our results show that everolimus toxicity is related to everolimus Ctrough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.

[Risks associated with phytoestrogen dietary supplementation and adjuvant hormonal therapy for breast cancer]. / Risico's van fyto-oestrogenen uit voedingssupplementen bij adjuvante hormonale therapie voor borstkanker.

OBJECTIVE: Adjuvant hormonal therapy using tamoxifen or aromatase inhibitors result in menopausal symptoms. Non-prescription dietary supplements containing plant-based phytoestrogens are often used to relieve menopausal symptoms. Phytoestrogens may reduce the action of tamoxifen and aromatase inhibitors. The purpose of this study is to gain insight into the potential risks of phytoestrogen supplementation during adjuvant hormonal therapy for breast cancer using tamoxifen or aromatase inhibitors. DESIGN: Literature survey. METHOD: We performed a PubMed search for articles about studies on the effects of phytoestrogens on breast cancer treatment efficacy. We also searched on the basis of references in the articles we found in PubMed. RESULTS: Studies based on in-vitro models as well as experimental animal models were identified. The studies on the interaction between phytoestrogen and tamoxifen showed contradictory results. The few studies pertaining to the interactive effect of phytoestrogens on aromatase inhibitors all showed a reduction in therapeutic efficacy of aromatase inhibitors caused by phytoestrogens. CONCLUSION: The outcomes of the studies we found suggest that caution should be exercised when taking phytoestrogen in combination with either tamoxifen or aromatase inhibitors. We believe that patients with breast cancer should be informed of this as a matter of routine.

Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs).

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC(50) values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent K(i)/K(i)' of 7.68/0,02 microM and 5.01/0.04 microM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a wide range of OH-PBDEs have the potential to disturb steroidogenesis and indicate a potential mechanism of action of these brominated flame retardant derivatives as endocrine disruptors in humans and wildlife.

Inhibition of aromatase activity by methyl sulfonyl PCB metabolites in primary culture of human mammary fibroblasts.

In this study, the effects on catalytic activity and mRNA levels of aromatase in primary human mammary fibroblasts were evaluated after exposure to promoter-specific modulators of aromatase expression and methyl sulfonyl polychlorinated biphenyl metabolites (MeSO(2)-PCBs). A method for fibroblast isolation from primary breast tissue was developed and optimized, and aromatase activity and promoter-specific mRNA levels were assessed in these cells after exposure to test compounds. A 24-h exposure of fibroblasts to dexamethasone (DEX) (1-100 nM) increased aromatase activity to a maximum of 313-fold. DEX also elevated promoter I.4-specific RNA levels. A 24-h exposure of fibroblasts to 3-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-91, or 4-MeSO(2)-PCB-149 (0.1-10 microM) resulted in a concentration-dependent decrease of aromatase activity. Exposure of fibroblasts to MeSO(2)-PCBs just for the limited duration (6 h) of the catalytic assay caused a concentration-dependent inhibition of aromatase enzyme activity. mRNA levels were not altered by a 24-h MeSO(2)-PCB exposure nor was cytotoxicity observed. In aromatase-expressing human adrenocortical carcinoma H295R cells, a 24-h exposure to 3-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-91, or 4-MeSO(2)-PCB-149 (0.1-10 microM) also resulted in a concentration-dependent decrease of aromatase activity. Additionally, there were no changes in aromatase mRNA levels after 24-h exposure of H295R cells to MeSO(2)-PCBs. We conclude that in primary human mammary fibroblasts as well as in H295R cells, aromatase inhibition by MeSO(2)-PCBs is likely to be due to catalytic inhibition.

Co-culture of primary human mammary fibroblasts and MCF-7 cells as an in vitro breast cancer model.

Approximately 60% of all breast tumors are estrogen-responsive and chemicals that show estrogenic or anti-estrogenic properties are able to interact with breast tumor growth. In a breast tumor, adipose stromal cells (fibroblasts) surrounding the epithelial tumor contain the aromatase enzyme, which converts androgens into estrogens. Exposure to aromatase inducers can therefore lead to increased estrogen levels and possibly to accelerated breast tumor growth. Subsequently, breast tumor cells synthesize and secrete elevated levels of factors such as prostaglandin E2 (PGE2), interleukin-6 (IL-6), and IL-6 soluble receptor (IL-6sR), which in turn have the ability to stimulate aromatase gene transcription in fibroblasts, establishing a positive feedback loop. In this study, a technique that allows for culturing MCF-7 epithelial breast tumor cells and healthy primary human mammary fibroblasts together in one compartment was developed. To establish the positive feedback loop, the co-culture was exposed to estrogenic compounds. RNA was isolated and reverse-transcriptase polymerase chain reaction (RT-PCR) was performed on the aromatase and pS2 genes. Exposure of the co-culture to estradiol (E2), diethylstilbestrol (DES), and bisphenol-A (BPA), resulted in a three- to seven-fold increase of pS2 transcription levels. Furthermore, pS2 transcription levels increased even more when the aromatase substrate testosterone (20 nM) was present in the co-culture medium. Exposure of the co-culture to the aromatase inducer dexamethasone (DEX) resulted in increased pS2 transcription levels, as well as increased aromatase transcription levels. Simultaneous exposure to DEX and the synthetic anti-estrogen ICI 182,780 almost completely blocked the pS2 response. The aromatase induction response was not altered by ICI 182,780 treatment. Simultaneous exposure to DEX and the non-steroidal aromatase inhibitor fadrozole, abolished the effect of the presence of testosterone in the co-culture medium, but did not result in pS2 gene transcription levels as low as seen after exposure to ICI 182,780. These observations indicate the presence of a positive feedback loop in our co-culture system. This co-culture provides a more sophisticated and sensitive system to detect direct and indirect estrogenic effects of compounds and their possible effects on breast tumor promotion.

Phytochemicals inhibit catechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues: implications for catechol estrogen-induced DNA damage.

Phytochemicals are natural dietary constituents of fruits and vegetables. Some of these phytochemicals are known to affect estrogen-metabolizing enzymes. In breast tissue, estradiol can be metabolized to the catechol estrogens 2- and 4-hydroxyestradiol (2-OHE(2) and 4-OHE(2)). Catechol estrogens are suspected carcinogens potentially involved in the etiology of breast cancer. Catechol-O-methyltransferase (COMT) converts the catechol estrogens to their inactive methoxy derivatives (2-MeOE(2) and 4-MeOE(2)). In this study we investigated the effects of several phytochemicals on COMT activity in cytosolic fractions of seven healthy human mammary tissues from reduction mammoplasty. Large interindividual variations were observed in the constitutive levels of COMT activity. However, in all cytosol samples the catalytic efficiency of COMT was greater for 2-MeOE(2) formation than for 4-MeOE(2) formation. The known COMT inhibitor Ro 41-0960 and several phytochemicals with a catechol structure (quercetin, catechin, and (-)-epicatechin) concentration-dependently inhibited COMT activity, while phytochemicals without a catechol structure (genistein, chrysin, and flavone) showed no effect up to 30 microM. Distinct interindividual variations were observed in sensitivity toward COMT inhibition among the various tissue samples, as was shown by the range in IC(50) values for Ro 41-0960 (5-42 nM). The toxicological relevance of COMT inhibition and the effect of reduced inactivation of catechol estrogens was studied by determining the amount of catechol estrogen-induced DNA damage in MCF-7 cells using the comet assay. Catechol estrogens alone caused no increase of DNA damage compared with control treated cells. However, both Ro 41-0960 and quercetin caused a decrease of methoxy estradiol formation and an increase of catechol estrogen-induced DNA damage in MCF-7 cells. This suggests that phytochemicals with a catechol structure have the potential to reduce COMT activity in mammary tissues and may consequently reduce the inactivation of potentially mutagenic estradiol metabolites and increase the chance of DNA damage.