A complex communication skills training program for physicians providing advanced cancer care - content development and barriers and solutions for implementation.

Background: Early integration of oncology and patient-centered palliative care is the recommended clinical practice model for patients with advanced cancer. General and specific communication skills are necessary to achieve integrated patient-centered care, but require organized training to be adequately mastered. Challenges and barriers on several levels, i.e. organizational, professional and individual may, however, hamper implementation. The development, implementation, and evaluation of such an educational program focusing on communication skills contain many steps, considerations and lessons learned, which are described in this article.Methods: A multi-professional faculty developed, implemented, and evaluated an educational program through a 5-step approach. The program was part of a Norwegian cluster-randomized controlled trial aiming to test the effect of early integration of oncology and palliative care for patients with advanced cancer.Results: The result is the PALLiON educational program; a multi-faceted, evidence-based, and learner-centered program with a specific focus on physicians' communication skills. Four modules were developed: lectures, discussion groups, skills training, and coaching. These were implemented at the six intervention hospitals using different teaching strategies. Evaluation in a subgroup of participants showed a positive appraisal of the group discussions and skills training.Conclusion:We present our experiences and reflections regarding implementation and lessons learned, which should be considered in future developments and implementations; (1) Include experienced faculty with various backgrounds, (2) Be both evidence-based and learner-centered, (3) Choose teaching strategies wisely, (4) Expect resistance and skepticism, (5) Team up with management and gatekeepers, (6) Expect time to fly, and (7) Plan thorough assessment of the evaluation and effect.Trial registration: ClinicalTrials.gov identifier: NCT03088202.

The influence of metabolic factors and ethnicity on breast cancer risk, treatment and survival: The Oslo ethnic breast cancer study.

BACKGROUND: Breast cancer risk remains higher in high-income compared with low-income countries. However, it is unclear to what degree metabolic factors influence breast cancer development in women 30 years after immigration from low- to a high-incidence country. METHODS: Using Cox regression models, we studied the association between pre-diagnostic metabolic factors and breast cancer development, and whether this association varied by ethnicity among 13,802 women participating in the population-based Oslo Ethnic Breast Cancer Study. Ethnic background was assessed and pre-diagnostic metabolic factors (body mass index, waist:hip ratio, serum lipids and blood pressure) were measured. A total of 557 women developed invasive breast cancer, and these women were followed for an additional 7.7 years. RESULTS: Among women with an unfavorable metabolic profile, women from south Asia, compared with western European women, had a 2.3 times higher breast cancer risk (HR 2.30, 95% CI 1.18-4.49). Compared with the western European women, the ethnic minority women were more likely to present with triple-negative breast cancer (TNBC) (OR 2.11, 95% CI 0.97-4.61), and less likely to complete all courses of planned taxane treatment (OR 0.26, 95% CI 0.08-0.82). Among TNBC women, above-median triglycerides:HDL-cholesterol (>0.73) levels, compared with below-median triglycerides:HDL-cholesterol (≤0.73) levels, was associated with 2.9 times higher overall mortality (HR 2.88, 95% CI 1.02-8.11). CONCLUSIONS: Our results support the importance of metabolic factors when balancing breast cancer prevention and disease management among all women, and in particular among non-western women migrating from a breast cancer low-incidence to a high-incidence country.

Immune phenotype of tumor microenvironment predicts response to bevacizumab in neoadjuvant treatment of ER-positive breast cancer.

Antiangiogenic drugs are potentially a useful supplement to neoadjuvant chemotherapy for a subgroup of patients with human epidermal growth factor receptor 2 (HER2) negative breast cancer, but reliable biomarkers for improved response are lacking. Here, we report on a randomized phase II clinical trial to study the added effect of bevacizumab in neoadjuvant chemotherapy with FEC100 (5-fluorouracil, epirubicin and cyclophosphamide) and taxanes (n = 132 patients). Gene expression from the tumors was obtained before neoadjuvant treatment, and treatment response was evaluated by residual cancer burden (RCB) at time of surgery. Bevacizumab increased the proportion of complete responders (RCB class 0) from 5% to 20% among patients with estrogen receptor (ER) positive tumors (P = .02). Treatment with bevacizumab was associated with improved 8-year disease-free survival (P = .03) among the good responders (RCB class 0 or I). Patients treated with paclitaxel (n = 45) responded better than those treated with docetaxel (n = 21; P = .03). Improved treatment response was associated with higher proliferation rate and an immune phenotype characterized by high presence of classically activated M1 macrophages, activated NK cells and memory activated CD4 T cells. Treatment with bevacizumab increased the number of adverse events, including hemorrhage, hypertension, infection and febrile neutropenia, but despite this, the ECOG status was not affected.

Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations.

BACKGROUND: Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels. METHODS: A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods. RESULTS: In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime. CONCLUSIONS: Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy. TRIAL REGISTRATION: NCT00773695 . Registered 15 October 2008.

Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment.

BACKGROUND: Breast cancer treatment has metabolic side effects, potentially affecting risk of cardiovascular disease (CVD) and recurrence. We aimed to compare alterations in serum metabolites and lipoproteins during treatment between recipients and non-recipients of chemotherapy, and describe metabolite profiles associated with treatment-related weight gain. METHODS: This pilot study includes 60 stage I/II breast cancer patients who underwent surgery and were treated according to national guidelines. Serum sampled pre-surgery and after 6 and 12 months was analysed by MR spectroscopy and mass spectrometry. In all, 170 metabolites and 105 lipoprotein subfractions were quantified. RESULTS: The metabolite and lipoprotein profiles of chemotherapy recipients and non-recipients changed significantly 6 months after surgery (p < 0.001). Kynurenine, the lipid signal at 1.55-1.60 ppm, ADMA, 2 phosphatidylcholines (PC aa C38:3, PC ae C42:1), alpha-aminoadipic acid, hexoses and sphingolipids were increased in chemotherapy recipients after 6 months. VLDL and small dense LDL increased after 6 months, while HDL decreased, with triglyceride enrichment in HDL and LDL. At baseline, weight gainers had less acylcarnitines, phosphatidylcholines, lyso-phosphatidylcholines and sphingolipids, and showed an inflammatory lipid profile. CONCLUSION: Chemotherapy recipients exhibit metabolic changes associated with inflammation, altered immune response and increased risk of CVD. Altered lipid metabolism may predispose for treatment-related weight gain.

Impact of pre-diagnostic triglycerides and HDL-cholesterol on breast cancer recurrence and survival by breast cancer subtypes.

BACKGROUND: High triglycerides and low levels of high density lipoprotein (HDL)-cholesterol are observed to promote tumor growth. However, whether breast cancer heterogeneity may explain the contradictory influence of triglycerides and cholesterol observed on breast cancer prognosis remains unclear. METHODS: A population-based survival study among 464 breast cancer cases identified within the Tromsø study was conducted. Pre-diagnostic triglycerides, total-cholesterol and HDL-cholesterol were measured, and detailed clinical and histopathological data were obtained. Using tissue microarray, all breast cancer cases were reclassified into the following subtypes: Luminal A, Luminal B, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable Cox proportional hazards regression models were used to study the associations between pre-diagnostic lipids and breast cancer recurrence, mortality, and survival. RESULTS: A total of 464 breast cancer patients, with mean age at diagnosis of 57.9 years, were followed for a mean 8.4 years. TNBC patients in the highest tertile of triglycerides (≥ 1.23 mmol/l) had 3 times higher overall mortality compared to TNBC patients in the lowest tertile (≤ 0.82 mmol/l) (HR 2.99, 95% CI 1.17-7.63), and the 5-year overall survival was 19% lower for TNBC patients in the highest vs. lowest tertile of triglycerides (65% vs. 84%). TNBC patients in the highest tertile of the HDL-cholesterol/total-cholesterol ratio (≥0.35), compared to those in the lowest tertile (≤0.27), had a 67% reduced overall mortality risk (HR 0.33, 95% CI 0.12-0.89). No associations were observed between lipids and prognostic outcome among breast cancer patients overall, or among patients with luminal A and luminal B subtypes. Among HER2-enriched patients, pre-diagnostic triglyceride level was inversely associated with overall mortality. CONCLUSION: Our study suggests that pre-diagnostic triglycerides and the HDL-cholesterol/total-cholesterol ratio may independently provide unique information regarding prognostic outcome among triple negative breast cancer patients. However, a small sample size underlines the need for additional studies.

Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial.

PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2- advanced breast cancer. METHODS: 668 postmenopausal women with HR+, HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was PFS, which was evaluated in elderly (≥ 65 years) and younger (< 65 years) patients. Secondary endpoints included response rates and safety. RESULTS: Ribociclib plus letrozole significantly improved PFS vs placebo plus letrozole in elderly (hazard ratio: 0.608; 95% CI 0.394-0.937) and younger patients (hazard ratio: 0.523; 95% CI 0.378-0.723). Overall response rates were numerically higher in the ribociclib vs placebo arm, regardless of age. Ribociclib plus letrozole was well tolerated in elderly patients, with the safety profile similar to the overall study population. Nausea, vomiting, alopecia, and diarrhea were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm in both subgroups; most events were grade 1/2. In elderly patients, grade 1/2 anemia and fatigue were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm and discontinuation rates were similar in both arms. CONCLUSIONS: Addition of ribociclib to letrozole is a valid therapeutic option for elderly patients with HR+, HER2- advanced breast cancer in the first-line setting.

Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up.

BACKGROUND: The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) pN0 patients not treated with chemotherapy. METHODS: Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995-1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). RESULTS: Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2- patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2- patients) yielded strong prognostic information. Among the HR+/HER2- pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2- pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2- population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). CONCLUSIONS: The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.

Erratum: Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer.

[This corrects the article DOI: 10.1038/s41523-017-0015-9.].

Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer.

Growing evidence indicates that adiposity is associated with breast cancer risk and negatively affects breast cancer recurrence and survival, a paracrine role of mammary adipose tissue being very likely in this process. In contrast to other adipose depots, occurrence of a sub-inflammatory state of mammary adipose tissue defined by dying adipocytes surrounded by macrophages forming crown-like structures in overweight and obese subjects, remains only partially described. In a general population of breast cancer patients (107 patients) mostly undergoing breast-conserving surgery, we found a positive association between patient's body composition, breast adipocytes size, and presence of crown-like structures in mammary adipose tissue close to the tumor. Overweight (BMI: 25.0-29.9 kg/m2) and obese (BMI ≥ 30.0 kg/m2) patients have 3.2 and 6.9 times higher odds ratio of crown-like structures respectively, compared with normal weight patients. The relatively small increase in adipocyte size in crown-like structures positive vs. negative patients suggests that mammary adipose tissue inflammation might occur early during hypertrophy. Our results further highlight that body mass index is an adequate predictor of the presence of crown-like structures in mammary adipose tissue among postmenopausal women, whereas in premenopausal women truncal fat percentage might be more predictive, suggesting that mammary adipose tissue inflammation is more likely to occur in patients exhibiting visceral obesity. Finally, the presence of crown-like structures was positively associated with systemic markers such as the Triglyceride/High-density lipoprotein-cholesterol ratio serum C-reactive protein and glucose/(HbA1c) glycated Haemoglobin. These compelling results demonstrate that excess adiposity, even in overweight patients, is associated with mammary adipose tissue inflammation, an event that could contribute to breast cancer development and progression.

The Longitudinal Transcriptional Response to Neoadjuvant Chemotherapy with and without Bevacizumab in Breast Cancer.

Purpose: Chemotherapy-induced alterations to gene expression are due to transcriptional reprogramming of tumor cells or subclonal adaptations to treatment. The effect on whole-transcriptome mRNA expression was investigated in a randomized phase II clinical trial to assess the effect of neoadjuvant chemotherapy with the addition of bevacizumab.Experimental Design: Tumor biopsies and whole-transcriptome mRNA profiles were obtained at three fixed time points with 66 patients in each arm. Altogether, 358 specimens from 132 patients were available, representing the transcriptional state before treatment start, at 12 weeks and after treatment (25 weeks). Pathologic complete response (pCR) in breast and axillary nodes was the primary endpoint.Results: pCR was observed in 15 patients (23%) receiving bevacizumab and chemotherapy and 8 patients (12%) receiving only chemotherapy. In the estrogen receptor-positive patients, 11 of 54 (20%) treated with bevacizumab and chemotherapy achieved pCR, while only 3 of 57 (5%) treated with chemotherapy reached pCR. In patients with estrogen receptor-positive tumors treated with combination therapy, an elevated immune activity was associated with good response. Proliferation was reduced after treatment in both treatment arms and most pronounced in the combination therapy arm, where the reduction in proliferation accelerated during treatment. Transcriptional alterations during therapy were subtype specific, and the effect of adding bevacizumab was most evident for luminal-B tumors.Conclusions: Clinical response and gene expression response differed between patients receiving combination therapy and chemotherapy alone. The results may guide identification of patients likely to benefit from antiangiogenic therapy. Clin Cancer Res; 23(16); 4662-70. ©2017 AACR.

Fatigue During and After Breast Cancer Therapy-A Prospective Study.

CONTEXT: Chronic fatigue (CF) in breast cancer (BC) survivors is multifactorial and may be caused by immune activation triggered by BC or its treatment. In the Neoadjuvant Avastin in Breast Cancer study, BC patients received neoadjuvant chemotherapy (FEC100→taxane) ± bevacizumab, a monoclonal antibody with fatigue as a potential side effect. OBJECTIVES: To examine fatigue levels and prevalence of CF before and during chemotherapy and at follow-up, and their associations with C-reactive protein (CRP) and clinical variables. METHODS: Eighty-four HER2-negative patients with cT2-4N0-3M0 BC responded to questionnaires and had CRP measured before treatment (T0), after FEC100 (T1), after taxanes before surgery (T2), and at two-year follow-up (T3). RESULTS: The prevalence of CF increased from 8% at T0 to 36% at T3, P < 0.0001. Fatigue levels peaked during chemotherapy from 12.0 at T0 to 20.0 at T2, and declined to 16.7 at T3, P < 0.001. Women with CF at T3 had higher fatigue levels at T0, T2, and T3 than those without CF (P ≤ 0.01). Psychological distress (P = 0.03) and pain (P = 0.04) at T3 were associated with CF at T3. Only psychological distress remained a significant predictor in multivariate analysis. CRP increased from T0 to T1 (P < 0.01) and declined to baseline values at T3, but changes were not associated with bevacizumab treatment. No association was found between bevacizumab or CRP, and fatigue levels or CF. CONCLUSION: Neither bevacizumab treatment nor low-grade systemic inflammation as measured by CRP was associated with the increased fatigue levels and raised prevalence of CF, observed during and after BC therapy. Increased fatigue levels at baseline and psychological distress at T3 were associated with CF at T3.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer.

BACKGROUND: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. METHODS: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. RESULTS: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (≥ 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (≥ 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (ß 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (ß 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (ß 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (ß 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (ß -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. CONCLUSION: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.

Aspects of posttraumatic stress disorder in long-term testicular cancer survivors: cross-sectional and longitudinal findings.

PURPOSE: The purpose of this research is to study the prevalence of posttraumatic stress disorder (PTSD) and variables associated with PTSD in Norwegian long-term testicular cancer survivors (TCSs) both cross-sectionally and longitudinally. METHODS: At a mean of 11 years after diagnosis, 1418 TCSs responded to a mailed questionnaire, and at a mean of 19 years after diagnosis, 1046 of them responded again to a modified questionnaire. Posttraumatic symptoms related to testicular cancer were self-rated with the Impact of Event Scale (IES) at the 11-year study only. An IES total score ≥35 defined Full PTSD, and a score 26-34 identified Partial PTSD, and the combination of Full and Partial PTSD defined Probable PTSD. RESULTS: At the 11-year study, 4.5 % had Full PTSD, 6.4 % had Partial PTSD, and 10.9 % Probable had PTSD. At both studies, socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxic adverse effects were significantly associated with Probable PTSD in bivariate analyses. Probable anxiety disorder, poor self-rated health, and neurotoxicity remained significant with Probable PTSD in multivariate analyses at the 11-year study. In bivariate analyses, probable PTSD at that time significantly predicted socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxicity among participants of the 19-year study, but only probable anxiety disorder remained significant in multivariable analysis. CONCLUSIONS: In spite of excellent prognosis, 10.9 % of long-term testicular cancer survivors had Probable PTSD at a mean of 11 years after diagnosis. Probable PTSD was significantly associated with a broad range of problems both at that time and was predictive of considerable problems at a mean of 19 year postdiagnosis. IMPLICATIONS FOR CANCER SURVIVORS: Among long-term testicular cancer survivors, 10.9 % have Probable PTSD with many associated problems, and therefore health personnel should explore stress symptoms at follow-up since efficient treatments are available.

High-density lipoprotein-cholesterol, daily estradiol and progesterone, and mammographic density phenotypes in premenopausal women.

High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17ß-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL-C, each one SD increase of salivary mid-menstrual 17ß-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above-median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above-median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies.

Gene variations in oestrogen pathways, CYP19A1, daily 17ß-estradiol and mammographic density phenotypes in premenopausal women.

INTRODUCTION: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women. METHODS: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17ß-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17ß-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models. RESULTS: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17ß-estradiol. We observed an 87% lower level of daily 17ß-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)). CONCLUSION: Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.

Clinical outcome with correlation to disseminated tumor cell (DTC) status after DTC-guided secondary adjuvant treatment with docetaxel in early breast cancer.

PURPOSE: The presence of disseminated tumor cells (DTCs) in bone marrow (BM) predicts survival in early breast cancer. This study explores the use of DTCs for identification of patients insufficiently treated with adjuvant therapy so they can be offered secondary adjuvant treatment and the subsequent surrogate marker potential of DTCs for outcome determination. PATIENTS AND METHODS: Patients with early breast cancer who had completed six cycles of adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy underwent BM aspiration 2 to 3 months (BM1) and 8 to 9 months (BM2) after FEC. Presence of DTCs in BM was determined by immunocytochemistry using pan-cytokeratin monoclonal antibodies. If one or more DTCs were present at BM2, six cycles of docetaxel (100 mg/m(2), once every 3 weeks) were administered, followed by DTC analysis 1 and 13 months after the last docetaxel infusion (after treatment). Cox regression analysis was used to evaluate disease-free interval (DFI). RESULTS: Of 1,066 patients with a DTC result at BM2 and available follow-up information (median follow-up, 71.9 months from the time of BM2), 7.2% were DTC positive. Of 72 docetaxel-treated patients analyzed for DTCs after treatment, 15 (20.8%) had persistent DTCs. Patients with remaining DTCs had markedly reduced DFI (46.7% experienced relapse) compared with patients with no DTCs after treatment (adjusted hazard ratio, 7.58; 95% CI, 2.3 to 24.7). The docetaxel-treated patients with no DTCs after treatment had comparable DFI (8.8% experienced relapse) compared with those with no DTCs both at BM1 and BM2 (12.7% experienced relapse; P = .377, log-rank test). CONCLUSION: DTC status identifies high-risk patients after FEC chemotherapy, and DTC monitoring status after secondary treatment with docetaxel correlated strongly with survival. This emphasizes the potential for DTC analysis as a surrogate marker for adjuvant treatment effect in breast cancer.

A randomized clinical trial of the efficacy of a self-care intervention to improve cancer pain management.

BACKGROUND: The undertreatment of cancer pain remains a significant clinical problem. OBJECTIVE: The aim of this randomized controlled trial was to evaluate the efficacy of the PRO-SELF Pain Control Program that was modified for Norwegian cancer patients in decreasing pain and increasing opioid intake compared with control care. INTERVENTIONS/METHODS: Oncology outpatients with pain from bone metastasis were randomized into the PRO-SELF (n = 87) or control (n = 92) groups. A nurse visited patients in the PRO-SELF group in their home at weeks 1, 3, and 6 and conducted telephone interviews at weeks 2, 4, and 5. Patients in both groups completed a daily diary of pain intensity ratings and analgesic intake. RESULTS: For both groups, significant decreases in pain intensity scores and in hours per day in pain (both, P < .001) were found over the 6 weeks of the study. However, no significant group × time interactions were found for any of the pain measures. In both groups, total dose of opioid taken increased over time. However, no significant group × time interactions were found for changes over time in the total dose, around-the-clock dose, or as-needed dose of opioid analgesics taken. CONCLUSIONS: Possible reasons for the lack of efficacy include an inadequate dose of the psychoeducational intervention, inadequate changes in analgesic prescriptions, and/or the impact of attention provided to the control group. IMPLICATIONS FOR PRACTICE: Coaching, nursing support, and the use of a pain diary may be important interventions to reduce pain intensity.

Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study.

BACKGROUND: Presence of disseminated tumor cells (DTCs) in bone marrow (BM) after completion of systemic adjuvant treatment predicts reduced survival in breast cancer. The present study explores the use of DTCs to identify adjuvant insufficiently treated patients to be offered secondary adjuvant treatment intervention, and as a surrogate marker for therapy response. METHODS: A total of 1121 patients with pN1-3 or pT1c/T2G2-3pN0-status were enrolled. All had completed primary surgery and received 6 cycles of anthracycline-containing chemotherapy. BM-aspiration was performed 8-12 weeks after chemotherapy (BM1), followed by a second BM-aspiration 6 months later (BM2). DTC-status was determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. If DTCs were present at BM2, docetaxel (100 mg/m², 3qw, 6 courses) was administered, followed by DTC-analysis 1 month (BM3) and 13 months (BM4) after the last docetaxel infusion. RESULTS: Clinical follow-up (FU) is still ongoing. Here, the descriptive data from the study are presented. Of 1085 patients with a reported DTC result at both BM1 and BM2, 94 patients (8.7%) were BM1 positive and 83 (7.6%) were BM2 positive. The concordance between BM1 and BM2 was 86.5%. Both at BM1 and BM2 DTC-status was significantly associated with lobular carcinomas (p = 0.02 and p = 0.03, respectively; chi-square). In addition, DTC-status at BM2 was also associated with pN-status (p = 0.009) and pT-status (p = 0.03). At BM1 28.8% and 12.8% of the DTC-positive patients had ≥2 DTCs and ≥3 DTCs, respectively. At BM2, the corresponding frequencies were 47.0% and 25.3%. Of 72 docetaxel-treated patients analyzed at BM3 and/or BM4, only 15 (20.8%) had persistent DTCs. Of 17 patients with ≥3 DTCs before docetaxel treatment, 12 patients turned negative after treatment (70.6%). The change to DTC-negativity was associated with the presence of ductal carcinoma (p = 0.009). CONCLUSIONS: After docetaxel treatment, the majority of patients experienced disappearance of DTCs. As this is not a randomized trial, the results can be due to effects of adjuvant (docetaxel/endocrine/trastuzumab) treatment and/or limitations of the methodology. The clinical significance of these results awaits mature FU data, but indicates a possibility for clinical use of DTC-status as a residual disease-monitoring tool and as a surrogate marker of treatment response. TRIAL REGISTRATION: Clin Trials Gov NCT00248703.