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.

Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer.

INTRODUCTION: Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy. METHODS: We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status. RESULTS: While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5). CONCLUSIONS: Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.

Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival.

INTRODUCTION: Presence of disseminated tumor cells (DTCs) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood (PB) predicts reduced survival in early breast cancer. The aim of this study was to determine the presence of and alterations in DTC- and CTC-status in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy (NACT) and to evaluate their prognostic impact. METHODS: Bone marrow and peripheral blood were collected before NACT (BM1: n = 231/PB1: n = 219), at surgery (BM2: n = 69/PB2: n = 71), and after 12 months from start of NACT (BM3: n = 162/PB3: n = 141). Patients were included from 1997 to 2003 and followed until 2009 (or ten years follow-up). DTC- and CTC-status were determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. The prognostic significance of DTCs/CTCs was assessed by univariate and multivariate Cox-regression analyses. RESULTS: Before NACT, DTCs and CTCs were detected in 21.2% and 4.9% of the patients, respectively. At surgery, 15.9% and 1.4% had DTC- and CTC-presence, compared to 26.5% and 4.3% at 12 months from start of NACT. Of patients for whom DTC results both before NACT and at 12 months were available, concordant results were observed in 68%, and 14 out of 65 had positive DTC-status at both time points. Presence of ≥ 1 DTC 12 months from start of NACT, but not at other time points, predicted reduced disease-free survival (DFS; HR 2.3, p = 0.003), breast cancer-specific survival (BCSS; HR 3.0, p < 0.001) and overall survival (OS; HR 2.8, p < 0.001). Before NACT, presence of ≥ 3 DTCs was also associated with unfavorable outcome, and reduced BCSS was observed for CTC-positive patients (HR 2.2, p = 0.046). In multivariate analysis, DTC status (

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.

Medical students' cognitive and affective attitudes towards learning and using communication skills--a nationwide cross-sectional study.

AIMS: We wanted to explore cognitive and affective attitudes towards communication skills among students in Norwegian medical schools. METHOD: 1833 (60% response rate) medical students at the four medical schools in Norway filled in questionnaires by the end of term in May 2003. The Communication Skills Attitudes Scale (CSAS) was used for assessing affective and cognitive attitudes separately. RESULTS AND CONCLUSIONS: Medical students have positive attitudes towards learning and using communication skills. Cognitive and affective attitudes displayed different patterns. Being female and having worked in the health services before admission to the medical school predicted more positive scores both towards cognitive and affective attitudes. Having worked as a junior doctor during medical school predicted more positive cognitive attitudes. Cognitive attitudes towards communication skills did not vary significantly between year groups in any of the medical schools. Scores reflecting affective attitudes gradually fell for each year in all schools, but rose again in the final year in two of them. Implications for curriculum design are discussed.

The novel p21 polymorphism p21G251A is associated with locally advanced breast cancer.

PURPOSE: p21 is a main effector of growth arrest induced by p53. In addition, a second transcript from the same gene (p21B) has been linked to apoptosis. We previously analyzed p21 status in breast cancer and reported two novel polymorphisms of the p21 gene. In the present study, we present a larger study designed to explore a possible association between these novel polymorphisms and breast cancer. EXPERIMENTAL DESIGN: The p21/p21B polymorphisms were analyzed in 507 breast cancer patients and 1,017 healthy individuals using cDNA or genomic DNA from tumor and/or blood samples. RESULTS: We detected five polymorphisms of the p21 gene. Three of these polymorphisms are earlier reported by others, whereas two were reported for the first time in a recent study by us. The presence of the A allele of the p21G251A polymorphism was observed more frequently among patients with primary stage III breast cancer (4.5%) compared with stage I and II tumors (1.5%) and healthy female controls (1.4%; P = 0.007, comparing the three groups; P = 0.0049 and P = 0.0057, comparing locally advanced to stage I/II and healthy controls, or to healthy controls alone, respectively). The allele frequencies of the remaining four polymorphisms were evenly distributed among patients and healthy individuals. DISCUSSION: The finding of an association between locally advanced breast cancer and one particular polymorphism of the p21 gene suggests this polymorphism to be related to tumor behavior, including enhanced growth rate. If confirmed in other studies, this may add significant information to our understanding of the biology as well as of the clinical behaviour of locally advanced breast cancers.

Assessing medical students' attitudes towards learning communication skills--which components of attitudes do we measure?

BACKGROUND: The Communication Skills Attitudes Scale (CSAS) created by Rees, Sheard and Davies and published in 2002 has been a widely used instrument for measuring medical students' attitudes towards learning communication skills. Earlier studies have shown that the CSAS mainly tests two dimensions of attitudes towards communication; positive attitudes (PAS) and negative attitudes (NAS). The objectives of our study are to explore the attitudes of Norwegian medical students towards learning communication skills, and to compare our findings with reports from other countries. METHODS: The CSAS questionnaire was mailed simultaneously to all students (n = 3055) of the four medical schools in Norway in the spring of 2003. Response from 1833 students (60.0%) were analysed by use of SPSS ver.12. RESULTS: A Principal component analysis yielded findings that differ in many respects from those of earlier papers. We found the CSAS to measure three factors. The first factor describes students' feelings about the way communication skills are taught, whereas the second factor describes more fundamental attitudes and values connected to the importance of having communication skills for doctors. The third factor explores whether students feel that good communication skills may help them respecting patients and colleagues. CONCLUSION: Our findings indicate that in this sample the CSAS measures broader aspects of attitudes towards learning communication skills than the formerly described two-factor model with PAS and NAS. This may turn out to be helpful for monitoring the effect of different teaching strategies on students' attitudes during medical school.

Curriculum factors influencing knowledge of communication skills among medical students.

BACKGROUND: Communication training builds on the assumption that understanding of the concepts related to professional communication facilitates the training. We know little about whether students' knowledge of clinical communication skills is affected by their attendance of communication training courses, or to what degree other elements of the clinical training or curriculum design also play a role. The aim of this study was to determine which elements of the curriculum influence acquisition of knowledge regarding clinical communication skills by medical students. METHODS: The study design was a cross-sectional survey performed in the four Norwegian medical schools with different curricula, spring 2003. A self-administered questionnaire regarding knowledge of communication skills (an abridged version of van Dalen's paper-and-pencil test) was sent to all students attending the four medical schools. A total of 1801 (59%) students responded with complete questionnaires. RESULTS: At the end of the 1st year of study, the score on the knowledge test was higher in students at the two schools running communication courses and providing early patient contact (mean 81%) than in the other two medical schools (mean 69-75%, P < or = 0.001), with students studying a traditional curriculum scoring the lowest. Their scores increased sharply towards the end of the 3rd year, during which they had been subjected to extensive patient contact and had participated in an intensive communication course (77% vs. 72% the previous year, P

Comparing self-reported communication skills of medical students in traditional and integrated curricula: a nationwide study.

OBJECTIVES: To investigate medical students' self-assessments of their communication skills through medical school related to background factors, curriculum design and perceived medical school stress. METHODS: Medical students at all year levels attending Norwegian universities in the spring of 2003 were mailed the Oslo Inventory of Self-reported Communication Skills (OSISCS) developed by the authors. Of the total number of students (N=3055), 60% responded. One school had a traditional curriculum, the other three ran integrated models. RESULTS: Students assessed their instrumental communication skills to increase linearly year by year, while the relational skills showed a curve-linear trajectory reaching the optimum level half-way into the curriculum. Students attending the traditional school reported lower levels of instrumental skills compared to the students from the integrated schools. In relational skills, a similar difference was maintained half-way into the curriculum, but disappeared towards the end. Perceived medical school stress correlated to the self-reported end point levels of the two types of communication skills. DISCUSSION: The trajectories of self-reported instrumental and relational skills indicate significant variations in facilitating mechanisms between curricula, cognitive processing and perceived medical school stress. CONCLUSIONS: Self-reported instrumental and relational communication skills develop differently in medical students over the years according to the type of curriculum. PRACTICE IMPLICATIONS: Curricula should be evaluated for improvement implementations.

Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo.

Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells. Here, we assessed genetic alterations of the retinoblastoma gene (RB1) and its key regulators: Cyclin D and E as well as their inhibitors p16 and p27. In an exploratory cohort of 69 patients selected from two prospective studies treated with either doxorubicin monotherapy or 5-FU and mitomycin for locally advanced breast cancers, we found defects in the pRB-pathway to be associated with therapy resistance (p-values ranging from 0.001 to 0.094, depending on the cut-off value applied to p27 expression levels). Although statistically weaker, we observed confirmatory associations in a validation cohort from another prospective study (n = 107 patients treated with neoadjuvant epirubicin monotherapy; p-values ranging from 7.0 × 10(-4) to 0.001 in the combined data sets). Importantly, inactivation of the p53-and the pRB-pathways in concert predicted resistance to therapy more strongly than each of the two pathways assessed individually (exploratory cohort: p-values ranging from 3.9 × 10(-6) to 7.5 × 10(-3) depending on cut-off values applied to ATM and p27 mRNA expression levels). Again, similar findings were confirmed in the validation cohort, with p-values ranging from 6.0 × 10(-7) to 6.5 × 10(-5) in the combined data sets. Our findings strongly indicate that concomitant inactivation of the p53- and pRB- pathways predict resistance towards anthracyclines and mitomycin in breast cancer in vivo.

Use of Alternative Medicine Among Norwegian Cancer Patients is Associated with Mental Distress - A Follow-up Study.

The purpose of this study was to investigate the relationship between the use of alternative medicine (AM) by cancer patients' and the level of self-perceived mental distress. One hundred and fifty-seven cancer patients were included in a longitudinal questionnaire-based study 12 months after their first contact with the Department of Oncology, University Hospital of Tromsø, during the period 1990 to 1991. Eligible patients received follow-up questionnaires after 24 and 60 months recording their use of AM and measuring their perceived mental distress (GHQ-20). A total of 64 (41%) of the 157 patients who completed at least one questionnaire reported using AM one or more times during follow-up (ever-use). Between 65% and 79% of patients who were eligible at each point of the study completed the GHQ questionnaire. After 60 months of follow-up, 104 patients were still alive and 54 patients (52% of the survivors) had completed all the questionnaires. At inclusion in the study, significantly more AM users reported mental distress (57%) than non-users (20%) (p=0.001). After 24 and 60 months, the corresponding figures were 42% versus 29% (p=0.18), and 30% versus 10% (p=0.02), respectively. When adjusted for sex, age and disease progression, use of AM was found to be an independent factor highly associated with mental distress at 12 months (OR=5.5, 95% CI 2.1-14.4). Later in the study, progression/relapse of cancer proved to be a more important predictor of mental distress. These findings suggest that, in North Norway, seeking alternative treatment is more common among mentally distressed cancer patients.

[Should complementary therapies be offered in hospitals?]. / Tilbud om komplementaer behandling i sykehus?

BACKGROUND: This study compares attitudes among oncology professionals to whether complementary therapies should be offered in integrated units affiliated with departments of oncology. MATERIAL AND METHODS: In June 2002 a questionnaire on alternative and complementary medicine was distributed among 156 physicians, 414 nurses, 164 radiation therapists and 94 administrative staff members in the five Norwegian university hospitals responsible for cancer treatment. 61% returned the questionnaire. RESULTS: More than half of the physicians (56%) and most of the other health care workers (85-93%) had a positive attitude to departments of integrative medicine. If the service was provided, about half of the physicians expressed the opinion that the cost of treatment should be covered by the patient. By contrast, more than 80% of nurses, clerks and therapeutic radiographers answered that the cost had to be covered by public funding. Most oncology professionals, including the physicians, felt that the decision on the type of treatment to be offered to patients should be made in collaboration between patients, complementary therapists and oncology health care workers. However, one third of the physicians thought that treatment decisions had to be made by health care workers only. INTERPRETATION: In general, this survey demonstrated a positive attitude towards integrated units offering complementary therapies, also among oncologists. However, major differences among professions were found.

[Should alternative therapists treat cancer--what is the opinion of oncology health personnel?]. / Skal alternative utøvere behandle kreft--hva mener onkologiske helsearbeidere?

BACKGROUND: This study compares attitudes to the proposed new Alternative medicine act that would give Norwegian practitioners of alternative medicine more scope in treating patients with cancer. MATERIAL AND METHODS: In June 2002 a questionnaire on alternative and complementary medicine was distributed among 156 physicians, 414 nurses, 164 radiation therapists and 94 administrative staff members in the five Norwegian university hospitals responsible for cancer treatment. 61% returned the questionnaire. RESULTS: Of all respondents, 29% described themselves as having a positive attitude to alternative medicine. When the health services can offer no healing or palliative treatment to offer, 41% of the physicians and 60% of other health care workers were of the opinion that alternative practitioners could treat cancer. More than 50% of respondents were of the opinion that the patients themselves had the right to determine whether or not to use alternative medicine. When health authorities require communication between practitioners and physicians more than 70% of all health care workers felt that this contact had to be in writing. INTERPRETATION: Most health care workers treating cancer are of the opinion that practitioner of alternative medicine might treat cancer if the health services have no healing or palliative treatment. Required contact between physicians and alternative practitioners must be in writing.

[Teaching clinical communication to medical students in Norway]. / Undervisning i klinisk kommunikasjon for medisinstudenter i Norge.

BACKGROUND: Clinical communication as part of the doctor-patient relationship has gained increased attention in the undergraduate medical education in Norway. Such teaching programmes require considerable resources, as much of the instruction has to be carried out in small groups, and they should be subjected to a thorough assessment from a cost-benefit perspective. MATERIALS AND METHODS: A working group representing the four medical faculties in Norway initiated EKKO, a project designed as a quality assurance of the instruction in clinical communication. In this paper comparable data are presented relating to the extent, form and content of the instruction. RESULTS AND INTERPRETATION: There are great variations as to what part of the curriculum the instruction is placed in, the extent of faculty-based teaching, training periods in general practice and hospital settings with feed-back on communication skills, as well as in faculty development. To what degree these variations influence doctors' communication skills when fully qualified could be assessed in a further stage of this project, which could also provide an empirical basis for improvements in the instruction given.

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.

Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel.

BACKGROUND: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy. EXPERIMENTAL DESIGN: Each patient was randomly assigned to treatment with epirubicin 90 mg/m(2) (n = 109) or paclitaxel 200 mg/m(2) (n = 114) every 3rd week as monotherapy for 4-6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy. PRINCIPAL FINDINGS: While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007) but also MDM2 309TG/GG genotype status (p = 0.012) were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039) but not among individuals with TP53 mutated tumors (p>0.5). CONCLUSION: TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy.

CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer.

BACKGROUND: Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m(2) every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14((ARF)) genes; and 4) Explore potential CHEK2 or p14((ARF)) germline mutations with respect to family cancer incidence. METHODS AND FINDINGS: Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14((ARF)) mutations by sequencing the coding region and p14((ARF)) promoter methylations. TP53 mutations were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14((ARF)) were detected. CONCLUSION: This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.

Use of alternative medicine among Norwegian cancer patients is associated with mental distress--a follow-up study.

The purpose of this study was to investigate the relationship between the use of alternative medicine (AM) by cancer patients' and the level of self-perceived mental distress. One hundred and fifty-seven cancer patients were included in a longitudinal questionnaire-based study 12 months after their first contact with the Department of Oncology, University Hospital of Tromsø, during the period 1990 to 1991. Eligible patients received follow-up questionnaires after 24 and 60 months recording their use of AM and measuring their perceived mental distress (GHQ-20). A total of 64 (41%) of the 157 patients who completed at least one questionnaire reported using AM one or more times during follow-up (ever-use). Between 65% and 79% of patients who were eligible at each point of the study completed the GHQ questionnaire. After 60 months of follow-up, 104 patients were still alive and 54 patients (52% of the survivors) had completed all the questionnaires. At inclusion in the study, significantly more AM users reported mental distress (57%) than non-users (20%) (p = 0.001). After 24 and 60 months, the corresponding figures were 42% versus 29% (p = 0.18), and 30% versus 10% (p = 0.02), respectively. When adjusted for sex, age and disease progression, use of AM was found to be an independent factor highly associated with mental distress at 12 months (OR = 5.5, 95% CI 2.1-14.4). Later in the study, progression/relapse of cancer proved to be a more important predictor of mental distress. These findings suggest that, in North Norway, seeking alternative treatment is more common among mentally distressed cancer patients.

Weekly one-hour paclitaxel as first-line chemotherapy for metastatic breast cancer.

In this first reported study of weekly paclitaxel administered as first-line chemotherapy for metastatic breast cancer, paclitaxel 100 mg/m2 was administered in a 1-h infusion on a weekly basis to 35 patients who may previously have received adjuvant chemotherapy (but not taxane-containing regimens), but not for advanced or metastatic disease. A median of 14 infusions per patient was given at a mean delivered dose intensity of 94 mg/m2 per week. In 33 assessable patients, a complete response (CR) was observed in 1 patient and partial responses (PRs) in 12 patients, producing an overall response rate of 40%. Stable disease (SD) was observed in 17 patients, of whom 9 were stabilized for more than 24 weeks. Thus, clinical benefit (CR+PR+SD(> or = 24 weeks)) was observed in 67% of the patients. Time to progression was 189 days, the duration of response 180 days and overall survival 544 days. Five patients developed grade 3 neutropenia and five patients grade 3 neurotoxicity. Thus, this study has shown that weekly paclitaxel as first-line therapy for metastatic or advanced breast cancer produces comparable response rates and less toxicity than when the drug is given every three weeks.

Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer.

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35-74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR + SD > 24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.