Lessons learned from the intrinsic subtypes of breast cancer in the quest for precision therapy.

BACKGROUND: Wide variability in breast cancer, between patients and within each individual neoplasm, adds confounding complexity to the treatment of the disease. In clinical practice, hormone receptor status has been used to classify breast tumours and to guide treatment. Modern classification systems should take the wide tumour heterogeneity into account to improve patient outcome. METHODS: This article reviews the identification of the intrinsic molecular subtypes of breast cancer, their prognostic and therapeutic implications, and the impact of tumour heterogeneity on cancer progression and treatment. The possibility of functionally addressing tumour-specific characteristics in in vivo models to inform decisions for precision therapies is also discussed. RESULTS: Despite the robust breast tumour classification system provided by gene expression profiling, heterogeneity is also evident within these molecular portraits. A complicating factor in breast cancer classification is the process of selective clonality within developing neoplasms. Phenotypically and functionally distinct clones representing the intratumour heterogeneity might confuse molecular classification. Molecular portraits of the heterogeneous primary tumour might not necessarily reflect the subclone of cancer cells that causes the disease to relapse. Studies of reciprocal relationships between cancer cell subpopulations within developing tumours are therefore needed, and are possible only in genetically engineered mouse models or patient-derived xenograft models, in which the treatment-induced selection pressure on individual cell clones can be mimicked. CONCLUSION: In the future, more refined classifications, based on integration of information at several molecular levels, are required to improve treatment guidelines. Large-scale translational research efforts paved the way for identification of the intrinsic subtypes, and are still fundamental for ensuring future progress in cancer care.

Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer-a prospective national multicentre study (EMIT-1).

BACKGROUND: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. RESULTS: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). CONCLUSION: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

Different labour outcomes in primiparous women that have been subjected to childhood sexual abuse or rape in adulthood: a case-control study in a clinical cohort.

OBJECTIVE: To compare the duration and outcome of the first labour in women who have been subjected to childhood sexual abuse (CSA) and women who have been raped in adulthood (RA). DESIGN: Case-control study in a clinical cohort. SETTING: University Hospital of North Norway. SAMPLE: In all, 373 primiparas: 185 subjected to CSA, 47 to RA and 141 controls without a history of abuse. METHODS: Data on birth outcomes were retrieved from the patient files. Information on sexual abuse was reported in consultation with specialised midwives in the mental health team. Birth outcomes were analysed by multinominal regression analysis. MAIN OUTCOME MEASURES: Vaginal births, delivery by caesarean section, operative vaginal delivery and duration of labour. RESULTS: As compared with controls, the RA group showed a significantly higher risk for caesarean section (adjusted OR 9.9, 95% CI 3.4-29.4) and operative vaginal delivery (adjusted OR 12.2, 95% CI 4.4-33.7). There were no significant differences between the CSA and the control group. The RA group displayed significantly longer duration of labour in all phases as compared with the control and CSA groups. CONCLUSIONS: There were major differences in the duration of labour and birth outcomes in the two abuse groups. Despite a higher proportion of obstetric risk factors at onset of labour in the CSA group, women subjected to CSA had shorter labours and less risk for caesarean section and operative vaginal deliveries than women subjected to RA. The best care for birthing women subjected to sexual abuse needs to be explored in further studies.

Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement.

The 2012 IMPAKT task force investigated the medical usefulness of current methods for the classification of breast cancer into the 'intrinsic' molecular subtypes (luminal A, luminal B, basal-like and HER2). A panel of breast cancer and/or gene expression profiling experts evaluated the analytical validity, clinical validity and clinical utility of two approaches for molecular subtyping of breast cancer: the prediction analysis of microarray (PAM)50 assay and an immuno-histochemical (IHC) surrogate panel including oestrogen receptor (ER), HER2 and Ki67. The panel found the currently available evidence on the analytical validity and clinical utility of Ki67 based on a 14% cut-off and PAM50 to be inadequate. The majority of the working group members found the available evidence on the analytical validity, clinical validity and clinical utility of ER/HER2 to be convincing. The panel concluded that breast cancer classification into molecular subtypes based on the IHC assessment of ER, HER2 and Ki67 with a 14% cut-off and on the PAM50 test does not provide sufficiently robust information to modify systemic treatment decisions, and recommended the use IHC for ER and HER2 for the identification of clinically relevant subtypes of breast cancers. Methods for breast cancer classification into molecular subtypes should, however, be incorporated into clinical trial design.

Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer.

BACKGROUND: Glomeruloid microvascular proliferation (GMP), a novel histology-based angiogenesis marker, has been associated with decreased survival in several human cancers. METHODS: In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n=112). RESULTS: Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P=0.004). INTERPRETATION: The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies.

Birth outcomes in primiparous women who were raped as adults: a matched controlled study.

OBJECTIVE: To compare the duration of labour and the birth outcome in a group of primiparous women who had been raped after the age of 16, with a control group from the same birth cohort. DESIGN: Cohort study. SETTING: University Hospital of North Norway. SAMPLE: Fifty women raped as adults and 150 controls. METHODS: Data about birth outcomes in the first pregnancy were collected from the patient files and data concerning the assault were obtained in a subsequent pregnancy through consultations with the women who had been raped. Birth outcomes in the group of women who had been raped were compared with matched controls using a multivariable logistic regression model. MAIN OUTCOME MEASURES: Caesarean section, operative vaginal delivery and duration of labour. RESULTS: During their first delivery, the women who had been raped had an increased risk for caesarean section (adjusted odds ratio 15.7, 95% CI 5.0-49.1) and for assisted vaginal delivery (adjusted odds ratio 13.1, 95% CI 4.9-34.5) when compared with controls. The group of women who had been raped had a longer second stage of labour than the control group (120 versus 55 minutes, P < 0.01). They were more often single mothers, unemployed and smokers, and had a higher body mass index and more previous pregnancy terminations and miscarriages than the control group. CONCLUSIONS: The women who had been raped had a longer second stage of labour, and an increased risk of caesarean section and operative vaginal delivery compared with controls from the general birth cohort. These findings indicate that the consequences for delivery for women who had been raped as adults could be specific and may warrant particular attention. The birth experience of women who had been raped should also be illuminated in future studies.

[Psychogenic non-epileptic seizures: issues of comorbidity in the diagnosis and treatment].

The paper presents a case report of seizures in a man of 40 years who was assessed by neurologists and psychiatrists for 15 years. Due to the low efficacy of treatment and permanent health deterioration, the patient was recognized as disabled. Later initial diagnosis of psychogenic non-epileptic seizures was completed by comorbid diagnosis of bipolar affective disorder, type II. Treatment with lamotrigine improved the patient's condition. It has been regarded as a positive effect on organic changes in the brain that are associated with affective and epileptic disorders.

Microarrays in primary breast cancer--lessons from chemotherapy studies.

Current development in molecular techniques has extended the opportunities to explore genetic alterations in malignant tissue. There is a need to improve prognostication and, in particular, to understand the mechanisms of treatment resistance in different tumours. Gene analyses by microarrays allow concomitant analyses of several genes in concert, providing new opportunities for tumour classification and understanding of key biological disturbances. This paper outlines our continuing studies exploring prognostic and, we hope, predictive factors in breast cancer therapy.

A global measure of physical functioning: psychometric properties.

OBJECTIVE: To examine the psychometric properties of a global physical functioning scale (GPFS) developed as a self-report measure and constructed to scale physical functioning from very poor (1) to excellent (100). DATA SOURCES: Data collection took place between January 1997 and September 1999. It consisted of self-ratings of surgical patients and the ratings of clinicians. The setting was the surgical department at a university hospital. STUDY DESIGN: Test-retest reliability and the convergence of the scores of patients and clinicians were examined in 106 patients before elective coronary or gastrointestinal surgery. Inter-rater reliability was tested in 36 hospitalized patients with cardiologic or vascular surgical diseases who were rated by random selection from a pool of 91 clinicians. The patients also rated their physical functioning. Discriminative validity, sensitivity to change, ceiling and floor effects, and influence of emotional state upon the scores were tested in 127 patients in six diagnostic groups who scored the GPFS before and subsequent to surgery. The concurrent validity was examined in 101 patients who scored the GPFS and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) before elective coronary surgery. PRINCIPAL FINDINGS: The test-retest correlation (.90), correlation of the scores of the clinicians and patients (.87), and rater intraclass correlation coefficient (.82) were high. The GPFS discriminated among patients with different levels of physical functioning, and it was sensitive to change following coronary surgery. There were moderate ceiling and no floor effects. The correlation with the physical functioning scale of the SF-36 (PF-10) was .67. The GPFS differentiated patients with middle levels of physical functioning better than did the PF-10. CONCLUSIONS: The psychometric properties of the GPFS appeared adequate as a measure of general physical functioning. The scale is easy to use and also appears suitable for outcome studies following substantial changes in physical functioning as after coronary surgery.

Screening for p53 gene mutations in archived tumors of workers occupationally exposed to carcinogens: examples from analysis of bladder tumors.

Point mutations in the p53 tumor suppressor gene are the most common genetic alterations in human cancers. The nature and location of these mutations can be informative in assessing the importance of putative carcinogenic agents. Potential associations between a given carcinogen and a specific mutation pattern can be substantiated when the exposure history of the patients is known. While the past exposure to environmental risk factors is often difficult to determine, documented occupational exposure to carcinogens presents a unique situation for evaluating this approach. Analysis usually involves working with paraffin-embedded tissues, fixed under conditions suboptimal for genetic analysis and stored for many years, since frozen tissues are not available in sufficient numbers. The particular methodological problems encountered with fixed samples are discussed here, using as illustration an ongoing study of oncogene and tumor suppressor gene mutations in archived bladder tumors of workers exposed to aromatic amines and nonexposed patients.

Psychotherapy supervision conducted by videoconferencing: a qualitative study of users' experiences.

Psychiatry residents in Norway have 70 hours of mandatory psychotherapy supervision to develop insights into the therapeutic relationship. Six supervision pairs (six candidates and two supervisors) conducted five videoconferencing-based supervision sessions (384 kbit/s) and five face-to-face sessions alternating weekly for 10 sessions. Following completion of the 10 sessions for candidates and supervisor B, and the 50 sessions for supervisor A, all subjects completed a semi-structured interview within two weeks. The eight subjects reported a wide range of experiences and attitudes. The results suggested that the quality of supervision can be satisfactorily maintained by using videoconferencing for up to half of the 70 hours required. The precondition for this estimate is that the pair in question have met face to face and established a relationship characterized by mutual trust and respect. Further studies, which include supervision pairs not having previously established relationships, are needed in order to indicate the generality of this precondition. The most obvious implication of this study is the potential for implementing decentralized models for recruiting and educating psychiatrists.

Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome.

Prediction of the clinical outcome of breast cancer is multi-faceted and challenging. There is growing evidence that the complexity of the tumour micro-environment, consisting of several cell types and a complex mixture of proteins, plays an important role in development, progression, and response to therapy. In the current study, we investigated whether invasive breast tumours can be classified on the basis of the expression of extracellular matrix (ECM) components and whether such classification is representative of different clinical outcomes. We first examined the matrix composition of 28 primary breast carcinomas by morphology and gene expression profiling using 22K oligonucleotide Agilent microarrays. Hierarchical clustering of the gene expression profile of 278 ECM-related genes derived from the literature divided the tumours into four main groups (ECM1-4). A set of selected differentially expressed genes was validated by immunohistochemistry. The robustness of the ECM classification was confirmed by studying the four ECM groups in a previously published gene expression data set of 114 early-stage primary breast carcinomas profiled using cDNA arrays. Univariate survival analysis showed significant differences in clinical outcome among the various ECM subclasses. One set of tumours, designated ECM4, had a favourable outcome and was defined by the overexpression of a set of protease inhibitors belonging to the serpin family, while tumours with an ECM1 signature had a poorer prognosis and showed high expression of integrins and metallopeptidases, and low expression of several laminin chains. Furthermore, we identified three surrogate markers of ECM1 tumours: MARCO, PUNC, and SPARC, whose expression levels were associated with breast cancer survival and risk of recurrence. Our findings suggest that primary breast tumours can be classified based upon ECM composition and that this classification provides relevant information on the biology of breast carcinomas, further supporting the hypothesis that clinical outcome is strongly related to stromal characteristics.

[To what degree can patient satisfaction be explained? An analysis of a retrospective study]. / I hvilken grad kan pasienttilfredshet forklares? Analyse av et etterundersøkelsesmateriale.

A retrospective survey comprising 1198 randomly chosen former surgical patients was carried out on average ten months after treatment. The goal of the research project was to investigate the associations between global satisfaction with treatment and issues that might influence how the treatment was experienced. There were no significant differences between the 610 responders and the sample of 1198 patients with respect to age, sex, length of treatment and diagnosis. The following five variables explained together 36.2% of the variance in global treatment satisfaction: Subjective health at time of investigation, the personality dimension conscientiousness, the "degree of severity of the illness", "contact with doctors and nurses" and "conveyed information and supervision". "Contact with doctors and nurses" alone explained 25.1% of the variance.

[Development of cooperation in a surgical department. A group dynamics approach]. / Samarbeidsutvikling i en kirurgisk avdeling. En gruppedynamisk tilnaerming.

Knowledge of group dynamics is considered as an essential precondition in establishing good functioning teams. In order to develop cooperation within an administrative council at a surgical ward, a training programme primarily based on the participants own experiences in unstructured groups, was established. We present the theoretical background and the practical amplification of the programme and describe the process and the evaluation of it. In a time when the health services are exposed to great demands concerning quality and effectivity, we will recommend long lasting programmes for the development of communication and cooperation.

Truncating somatic mutation in exon 15 of the APC gene is a rare event in human breast carcinomas. Mutations in brief no. 179. Online.

Inactivation of the adenomatous polyposis coli (APC) gene is an early event in sporadic colorectal cancer. Somatic mutations have also been detected in cancers of the stomach, pancreas, thyroid, ovary and breast. Over 95% of the mutations reported in the APC gene are frameshift and nonsense mutations. The large exon 15 accounts for 77% of the coding sequence. The APC gene product interacts with cytoplasmic beta-catenin, mediates its degradation and thereby downregulates transcription exerted by the beta-catenin-Tcf complex. In the absence of a functional APC protein, beta-catenin is stabilized and accumulates in the cytoplasm. This results in uncontrolled transcriptional activation of Tcf responsive genes which may contribute to cancer progression. In order to investigate whether this pathway is disrupted by APC mutations in breast carcinoma cells, we screened 227 breast tumors for truncating mutations in exon 15 using the protein truncation test (PTT). Only one mutation, 4678delA, which was shown to be somatic, was detected by this approach. The mutation resided just outside the mutation cluster region (MCR) and resulted in a premature stop in codon 1564. Our findings do not indicate that the suppressive function of APC is commonly abrogated by truncating mutations in human breast carcinomas.

Predictors of satisfaction with surgical treatment.

OBJECTIVE: To investigate prospectively which medical, psychosocial or treatment-related factors predicted treatment satisfaction and to evaluate the adequacy of a preceding retrospective study which had examined the same factors. Furthermore, to examine the predictors and the stability of the major determinants of patient treatment satisfaction. DESIGN: Assessments made before admission, at discharge and 2 and 4 months after discharge were used to predict both the level and the rate of change in satisfaction with different aspects of treatment. SETTING: Three surgical departments at a University Hospital. STUDY PARTICIPANTS: Four-hundred and eighty-two patients electively admitted for several surgical conditions. RESULTS: The central treatment-related measures were the same in the retrospective and prospective studies: global satisfaction with treatment (GS), perceived quality of contact with the nursing (QCN) and medical staff (QCM) and provision of adequate treatment information (INF). More of the variance in GS was explained in the prospective study (48.7% versus 36.3%). GS was most influenced by treatment-related factors with QCN as the strongest predictor in both studies. Only a small portion of the variance in QCN and QCM could be accounted for by the characteristics of the patients. INF was predicted by characteristics of the patients, their illness and life situation and by treatment-related factors. QCN was the strongest predictor of INF. The relationships with the nursing and medical personnel appear to be the major determinants of both patient treatment satisfaction and patients' reception of adequate information about their condition and its treatment.

Long-term changes after brief dynamic psychotherapy: symptomatic versus dynamic assessments.

Dynamic change in psychotherapy, as measured by theory-related or mode-specific instruments, have been criticized for being too intercorrelated with symptomatic change measures. In this study, long-term changes after brief dynamic psychotherapy were studied in 45 moderately disturbed neurotic patients by a reliable outcome battery. The factor structure of all the change variables suggested that they tapped 2 distinct and stable sources of variance: dynamic and symptomatic change. The categories of overall dynamic change were different from categories of change on the Global Assessment Scale. A small systematic difference was found between the categories of overall dynamic change and the categories of target complaints change also, due to false solutions of dynamic conflicts.

[Microarray technology--potential in cancer research]. / Mikromatriser i kreftforskning--nå trenger vi ikke lete bare under gatelyktene!

BACKGROUND: Researchers have worked for decades to solve the enigma of cancer. We know that essential checkpoints in the life cycle of cells have to be disrupted in order to create a tumour cell, and some of the genes and proteins involved have been identified. Most of the previous work on identifying these genes have been based on "educated guesswork", as the methods and technologies used have been limited to the examination of genes one by one, or a few at a time. MATERIAL AND METHODS: Microarray technology allows tens of thousands of genes to be examined at the same time, without any previous information on the genes. Both expression levels and copy numbers of the genes can be evaluated. Our studies of breast cancer and bone tumours are presented, as well as examples from the literature. RESULTS AND DISCUSSION: Microarray analyses have been used to produce molecular portraits of breast cancer, malignant melanomas and other cancers. These portraits may help in sub-classification of tumours, in prognosis, and in the general understanding of cancer. For example, studies of gene expression patterns of breast carcinomas, similar with respect to classic prognostic markers (such as ER status, grading and morphology), have identified subgroups of patients that show differences in survival.

Brief dynamic psychotherapy : patient suitability, treatment length, and outcome.

Forty-three neurotic outpatients were treated according to common practice with dynamic psychotherapy of brief to moderate length. Suitability for brief dynamic psychotherapy, measured by quality of interpersonal relations, was independent of DSM-III diagnoses. Suitability was a significant direct predictor of symptomatic and dynamic change 2 and 4 years after therapy. Treatment length added no explained outcome variance over patient characteristics. However, patients with high suitability had a relatively more favorable dynamic outcome with a brief, focused treatment approach, whereas patients with low suitability had relatively more favorable outcome with a longer, less focused treatment of more than 1 year's duration. The significant interaction emerged at 4-year follow-up.