Eva Karlsson

Clinically Used Breast Cancer Markers Such as Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Are Unstable Throughout Tumor Progression

PURPOSE To investigate whether hormonal receptors and human epidermal growth factor receptor 2 (HER2) change throughout tumor progression, because this may alter patient management. PATIENTS AND METHODS The study cohort included female patients with breast cancer in the Stockholm health care region who relapsed from January 1, 1997, to December 31, 2007. Either biochemical or immunohistochemical (IHC)/immunocytochemical (ICC) methods were used to determine estrogen receptor (ER), progesterone receptor (PR), and HER2 status, which was then confirmed by fluorescent in situ hybridization for IHC/ICC 2+ and 3+ status. Results ER (459 patients), PR (430 patients), and HER2 (104 patients) from both primary tumor and relapse were assessed, revealing a change in 32.4% (McNemars test P < .001), 40.7% (P < .001), and 14.5% (P = .44) of patients, respectively. Assessment of ER (119 patients), PR (116 patients), and HER2 (32 patients) with multiple (from two to six) consecutive relapses showed an alteration in 33.6%, 32.0%, and 15.7% of patients, respectively. A statistically significant differential overall survival related to intraindividual ER and PR status in primary tumor and relapse (log-rank P < .001) was noted. In addition, women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio, 1.48; 95% CI, 1.08 to 2.05) compared with women with stable ER-positive tumors. CONCLUSION Patients with breast cancer experience altered hormone receptor and HER2 status throughout tumor progression, possibly influenced by adjuvant therapies, which significantly influences survival. Hence, marker investigations at relapse may potentially improve patient management and survival.

HER2 status in a population-derived breast cancer cohort: discordances during tumor progression

This retrospective study investigates the correlation of intra-individual HER2 status between primary breast cancers and corresponding recurrences in a population derived cohort. The REMARK criteria were used as reference. In 151 breast cancer patients, primary tumors were analyzed for HER2 status on histopathology sections using immunohistochemistry (IHC) confirmed by fluorescence in situ hybridization (FISH) for IHC 2+ and 3+. Recurrences (loco regional and distant) were investigated by aspiration cytology, using HER2 immunocytochemistry (ICC) or FISH (ICC in 84 patients and FISH in 102 patients). In the 151 patients, sites of recurrence were bone/bone marrow 30%, liver 16%, local recurrence 18%, lung/pleura 10%, axillary lymph nodes 9%, skin (non-local) 7%, supra clavicular lymph nodes 5%, and other sites 7%. In 15 patients (10%) HER2 status changed, 7 of 108 patients (6%) from HER2 negative to HER2 positive and 8 of 43 (19%) from HER2 positive to HER2 negative. Intra-patient agreement in HER2 status was 76% (95% CI 64–87%), and the disagreement was 10% (95% CI 5–15%). The multivariable Cox analysis showed a significantly increased risk of dying in the patient group with changed HER2 status compared to patients with concordant positive HER2 status. Overall survival HR is 5.47 (95% CI 2.01–14.91) and survival from relapse HR is 3.22 (95% CI 1.18–8.77). The unstable status for HER2 in breast cancer is clinically significant and should motivate more frequent testing of recurrences.

Nurse-led medication reviews and the quality of drug treatment of elderly hospitalized patients.

PurposeTo evaluate if nurses after receiving training in clinical pharmacology can improve the quality of the drug therapy in elderly hospitalized patients.MethodsNurses were given a 1-day training in clinical pharmacology to identify drug-related problems (DRPs). All patients admitted to the ward aged 65 or more were studied. Patients at the same ward before the intervention were considered as control group. Outcome variables were re-hospitalized 3 months from discharge, drug-related re-admissions, the proportion of inappropriate drug use (IDU), and DRPs found by the nurses.ResultsOf 460 patients (250 intervention group and 210 in the control group) 38 and 36%, respectively, had at least one re-admission to hospital (p = 0.86) and 24% of the patients died. Eighteen and 17% (43/37), respectively, used one or more inappropriate drug (p 0.90). The nurses found 86 clinically significant DRPs not detected by the usual care. A substantial part of the DRPs detected by the nurses were revealed with assistance of Symptoms Assessment Form (SYM). There were no statistical difference in the number of drug-related re-admissions between the groups, 14/16, respectively, (p = 0.40).ConclusionsNurses are able to detect a high proportion of clinically relevant DRPs not detected by the usual care and thereby increase the quality of the drug treatment in elderly hospitalized patients. Our study showed no effect on re-hospitalization or IDU. By using a SYM nurses can find DRPs that computer-based decision support systems miss.

Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: A randomized clinical trial

Importance Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. Objective To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. Design, Setting, and Participants A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. Interventions Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. Main Outcomes and Measures The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. Results Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. Conclusions and Relevance Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. Trial Registration clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

A nurse-led intervention for identification of drug-related problems

Drugs are important for treatment and prevention of symptoms and illnesses, but on the other hand, adverse drug reactions (ADRs) are a common cause for hospitalisation, especially among the elderly. The proportion of patients admitted to hospital due to ADRs, or when ADRs have been a contributing factor for admission, varies from 0.7% to 17 % [1–6]. Drugrelated problems (DRPs) are a broad category defined as “An event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes” [7, 8]. The majority of DRPs are predictable and potentially avoidable [3, 9]. There are methods aimed at the prevention of DRPs, such as medication reviews led by pharmacists or clinical pharmacologists. Nevertheless, there is no consistent evidence for the effectiveness of this kind of intervention [10–12]. There is a need for new methods for DRP detection and prevention. Although the medication process is multidisciplinary, there has been no progress in developing formal collaboration involving nurses. Nurses have a unique role as caregivers, educators, and administrators of drugs, and they are particularly well positioned to alert for DRPs [13]. One of the nurses’ responsibilities is indeed to observe patients’ response to drug treatment. Griffiths et al. [14] have shown that patients participating in a nurse-initiated intervention for medication review had a better knowledge of medication and were able to manage medication in a better way after the intervention. Other studies have shown that specialist nurses can reduce readmission to hospital of patients with heart failure [15, 16]. In Sweden, interested and specially educated nurses can detect and report suspected ADRs [17, 18] and contribute to approximately 12% of all ADR reporting [13]. The nurses’ reports are dominated by local reactions to vaccination [13]. To our knowledge, there are no studies published in which nurses are given a central role for identifying, preventing and resolving DRPs. The aim of this study was to investigate whether nurses can identify DRPs in patients during their hospital stay by using a new, structured, nurse-led medication review model and to assess the feasibility and effectiveness of this model.

Clonal alteration of breast cancer receptors between primary ductal carcinoma in situ (DCIS) and corresponding local events

BACKGROUND Emerging data propose biomarker alteration due to clonal selection between the primary invasive breast cancer and corresponding metastases. In addition, impact on survival has been demonstrated. The present study investigates the relationship between the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between primary ductal carcinoma in situ (DCIS) and intra-individually matched ipsilateral event. MATERIALS AND METHODS The cohort includes 1504 patients, diagnosed with a primary DCIS between 1986 and 2004. Of the 274 patients who developed a local relapse, 135 developed a new in situ carcinoma and 139 an invasive cancer up to 31st December 2011. ER and PR were identified by immunohistochemistry (IHC) and HER2 by silver-enhanced in situ hybridisation (SISH) as well as IHC. RESULTS ER (n=112), PR (n=113) and HER2 (n=114) status from both the primary DCIS and the corresponding relapse were assessed and were demonstrated to be discordant in 15.1%, 29.2% and 10.5% respectively. The receptor conversion was both from negative to positive and from positive to negative with no general pattern being seen in spite of sub-dividing into in situ relapse and invasive relapse. However, primary DCIS was HER2 positive in 40.3% whereas in situ and invasive relapses were HER2 positive in 42.9% and 34.5% respectively. CONCLUSIONS Receptor conversion for ER, PR and HER2 status occurred between primary DCIS and corresponding local relapse in 10-30%. This study could not confirm that HER2 overexpression in primary DCIS had any impact on tumour progression to invasive cancer which has been proposed.

Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs)

BackgroundTumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease.MethodsWe performed full exome sequencing of primary breast cancers and their metastases in a cohort of ten patients and further confirmed our findings in an additional cohort of 20 patients with paired primary and metastatic tumors. Furthermore, we used gene expression from the metastatic lesions and a primary breast cancer data set to study the gene expression of the AKAP gene family.ResultsWe report that somatic mutations in A-kinase anchoring proteins are enriched in metastatic lesions. The frequency of mutation in the AKAP gene family was 10% in the primary tumors and 40% in metastatic lesions. Several copy number variations, including deletions in regions containing AKAP genes were detected and showed consistent patterns in both investigated cohorts. In a second cohort containing 20 patients with paired primary and metastatic lesions, AKAP mutations showed an increasing variant allele frequency after multiple relapses. Furthermore, gene expression profiles from the metastatic lesions (n = 120) revealed differential expression patterns of AKAPs relative to the tumor PAM50 intrinsic subtype, which were most apparent in the basal-like subtype. This pattern was confirmed in primary tumors from TCGA (n = 522) and in a third independent cohort (n = 182).ConclusionSeveral studies from primary cancers have reported individual AKAP genes to be associated with cancer risk and metastatic relapses as well as direct involvement in cellular invasion and migration processes. Our findings reveal an enrichment of mutations in AKAP genes in metastatic breast cancers and suggest the involvement of AKAPs in the metastatic process. In addition, we report an AKAP gene expression pattern that consistently follows the tumor intrinsic subtype, further suggesting AKAP family members as relevant players in breast cancer biology.