Influence of sample storage duration on serum protein profiles assessed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS)

Background: Issues have been raised concerning the robustness and validity of alleged serum markers discovered by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS). Pre-analytical variables have been shown to exert a profound effect on protein profiles, irrespective of true biological variation. However, little is known about the possible effects of sample storage duration on protein profiles. We, therefore, aimed to investigate the effects of extended storage duration on the serum protein profile. Methods: Archival sera from 140 breast cancer patients, stored at –30°C for 1–11 years, were profiled by SELDI-TOF MS using immobilised metal affinity capture (IMAC) arrays, a condition applied in the majority of breast cancer biomarker discovery studies. Results: Fourteen peak clusters, structurally identified as C3a des-arginine anaphylatoxin and multiple fragments of albumin and fibrinogen, were found to be significantly associated with sample storage duration by five distinct patterns. These proteins have been described previously as potential cancer markers, rendering them specific to both disease and sample handling issues. Conclusions: To prevent experimental variation being interpreted erroneously as disease associated variation, assessment of potential confounding pre-analytical parameters is a pre-requisite in biomarker discovery and validation studies. In addition, with respect to the different (non-)linear patterns observed in the current study, simply performing linear corrections to account for sample storage duration will not necessarily suffice. Clin Chem Lab Med 2009;47:694–705.Peer Reviewe

Lokale recidieven na operatie voor borstkanker: Verbetering in recente jaren

Objective: All Dutch hospitals are obliged to report their 5-year ipsilateral breast tumor recurrence (IBTR) rate after breast cancer surgery. Experts decided that these rates should not exceed 5%. This study determined the value of IBTR as an indicator to compare quality of care between hospitals. Design: Cohort study Method: All patients with breast cancer (pT1-3, any N, M0) who underwent surgery in 1 of 92 Dutch hospitals from 2003 to 2006 were identified in the Netherlands Cancer Registry. Data of recurrence was retrieved from hospital records. Five-year IBTR rates for breastconserving surgery (BCS) and mastectomy were calculated using the Kaplan-Meier method. Hospital variation was presented in funnel plots. Multivariate analysis was used to assess hospital characteristics associated with IBTR rates. Result: A total of 40,892 breast cancer patients were included. The overall 5-year IBTR rate was 2.85% (95%-CI 2.68-3.03) and was significantly lower for BCS than for mastectomy (2.38% vs 3.45%, p < 0.001). IBTR rates decreased over time in both groups. Rates varied between 0.77 and 5.70% between hospitals. When random variation is taken into account, only extremely high IBTR rates can be detected as deviant from the target value of 5%. Adjusting for tumor and patient characteristics, analyses showed that a higher volume of mastectomies is associated with lower IBTR rates. Conclusion: Our populationbased findings show that IBTR rates in the Netherlands are low and have improved over time. The 5-year IBTR rate as an indicator for quality of care of individual hospitals is of limited value

MammaPrint is cost-effective compared to clinical risk assessment in early stage breast cancer

Rationale: The 70-gene signature (MammaPrint®, MP) is a prognostic test which guides treatment decisions in patients with early breast cancer. After level 1A evidence for clinical utility of MP has been proven, cost-effectiveness data is important to inform reimbursement. Research objectives: To compare cost-effectiveness of adding MP to clinical risk assessment versus clinical risk assessment alone for the US and EU. Clinical risk was assessed by Adjuvant Online! (AOL) as described in Cardoso et al. NEJM 2016. We used prospective survival data from the large randomized phase 3 trial 'Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy' (MINDACT). Methods: We used a Markov decision model to estimate the expected costs and outcomes (quality adjusted life years; QALYs) for MP versus AOL in early breast cancer patients from a payers perspective in the US and a societal perspective in the EU over a 5 year time horizon. Five year breast cancer overall- and distant metastasis free survival was calculated based on the MINDACT population (n=6,693). Utility scores were collected by means of the EuroQol-5D in the pilot phase of MINDACT(the first n=800 MINDACT patients). Cost data were for the US based on published insurance claim data, for the EU on published health care- and societal costs. The cost-effectiveness was calculated for: (1) total early stage breast cancer population, (2) clinical high risk population and (3) clinical high risk group in the ER+/HER2- population. Finally, budget impact for a high-low range of different countries was calculated, as the application and costs of chemotherapy can be highly variable between countries. Results: For all groups (1,2,and 3) in the US, using MINDACT survival data and insurance claim data, adding MP to AOL saved costs and gained more QALYs compared to AOL alone (total costs per patient $42,223 vs$45,566 and 4.035 vs 4.031 QALYs respectively). Thus, a small difference in quality adjusted life years (0,0041) was observed, whereas a large difference in costs (3,342) renders MP a highly cost-effective test (less costly & more effective in 64% of the cases). The largest cost-benefit effect was seen for group 3. The cut-off point for MP being cost-effective in the total population (group 1) is when the chemotherapy costs (and consequences) together are above 30,000. In the US, with approximately 250,000 new breast cancer patients per year, and a cost saving of $3,342, annual budget savings are expected to be$836M. Similar results for the Netherlands (15,000 breast cancer patients per year), reveal a cost difference of $300 per patient, and overall annual budget savings are expected to be$4,5M. Conclusion: Adding MP to clinical risk assessment is highly cost-effective compared to clinical risk assessment alone, based on the MINDACT survival data and US insurance claim data, for all above mentioned groups. When costs for chemotherapy (and consequences) exceed $30,000, MP is cost-effective for the total early breast cancer population. When costs for chemotherapy (and consequences) are below$30,000, the MP is cost-effective for the clinical high risk early breast cancer group. The separate results for EU countries will follow

Weinig lokaal recidieven na mammachirurgie: goede kwaliteit van de Nederlandse borstkankerzorg

Doel: Het beschrijven van het percentage lokaal recidief binnen 5 jaar na operatie van mammacarcinoom als prestatie-indicator van de Nederlandse ziekenhuizen. Opzet: Beschrijvend, cohortonderzoek. Methode: Alle vrouwen bij wie in 2003 een eerste invasief mammacarcinoom was gediagnosticeerd en die in opzet curatief waren geopereerd (met of zonder radiotherapie), werden geselecteerd uit de Nederlandse kankerregistratie (NKR). Registratiemedewerkers van de NKR verzamelden gegevens over het optreden van recidieven binnen 5 jaar bij deze patiënten aan de hand van een gestandaardiseerd protocol. Recidiefpercentages werden bepaald per ziekenhuis met de kaplan-meier-methode en weergegeven in ‘forest’-plots en ‘funnel’-plots. Resultaten: In 2003 werden 9898 patiënten in 99 Nederlandse ziekenhuizen gediagnosticeerd en curatief behandeld voor een eerste mammacarcinoom. 266 patiënten kregen een lokaal recidief binnen 5 jaar. Het 5-jaarsrecidiefpercentage was 3,03 (95%-BI: 2,69-3,41). Na een borstsparende operatie was het 5-jaarsrecidiefpercentage 2,63 (95%-BI: 2,21-3,12); na borstamputatie was dit 3,50% (95%-BI: 2,97-4,13). Er was een grote variatie in recidiefpercentage tussen ziekenhuizen (0-17%). De aantallen behandelde patiënten waren in de meeste ziekenhuizen echter te laag om betrouwbare schattingen te geven. Conclusie: Het percentage lokale recidieven na chirurgische behandeling voor mammacarcinoom lag in Nederland onder de norm van 5% binnen 5 jaar. Het is niet mogelijk om op basis van deze indicator een uitspraak te doen over verschillen in de kwaliteit van zorg tussen ziekenhuizen door de lage gemiddelde recidiefkans en het relatief lage aantal patiënten met een lokaal recidief per ziekenhuis

Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: Ten-year results of european organisation for research and treatment of cancer randomized phase III trial 10853 - A study by the EORTC breast cancer cooperative group and EORTC radiotherapy group

Purpose: The European Organisation for Research and Treatment of Cancer conducted a randomized trial investigating the role of radiotherapy (RT) after local excision (LE) of ductal carcinoma-in-situ (DCIS) of the breast. We analyzed the efficacy of RT with 10 years follow-up on both the overall risk of local recurrence (LR) and related to clinical, histologic, and treatment factors. Patients and Methods: After complete LE, women with DCIS were randomly assigned to no further treatment or RT (50 Gy). One thousand ten women with mostly (71%) mammographically detected DCIS were included. The median follow-up was 10.5 years. Results: The 10-year LR-free rate was 74% in the group treated with LE alone compared with 85% in the women treated by LE plus RT (log-rank P < .0001; hazard ratio [HR] = 0.53). The risk of DCIS and invasive LR was reduced by 48% (P = .0011) and 42% (P = .0065) respectively. Both groups had similar low risks of metastases and death. At multivariate analysis, factors significantly associated with an increased LR risk were young age (≤ 40 years; HR = 1.89), symptomatic detection (HR = 1.55), intermediately or poorly differentiated DCIS (as opposed to well-differentiated DCIS; HR = 1.85 and HR = 1.61 respectively), cribriform or solid growth pattern (as opposed to clinging/micropapillary subtypes; HR = 2.39 and HR = 2.25 respectively), doubtful margins (HR = 1.84), and treatment by LE alone (HR = 1.82). The effect of RT was homogeneous across all assessed risk factors. Conclusion: With long-term follow-up, RT after LE for DCIS continued to reduce the risk of LR, with a 47% reduction at 10 years. All patient subgroups benefited from RT

Impact of 70-gene signature use on adjuvant chemotherapy decisions in patients with estrogen receptor–positive early breast cancer: Results of a prospective cohort study

Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) –positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (k, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early-stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients