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Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking., Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer., Design, Setting, and Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019., Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant., Main Outcomes and Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events., Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005)., Conclusions and Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events., Trial Registration: ClinicalTrials.gov Identifier: NCT03087409.

Between January 1, 2011, and December 31, 2016, we studied the incidence, management and outcome of high-risk breast lesions in a consecutive series of 376,519 screens of women who received biennial screening mammography. During the 6-year period covered by the study, the proportion of women who underwent core needle biopsy (CNB) after recall remained fairly stable, ranging from 39.2% to 48.1% (mean: 44.2%, 5,212/11,783), whereas the proportion of high-risk lesions at CNB (i.e., flat epithelial atypia, atypical ductal hyperplasia, lobular carcinoma in situ and papillary lesions) gradually increased from 3.2% (25/775) in 2011 to 9.5% (86/901) in 2016 (p < 0.001). The mean proportion of high-risk lesions at CNB that were subsequently treated with diagnostic surgical excision was 51.4% (169/329) and varied between 41.0% and 64.3% through the years, but the excision rate for high-risk lesions per 1,000 screens and per 100 recalls increased from 0.25 (2011) to 0.70 (2016; p < 0.001) and from 0.81 (2011) to 2.50 (2016; p < 0.001), respectively. The proportion of all diagnostic surgical excisions showing in situ or invasive breast cancer was 29.0% (49/169) and varied from 22.2% (8/36) in 2014 to 38.5% (5/13) in 2011. In conclusion, the proportion of high-risk lesions at CNB tripled in a 6-year period, with a concomitant increased excision rate for these lesions. As the proportion of surgical excisions showing in situ or invasive breast cancer did not increase, a rising number of screened women underwent invasive surgical excision with benign outcome., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

Background: The effect of extended adjuvant aromatase inhibition in hormone-positive breast cancer after sequential tamoxifen, aromatase inhibitor treatment of 5 years was recently investigated by the DATA study. This study found no statistically significant effect of prolonged aromatase therapy. However, subgroup analysis showed post hoc statistically significant benefits in certain sub-populations. The trans-DATA study is a translational sub-study aiming to identify DNA methylation markers prognostic of patient outcome., Methods: Patients from the DATA study are included in the trans-DATA study. Primary breast tumour tissue will be collected, subtyped and used for DNA isolation. A genome-wide DNA methylation discovery assay will be performed on 60 patients that had a distant recurrence and 60 patients that did not have a distant recurrence using the Infinium Methylation EPIC Bead Chip platform. Differentially methylated regions of interest will be selected based on Akaike's Information Criterion, Gene Ontology Analysis and correlation between methylation and expression levels. Selected candidate genes will subsequently be validated in the remaining patients using qMSP., Discussion: The trans-DATA study uses a cohort derived from a clinical randomised trial. This study was designed to avoid common pitfalls in marker discovery studies such as selection bias, confounding and lack of reproducibility. In addition to the usual clinical risk factors, the results of this study may identify predictors of high recurrence risk in hormone receptor-positive breast cancer patients treated with sequential tamoxifen and aromatase inhibitor therapy., Competing Interests: Competing interestsProf. dr. Tjan-Heijnen reports grants from AstraZeneca, during the conduct of the study; grants and non-financial support from Roche, grants and non-financial support from Pfizer, grants and non-financial support from Novartis, grants from Eisai, outside the submitted work. Dr. Peer reports grants from AstraZeneca, during the conduct of the study., (© The Author(s) 2019.)

The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.

In the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G), pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer. The objective of this analysis was to assess the pharmacokinetics of pertuzumab in combination with trastuzumab in Chinese patients with early breast cancer. Samples for pertuzumab and trastuzumab pharmacokinetic analysis were taken from Chinese patients during cycle 1 of treatment and at steady-state in cycle 10. Noncompartmental analysis was used to estimate minimum and maximum serum concentrations (Cmax and Cmin), area under the concentration-time curve, clearance, and other pharmacokinetic parameters. In 15 patients, mean steady-state Cmax and Cmin pertuzumab serum concentrations (368 ± 177 μg/ml, and 122 ± 47 μg/ml, respectively) were numerically higher than observed previously in a pharmacokinetic analysis of the global population in APHINITY and in patients treated in the metastatic setting. The geometric mean ratio and corresponding 90% confidence interval for trastuzumab Cmax and Cmin in the presence (n = 15) or absence (n = 17) of pertuzumab were 104.6 (91.09-120) and 98.23 (84.58-114), respectively, indicating no apparent impact of pertuzumab on the pharmacokinetics of trastuzumab. Increases in pertuzumab Cmax and Cmin were not associated with an increase in adverse events. The APHINITY Chinese pharmacokinetic substudy analysis supports the dosing regimen for pertuzumab (840 mg loading dose followed by 420 mg maintenance doses every 3 weeks administered by intravenous infusion) in a Chinese HER2-positive early breast cancer patient population.

The phase III DATA study investigates the efficacy of adjuvant anastrozole (6 vs. 3 year) in postmenopausal women with breast cancer previously treated with 2-3 years of tamoxifen. This planned side-study assessed patterns of care regarding detection and treatment of osteopenia/osteoporosis, and trends in bone mineral density (BMD) during and after therapy. We registered all BMD measurements and bisphosphonate-use. Time to osteopenia/osteoporosis was analysed by Kaplan Meier methodology. For the trend in T-scores we used linear mixed models with random patients effects. Of 1860 eligible DATA patients, 910 (48.9%) had a baseline BMD measurement. Among patients with a normal baseline BMD (n = 417), osteopenia was observed in 53.5% and 55.4% in the 6- and 3-year group respectively (p = 0.18), during follow-up. Only two patients (3-year group) developed osteoporosis. Of the patients with osteopenia at baseline (n = 408), 24.4% and 20.4% developed osteoporosis respectively (p = 0.89). Three years after randomisation 18.3% and 18.2% used bisphosphonates in the 6- and 3-year groups respectively and 6 years after randomisation this was 23.7% and 20.9% respectively (p = 0.90) of which the majority used oral bisphosphonates. The yearly mean BMD-change during anastrozole in the lumbar spine showed a T-score decline of 0.075. After bisphosphonate addition the decline became less prominent (0.047 (p < 0.001)) and after anastrozole cessation, while continuing bisphosphonates, the mean BMD yearly increased (0.047 (p < 0.001)). In conclusion, extended anastrozole therapy was not associated with a higher incidence of osteoporosis. Anastrozole-use was associated with a BMD decrease; however, the decline was modest and partially reversible after anastrozole cessation., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: This study aimed to develop an easy to use prediction model to predict the risk of having a total of 1 to 2, ≥3, or ≥4 positive axillary lymph nodes (LNs), for patients with sentinel lymph node (SLN) positive breast cancer., Methods: Data of 911 SLN positive breast cancer patients were used for model development. The model was validated externally in an independent population of 180 patients with SLN positive breast cancer., Results: Final pathology after ALND showed additional positive LN for 259 (28%) of the patients. A total of 726 (81%) out of 911 patients had a total of 1 to 2 positive nodes, whereas 175 (19%) had ≥3 positive LNs. The model included three predictors: the tumor size (in mm), the presence of a negative SLN, and the size of the SLN metastases (in mm). At external validation, the model showed a good discriminative ability (area under the curve = 0.82; 95% confidence interval = 0.74-0.90) and good calibration over the full range of predicted probabilities., Conclusion: This new and validated model predicts the extent of nodal involvement in node-positive breast cancer and will be useful for counseling patients regarding their personalized axillary treatment., (© 2019 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc.)

Introduction: We evaluated the use and value of breast surgical excision biopsies for diagnostic purposes over the last decades in women undergoing mammographic screening, either as a primary procedure or following an inconclusive percutaneous biopsy., Methods: All women with an excision biopsy among 817,656 screens, obtained from January 1997 to January 2017, were included., Results: Of 18,593 recalled women (recall rate, 2.3%) with screen-detected abnormalities, 908 (4.9%) underwent excision biopsy. Of these, 411 (45.3%) were performed as first diagnostic intervention, decreasing from 4.3 per 1000 screens in 1997-1998 to 0 per 1000 screens in 2015-2016. The remaining 497 (54.7%) excision biopsies were performed secondary to pathologic findings at percutaneous biopsy. During 1997-1998, 1.0 secondary biopsies per 1000 screens were performed, decreasing to 0.3 per 1000 in 2005-2006 and afterwards increased to 0.6 per 1000 in 2015-2016 (p = 0.003). Of all 487 secondary biopsies, 303 (61.0%) had a benign pathology outcome, increasing from 40.4% in 1997-1998 to 70.2% in 2015-2016. Of all 211 biopsies in the three most recent cohorts (2011-2016) the overall upgrade rate was 26.5%, consisting of 39 (18.5%) DCIS (27 low grade) and 17 (8.1%) invasive carcinomas., Conclusions: Although the use of excision biopsy significantly decreased over the past two decades, we observed a significant increased rate in more recent years. Since the vast majority of currently performed excision biopsies reveals a benign diagnosis or shows low grade DCIS, a secondary excision biopsy should only be considered if radiologic surveillance and repeated percutaneous biopsy continues to yield indeterminate results., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The DATA study (NCT00301457) compared 6 and 3 years of anastrozole in postmenopausal women with hormone receptor-positive early breast cancer after 2-3 years of tamoxifen. Patients with chemotherapy-induced ovarian function failure (CIOFF) were also eligible, but could be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definitely postmenopausal women and examined the influence of OFR on survival. Therefore, we selected patients from the DATA study aged 45-57 years at randomization who had received (neo)adjuvant chemotherapy. They were classified by reversibility of postmenopausal status: possibly reversible in case of CIOFF (n = 395) versus definitely postmenopausal (n = 261). The former were monitored by E2 measurements for OFR. The occurrence of OFR was incorporated as a time-dependent covariate in a Cox-regression model for calculating the hazard ratio (HR). We used the landmark method to calculate residual 5-year survival rates. When comparing CIOFF women with definitely postmenopausal women, the survival was not different. Among CIOFF women with available E2 follow-up values (n = 329), experiencing OFR (n = 39) had an unfavorable impact on distant recurrence-free survival (HR 2.27 [95% confidence interval [CI] 0.98-5.25; p = 0.05] and overall survival (HR 2.61 [95% CI 1.11-6.13; p = 0.03]). After adjusting for tumor features, the HRs became 2.11 (95% CI 0.89-5.02; p = 0.09) and 2.24 (95% CI 0.92-5.45; p = 0.07), respectively. The residual 5-year rate for distant recurrence-free survival was 76.9% for women with OFR and 92.1% for women without OFR, and for 5-year overall survival 80.8% and 94.4%, respectively. Women with CIOFF receiving anastrozole may be at increased risk of disease recurrence if experiencing OFR., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objectives: To analyse which mammographic and tumour characteristics led to concordant versus discordant recalls at blinded double reading to further optimise our breast cancer screening programme., Methods: We included a consecutive series of 99,013 screening mammograms obtained between July 2013 and January 2015. All mammograms were double read in a blinded fashion. Discordant readings were routinely recalled without consensus or arbitration. During the 2-year follow-up, relevant data of the recalled women were collected. We compared mammographic characteristics, screening outcome and tumour characteristics between concordant and discordant recalls., Results: There were 2,543 concordant recalls (71.4%) and 997 discordant recalls (28.0%). The positive predictive value of a concordant recall was significantly higher (23.5% vs. 10.0%, p < 0.001). The proportion of BI-RADS 0 was significantly higher in the discordant recall group (75.7% vs. 56.3%, p < 0.001). Discordant recalls were more often an asymmetry or architectural distortion (21.8% vs. 13.2% and 9.3% vs. 6.5%, respectively, p < 0.001). There were no differences in the distribution of DCIS and invasive cancers and tumour characteristics were comparable for the two groups, except for a more favourable tumour grade in the discordant recall group (54.7% vs. 39.9% grade I tumours, p = 0.022)., Conclusions: Screen-detected cancers detected by a discordant reading show a more favourable tumour grade than cancers diagnosed after a concordant recall. The higher proportion of asymmetries and architectural distortions in this group provide a possible target for improving screening programmes by additional training of screening radiologists and the implementation of digital breast tomosynthesis., Key Points: • With blinded double reading of screening mammograms, screen-detected cancers detected by a discordant reading show a more favourable tumour grade than cancers diagnosed after a concordant recall. • The proportions of asymmetries and architectural distortions are higher in case of a discordant reading. • Possible improvement strategies could target additional training of screening radiologists and the implementation of digital breast tomosynthesis in breast cancer screening programmes.

Objective: The aim of this systematic review was to investigate patient-related factors (e.g. depressive symptoms, cognition, mobility, activities of daily living (ADL)) as well as tumor-related factors (e.g. tumor type, chemotherapy regimen) influencing chemotherapy intolerance in cancer patients aged 65 years or older., Methods: We included observational studies that reported data on possible predictors of chemotherapy intolerance in older patients with cancer. We studied chemotherapy intolerance using the following outcomes: chemotherapy toxicity grade 3 to 5, unplanned hospitalization, chemotherapy discontinuation, chemotherapy dose reduction, functional decline, and chemotherapy mortality. We searched PubMed, Embase, and PsycInfo for articles between January 1995 and July 2016. The quality of the included studies was assessed using the Quality in Prognosis Studies (QUIPS) tool., Results: The search yielded 1774 articles, and 30 articles from 27 studies were included. The patient-related factors associated with chemotherapy intolerance, in terms of the size of the association and the consistency of the results, were more than one fall in the last six months, mobility problems, poor performance status and the presence of severe comorbid conditions. The tumor-related factors that were associated with chemotherapy intolerance in older patients with cancer were certain regimens of chemotherapy and polychemotherapy, as compared to monochemotherapy. The number of studies on unplanned hospitalization and functional decline was small., Conclusion: The included studies were heterogeneous with respect to endpoints and included parameters. Nevertheless, the size of the association and the consistency of results suggest that all these factors are relevant for everyday oncological practice., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples' decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest-posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision.

Purpose: We determined if intermittent first-line treatment with paclitaxel plus bevacizumab was not inferior to continuous treatment in patients with HER2-negative, advanced breast cancer., Methods: Patients were randomized to 2 × 4 cycles or continuous 8 cycles of paclitaxel plus bevacizumab, followed by bevacizumab maintenance treatment until disease progression or unacceptable toxicity. The primary endpoint was overall progression-free survival (PFS). A proportional-hazards regression model was used to estimate the HR. The upper limit of the two-sided 95% CI for the HR was compared with the non-inferiority margin of 1.34., Results: A total of 420 patients were included with well-balanced characteristics. In the intention-to-treat analysis, median overall PFS was 7.4 months (95% CI 6.4-10.0) for intermittent and 9.7 months (95% CI 8.9-10.3) for continuous treatment, with a stratified HR of 1.17 (95% CI 0.88-1.57). Median OS was 17.5 months (95% CI 15.4-21.7) versus 20.9 months (95% CI 17.8-24.0) for intermittent versus continuous treatment, with a HR of 1.38 (95% CI 1.00-1.91). Safety results and actually delivered treatments revealed longer durations of treatment in the continuous arm, without significant unexpected findings., Conclusion: Intermittent first-line treatment cannot be recommended in patients with HER2-negative advanced breast cancer., Clinical Trial Registration: EudraCT 2010-021519-18; BOOG 2010-02.

Background: Unilateral interval breast cancers show less favourable prognostic features than unilateral screen-detected cancers, but data on tumour characteristics of bilateral interval cancers in a systematically screened population are sparse. Therefore, we compared tumour characteristics of bilateral interval cancers with those of bilateral screen-detected cancers., Methods: We included all 468,720 screening mammograms of women who underwent biennial screening mammography in the South of the Netherlands between January 2005 and January 2015. We collected breast imaging reports, biopsy results and surgical reports of all recalled women and of all women who presented with interval breast cancer. In women with synchronous bilateral breast cancer, the tumour with the highest tumour stage was defined as the index cancer. For comparison of data between both groups Fisher exact test and Chi-square test were used., Results: Synchronous bilateral cancer was diagnosed in 2.2% of screen-detected cancers (64/2947) and in 3.2% of interval cancers (24/753) (P = 0.1). Index tumours of bilateral screen-detected cancers and interval cancers showed similar characteristics, except for a larger proportion of T-stage 2 or worse (T2+) cancers among interval cancers (16/24 (66.7%) versus 23/58 (39.7%) (P = 0.03). Index cancers, compared to contralateral cancers, were less frequently stage T1 in both bilateral screen-detected cancers and bilateral interval cancers (35/64 (60.3%) versus 40/64 (88.9%) (P = 0.001) and 8/24 (33.3%) versus 18/24 (85.7%) (P < 0.001), respectively). In bilateral screen-detected cancers, contralateral cancers were more often stage 1a-c (P < 0.001) compared to index cancers. In bilateral index cancers, index cancers were more often of the lobular subtype (P < 0.001)., Conclusion: Index cancers of bilateral screen-detected cancers and bilateral interval cancers show significant differences in tumour size, whereas nodal status, receptor status and final surgical treatment are comparable. In bilateral screen-detected cancer, index cancers had a significantly higher tumour stage. In bilateral screen-detected cancer, index cancers were more often the ductal invasive subtype compared to contralateral cancers., (Copyright © 2018. Published by Elsevier B.V.)

Background: To determine the impact of the second reader on screening outcome at blinded double reading of digital screening mammograms., Methods: We included a consecutive series of 99,013 digital screening mammograms, obtained between July 2013 and January 2015 and double read in a blinded fashion. During 2-year follow-up, we collected radiology, surgery and pathology reports of recalled women., Results: Single reading resulted in 2928 recalls and 616 screen-detected cancers (SDCs). The second reader recalled another 612 women, resulting in 82 additional SDCs. Addition of the second reader increased the recall rate (3.0% to 3.6%, p < 0.001), cancer detection rate (6.2-7.0 per 1000 screens, p < 0.001) and false positive recall rate (24.4-28.7 per 1000 screens, p < 0.001). Positive predictive value of recall (21.0% vs. 19.7%, p = 0.20) and of biopsy (52.1% vs. 50.9%, p = 0.56) were comparable for single reading and blinded double reading. Tumour characteristics were comparable for cancers detected by the first reader and cancers additionally detected by the second reader, except of a more favourable tumour grade in the latter group., Conclusions: At blinded double reading, the second reader significantly increases the cancer detection rate, at the expense of an increased recall rate and false positive recall rate.

Background: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers., Methods: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility., Results: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk., Conclusion: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.

Opinion Statement: In the past decade, several endocrine treatment regimens have been developed for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, including tamoxifen, aromatase inhibitors (AI), or a combination of these. The standard duration of adjuvant endocrine treatment has been 5 years for a long time. Nevertheless, the high number of recurrences occurring after 5 years suggested that extended endocrine therapy could further improve outcome, which led to the start of several randomized clinical trials investigating the effects of extended use of endocrine therapy. The extended duration of tamoxifen has been shown to improve disease-free survival and overall survival in the ATLAS and aTTom trials. However, in postmenopausal women, AIs have been shown to be more effective when compared with tamoxifen. Based hereon, it is recommended that adjuvant endocrine therapy in postmenopausal women with early breast cancer should include an AI. Recently, the DATA, IDEAL, and NSABP B42 trials showed that extended adjuvant endocrine therapy with AIs beyond 5 years in postmenopausal women with early breast cancer did reduce the occurrence of secondary breast tumors, but had no or only a small impact on distant metastasis free survival. Furthermore, toxicity of adjuvant AIs led to gradually decreasing compliance rates and long-term toxicities to non-breast cancer-related deaths. Therefore, we suggest considering extended adjuvant treatment only in women with high-risk early breast cancer who tolerate treatment well.

Background: Detected by screening mammography, bilateral breast cancer has a different pathological profile compared to unilateral breast cancer. We investigated the incidence of bilateral interval breast cancers and compared their characteristics with those of unilateral interval breast cancers., Methods: We included all 468,720 screening mammograms of women who underwent biennial screening mammography in the South of the Netherlands between January 2005 and January 2015. We collected breast imaging reports, biopsy results and surgical reports of all referred women and of all women who presented with interval breast cancer. The tumour with the highest tumour stage (index cancer) was used for comparison with unilateral interval cancers., Results: A total of 753 interval cancers were detected, of which 24 (3.2%) were bilateral. Among the invasive interval cancers, bilateral cancers more frequently showed a lobular histology than unilateral cancers (37.5% (9/24) vs. 16.1% (111/691), P = .01). There is a trend towards a larger proportion of bilateral than unilateral interval cancers graded 1 (45.8% (11/24) vs. 27.8% (192/691), P = .08). There were no other statistically significant differences in tumour characteristics. Also, the proportion of interval cancers showing significant mammographic abnormalities at the latest screen was comparable for unilateral and bilateral interval cancers (23.0% vs. 25.0%, P = .9)., Discussion: Bilateral interval cancers comprise a small proportion of all interval cancers. Except of a higher proportion of invasive lobular cancers and a more favourable histological grade of invasive cancers, tumour characteristics are comparable for bilateral and unilateral interval breast cancers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard. Subsequently, everolimus was separated and analyzed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The UPLC-MS/MS method was validated according to the European Medicine Agency (EMA) guideline. Everolimus concentrations could be quantified over the range of 3-75μg/L. The intra- and inter-assay precision and accuracy of the method were shown to be acceptable (coefficient of variation ≤10.7% and relative error ≤4.4%, respectively). The matrix effects appeared to be influenced by the hematocrit effect. The hematocrit effect was tested in a range of 0.20-0.50L/L, at which hematocrit accuracy and precision were satisfactory at values ≥0.25L/L. However, at 0.20L/L hematocrit in combination with high everolimus concentrations of 20 and 40μg/L, the precision was adequate (≤7.4%), but the accuracy was >15% of the nominal concentration. Everolimus was stable in DBS for at least 80days at 2-8°C. Given these results, the everolimus DBS method has been successfully developed and validated. Special attention is necessary for cancer patients with both a 0.20L/L hematocrit in combination with everolimus concentrations ≥20μg/L. A clinical validation for the use of everolimus DBS in cancer patients is currently being undertaken., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors., Methods: BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients., Findings: Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8-4·2] vs 1·8 months [1·5-2·8]; hazard ratio [HR] 0·67, 95% CI 0·53-0·84, one-sided p=0·00030). The most frequent grade 3-4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group)., Interpretation: The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen., Methods: We identified all patients with chemotherapy-induced ovarian function failure. Women who underwent a bilateral ovariectomy or used luteinizing hormone-releasing hormone agonists before random assignment were excluded. Plasma estradiol and follicle-stimulating hormone levels were monitored until 30 months after random assignment at local laboratories. We aimed to determine the ovarian function recovery (OFR) rate during AI use by the cumulative incidence competing risk method and analyzed the trend of estradiol levels during AI use by a nested case-control approach in which a subset of control subjects were compared with the OFR patients excluding the value at OFR diagnosis., Results: The 329 eligible patients had a median age of 50.0 years (range = 45-57 years) at random assignment. Thirty-nine patients developed OFR, corresponding with a 30-month recovery rate of 12.4%. Of these, 11 (28.2%) were age 50 years or older at AI initiation. The estradiol level decreased statistically significantly by 37.8% (95% CI = 27.4% to 46.7%) over the initial 30 months of AI treatment in both groups. However, the estradiol levels in the women who experienced OFR remained statistically significantly higher (difference = 20.6%, 95% CI = 2.0% to 42.7%) prior to OFR diagnosis compared with those who did not experience OFR., Conclusions: The risk of OFR during AI treatment in breast cancer patients with chemotherapy-induced ovarian function failure is relevant, even beyond 45 years. Furthermore, women experiencing OFR had statistically significant higher estradiol levels during AI treatment (before OFR) than those without, with potential consequences regarding efficacy.

Background: The Z0011 trial initiated a paradigm shift in the axillary treatment of breast cancer patients with a positive sentinel lymph node biopsy (SLNB), disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). We examined whether relevant differences exist between these patients to determine if the conclusions of the ACOSOG Z0011 trial are applicable to UGLNB-positive patients., Methods: Patients diagnosed with invasive breast cancer in the Netherlands between January 2008 and December 2014 were selected from the Netherlands Cancer Registry., Results: A total of 11,820 cases were included: 9149 cases in the SLNB group and 2671 in the UGLNB group. Multivariate analyses showed that UGLNB-positive patients were older (p < 0.001), more likely to have a poorly differentiated tumor (p < 0.001), had a negative hormone receptor status (p < 0.001), and more often had extensive nodal involvement (p < 0.001). However, they were less likely to undergo adjuvant radiation (p = 0.004) or systemic therapy (p < 0.001). Even after adjusting for these factors, UGLNB-positive patients had a worse overall survival (HR = 1.38; 95% CI 1.23-1.56) than SLNB-positive patients., Conclusion: This nationwide retrospective study shows that young patients found positive by UGLNB have less favorable disease characteristics and a worse prognosis compared to patients with a positive SLNB. Selection by ultrasound plays an important role when axillary treatment strategies are considered. Hence, the conclusions of the Z0011 trial cannot unconditionally be applied to patients with a positive UGLNB.

Introduction: International guidelines differ regarding their recommendations on axillary treatment of patients with non-visualized sentinel lymph nodes (non-vSLN). Therefore, we distributed a survey among Dutch oncological surgeons to determine their routine practice and opinion regarding axillary treatment in case of a non-vSLN, with the emphasis on whether these practices and opinions have changed since publication of the Z0011 trial., Methods: A Dutch nationwide survey containing 10 questions regarding clinical routine during the sentinel node procedure and axillary treatment of non-vSLN patients was distributed among 510 oncological surgeons., Results: The survey was completed by 122 (24%) oncological surgeons, of whom 116 (95%) were registered as specialized breast surgeons. These surgeons had, on average, 13 years of experience. The majority of respondents used both lymphoscintigraphy and Patent Blue during the sentinel node procedure, and 39% estimated the prevalence of a non-vSLN to be 1-2%. Most surgeons are currently more reserved when considering whether to perform an axillary lymph node dissection (ALND) than prior to publication of the Z0011 trial (15 vs. 80%, respectively). Sixty percent base their decision on various clinicopathological characteristics. Twenty-three respondents (20%) opted for an alternative axillary treatment., Conclusion: This study shows that, in daily practice, most specialized breast surgeons think that a non-vSLN is rare. If so, most currently opt not to perform an ALND, whereas a small proportion consider an alternative axillary treatment. These decisions differ than in the period prior to the Z0011 trial. More research is needed to provide optimal treatment recommendations in case of a non-vSLN.

Background: To assess the impact of breast magnetic resonance imaging (MRI) use on surgical outcome per histological breast cancer subtype in patients treated with neoadjuvant chemotherapy., Patients and Methods: All patients aged 18-70 years who underwent neoadjuvant chemotherapy for stage I-III invasive breast cancer in the Netherlands in the years 2011-2013 were identified from the Netherlands Cancer Registry. Patients with cT4 tumours were excluded from the analysis. Use of breast MRI and impact on surgical treatment, resection margins and detection of contralateral breast cancer were analysed by multivariable analyses., Results: Breast MRI was performed in 2879 (83.9%) out of 3433 patients treated with neoadjuvant chemotherapy. Younger age (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.17-1.71 for 18-50 years compared with 50-70 years), larger tumour stage (OR 1.46 [95% CI 1.15-1.86] for cT3, compared to cT1-2 tumours) and multifocality (OR 1.30; 95% CI 1.04-1.61, versus unifocality) were associated with increased breast MRI use. In ductal breast cancer, after stratification for cT-status, breast MRI use is associated with a significant lower OR for mastectomy as final surgery in cT3 tumours (OR 0.45, 95% CI 0.21-0.99). Resection margin involvement and detection of contralateral breast cancer were not associated with breast MRI use., Conclusion: In patients treated with neoadjuvant chemotherapy, the use of breast MRI was associated with a reduced mastectomy rate, particularly in patients with large invasive ductal breast tumours but not in patients with lobular breast cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Primary aim of our study was to assess the impact of timing of sentinel node procedure, pre- versus post-neoadjuvant chemotherapy, on final pathologic node-negative rate (pN0) in patients with clinically node-negative (cN0) breast cancer. Secondary endpoint was the usability of the sentinel node procedure in patients with clinically node-positive disease that converted to cN0 after neoadjuvant chemotherapy., Patients and Methods: Patients were enrolled in two sequentially conducted Dutch phase III trials, studying the impact of two neoadjuvant chemotherapy schedules and use of zoledronic acid on complete pathologic response rate. For the present analyses, patients were excluded if they had not undergone surgical axillary staging., Results: In total 439 patients were included, of whom 230 (52%) had pre-treatment cN0. In this group, pN0 status was seen in 58% (N = 23) of patients with a sentinel node biopsy post-neoadjuvant chemotherapy compared to 51% (N = 83) pre-neoadjuvant chemotherapy, including the axillary lymph node dissection whenever performed. In multivariable analysis, timing of sentinel node procedure (pre- versus post- neoadjuvant chemotherapy) was, however, not significantly associated with final pN0/pN0(i+) status, with an odds ratio of 1.18 (95% CI 0.64 - 2.18) after correction for age, clinical tumor status, histology, grade, hormone- and HER2 receptor. Of patients with clinically node-positive disease only 15% had a final pN0 status, with a false-negative rate of the sentinel node of 30%., Conclusion: In breast cancer patients with cN0 disease, sentinel node procedure performed post-neoadjuvant chemotherapy led to nodal down staging, although not statistically significant after multivariate correction for patient and tumor characteristics.

Background: Differences in estrogen (ER) and progesterone (PR) expression between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) could be an underlying reason for the difference in chemo-sensitivity and response to hormonal therapy between ILC and IDC. The aim of this study was to investigate the differences in ER and PR expression levels between postmenopausal patients with hormonal receptor-positive ILC and IDC., Methods: We included all ER and/or PR receptor-positive ILC and IDC, diagnosed between January 2011 and December 2013 from the population-based Netherlands Cancer Registry. A semi-quantitative classification was used to analyze differences in ER/PR expression, which consisted of three ER expression classes: 10-69, 70-89, and ≥90%. Differences in ER and PR expression levels between IDC and ILC were analyzed according to age group, tumor size, axillary nodal status, grade, and HER2 status., Results: In total, 26,339 ER and/or PR-positive breast cancers were included in the study, of which 17% were ILC and 83% IDC. In patients with IDC, 86% of the tumors showed an ER expression level of 90% or more, compared to 84% in those with ILC. In both IDC and ILC a PR expression level of 90% or more was observed in 54% of the tumors. In postmenopausal patients aged 50-69 years no significant differences could be observed in ER and PR expression levels between ILC and IDC., Conclusion: Patients with ER and PR-positive ILC and IDC have similar quantitative ER and PR expression profiles, implicating that ER/PR expression is unlikely to be a confounding factor in studies concerning chemo-sensitivity of ILC and IDC.

Background: We assessed the real world costs and cost-effectiveness of the addition of trastuzumab in HER2 positive early breast cancer compared to chemotherapy alone in the Dutch daily practice as opposed to the results based on trial data and based on a subset of patients that were treated according to the guidelines., Patients and Methods: In a cohort study, we included all patients with stage I-III invasive breast cancer treated with curative intent in 5 Dutch hospitals between 2005 and 2007 ( n =2684).We assessed three scenarios: a real-world scenario, a trial scenario and a guideline scenario, with costs and effectiveness based on either the cohort study, the published trials or the guidelines. Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves (CEACs) were constructed., Results: Costs were €243,216 and €239,657 for trastuzumab and no trastuzumab for the real world scenario, €224,443 and €218,948 for the guideline scenario and €253,666 and €265,116 for the trial scenario. The QALYs were 0.827, 0.861, 0.993 for the real world, guideline and trial scenario. The corresponding ICERs were €4,304, €6,382 and dominance, respectively. CEACs showed that the probability that trastuzumab is cost-effective is ≥99% in each scenario., Conclusion: Adjuvant trastuzumab in the real world can be considered cost-effective., Competing Interests: CONFLICTS OF INTEREST There is no conflict of interest.

Purpose: In this retrospective population-based cohort study, we analyzed breast MRI use and its impact on type of surgery, surgical margin involvement, and the diagnosis of contralateral breast cancer., Methods: All Dutch patients with cT 1-4 N 0-3 M 0 breast cancer diagnosed in 2011-2013 and treated with primary surgery were eligible for inclusion. Using multivariable analyses, we analyzed in different categories whether MRI use was related to surgery type, margin involvement, and diagnosis of contralateral breast cancer (CBC)., Results: MRI was performed in 10,740 out of 36,050 patients (29.8%). Patients with invasive ductal cancer undergoing MRI were more likely to undergo primary mastectomy than those without MRI (OR 1.30, 95% confidence interval (CI) 1.22-1.39, p < 0.0001). Patients with invasive lobular cancer undergoing MRI were less likely to undergo primary mastectomy than those without MRI (OR 0.86, 95% CI 0.76-0.99, p = 0.0303). A significantly lower risk of positive surgical margins after breast-conserving surgery was only seen in patients with lobular cancer who had undergone MRI as compared to those without MRI (OR 0.59, 95% CI 0.44-0.79, p = 0.0003) and, consequently, a lower risk of secondary mastectomy (OR 0.61, 95% CI 0.42-0.88, p = 0.0088). Patients who underwent MRI were almost four times more likely to be diagnosed with CBC (OR 3.55, 95% CI 3.01-4.17, p < 0.0001)., Conclusions: Breast MRI use was associated with a reduced number of mastectomies and less positive surgical margins in invasive lobular cancer, but with an increased number of mastectomies in ductal cancers. Breast MRI use was associated with a fourfold higher incidence of CBC.

Background: In 2011, the NABON Breast Cancer Audit (NBCA) was instituted as a nation-wide audit to address quality of breast cancer care and guideline adherence in the Netherlands. The development of the NBCA and the results of 4 years of auditing are described., Methods: Clinical and pathological characteristics of patients diagnosed with invasive breast cancer or in situ carcinoma (DCIS) and information regarding diagnosis and treatment are collected in all hospitals (n = 92) in the Netherlands. Thirty-two quality indicators measuring care structure, processes and outcomes were evaluated over time and compared between hospitals., Results: The NBCA contains data of 56,927 patients (7,649 DCIS and 49,073 invasive cancers). Patients being discussed in pre- and post-operative multidisciplinary team meetings improved (2011: 83% and 91%; 2014: 98% and 99%, respectively) over the years. Tumour margin positivity rates after breast-conserving surgery for invasive cancer requiring re-operation were consistently low (∼5%). Other indicators, for example, the use of an MRI-scan prior to surgery or immediate breast reconstruction following mastectomy showed considerable hospital variation., Conclusions: Results shown an overall high quality of breast cancer care in all hospitals in the Netherlands. For most quality indicators improvement was seen over time, while some indicators showed yet unexplained variation. J. Surg. Oncol. 2017;115:243-249. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: To assess the incidence of chemotherapy-induced ovarian function failure (COFF) based on estradiol and follicle stimulating hormone (FSH) monitoring in premenopausal women with hormone-receptor positive breast cancer treated with second and third generation (neo-)adjuvant chemotherapy., Results: We identified 115 eligible women. Two years after start of chemotherapy, COFF was significantly more often present in women ≥ 40 years (85.6%) as compared to women < 40 years (8.7%). Only age was significantly associated with COFF two years after start of chemotherapy (HR 12.26; 95% CI 5.21-28.86). In 50% of the patients, premenopausal hormone levels were the first or only evidence of ovarian function recovery (OFR)., Materials and Methods: We included all premenopausal women with hormone-receptor positive breast cancer treated with anthracycline-based chemotherapy, with or without taxanes, in our university hospital in the Netherlands in the years 2005-2013. Patients were 3-monthly monitored for ovarian function. Cox proportional hazards model was used to determine the predictive impact of various parameters on the occurrence of COFF., Conclusions: After second- or third generation (neo-)adjuvant chemotherapy, COFF was still present in 8.7% of patients < 40 years after two years. FSH and estradiol monitoring may be relevant for those in whom ovarian function suppression is considered an additional effective endocrine treatment.

Objective: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts., Methods: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only., Results: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle., Conclusion: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles., (The Author(s). Published by S. Karger AG, Basel.)

Background: This study aimed to compare the type and extent of surgery in patients with screen-detected and interval cancers after blinded or nonblinded double-reading of screening mammograms., Methods: The study investigated a consecutive series of screens double-read in either a blinded (n = 44,491) or nonblinded (n = 42,996) fashion between 2009 and 2011. During a 2 year follow-up period, the radiology reports, surgical correspondence, and pathology reports of all the screen-detected and interval cancers were collected., Results: Screen-detected breast cancer was diagnosed for 325 women at blinded and 284 women at nonblinded double-reading. The majority of the women were treated by breast-conserving surgery (BCS) at both reading strategies (78.2 vs. 81.7 %; p = 0.51). Larger total resection volumes were observed at BCS for ductal carcinoma in situ (DCIS) treatment for patients after blinded double-reading (p = 0.005). The proportions of positive resection margins after BCS were comparable for patients with DCIS (p = 0.81) or invasive screen-detected cancers (p = 0.38) for the two reading strategies. A total of 158 interval cancers were diagnosed. The proportions of patients treated with BCS were comparable for the two reading strategies (p = 0.42). The total resection volume (p = 0.13) and the proportion of positive resection margins after BCS (p = 0.32) for invasive interval cancer were comparable for the two cohorts. The BCS rate was higher for women after nonblinded double-reading (p = 0.04)., Conclusions: Blinded and nonblinded double-reading yielded comparable surgical treatments for women with screen-detected or interval breast cancer except for larger total resection volumes at BCS for screen-detected DCIS and a higher BCS rate for interval cancers at nonblinded double-reading.

We determined the characteristics and prognosis of interval breast cancers (IC) at screen-film (SFM) and full-field digital (FFDM) screening mammography. The study population consisted of 417,746 consecutive screening mammograms (302,699 SFM screens and 115,047 FFDM screens), obtained between 2000 and 2011. During 2-year follow-up, we collected breast imaging reports, surgical reports, and pathology results. A total of 800 ICs had been diagnosed in the screened population, of which 288 detected in the first year (early ICs) and 512 in the second year (late ICs) after a negative screen. 31.3 % of early IC's and 19.1 % of late IC's, respectively, were visible in retrospect on the latest previous screens, but had been missed during screening (P < 0.001). Missed invasive ICs were larger (28.5 mm vs. 23.9 mm, P = 0.003) and showed a higher fraction of T3+cancers (16.9 vs. 8.5 %, P = 0.02) than true ICs (i.e., not visible at the latest screen). A higher portion of missed than true ICs underwent mastectomy (44.7 vs. 30.8 %, P = 0.002). We found no differences in mammographic and tumor characteristics for early ICs, detected either after SFM or FFDM. Late ICs following FFDM were more often true ICs than missed ICs (69.0 vs. 57.6 %, P = 0.03) and more often receptor triple negative (P = 0.02), compared to late ICs at SFM. Interval cancer subgroups showed comparable overall survival. Interval cancer subgroups show distinctive mammographic and tumor characteristics but a comparable overall survival.

Context: Cancer pain has a severe impact on quality of life and is associated with numerous psychosocial responses. Recent studies suggest that treatment of cancer pain has improved during the last decade., Objectives: The aim of this review was to examine the present status of pain prevalence and pain severity in patients with cancer., Methods: A systematic search of the literature published between September 2005 and January 2014 was performed using the databases PubMed, Medline, Embase, CINAHL, and Cochrane. Articles in English or Dutch that reported on the prevalence of cancer pain in an adult population were included. Titles and abstracts were screened by two authors independently, after which full texts were evaluated and assessed on methodological quality. Study details and pain characteristics were extracted from the articles with adequate study quality. Prevalence rates were pooled with meta-analysis; meta-regression was performed to explore determinants of pain prevalence., Results: Of 4117 titles, 122 studies were selected for the meta-analyses on pain (117 studies, n = 63,533) and pain severity (52 studies, n = 32,261). Pain prevalence rates were 39.3% after curative treatment; 55.0% during anticancer treatment; and 66.4% in advanced, metastatic, or terminal disease. Moderate to severe pain (numerical rating scale score ≥5) was reported by 38.0% of all patients., Conclusion: Despite increased attention on assessment and management, pain continues to be a prevalent symptom in patients with cancer. In the upcoming decade, we need to overcome barriers toward effective pain treatment and develop and implement interventions to optimally manage pain in patients with cancer., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: This study describes the differences between the two largest histological breast cancer subtypes (invasive ductal carcinoma (IDC) and invasive (mixed) lobular carcinoma (ILC) with respect to patient and tumor characteristics, treatment-choices and outcome in metastatic breast cancer., Results: Patients with ILC were older at diagnosis of primary breast cancer and had more often initial bone metastasis (46.5% versus 34.8%, P = 0.01) and less often multiple metastatic sites compared to IDC (23.7% versus 30.9%, P = 0.11). Six months after diagnosis of metastatic breast cancer, 28.1% of patients with ILC and 39.8% of patients with IDC had received chemotherapy with a longer median time to first chemotherapy for those with ILC (P = 0.001). After six months 84.8% of patients with ILC had received endocrine therapy versus 72.5% of patients with IDC (P = 0.0001). Median overall survival was 29 months for ILC and 25 months for IDC (P = 0.53)., Materials and Methods: We included 437 patients with hormone receptor-positive IDC and 131 patients with hormone receptor-positive ILC, all diagnosed with metastatic breast cancer between 2007-2009, irrespective of date of the primary diagnosis. Patient and tumor characteristics and data on treatment and outcome were collected. Survival curves were obtained using the Kaplan-Meier method., Conclusions: Treatment strategies of hormone receptor-positive metastatic breast cancer were remarkably different for patients with ILC and IDC. Further research is required to understand tumor behavior and treatment-choices in real-life., Competing Interests: The authors have declared no conflicts of interest.

Introduction: We assessed the incidence and timing of first cardiac events, impact on trastuzumab prescription, and role of left ventricular ejection fraction (LVEF) monitoring in daily practice of trastuzumab-treated patients with human epidermal growth receptor 2 (HER2)-positive early breast cancer., Methods: We included all patients with stage I-III breast cancer diagnosed in the early years (2005-2007) after the introduction of adjuvant trastuzumab in five hospitals in Southeast Netherlands. We studied the incidence and timing of cardiotoxicity in patients treated with adjuvant trastuzumab, using similar cardiac endpoints as in the Herceptin Adjuvant (HERA) trial., Results: Of 2,684 included patients, 476 (17.7%) had a HER2-positive tumor. Of these, 269 (56.9%) were treated with adjuvant chemotherapy, and of these, 230 (85.5%) also received trastuzumab. Cardiotoxicity was observed in 29 of 230 patients (12.6%). Twenty of the 230 patients (8.7%) had symptomatic cardiotoxicity, defined as a drop in LVEF of at least 10 percentage points and to below 50%, accompanied by symptoms of congestive heart failure. Trastuzumab was definitely discontinued because of supposed cardiotoxicity in 36 patients (15.6%), of whom only 15 (6.5%) had a significant LVEF drop. Of the 36 patients who prematurely discontinued trastuzumab (including the 29 in whom cardiotoxicity was observed), 84.8% stopped in the first 6 months. No cardiac deaths were seen., Conclusion: In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from LVEF outcome. We suggest that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. Nonetheless, further research is needed., Implications for Practice: Knowledge of when cardiotoxicity occurs in daily practice will help shape the best follow-up method for cardiac monitoring in trastuzumab-treated patients with human epidermal growth receptor 2-positive early breast cancer. In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from left ventricular ejection fraction (LVEF) outcome. When cardiotoxicity was found in daily practice, it occurred mainly in the first 6 months after start of trastuzumab. This study suggests that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. This insight stresses the relevance of performing real-world analyses., (©AlphaMed Press.)

Background: Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC)., Methods: Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0., Results: Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm., Conclusions: This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients (ClinicalTrials.gov number, NCT00066378)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.

Background: The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials., Methods: We included all patients with stage I-III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005-2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice., Results: Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37-1.06) for trastuzumab when adjusting for potential confounders., Conclusion: This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment., (©AlphaMed Press.)

Objective: Depression is an important health issue in cancer patients. People use different coping strategies and health locus of control to manage stressful situations, which relate to different risks of depression. Coping strategies and health locus of control can be changed by cognitive behavioral interventions., Methods: In a cohort study, we investigated differences in coping strategy and health locus of control in older (≥70 years) and middle-aged (50-69 years) cancer patients, and older patients without cancer (≥70 years), and their association with presence of depression. We also investigated how these factors interact. We used the short version of the Utrecht Coping List, the Multidimensional Health Locus of Control scale, and the 15-item Geriatric Depression Scale., Results: Data were available from 1317 participants. Overall prevalence of depression was 12%. Older cancer patients tended to use an avoiding coping strategy more frequently than middle-aged cancer patients. This was associated with higher risk of depression. Older cancer patients less often used an active coping strategy, in comparison with middle-aged cancer patients, which was associated with a lower risk of depression. Especially in women using a seeking social support strategy, there was a lower risk of depression. Overall, the internal health locus of control was associated with higher and the external 'powerful others' locus with lower risk of depression., Conclusions: Older cancer patients strongly differ from middle-aged cancer patients, in particular with respect to coping. Interventions to prevent or alleviate depression should incorporate these differences., (Copyright © 2015 John Wiley & Sons, Ltd.)

Current genome-wide methods to detect DNA-methylation in healthy and diseased tissue require high-quality DNA from fresh-frozen (FF) samples. However, well-annotated clinical samples are mostly available as formalin-fixed, paraffin-embedded (FFPE) tissues containing poor-quality DNA. To overcome this limitation, we here aimed to evaluate a DNA restoration protocol for usage with the genome-wide Infinium HumanMethylation450 BeadChip assay (HM-450K). Sixty-six DNA samples from normal colon (n=9) and breast cancer (n=11) were interrogated separately using HM-450K. Analyses included matched FF/FFPE samples and technical duplicates. FFPE DNA was processed with (FFPEr) or without a DNA restoration protocol (Illumina). Differentially methylated genes were finally validated in 24 additional FFPE tissues using nested methylation-specific PCR (MSP). In summary, β-values correlation between FFPEr duplicates was high (ρ=0.9927 (s.d. ±0.0015)). Matched FF/FFPEr correlation was also high (ρ=0.9590 (s.d. ±0.0184)) compared with matched FF/FFPE (ρ=0.8051 (s.d. ±0.1028). Probe detection rate in FFPEr samples (98.37%, s.d. ±0.66) was comparable to FF samples (99.98%, s.d. ±0.019) and substantially lower in FFPE samples (82.31%, s.d. ±18.65). Assay robustness was not decreased by sample archival age up to 10 years. We could also demonstrate no decrease in assay robustness when using 100 ng of DNA input only. Four out of the five selected differentially methylated genes could be validated by MSP. The gene failing validation by PCR showed high variation of CpG β-values in primer-binding sites. In conclusion, by using the FFPE DNA restoration protocol, HM-450K assays provide robust, accurate and reproducible results with FFPE tissue-derived DNA, which are comparable to those obtained with FF tissue. Most importantly, differentially methylated genes can be validated using more sensitive techniques, such as nested MSP, altogether providing an epigenomics platform for molecular pathological epidemiology research on archived samples with limited tissue amount.

Background: Lifetime risks are often used in communications on cancer to the general public. The most-cited estimate for breast cancer risk (1 in 8 women), however, appears to be outdated. Here we describe the breast cancer burden in the Netherlands over time by means of lifetime and age-conditional risks. The aim is to identify changes in absolute risk of primary breast cancer diagnosis and death., Methods: Data on breast cancer incidence, mortality and size of the female population were retrieved from the Netherlands Cancer Registry and Statistics Netherlands. Lifetime and age-conditional risks were calculated for 1990, 2000 and 2010 using the life-table method (DevCan software)., Results: The lifetime risk of developing breast cancer (ductal carcinoma in situ and invasive) in 1990, 2000 and 2010 was estimated at 10.8 (1 in 9.3 women), 13.5 (1 in 7.4) and 15.2% (1 in 6.6), respectively. Most women were still diagnosed after the age of 50, with the highest risk between 60 and 70 years in 2010. The lifetime risk of breast cancer death was 3.8% (1 in 27) in 2010, which is lower than in 1990 (4.5%; 1 in 22) and 2000 (4.2%; 1 in 24)., Conclusion: Breast cancer risk has increased to 1 in 6.6 women being diagnosed during their lifetime (invasive cancer only: 1 in 7.4), whereas risk of breast cancer death has decreased from 1 in 22 to 1 in 27 women. To keep cancer management and prevention up-to-date, it remains important to closely monitor the ever-changing breast cancer burden., (© The Author 2014. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: In breast cancer studies, many different endpoints are used. Definitions are often not provided or vary between studies. For instance, "local recurrence" may include different components in similar studies. This limits transparency and comparability of results. This project aimed to reach consensus on the definitions of local event, second primary breast cancer, regional and distant event for breast cancer studies., Methods: The RAND-UCLA Appropriateness method (modified Delphi method) was used. A Consensus Group of international breast cancer experts was formed, including representatives of all involved clinical disciplines. Consensus was reached in two rounds of online questionnaires and one meeting., Results: Twenty-four international breast cancer experts participated. Consensus was reached on 134 items in four categories. Local event is defined as any epithelial breast cancer or ductal carcinoma in situ (DCIS) in the ipsilateral breast, or skin and subcutaneous tissue on the ipsilateral thoracic wall. Second primary breast cancer is defined as epithelial breast cancer in the contralateral breast. Regional events are breast cancer in ipsilateral lymph nodes. A distant event is breast cancer in any other location. Therefore, this includes metastasis in contralateral lymph nodes and breast cancer involving the sternal bone. If feasible, tissue sampling of a first, solitary, lesion suspected for metastasis is highly recommended., Conclusion: This project resulted in consensus-based event definitions for classification of recurrence in breast cancer research. Future breast cancer research projects should adopt these definitions to increase transparency. This should facilitate comparison of results and conducting reviews as well as meta-analysis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, non-everolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.

For low-volume tumours, high surgical hospital volume is associated with better survival. For high-volume tumours like breast cancer, this association is unclear. The aim of this study is to determine to what extent the yearly surgical hospital breast cancer volume is associated with overall survival. All patients, diagnosed with primary invasive non-metastatic breast cancer in the period 2001-2005, were selected from the Netherlands Cancer Registry. Hospitals were grouped by their annual volume of surgery for invasive breast cancer. Cox proportional hazard models were used including patient and tumour characteristics as covariates. Follow-up was completed until the 1st of February 2013. Primary endpoint was 10-year overall survival rate. In total, 58,982 patients with invasive non-metastatic breast cancer were diagnosed during the period 2001-2005. Hospitals were grouped by their (mean) annual surgical volume: <75 (n = 19), 75-99 (n = 30), 100-149 (n = 29), 150-199 (n = 9) and ≥200 (n = 14). The 10-year observed survival rates were 77, 81, 80, 82 and 82 %, respectively. After case-mix adjustment, patients in low-volume hospitals had a HR of 1.09 (<75 vs. ≥200; 95 % CI 1.03-1.15). Survival was significantly higher for lobular carcinoma and for diagnosis in the most recent year (2005). Being a male, having a higher age at diagnosis, a higher tumour grade, a larger tumour size, a higher number of positive lymph nodes, an earlier year of diagnosis and a lower SES resulted in a reduced survival and influenced death, all to a larger extent than surgical volume did. In the Netherlands, surgical hospital volume influences 10-year overall survival only marginally and far less than patient and tumour characteristics. No difference in survival was revealed for invasive non-metastatic breast cancer patients in hospitals with 75-99 operations per year compared with hospitals with over 200 operations per year.

Preimplantation genetic diagnosis (PGD) is a reproductive option for BRCA1/2 mutation carriers wishing to avoid transmission of the predisposition for hereditary breast and ovarian cancer (HBOC) to their offspring. Embryos obtained by in vitro fertilisation (IVF/ICSI) are tested for the presence of the mutation. Only BRCA-negative embryos are transferred into the uterus. The suitability and outcome of PGD for HBOC are evaluated in an observational cohort study on treatments carried out in two of Western-Europe's largest PGD centres from 2006 until 2012. Male carriers, asymptomatic female carriers and breast cancer survivors were eligible. If available, PGD on embryos cryopreserved before chemotherapy was possible. Generic PGD-PCR tests were developed based on haplotyping, if necessary combined with mutation detection. 70 Couples underwent PGD for BRCA1/2. 42/71 carriers (59.2 %) were female, six (14.3 %) of whom have had breast cancer prior to PGD. In total, 145 PGD cycles were performed. 720 embryos were tested, identifying 294 (40.8 %) as BRCA-negative. Of fresh IVF/PGD cycles, 23.9 % resulted in a clinical pregnancy. Three cycles involved PGD on embryos cryopreserved before chemotherapy; two of these women delivered a healthy child. Overall, 38 children were liveborn. Two BRCA1 carriers were diagnosed with breast cancer shortly after PGD treatment, despite negative screening prior to PGD. PGD for HBOC proved to be suitable, yielding good pregnancy rates for asymptomatic carriers as well as breast cancer survivors. Because of two cases of breast cancer shortly after treatment, maternal safety of IVF(PGD) in female carriers needs further evaluation.

The combination of exemestane and everolimus is a new treatment option for metastatic hormone-sensitive breast cancer. This treatment is used after progression on non-steroidal aromatase inhibitors. The treatment is generally well tolerated, but sometimes leads to minor or even serious side effects. It is important to be aware of these side effects and to treat them. We describe two patients who had to cope with various forms of toxicity: a 73-year-old woman with aphthous mouth lesions and a 49-year-old woman with pneumonitis. We then discuss the efficacy of the combination exemestane and everolimus and its positioning in the treatment of metastatic hormone-sensitive breast cancer. Finally, some common and some potentially serious side effects will be discussed, along with recommendations for their management and indications for distinguishing side effects from disease progression.

Background: Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC., Methods: Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m(2)., Results: In total, 46 patients were included. Median age was 59.6 years (range 41.3-74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin-gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin-gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin-gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin-gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity., Conclusion: Sequential chemotherapy with carboplatin-gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients.

Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2- subtype, 8 % the HR-/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2- subtype, 19.8 months for the HR-/HER2+ subtype and 8.8 months for the TN subtype (P < 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.