Kristien Keymeulen

Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis

Data on survival of BRCA1/2‐associated primary breast cancer (PBC) patients who opt for subsequent contralateral risk‐reducing mastectomy (CRRM) are scarce and inconsistent. We examined the efficacy of CRRM on overall survival in mutation carriers with a history of PBC. From a Dutch multicentre cohort, we selected 583 BRCA‐associated PBC patients, being diagnosed between 1980 and 2011. Over time, 242 patients (42%) underwent CRRM and 341 patients (58%) remained under surveillance. Survival analyses were performed using Cox models, with CRRM as a time‐dependent covariate. The median follow‐up after PBC diagnosis was 11.4 years. In the CRRM group, four patients developed contralateral breast cancer (2%), against 64 patients (19%) in the surveillance group (p < 0.001). The mortality was lower in the CRRM group than in the surveillance group (9.6 and 21.6 per 1000 person‐years of observation, respectively; adjusted hazard ratio 0.49, 95% confidence interval 0.29–0.82). Survival benefit was especially seen in young PBC patients (<40 years), in patients having a PBC with differentiation grade 1/2 and/or no triple‐negative phenotype, and in patients not treated with adjuvant chemotherapy. We conclude that CRRM is associated with improved overall survival in BRCA1/2 mutation carriers with a history of PBC. Further research is warranted to develop a model based on age at diagnosis and tumour and treatment characteristics that can predict survival benefit for specific subgroups of patients, aiming at further personalized counselling and improved decision making.

‘Reconstruction: Before or after postmastectomy radiotherapy?’ A systematic review of the literature

OBJECTIVE The aim of this review is to investigate the effect of timing of the reconstruction and radiotherapy, with respect to complication rate and cosmetic outcome, with a special focus on the timing of the placement of the definite implant. METHODS PubMed was searched for publications between January 2000 and December 2012. Of 37 eligible studies, timing of reconstruction, type, and incidence of complications were recorded. First, we calculated the weighted mean including confidence intervals for complications and cosmetic outcome overall, and for the following subgroups: (1) Autologous reconstruction after radiotherapy; (2) Definite implant reconstruction after radiotherapy; (3) Autologous reconstruction before radiotherapy; (4) Definite implant reconstruction before radiotherapy. A second analysis was performed using only studies that directly compared group 1 versus 3 and 2 versus 4. RESULTS A large variation in complication rates (8.7-70.0%) and in acceptable cosmetic outcome (41.4-93.3%) was reported. The first analysis showed more complications and a higher revision rate if an implant reconstruction was performed after radiotherapy; for autologous reconstruction fibrosis occurred more often if reconstruction was applied first. The second analysis showed no significant differences in total complication rate. Only implant failure occurred more often if applied after radiotherapy (odds ratio (OR) 3.03 [1.59-5.77]). No differences were found in both patient and physician satisfaction. CONCLUSIONS A definite implant reconstruction placed before radiotherapy limits the rate of complications. For autologous reconstruction, less fibrosis is seen if reconstruction is performed after radiotherapy, but timing had no significant impact on total complication rate.

A randomised controlled phase II trial of pre-operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer

IntroductionCyclooxygenase-2 (COX-2) is frequently over-expressed in primary breast cancer. In transgenic breast cancer models, over-expression of COX-2 leads to tumour formation while COX-2 inhibition exerts anti-tumour effects in breast cancer cell lines. To further determine the effect of COX-2 inhibition in primary breast cancer, we aimed to identify transcriptional changes in breast cancer tissues of patients treated with the selective COX-2 inhibitor celecoxib.MethodsIn a single-centre double-blind phase II study, thirty-seven breast cancer patients were randomised to receive either pre-operative celecoxib (400 mg) twice daily for two to three weeks (n = 22) or a placebo according to the same schedule (n = 15). Gene expression in fresh-frozen pre-surgical biopsies (before treatment) and surgical excision specimens (after treatment) was profiled by using Affymetrix arrays. Differentially expressed genes and altered pathways were bioinformatically identified. Expression of selected genes was validated by quantitative PCR (qPCR). Immunohistochemical protein expression analyses of the proliferation marker Ki-67, the apoptosis marker cleaved caspase-3 and the neo-angiogenesis marker CD34 served to evaluate biological response.ResultsWe identified 972 and 586 significantly up- and down-regulated genes, respectively, in celecoxib-treated specimens. Significant expression changes in six out of eight genes could be validated by qPCR. Pathway analyses revealed over-representation of deregulated genes in the networks of proliferation, cell cycle, extracellular matrix biology, and inflammatory immune response. The Ki-67 mean change relative to baseline was -29.1% (P = 0.019) and -8.2% (P = 0.384) in the treatment and control arm, respectively. Between treatment groups, the change in Ki-67 was statistically significant (P = 0.029). Cleaved caspase-3 and CD34 expression were not significantly different between the celecoxib-treated and placebo-treated groups.ConclusionsShort-term COX-2 inhibition by celecoxib induces transcriptional programs supporting anti-tumour activity in primary breast cancer tissue. The impact on proliferation-associated genes is reflected by a reduction of Ki-67 positive cells. Therefore, COX-2 inhibition should be considered as a treatment strategy for further clinical testing in primary breast cancer.Trial registrationClinicalTrials.gov NCT01695226.

Noninvasive nodal staging in patients with breast cancer using gadofosveset-enhanced magnetic resonance imaging: a feasibility study.

ObjectivesThe objectives of this study were to evaluate whether the axillary lymph nodes show enhancement on magnetic resonance imaging (MRI) after gadofosveset administration, to assess the time to peak enhancement, and to determine the diagnostic performance of gadofosveset-enhanced MRI for axillary nodal staging. Materials and MethodsTen women whose conditions had been diagnosed with invasive breast cancer (>2 cm) underwent both nonenhanced and gadofosveset-enhanced 3-dimensional T1-weighted axillary MRI. Signal intensity of the axillary lymph nodes and different adjacent tissues was measured, and relative signal intensity (rSI) was calculated. A Wilcoxon signed rank test was used to compare results of rSI between different time intervals. A radiologist evaluated all lymph nodes with regard to size, morphologic features, and gadofosveset uptake. All MRI-depicted lymph nodes were matched with the lymph nodes that were removed during surgery. Nodal status was investigated by a pathologist. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of gadofosveset-enhanced MRI for axillary lymph node staging were calculated. ResultsAfter contrast administration, a significant signal increase was observed in the lymph nodes (P < 0.05). When compared with muscle or fat, rSI of the lymph nodes demonstrated a significant postcontrast peak enhancement between 11 minutes and 30 seconds and 20 minutes and 50 seconds (P < 0.05). A total of 152 lymph nodes were harvested during sentinel lymph node biopsy or axillary lymph node dissection, of which 116 were matched with the lymph nodes that were depicted on MRI. Histopathological examination resulted in 21 macrometastases and 8 micrometastases. Using contrast-enhanced MRI, 20 lymph nodes were rated as true positive; 83 as true negative; 4 as false positive; and 9 as false negative. This resulted in an overall node-by-node sensitivity, specificity, PPV, and NPV of 69%, 95%, 83%, and 90%, respectively. If the micrometastases were excluded from the analysis, MRI showed a sensitivity of 86% and a specificity of 94%. Calculated PPV and NPV were 75% and 97%, respectively. ConclusionsThe axillary lymph nodes show enhancement on MRI after gadofosveset administration, with a peak enhancement between 11 minutes and 30 seconds and 20 minutes and 50 seconds. Diagnostic performance of gadofosveset-enhanced axillary lymph node imaging in patients with breast cancer is promising, but further studies need to confirm these results.

Customized computed tomography-based boost volumes in breast-conserving therapy: use of three-dimensional histologic information for clinical target volume margins

PURPOSE To determine the difference in size between computed tomography (CT)-based irradiated boost volumes and simulator-based irradiated volumes in patients treated with breast-conserving therapy and to analyze whether the use of anisotropic three-dimensional clinical target volume (CTV) margins using the histologically determined free resection margins allows for a significant reduction of the CT-based boost volumes. PATIENTS AND METHODS The CT data from 49 patients were used to delineate a planning target volume (PTV) with isotropic CTV margins and to delineate a PTV(sim) that mimicked the PTV as delineated in the era of conventional simulation. For 17 patients, a PTV with anisotropic CTV margins was defined by applying customized three-dimensional CTV margins, according to the free excision margins in six directions. Boost treatment plans consisted of conformal portals for the CT-based PTVs and rectangular fields for the PTV(sim). RESULTS The irradiated volume (volume receiving > or =95% of the prescribed dose [V(95)]) for the PTV with isotropic CTV margins was 1.6 times greater than that for the PTV(sim): 228 cm(3) vs. 147 cm(3) (p < .001). For the 17 patients with a PTV with anisotropic CTV margins, the V(95) was similar to the V(95) for the PTV(sim) (190 cm(3) vs. 162 cm(3); p = NS). The main determinant for the irradiated volume was the size of the excision cavity (p < .001), which was mainly related to the interval between surgery and the planning CT scan (p = .029). CONCLUSION CT-based PTVs with isotropic margins for the CTV yield much greater irradiated volumes than fluoroscopically based PTVs. Applying individualized anisotropic CTV margins allowed for a significant reduction of the irradiated boost volume.

Density is in the eye of the beholder: visual versus semi-automated assessment of breast density on standard mammograms

ObjectivesVisual inspection is generally used to assess breast density. Our study aim was to compare visual assessment of breast density of experienced and inexperienced readers with semi-automated analysis of breast density.MethodsBreast density was assessed by an experienced and an inexperienced reader in 200 mammograms and scored according to the quantitative BI-RADS classification. Breast density was also assessed by dedicated software using a semi-automated thresholding technique. Agreement between breast density classification of both readers as well as agreement between their assessment versus the semi-automated analysis as reference standard was expressed as the weighted kappa value.ResultsUsing the semi-automated analysis, agreement between breast density measurements of both breasts in both projections was excellent (ICC >0.9, P < 0.0001). Reproducibility of the semi-automated analysis was excellent (ICC >0.8, P < 0.0001). The experienced reader correctly classified the BI-RADS breast density classification in 58.5% of the cases. Classification was overestimated in 35.5% of the cases and underestimated in 6.0% of the cases. Results of the inexperienced reader were less accurate. Agreement between the classification of both readers versus the semi-automated analysis was considered only moderate with weighted kappa values of 0.367 (experienced reader) and 0.232 (inexperienced reader).ConclusionVisual assessment of breast density on mammograms is inaccurate and observer-dependent.

Diagnostic Performance of Dedicated Axillary T2- and Diffusion-weighted MR Imaging for Nodal Staging in Breast Cancer

PURPOSE To evaluate the diagnostic performance of unenhanced axillary T2-weighted and diffusion-weighted (DW) magnetic resonance (MR) imaging for axillary nodal staging in patients with newly diagnosed breast cancer, with node-by-node and patient-by-patient validation. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Fifty women (mean age, 60 years; range, 22-80 years) underwent high-spatial-resolution axillary 3.0-T T2-weighted imaging without fat suppression and DW imaging (b = 0, 500, and 800 sec/mm(2)), followed by either sentinel lymph node biopsy (SLNB) or axillary lymph node dissection. Two radiologists independently scored each lymph node on a confidence level scale from 0 (benign) to 4 (malignant), first on T2-weighted MR images, then on DW MR images. Two researchers independently measured the mean apparent diffusion coefficient (ADC) of each lymph node. Diagnostic performance parameters were calculated on the basis of node-by-node and patient-by-patient validation. RESULTS With respective node-by-node and patient-by-patient validation, T2-weighted MR imaging had a specificity of 93%-97% and 87%-95%, sensitivity of 32%-55% and 50%-67%, negative predictive value (NPV) of 88%-91% and 86%-89%, positive predictive value (PPV) of 60%-70% and 62%-75%, and area under the receiver operating characteristic curve (AUC) of 0.78 and 0.80-0.88, with good interobserver agreement (κ = 0.70). The addition of DW MR imaging resulted in lower specificity (59%-88% and 50%-84%), higher sensitivity (45%-64% and 75%-83%), comparable NPV (89% and 90%-91%), lower PPV (23%-42% and 34%-60%), and lower AUC (0.68-0.73 and 0.70-0.86). ADC measurement resulted in a specificity of 63%-64% and 61%-63%, sensitivity of 41% and 67%, NPV of 85% and 85%-86%, PPV of 18% and 35%-36%, and AUC of 0.54-0.58 and 0.69-0.74, respectively, with excellent interobserver agreement (intraclass correlation coefficient, 0.83). CONCLUSION Dedicated high-spatial-resolution axillary T2-weighted MR imaging showed good specificity on the basis of node-by-node and patient-by-patient validation, with good interobserver agreement. However, its NPV is still insufficient to substitute it for SLNB for exclusion of axillary lymph node metastasis. DW MR imaging and ADC measurement were of no added value.

Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial

BackgroundTo reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density.Methods/DesignThis Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor.DiscussionPersonalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition.Trial registrationNetherland Trial Register NTR2789

FDG-PET-CT for staging of high-risk breast cancer patients reduces the number of further examinations: A pilot study

Abstract Aim. To determine the additional value of FDG-PET-CT as compared to conventional staging (CS) in high-risk breast cancer patients. Patients and methods. Thirty-one high-risk breast cancer patients, 14 of whom had recurrent breast cancer, were included in this study, which took place between June 2005 and March 2008. None of the patients had clinical signs of distant metastases. FDG-PET-CT scanning was added to CS, which consisted of a chest x-ray, liver ultrasonography or CT, and bone scintigraphy. Median follow-up was 17 months (6–41 months). FDG-PET-CT was considered to have additional value to CS if it led to a change in treatment plan or if it made additional examinations to confirm or deny findings on CS unnecessary. Results. FDG-PET-CT was considered to have additional value to CS in 13 patients (42% [95% CI: 23–61]). In five patients (16% [95% CI: 1–31]), FDG-PET-CT led to a change in treatment plan by identifying nodal metastases in the internal mammary chain (IMC; N = 3) or in the mediastinum (N = 2). In nine patients (29% [95% CI: 11–47]), FDG-PET-CT would have prevented the need for additional examinations; in seven of these nine patients, distant metastases were suggested in bone or liver on CS, but these did not show FDG uptake. Conclusions. FDG-PET-CT was found to have additional value to CS in 42% of the patients. To optimize cost-effectiveness, the main challenge now is to improve the selection of patients in whom FDG-PET-CT has additional value to CS.

Comparison of sentinel gamma probes for 99mTc breast cancer surgery based on NEMA NU3-2004 standard.

PurposeHand-held &ggr;-probes are used for the identification of the sentinel node location during intra-operative radio-guided surgeries. Various &ggr;-probes, which use different detectors, collimation and electronics, are available on the market. Spatial resolution, sensitivity and angular resolution of the probes are believed to be determinant for the success of the identification of the sentinel node during radiosurgery. Materials and MethodsWe compared the above-mentioned performances of sentinel probes from six manufacturers available in the European market by means of the NEMA NU3-2004 standard, which allows the users to evaluate the probes during a situation which mimics a intra-operative radio-guided surgery. Results and conclusionThis study presents a summary of characteristics to be expected when using the tested &ggr;-probes during intra-operative radio-guided surgeries, with particular emphasis on breast cancer sentinel node surgery. The results from this study can be used as the guidance for the selection of a sentinel lymph node probe.