Liesbeth Jansen

89Zr-Bevacizumab PET Imaging in Primary Breast Cancer

Vascular endothelial growth factor (VEGF)-A is overexpressed in most malignant and premalignant breast lesions. VEGF-A can be visualized noninvasively with PET imaging and using the tracer 89Zr-labeled bevacizumab. In this clinical feasibility study, we assessed whether VEGF-A in primary breast cancer can be visualized by 89Zr-bevacizumab PET. Methods: Before surgery, breast cancer patients underwent a PET/CT scan of the breasts and axillary regions 4 d after intravenous administration of 37 MBq of 89Zr-bevacizumab per 5 mg. PET images were compared with standard imaging modalities. 89Zr-bevacizumab uptake was quantified as the maximum standardized uptake value (SUVmax). VEGF-A levels in tumor and normal breast tissues were assessed with enzyme-linked immunosorbent assay. Data are presented as mean ± SD. Results: Twenty-five of 26 breast tumors (mean size ± SD, 25.1 ± 19.8 mm; range, 4–80 mm) in 23 patients were visualized. SUVmax was higher in tumors (1.85 ± 1.22; range, 0.52–5.64) than in normal breasts (0.59 ± 0.37; range, 0.27–1.69; P < 0.001). The only tumor not detected on PET was 10 mm in diameter. Lymph node metastases were present in 10 axillary regions; 4 could be detected with PET (SUVmax, 2.66 ± 2.03; range, 1.32–5.68). VEGF-A levels in the 17 assessable tumors were higher than in normal breast tissue in all cases (VEGF-A/mg protein, 184 ± 169 pg vs. 10 ± 21 pg; P = 0.001), whereas 89Zr-bevacizumab tumor uptake correlated with VEGF-A tumor levels (r = 0.49). Conclusion: VEGF-A in primary breast cancer can be visualized by means of 89Zr-bevacizumab PET.

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.

Exposure to low-dose radiation and the risk of breast cancer among women with a familial or genetic predisposition: a meta-analysis

Background:Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the question of how low-dose radiation exposure affects breast cancer risk among high-risk women.Methods:A systematic search was conducted for articles addressing breast cancer, mammography screening, radiation and high-risk women. Effects of low-dose radiation on breast cancer risk were presented in terms of pooled odds ratios (OR).Results:Of 127 articles found, 7 were selected for the meta-analysis. Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9– 1.8). Exposure before age 20 (OR = 2.0, 95% CI: 1.3–3.1) or a mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1–3.0) was significantly associated with a higher radiation-induced breast cancer risk.Conclusion:Low-dose radiation increases breast cancer risk among high-risk women. When using low-dose radiation among high-risk women, a careful approach is needed, by means of reducing repeated exposure, avoidance of exposure at a younger age and using non-ionising screening techniques.

Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study

Purpose: To provide proof of principle of safety, breast tumor–specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab–IRDye800CW targeting VEGF-A in patients with breast cancer. Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab–IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue. Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level. Conclusions: Our study shows that systemic administration of the bevacizumab–IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730–41. ©2016 AACR.

Role of the general practitioner during the active breast cancer treatment phase : an analysis of health care use

PurposeLittle is known about the actual involvement of the general practitioner (GP) during the active breast cancer treatment phase. Therefore, this study explored (disease-specific) primary health care use among women undergoing active treatment for breast cancer compared with women without breast cancer.MethodsA total of 185 women with a first diagnosis of early-stage breast cancer between 1998 and 2007 were identified in the primary care database of the Registration Network Groningen and matched with a reference population of 548 women without breast cancer on birth year and GP.ResultsSince diagnosis, patients with breast cancer had twice as many face-to-face contacts compared with women from the reference population (median 6.0 vs 3.0/year, Mann–Whitney (M-W) test p < 0.001). The median number of drug prescriptions and referrals was also significantly higher among patients than among the reference population (11.0 vs 7.0/year, M-W test p < 0.001 and 1.0 vs 0.0/year, M-W test p < 0.001). More patients than women from the reference population had face-to-face contacts or were prescribed drugs for reasons related to breast cancer and its treatment, including gastrointestinal problems, psychological reasons and endocrine therapy.ConclusionsDuring the active breast cancer treatment phase, GPs are involved in the management of treatment-related side effects and psychological symptoms, as well as in the administration of endocrine therapy. Based on the findings of this study, interventions across the primary/secondary interface can be planned to improve quality of life and other outcomes in patients undergoing breast cancer treatment.

The value of surveillance mammography of the contralateral breast in patients with a history of breast cancer

PURPOSE To determine the contribution of surveillance mammography to the early detection of metachronous contralateral breast cancer (MCBC) and to assess its impact on the survival of breast cancer patients with relation to compliance. METHOD Breast cancer patients (5589) were identified using files from the regional cancer registry of the Comprehensive Cancer Centre North Netherlands (CCCN Groningen, The Netherlands). The programme sensitivity and the impact on prognosis of follow-up mammography with relation to compliance were evaluated in 114 patients who developed MCBC during hospital follow-up. RESULTS The cumulative MCBC incidence rate at year 10 was 3.4% (95% CI: 2.8-4.0%). The programme sensitivity of surveillance mammography was 59.6% (95% CI: 50.6-68.7). In patients who complied with annual mammography, sensitivity was increased to 70.8% (95% CI: 61.7-80.0). Patients with MCBCs detected by routine mammography have better survival rates than patients with MCBCs detected by other means (HR: 3.18; 95% CI: 1.59-6.34). Though there was a trend towards improved survival in patients being compliant with regular clinical follow-up (HR: 1.69; 95% CI: 0.72-3.96), this was not the case for patients being compliant with annual mammography (HR:1.02; 95% CI:0.50-2.09). CONCLUSION Mammography is a valuable tool for the early detection of MCBC during hospital follow-up of breast cancer patients and is probably beneficial to survival. The utilisation of follow-up surveillance in breast cancer patients and its potential impact on survival deserve further investigation.

Determination of Choline Concentration in Breast Lesions: Quantitative Multivoxel Proton MR Spectroscopy as a Promising Noninvasive Assessment Tool to Exclude Benign Lesions

PURPOSE To determine the optimal cutoff of choline (Cho) concentration in quantitative multivoxel magnetic resonance (MR) spectroscopic data to safely prove benignancy in breast lesions. MATERIALS AND METHODS The study was institutional review board approved, and informed consent was obtained from each patient. Between July 2009 and July 2010, multivoxel MR spectroscopy was performed in 24 consecutive patients with 25 breast lesions assessed as Breast Imaging Reporting and Data System 3 or 4 and larger than 1 cm in diameter at mammography. Two-dimensional point-resolved spatially localized spectroscopy chemical shift imaging was first performed without signal suppression (repetition time msec/echo time msec, 1500/30) as reference measurement and was performed subsequently with suppression of water and fat signals (1500/135) to detect Cho. Differences in mean and highest Cho concentration in the breast lesions were tested for significance by using the independent sample t test. The final diagnosis was confirmed with pathologic findings. RESULTS Fourteen of 25 breast lesions were malignant. The mean Cho concentration varied between 0.3 and 1.3 mmol/L (0.84 mmol/L ± 0.32 [standard deviation]) in benign lesions and between 1.3 and 9.5 mmol/L (3.10 mmol/L ± 2.21) in malignant lesions. The highest Cho concentrations in benign and malignant lesions were 0.4-1.5 mmol/L (1.19 mmol/L ± 0.33) and 1.7-11.8 mmol/L (4.08 mmol/L ± 2.81), respectively. Mean and highest Cho concentrations in benign and malignant breast lesions differed significantly (P = .02 for both). CONCLUSION The study, in a relatively small patient population, shows that quantitative multivoxel MR spectroscopy can be applied to exclude benign breast lesions from further invasive diagnostic work-up with the implementation of a Cho concentration of 1.5 mmol/L or lower as a cutoff. Further larger studies will be needed to confirm these results.

Improved staging of breast cancer through lymphatic mapping and sentinel node biopsy

Sentinel node biopsy is a less invasive technique for staging breast cancer than complete axillary lymph-node dissection and may be as accurate. In the case of a 71-year-old woman with a T1 breast cancer, sentinel node biopsy improved staging. Metastases were discovered in sentinel nodes outside the axilla while the axillary nodes were tumour-free.

Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers

OBJECTIVE Women with a BRCA1/2 mutation or members of a hereditary breast ovarian cancer family (HBOC) have an increased risk of developing ovarian cancer. The only effective strategy to reduce this risk is a risk reducing salpingo-oophorectomy (RRSO). The aim of this study was to evaluate the short-term surgical outcome and safety of a RRSO. PATIENT AND METHODS Included were all consecutive women with a BRCA1/2 mutation or members of a HBOC family who visited our Family Cancer Clinic between September 1995 and March 2006, and choose for RRSO. RESULTS 159 women were included, of which 97 (61.0%) BRCA1 and 32 (20.1%) BRCA2 mutation carriers, and 30 women of a HBOC family (18.9%). The median age at RRSO was 42.9 years (30.3-61.1) in the BRCA1 group, 48.4 years (33.5-66.9) in the BRCA 2 group and 46.4 (32.8-68.7) years in the HBOC group (p=0.02). The median body mass index (BMI) was 24.9 kg/m(2), 30.1% were overweighed (BMI 25-30) and 18.7% were obese (BMI>30). The RRSO was performed by primary laparoscopy (n=154) or laparotomy (n=5). Intraoperatively, one (0.6%) major complication occurred and laparoscopy was converted to laparotomy. In one patient (0.6%) a minor complication occurred. Post-operatively five minor complications (3.1%) were observed. Median hospital stay was 1 day (0-13 days). CONCLUSION Laparoscopic RRSO in BRCA1/2 mutation carriers seems to be a safe procedure with a low intraoperative and post-operative complication rate (1.3% and 3.1% respectively), a low conversion rate (0.6%) and a short median hospital stay (1.0 day).

A validated web-based nomogram for predicting positive surgical margins following breast-conserving surgery as a preoperative tool for clinical decision-making

BACKGROUND Breast-conserving therapy, consisting of lumpectomy and adjuvant radiotherapy, is considered standard treatment for early-stage breast cancer. One of the most important risk factors of local recurrence is the presence of positive surgical margins following lumpectomy. We aimed to develop and validate a predictive model (nomogram) to predict for positive margins following the first attempt at lumpectomy as a preoperative tool for clinical decision-making. METHODS Patients with clinical T1-2N0-1Mx-0 histology-proven invasive breast carcinoma who underwent BCT throughout the North-East region of The Netherlands between June 2008 and July 2009 were selected from the Netherlands Cancer Registry (n = 1185). Results from multivariate logistic regression analyses served as the basis for development of the nomogram. Nomogram calibration and discrimination were assessed graphically and by calculation of a concordance index, respectively. Nomogram performance was validated on an external independent dataset (n = 331) from the University Medical Center Groningen. RESULTS The final multivariate regression model included clinical, radiological, and pathological variables. Concordance indices were calculated of 0.70 (95% CI: 0.66-0.74) and 0.69 (95% CI: 0.63-0.76) for the modeling and the validation group, respectively. Calibration of the model was considered adequate in both groups. A nomogram was developed as a graphical representation of the model. Moreover, a web-based application (http://www.breastconservation.com) was build to facilitate the use of our nomogram in a clinical setting. CONCLUSION We developed and validated a nomogram that enables estimation of the preoperative risk of positive margins in breast-conserving surgery. Our nomogram provides a valuable tool for identifying high-risk patients who might benefit from preoperative MRI and/or oncoplastic surgery.