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Background: Intraoperative electron radiotherapy (IOERT) can be used to treat early breast cancer during the conservative surgery thus enabling shorter overall treatment times and reduced irradiation of organs at risk. We report on our first 996 patients enrolled prospectively in a registry trial., Methods: At Jules Bordet Institute, from February 2010 onwards, patients underwent partial IOERT of the breast. Women with unifocal invasive ductal carcinoma, aged 40 years or older, with a clinical tumour size ≤ 20 mm and tumour-free sentinel lymph node (on frozen section and immunohistochemical analysis). A 21 Gy dose was prescribed on the 90% isodose line in the tumour bed with the energy of 6 to 12 MeV (Mobetron®-IntraOp Medical)., Results: Thirty-seven ipsilateral tumour relapses occurred. Sixteen of those were in the same breast quadrant. Sixty patients died, and among those, 12 deaths were due to breast cancer. With 71.9 months of median follow-up, the 5-year Kaplan-Meier estimate of local recurrence was 2.7%., Conclusions: The rate of breast cancer local recurrence after IOERT is low and comparable to published results for IORT and APBI. IOERT is highly operator-dependent, and appropriate applicator sizing according to tumour size is critical. When used in a selected patient population, IOERT achieves a good balance between tumour control and late radiotherapy-mediated toxicity morbidity and mortality thanks to insignificant irradiation of organs at risk., (© 2022. The Author(s).)

ICG with other tracers can be injected pre and/or per operatively to identify the axillary Lymph Nodes (LN) draining the breast cancer (the SLN nodes) and/or the ipsilateral arm (the ARM nodes). to evaluate the impact on this temporal variable-variation on the identification of these ARM LN. Material and methods: One hundred and nine women, who were scheduled to undergo, either lumpectomy with selective lymphadenectomy (SLN), or mammary surgery (either lumpectomy, or mastectomy) with complete axillary node dissection (CALND) for a histologically proven mammary tumor, had administered the day before the surgery one subcutaneous injection of ICG in the first interdigital space of the ipsilateral hand (pre-op subgroup (SLN=28 and CALND=15), or the same day as the surgery (per op subgroup (SLN=26 and CALND= 20). The fluorescent characteristics of the SLN and/or axillary LN were then analyzed and compared between the two subgroups. Results: Basic characteristics were not significantly different between the pre and per op subgroups. The percentage of patients found with fluorescent SLN (28%), the percentage of patients with fluorescent LN in CALND (74.5%), or the percentage of LN fluorescent in CALND (38.5%) did not differ significantly too. Conclusion: Injection of ICG in the first interdigital space of the hand of operated side performed one day before the surgery or the same day as the surgery has no significant influence in our study on detection of the arm nodes. The timing of ICG injection is an independent variable with no effect on the results; this allows the injection to be performed either the day before the surgery or the day of the surgery., (Celsius.)

Background: Near-infrared fluorescence imaging (NIRFI) of breast cancer (BC) after the intravenous (IV) injection of free indocyanine green (fICG) has been reported to be feasible. However, some questions remained unclarified., Objective: To evaluate the distribution of fICG in BC and the axillary lymph nodes (LNs) of women undergoing surgery with complete axillary LN dissection (CALND) and/or selective lymphadenectomy (SLN) of sentinel LNs (NCT no. 01993576 and NCT no. 02027818)., Methods: An intravenous injection of fICG (0.25 mg/kg) was administered to one series of 20 women undergoing treatment with mastectomy, the day before surgery in 5 (group 1) and immediately before surgery in 15 (group 2: tumor localization, 25; and pN+ CALND, 4) as well as to another series of 20 women undergoing treatment with tumorectomy (group 3). A dedicated NIR camera was used for ex vivo fluorescence imaging of the 45 BC lesions and the LNs., Results: In group 1, two of the four BC lesions and one large pN+ LN exhibited fluorescence. In contrast, 24 of the 25 tumors in group 2 and all of the tumors in group 3 were fluorescent. The sentinel LNs were all fluorescent, as well as some of the LNs in all CALND specimens. Metastatic cells were found in the fluorescent LNs of the pN+ cases. Fluorescent BC lesions could be identified ex vivo on the surface of the lumpectomy specimen in 14 of 19 cases., Conclusions: When fICG is injected intravenously just before surgery, BC can be detected using NIRFI with high sensitivity, with metastatic axillary LNs also showing fluorescence. Such a technical approach seems promising in the management of BC and merits further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bourgeois, Veys, Noterman, De Neubourg, Chintinne, Vankerckhove and Nogaret.)

Introduction: Cytoreductive surgery of locally advanced ovarian cancer has evolved in the last few years from surgery to remove macroscopic residual disease (<1cm; R2b) to macroscopic complete cytoreductive surgery with no gross residual disease (R1). The aim of this study was to evaluate the impact of the adoption of a maximalist surgical approach on postoperative complications, disease recurrence and survival., Materials and Methods: This was a retrospective study using prospectively collected data on patients who received either conservative approach (CA) or radical approach (RA) surgical treatment for primary ovarian cancer stage IIIc/IVa/IVb between June 2006 and June 2013., Results: Data for 114 patients were included, 33 patients in the CA group and 68 patients in the RA group were consequently analysed. In the RA group, operative time was longer, in relation to more complex surgical procedures; with more blood losses and a higher rate of compete macroscopic resection. Totally, 77% of the patients had postoperative complications, with more grade I/II complications in the RA group but the same rates of grade III/IV complications in the both groups (P=0.14). For all patient study population, the overall and disease-free survivals were improved in case of no macroscopic residual disease. Overall survival was improved in the RA group (P=0.05), with no difference in terms of disease-free survival (P=0.29) CONCLUSION: A radical approach in advanced ovarian cancer allows a higher rate of complete cytoreductive surgery impacting overall survival. However, a non-significant trend for increased mild complications (grade I/II) rate is observed in this group., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: The size and focality of the primary tumor in breast cancer (BC) influence therapeutic decision making. The purpose of this study was to evaluate whether preoperative breast magnetic resonance imaging (MRI) is helpful for the assessment of tumor size and surgical planning in early BC., Methods: We performed a retrospective review of a prospectively collected database of 174 patients treated at a single institution for invasive BC who had complete documentation of the tumor size from mammography (MMG), ultrasonography (US), and MRI., Results: A total of 186 breast tumors were analyzed. Mean tumor size varied by imaging method: 14.7 mm by MMG, 13.8 mm by US, and 17.9 mm by MRI. The concordance between breast imaging techniques (BIT) and final pathology with a cutoff ≤ 2 mm was 34.8% for MRI, 32.1% for US, and 27.2% for MMG. US and MMG underestimated while MRI and MMG overestimated the real tumor size. Concordance was the same in premenopausal women for MRI and US at 35%, while concordance was higher in postmenopausal women for MRI. Correlations between size determined by BIT and histopathological size were best with MRI (0.59), compared to US (0.56) or MMG (0.42). Intrinsic subtypes of BC had different concordances according to imaging method, but no significant associations were found. MRI examination revealed additional lesions in 13.8% of patients, 69% of these lesions were malignant. MRI changed the surgical plan in 15 patients (8.6%), and the rate of mastectomy increased by 6.9%., Conclusions: MRI estimates BC tumor size more accurately than US or MMG, but a significant overestimation exists. Complementary MRI examination improved the concordance for tumor size between BIT and final pathology in 16.7%. MRI did not alter surgical planning for most patients and allowed more appropriate treatment for 8% of them., (© 2018 Wiley Periodicals, Inc.)

Background: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) frequently experience brain metastases (BM). We aimed to define risk factors for the development of BM in patients with HER2+ BC and to report on their outcome., Methods: This is a retrospective analysis of patients diagnosed with HER2+ BC between January 2000 and December 2014 at Institut Jules Bordet, Belgium. Statistical analyses were conducted with SAS V.9.4 using Kaplan-Meier method and Cox regression analyses., Results: A total of 483 patients were included of whom 108 (22.4%) developed metastases and 52 (10.8%) BM. Among 96 metastatic patients without BM at diagnosis, 40 (41.7%) developed BM in the course of their disease. In multivariate analysis, risk factors for the development of BM were age ≤40 years (HR 2.10, 95 % CI 1.02 to 4.36), tumour size >2 cm (HR 4.94, 95% CI 1.69 to 14.47), nodal involvement (HR 3.48, 95% CI 1.47 to 8.25), absence or late start (≥6 months after initial diagnosis) of adjuvant anti-HER2 treatment (HR 3.79, 95% CI 1.52 to 9.43 or HR 2.65, 95% CI 1.03 to 6.82) and the development of lung metastases as first site of relapse (HR 6.97, 95% CI 3.41 to 14.24). Twenty-two patients with HER2+ BC and BM sent to our institute for further treatment were included in the outcome analysis. Asymptomatic patients at the time of BM diagnosis showed a better overall survival than symptomatic patients (HR 0.49, 95% CI 0.25 to 0.94)., Conclusion: A considerable number of patients with metastatic HER2+ BC will develop BM. Screening of patients with risk factors for BM might lead to early detection and better outcome. However, randomised controlled trials examining the use of MRI as a screening method for BM in patients with metastatic BC are warranted before such an approach can be recommended., Competing Interests: Competing interests: MJP declares the following competing of interest: she has served as a consultant for Roche outside the submitted work. EdA declares the following competing of interests: he has received research grants and travel grants from Roche and served on an advisory board of Roche outside the submitted work. CM declares that he has received travel grants form Mundipharma and Amgen outside the submitted work. All other authors declare no competing interests.

Background: Response to neoadjuvant chemotherapy (NACT), particularly pathologic complete response (pCR), is an independent predictor of favorable clinical outcome in breast cancer (BC). The accuracy of residual disease measurement and reporting is of critical importance in treatment planning and prognosis for these patients. Currently, gross pathological evaluation of the residual tumor bed is the greatest determinant for accurate reporting of NACT response. Fluorescence imaging (FI) is a new technology that is being evaluated for use in the detection of tumors in different oncological conditions., Objective: The aim of this study was to evaluate whether indocyanine green fluorescence imaging (ICG-FI) is able to detect residual breast tumor tissue after NACT in breast surgical operative specimens., Methods: Patients who underwent NACT for BC and were admitted for breast surgery were selected for participation in this study. Free ICG (0.25 mg/kg) was injected intraoperatively. Tumor-to-background fluorescence ratio (TBFR) was calculated on ex vivo samples from the surgical specimen., Results: One hundred and seventy-two samples from nine breast surgical specimens were evaluated for their fluorescence intensity. Among them, 52 were malignant (30.2%) and 120 were benign (69.8%). The mean TBFR was 3.3 (SD 1.68) in malignant samples and 1.9 (SD 0.97) in benign samples (p = 0.0002). With a TBFR cut-off value of 1.3, the sensitivity, specificity, negative predictive value, false negative rate, and false positive rate of ICG-FI to predict residual tumoral disease in breast surgical samples post-NACT were 94.2%, 31.7%, 92.7%, 5.8%, and 68.3%, respectively. If we restricted our analysis to only patients who achieved pCR, the negative predictive value for ICG-FI was 100%., Conclusions: These first observations indicate that ex vivo ICG-FI is sensitive but not sufficiently specific to discriminate between benign breast tissue and malignant residual tissue. Nevertheless, its negative predictive value seems sufficiently accurate to exclude the presence of residual breast tumor tissue on the operative specimen of patients treated by NACT, representing a potential tool to assist pathologists in the assessment of breast surgical specimens., Competing Interests: The authors have declared that no competing interests exist.

Background: When managing patients with cancer, lymphedema of the lower limbs (LLL) is commonly reported as secondary to the surgical excision and/or irradiation of lymph nodes (LNs). In the framework of lymphoscintigraphic imaging performed to evaluate secondary LLL, some lympho-nodal presentations have been observed that could not be explained by the applied treatments, suggesting that these LLL might be primary. Therefore, all our lymphoscintigraphic examinations that were performed in patients for LLL after surgery for gynecological or urological cancer were retrospectively analyzed in order to evaluate the frequency in which these LLL might not be secondary (either completely or partially) but primary in origin., Methods: Lymphoscintigraphies performed in 33 patients who underwent LN dissection (limited to the intra-abdominal LN) with or without radiotherapy for histologically confirmed ovarian cancer (n = 6), uterine cancer (n = 14 with cervical cancer and n = 7 with endometrial cancer), or prostate cancer (n = 6) were compared to lymphoscintigraphies obtained in primary LLL., Results: In 12 (33% of the) patients (3 men plus 9 women, 4 with cervical cancer and 5 with endometrial cancer), scintigraphy of the lower limbs revealed lympho-nodal presentation that did not match with the expected consequences of the surgical and/or radiological treatments and were either suggestive or typical of primary lymphedema., Conclusions: This retrospective analysis of a limited but well-defined series of patients suggests that the appearance of LLL might not be related to cancer treatment(s) but that these LLL may represent the development of a primary lymphatic disease latent prior to the therapeutic interventions.

Background and Objectives: No intraoperative imaging techniques exist for detecting tumor nodules or tumor scar tissues in patients treated with upfront or interval cytoreductive surgery (CS) after neoadjuvant chemotherapy (NAC). The aims of this study were to evaluate the role of indocyanine green (ICG) fluorescence imaging (FI) for the detection of peritoneal metastases (PM) and evaluate whether it can be used to detect remnant tumor cells in scar tissue., Methods: Patients with PM from ovarian cancer admitted for CS were included. ICG, at 0.25 mg per kg of patient weight, was injected intraoperatively after explorative laparotomy before CS., Results: A total of 108 peritoneal lesions, including 25 scars, were imaged in 20 patients. Seventy-three were malignant (67.6%) and 35 benign (32.4%). The mean Tumor to Background Ratio (ex vivo) was 1.8 (SD 1.3) in malignant and 1.0 (SD 0.79) in benign nodules (P = 0.007). Of 25 post-NAC scars, the mean Tumor to Background Ratio (TBR) (in vivo) was 2.06 (SD 1.15) in malignant and 1.21 (SD 0.50) in benign nodules (P = 0.26). The positive predictive value of ICG-FI to detect tumor cells in scars was 57.1%., Conclusions: ICG-FI is accurate to demonstrate PM in ovarian cancer but unable to discriminate between benign and malignant post-NAC., (© 2017 Wiley Periodicals, Inc.)

Background: In cancer follow-up, in addition to the evaluation of survival probabilities, there is a fundamental need of assessing recurrence dynamics for optimal disease management. Although the time-dependent effect of the oestrogen receptor (ER) status of the tumour has already been described, so far no factor has proven to disentangle the multi-peak behaviour observed for breast cancer recurrences. Here, we aimed at investigating whether adiposity at diagnosis, reflected by increased patient's body mass index (BMI), could be associated with breast cancer recurrence patterns over time after primary cancer therapy., Methods: We retrieved BMI from 734 of 777 patients with node-positive breast cancer from a phase III randomised clinical trial, which compared different chemotherapy regimens and had a median follow-up of 15.4 years. Cumulative incidence estimation as well as piecewise exponential models were carried out to estimate the distant recurrence dynamics, in all patients, as well as in subgroups based on the ER status, with the ER-positive group being further split according to the menopausal status., Results: In patients with ER-negative breast cancer, time-dependent analyses revealed that the hazard of late relapses could mainly be attributed to the overweight and obese patients. Within the subgroup of premenopausal patients with ER-positive tumours, obesity was associated with an early high narrow peak of distant recurrences followed by another main peak after 5 years of follow-up. The risk for overweight patients was intermediate between obese and normal-weight patients. In the postmenopausal subgroup of patients with ER-positive tumours, the distant recurrence rate was significantly more elevated in the overweight patients compared to the other BMI categories, and a second late peak of recurrences was also observed for the obese patients., Conclusion: These results demonstrate that the patient's BMI at diagnosis is associated with cancer recurrence dynamics. Patient adiposity should therefore be central to the exploration of late adjuvant treatment modalities., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To compare in a multicenter randomized controlled trial the benefits in terms of anxiety regulation of a 15-session single-component group intervention (SGI) based on support with those of a 15-session multiple-component structured manualized group intervention (MGI) combining support with cognitive-behavioral and hypnosis components., Methods: Patients with nonmetastatic breast cancer were randomly assigned at the beginning of the survivorship period to the SGI (n = 83) or MGI (n = 87). Anxiety regulation was assessed, before and after group interventions, through an anxiety regulation task designed to assess their ability to regulate anxiety psychologically (anxiety levels) and physiologically (heart rates). Questionnaires were used to assess psychological distress, everyday anxiety regulation, and fear of recurrence. Group allocation was computer generated and concealed till baseline completion., Results: Compared with patients in the SGI group (n = 77), patients attending the MGI group (n = 82) showed significantly reduced anxiety after a self-relaxation exercise (P = .006) and after exposure to anxiety triggers (P = .013) and reduced heart rates at different time points throughout the task (P = .001 to P = .047). The MGI participants also reported better everyday anxiety regulation (P = .005), greater use of fear of recurrence-related coping strategies (P = .022), and greater reduction in fear of recurrence-related psychological distress (P = .017) compared with the SGI group., Conclusions: This study shows that an MGI combining support with cognitive-behavioral techniques and hypnosis is more effective than an SGI based only on support in improving anxiety regulation in patients with breast cancer., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel., Methods: HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated., Results: Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04)., Conclusions: The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization., Trial Registration: ClinicalTrials.gov NCT01537536.

Background We examined time trends in axilla management among patients with early breast cancer in European clinical settings. Material and methods EUROCANPlatform partners, including population-based and cancer center-specific registries, provided routinely available clinical cancer registry data for a comparative study of axillary management trends among patients with first non-metastatic breast cancer who were not selected for neoadjuvant therapy during the last decade. We used an additional short questionnaire to compare clinical care patterns in 2014. Results Patients treated in cancer centers were younger than population-based registry populations. Tumor size and lymph node status distributions varied little between settings or over time. In 2003, sentinel lymph node biopsy (SLNB) use varied between 26% and 81% for pT1 tumors, and between 2% and 68% for pT2 tumors. By 2010, SLNB use increased to 79-96% and 49-92% for pT1 and pT2 tumors, respectively. Axillary lymph node dissection (ALND) use for pT1 tumors decreased from between 75% and 27% in 2003 to 47% and 12% in 2010, and from between 90% and 55% to 79% and 19% for pT2 tumors, respectively. In 2014, important differences in axillary management existed for patients with micrometastases only, and for patients fulfilling the ACOSOG Z0011 criteria for omitting ALND. Conclusion This study demonstrates persisting differences in important aspects of axillary management throughout the recent decade. The results highlight the need for international comparative patterns of care studies in oncology, which may help to identify areas where further studies and consensus building may be necessary.

Male breast cancer is a rare disease, accounting for less than 1% of all breast cancer cases. It is often diagnosed late, at a more advanced stage than its female counterpart. Therefore, it is more commonly treated with mastectomy. In early stages, a conservative treatment associating lumpectomy, sentinel lymph node (SLN) biopsy and whole-breast external beam radiotherapy (EBRT) is possible and has been described. Recently, intra-operative radiation therapy (IORT) has been assessed as an alternative to EBRT in selected female breast cancer cases. Its use has never been described in male patients. In this article, we present the case of a 56 years old man treated with lumpectomy with the excision of the nipple-areola complex, SLN biopsy, and IORT with electron beams (IOERT), for early breast cancer disease. This case demonstrates that the IORT technique is feasible on men with early breast cancer (pT1N0).

Objectives. The aim of this prospective phase II study is to evaluate the treatment of early-stage breast cancer (T1 N0) with intraoperative electron radiation therapy (IOERT) in terms of local control, early complications, and cosmesis. Patients and Methods. From February 2010 to February 2012, 200 patients underwent partial IOERT of the breast. Inclusion criteria were unifocal invasive ductal carcinoma, age ≥40 years, histological tumour size ≤20 mm, and no lymph node involvement. A 21 Gy dose was prescribed over the 90% isodose line in the tumour bed. Median follow-up is 23.3 months (7-37). Results. Acute toxicity was not frequent (Grade 1: 4.5%, Grade 2: 1%). The cosmetic result was considered to be very good or good in 92.5%. One ipsi lateral out-quadrant recurrence at 18 months was observed. The crude and actuarial local recurrence rates after median follow-up were 0.5% and 0.9%, respectively. Conclusion. The preoperative diagnostic work-up must be comprehensive and the selection process must be rigorous for this therapeutic approach reserved for small ductal unifocal cancers. After a 23.3-month median follow-up time, the clinical results of IOERT for selected patients are encouraging for the locoregional recurrence and the toxicity rates. The satisfaction of our patients in terms of quality of life was extremely high.

Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset.

Background: Identifying new prognostic factors is important for guiding treatments and preventing metastasis in cancer. Vagal nerve activity may predict prognosis in cancer due to its roles in modulating inflammation, sympathetic activity and oxidative stress. This study tested the relationship between heart rate variability (HRV), a vagal nerve index, and the colon cancer (CC) marker carcinoembryonic antigen (CEA), in an 'historical prospective' design., Methods: We examined data of 72 CC patients, without inflammatory or cardiac diseases, of whom 38 had baseline electrocardiograms (ECG) and 12 month CEA levels. We measured HRV (SDNN, RMSSD) from brief archived ECG. Multiple confounders were considered., Results: Controlling for effects of tumor stage and treatment-orientation, baseline HRV predicted CEA levels at 12 months (r=-.43, p=.006). Patients with SDNN<20 ms had significantly higher CEA at 12months than those with SDNN>20 ms., Conclusion: These preliminary results showed that higher HRV predicts lower levels of a tumor marker, one year later, independent of confounders. This supports the hypothesized role of vagal activity in tumor modulation. Replication in larger samples is needed., (Copyright © 2011. Published by Elsevier B.V.)

Sentinel lymph node biopsy (SLNB) has almost completely replaced complete axillary lymph node dissection (CALND) as the first-line axillary procedure for clinically node-negative early stage breast cancer. We assessed the incidence of axillary relapse in patients with negative SLNB who had no additional CALND (group 1, n = 481) and in patients whose SLNB contained micrometastases and had no further CALND (group 2, n = 45). All patients were operated on between November 1997 and December 2005 and followed at the Jules Bordet Institute. The median follow-up was 48 months. A mean of 2.2 sentinel lymph nodes was removed per patient. Axillary relapse was observed in only one patient (0.2%) in group 1 and in none of the patients in group 2. This study confirms that the axillary recurrence rate after long-term follow-up of patients with a negative sentinel lymph node is very rare, provided that the selection criteria are judicious., (© 2011 Wiley Periodicals, Inc.)

Purpose: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines., Patients and Methods: The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes., Results: A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00)., Conclusion: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.

A RT-PCR assay (GeneSearch™, Veridex, LLC), FDA approved and CE marked to detect metastases > 0.2 mm in sentinel lymph nodes (SLNs) is used intra-operatively for the management of patients with breast cancer. The assay provides qualitative results by applying cut-off values to cycle times (Ct) for mammaglobin (MG) and cytokeratin-19 (CK19) genes. Aims of this study were to evaluate the performance of the quantitative Ct values to estimate the size of nodal metastases and the risk of additional disease in non-SLNs. SLNs from 367 patients were clinically processed using both BLN assay and post-operative histology. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of BLN assay positivity or tumour size > 2 cm. BLN positivity was reported in 19.6% of the patients for a sensitivity of 89%. BLN specificity (94.5%) and negative predictive value (97.5%) clearly demonstrated its reliability to guide ALND decision. All, except one, residual axillary metastases were found in BLN-positive patients. Considering the 78 patients with SLN positivity or discordant status according to both criteria, the metastases histological size was significantly correlated to the expression level of MG (ρ = 0.62) and CK19 (ρ = 0.64) genes (P < 10E-6). Moreover, ALND status positivity was significantly associated to Ct value of MG (z = 2.4; P = 0.018) and CK19 (z = 3.2; P = 0.001). The high intra-operative quality performance of the BLN assay minimizes the need for second surgeries for ALND. Results from this investigational study suggest that markers Ct value may provide, intra-operatively, valuable metastases size data and a risk prediction of additional disease in non-SLNs.

Background: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial., Methods: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment., Results: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy., Conclusions: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Background: The accuracy of a molecular reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay for metastases detection in axillary sentinel lymph nodes (SLNs) has recently been validated in our institution and adopted as an intraoperative test for breast cancer patient management., Methods: Molecular assay performance was compared to standard postoperative histology in 253 consecutive patients with clinically node-negative T1 early breast cancer (<2 cm)., Results: The molecular assay correctly identified 26/27 macrometastases and 11/15 micrometastases. Overall concordance with histopathology was 93%, with 87% sensitivity, 94% specificity, and 75% positive and 97% negative predictive values. The molecular assay was positive in 13/14 patients with SLNs and nonsentinel lymph node (axillary lymph node [ALN])-positive histology. Notably, 2/12 patients with assay-positive/histology-negative SLNs exhibited ALN positivity., Conclusions: This molecular assay can raise the standard of care for patient management as its accuracy is similar to that of standard postoperative histology with the advantage of being standardized, objective, and fast enough for intraoperative use.

Background: In breast cancer patients, the status of the sentinel lymph nodes (SLNs) has been shown to accurately reflect the presence of metastases in the axillary lymph nodes (ALNs). Intra-operative SLN evaluation by frozen section histology may miss positive cases, leading to a second surgery for complete ALN dissection. Permanent section histology itself has tissue sampling limitations and is partially dependent on pathologist expertise., Methods: A prospective study (N=78) was conducted in our institution to validate a new intra-operative molecular assay, the GeneSearch breast lymph node (BLN) assay. This assay quantifies the expression of mammaglobin and cytokeratin-19 genes using quantitative RT-PCR technology to determine SLN status. Fresh SLN sections (2 mm thick) were analyzed alternatively by BLN assay or post-operative histology (haematoxylin-eosin and immunohistochemistry). The subject was considered positive when histology revealed a focus >0.2 mm., Results: BLN assay results corroborated with histologic results in 75 out of 78 patients for an overall agreement of 96%, a sensitivity of 92%, and a specificity of 97%. The positive and negative predictive values of the BLN assay were of 86% (12/14) and 98% (63/64), respectively. Interestingly, a statistically significant correlation was observed between the metastases' histologic size and both assay markers' expression levels as represented by cycle time to positivity (rho > or = 0.71, all p<0.0001)., Conclusions: The performance of the BLN assay in identifying nodal metastases >0.2 mm was similar to that of permanent section histology, with the added advantages of an objective and rapid output that could be used for intra-operative decision to remove additional ALN.

Introduction: To investigate the influence of ageing on the incidence of breast cancer (BC) molecular subtypes, patient age at diagnosis was correlated with bio-pathological data collected retrospectively from 2723 consecutive patients diagnosed/treated at our Institute between 2000 and 2003., Methods: According to their bio-characteristics, 61% of the samples could be assigned to a molecular subtype: the "HER-2+", the "ER & HER2 negative" or one of the two "luminal-like" subtypes divided according to their histological grade ("A" [HER-2-/ER+/grade 1-2] and "B" [HER-2-/ER+/grade 3])., Results and Conclusion: Age is highly influencing the incidence of BC molecular subtypes. Patients younger than 40 develop a statistically higher rate of high grade proliferating "HER-2" (27%) and "ER & HER2 negative" (31%) BC whereas patients older than 50 develop mostly less aggressive hormone-dependant "luminal-A" BC (>67%). Nevertheless, a significant proportion of patients older than 70 develop "luminal-B" (19%) tumours associated with high proliferation, high grade, large size and nodal invasion.

Aims: The objective of this study was to assess the value of superficial (intradermal) and paratumoral (above the tumor) (ID) injection of labeled colloids for imaging sentinel lymph nodes (SLN) as a rescue technique in breast cancer patients for whom deep (intraparenchymatous) and peritumoral (around the tumor) (IP) injections had failed., Methods: We assessed data from 2 groups of women: 469 women for whom IP injections successfully visualized a SLN (IP-only) and 52 women for whom IP injections were unsuccessful and ID injection was performed (IP0-ID). Patient characteristics and SLN results were compared., Results: Most characteristics of the two patients series were similar. However, IP0-ID patients were on average 10years older than the IP-only patients and had more grade-III tumors. The false negative rate (FNR) for the IP0-ID patients (9/25, 23.8%) was significantly higher than for the IP-only patients (12/240, 5%; p<0.01) and for a subgroup of IP-only patients older than 50 years (8/159, 5%; p=0.009). Four of five false negatives in the IP0-ID group involved a tumor in the outer quadrants. The FNR for cases with external tumors was 33% for the IP0-ID patients, a percentage significantly higher than the corresponding values for the IP-only patients (5.8%) and for the IP-only patients older than 50 years (5.7%)., Conclusion: In patients with unsuccessful deep IP injections, superficial ID injections lead to a high percentage of false negative SLN conclusions, merely when tumours were located in the outer quadrants. Thus, it is recommended that patients with unsuccessful intra-parenchymatous and peritumoral injections of radiocolloids for tumors in outer quadrants undergo complete axillary dissection.

Purpose: Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results., Patients and Methods: Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point., Results: At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure., Conclusion: The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

Regarding the number of female cases (1/9) and incidence increasing, breast cancer remains the greatest public health issue. Presently, the best treatment for our patients is to screen and to treat the disease at an early stage. In our screening process " Mammotest", all women in Belgium, between 50 and 69 years, are called to a certify center every 2 years to have a mammogram. Therefore, the general practitioner has an important roll to play for a better contact in the screening process of the patients.

Objectives: Concomitant chemoradiation is the "new gold standard" for dealing with locally advanced cervical carcinoma, but what about surgery? We don't know yet to what extent surgery is necessary and how radical it must be when it is performed. In this study, we present the analysis of the results obtained in patients treated by concomitant chemoradiation followed by radical surgery., Materials and Methods: Twenty-two patients, median age 49 years, with I(b) - III(a) cervical tumors were enrolled to be treated by concomitant chemoradiation followed by radical surgery. The chemoradiation protocol included external radiotherapy to the pelvis: 45 Gy; Cisplatin 40 mg/m(2) in continuous intravenous infusion once a week (5 weeks) followed by brachytherapy one week later. Surgery was performed 4 to 6 weeks later and consisted in radical hysterectomy with pelvic lymphadenectomy., Results: 20/22 patients underwent surgery after chemoradiation because of a diagnosis of lung metastases in one and presence of a nonresectable metastasis for the other. A complete pathological response was demonstrated in 12/20 patients (60%), a microscopic residual tumor in 7 patients (35%), and residual disease <1cm in 1 patient (5%)., Conclusion: This study showed a particularly high rate of pathologic responses (T(0)+T(mic): 95%) and of local control. We don't know yet if surgery is a real necessity or if it could be less extended after concomitant chemoradiation.

Breast cancer remains one of the most frequent malignancies that general practitioners are confronted with. Given their key-counselling role for the affected families, they need regular updates on the multi-disciplinary management of the disease. This has been characterized by an evolution towards less aggressive surgery, sparing many women the morbidity of a full axillary node dissection; in parallel, there is increasing hope for "individualized" adjuvant medical treatment, given the development of new technologies that provide an "identity card" of the genes expressed by each tumour. These technologies should improve our ability to identify which women truly need adjuvant chemotherapy and to select the best medical treatment on an individual basis. While providing these messages of hope, this chapter also reviews the major classes of drugs used for the treatment of advanced breast cancer.

The aim of the study is to see if Bone Scan (BS) - when performed the day before the operation-interferes with the results of the Sentinel Lymph Node (SLN) technique using radiocolloids (their pre-operative imaging and their peroperative research). Therefore, the data of 393 patients who had one selective lymphadenectomy of the SLN(s) followed by the complete axillary node (AxN) clearance for Breast Cancer and among whom 309 patients had one BS the day before the operation (and just before the injection-s for the SLN) and 84 did not, were analysed and compared. The two series presented the same characteristics with regard to: age, clinical staging of the tumour, kind of injection-s performed (intradermic and paratumoural and/or intraparenchymal and peritumoral), pathological size of the tumour, percentage of cases with no AxN invasion, total number of AxN removed by the surgeons. The percentages of no axillary SLN visualisation, the mean numbers of axillary SLN visualised on pre-operative lymphoscintigram as well as of SLN removed by the surgeons were not statistically different in the groups of patients with (respectively, 12.11, 2.6 and 3.03) and without BS (respectively, 12.99, 2.7 and 2.96). More noteworthy, the false negative (FN) rate of the SLN technique, albeit having a higher observed value in the group with BS (9.6%, 12/125), did not differ significantly from that in the group without BS (5.6%, 2/36). The accuracies (overall correct classification rates), the sensitivities and the negative predictive values of the SLN technique also did not differ significantly between the two groups. It is concluded that the SLN technique can be accurately performed just after one BS.

When many lymph nodes are found by using lymphoscintigraphic techniques performed to detect the sentinel lymph nodes (SLNs) in breast cancer, it is usual to find that the 'hottest' SLN is not always the node that is pathologically positive (pN+). Various criteria have been proposed to define which radioactive lymph nodes should be removed. In order to determine the frequency with which the hottest SLN 'fails' to be pN+, and to determine which criteria best define the radioactive lymph node to be removed, we reviewed and analysed our cases in which more than one SLN was detected and where there was also at least one pN+ node. From a series of 181 patients, 40 were selected. In 11 of these 40 cases (27.5%), the hottest SLN was not pN+. Radioactivity levels in the pN+SLN of these 11 patients ranged from 2% to 94% of the activity of the hottest SLN. Twenty-one patients (52.5%) showed only micrometastatic (pN1a) disease in one or more SLNs. In four of these patients (19%) the pN1a SLN was not the hottest node. Two of the patients had radioactivity levels in the pN+SLN which were more than 50% of that of the hottest SLN. In another two of these patients (9.5%), radioactivity levels were lower than 50% of that of the hottest node (respectively, 38% and 2%). However, in these two last cases, the first and hottest SLN removed surgically was found, by the pathologist, to consist of six nodes. Macrometastases (dimensions greater than 2 mm) were found in 19 patients. In 12 of these patients, the hottest SLN was macrometastatic although macrometastases and/or micrometastases were found in other 'cooler' SLNs in four of them. In another seven of these patients (36.8%), macrometastases were found in SLNs with radioactive levels lower than 51% of that of the hottest node. One patient (with three SLNs) out of the 40 (2.5%) had one SLN pN+ with less than 10% of that of the hottest. In fact, it contained only one micrometastasis and its activity was equal to 2%. Upon pathological examination, however, the hottest lymph 'node' was found to consist of six nodes. It is concluded that, with four intra-mammary and peritumoural injections of 99mTc labelled nanosized colloids of Human Serum Albumin (Nanocoll R: Sorin: 74 MBq and 0.05 mg per injection) performed 18-24 h before using a gamma probe to detect the SLNs, the hottest SLN was not the pathologically positive node in 27.5% of patients in our series. By using the activity in the hottest SLN as the reference point, and 10% of this activity as the lower threshold for removing active SLNs, the sensitivity of the technique is 97.5%.

Immediate breast reconstruction using implants is a currently practiced intervention. However, it is exposed to the potential adverse effects of adjuvant therapies necessitated for cancer control. Patients with implants, receiving adjuvant chemotherapy, were compared with those not necessitating chemotherapy to evaluate the real impact of this combination of treatment modalities on the final outcome. Cosmetic results were not influenced by the adjunction of chemotherapy, but a higher rate of implant infection was observed in the chemotherapy group (10.7% versus 1.5% p = 0.0084). This observation needs to be kept in mind when selecting patients for immediate breast reconstruction with implants.

Background: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer., Patients and Methods: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF., Results: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%)., Conclusion: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Objectives: To describe the endometrial appearance in postmenopausal breast cancer patients on tamoxifen and to assess a routine surveillance scheme for endometrial lesions., Study Design: Three hundred and seventeen postmenopausal breast cancer women already on tamoxifen at the start of the study (group I) and 89 breast cancer women assessed before any tamoxifen intake (group II) underwent an initial and then yearly scans with transvaginal ultrasonography, followed by an hysteroscopy and biopsy for women with an endometrium thickened above 8mm. Endometrial thickness was also measured in 823 women with no breast cancer nor tamoxifen intake (group III)., Results: Initial mean endometrial thickness was 8.2mm in group I, 4.4mm in group II and 3.4mm in group III (P<0.001). Eighteen percent endometrial lesions were found in group I and 3.3% in group II. We observed a significant association between endometrial pathology and both cumulated dose and total duration. Polyps were the most frequent and first to appear pathology. Five cancers were detected in group I, and all of them had taken tamoxifen for more than 3 years., Conclusion: Our surveillance scheme could be lightened; an acceptable screening scheme might include a baseline assessment before the start of tamoxifen and, if normal, yearly screening after 3 years of tamoxifen therapy, yearly surveillance for women with an abnormal baseline assessment and immediate investigation for symptomatic women.

In our institute, the oestrogen and progesterone receptors of breast cancer samples are analyzed by biochemistry and immunohistochemistry. The purpose of this study is to evaluate and compare both techniques and establish whether one of them should be used in preference to the other. The probability of getting a positive or negative result with each technique was the same regardless of the method used as reference. The biochemical method uses a larger volume of tissue to determine the receptor status than immunohistochemistry. In some cases, this means a loss of valuable information. If we only use one technique, there is the potential to misclassify +/- 11% of patients. According to these results and in the knowledge that the major interest of steroid receptors' status remains in the domain of therapeutic decisions, we advise using immunohistochemistry first and biochemistry if there is a negative result. This would spare tumour tissue for new research studies.

Study Aim: Determination of axillary lymph node status is crucial in diagnosis of early breast cancer. However thanks to an early diagnosis, an increasing number of axillary lymph node dissections are free of disease. This raises questions about the need for this procedure. The study aim was to report an experience with lymphadenectomy and sentinel node mapping in patients with T0-T1 carcinoma of the breast., Methods: Between November 1997 and December 1999, 84 consecutive women (T0-T1 N0 according to the 1987 UICC classification) with recently diagnosed breast cancer, were included in this study for identification of the sentinel lymph node (SLN). The SLN was removed and submitted for histological examination. All patients underwent axillary dissection; nodes from levels I and II (Berg's classification) were excised and submitted to histological examination., Results: The average tumor diameter was 12.7 mm (range, 3 to 25 mm). The lymphatic mapping technique was obtained after injection of the isotope into the breast around the tumor in 53/84 patients: the sentinel lymph node was the only positive node in 10 patients and it was positive in 5 patients with other axillary nodes. In 15/84 patients, an intradermal injection of blue dye was used; two sentinel nodes were positive and one falsely negative. In 16/84 patients, an interdermal injection of blue dye was used to make up for. In this study, the sentinel node was positive in three patients and falsely negative in one patient. The discrepancy was due to an important involvement of an axillary area excluded from the lymphatic channels. 22/84 patients (26%) had a metastatic spread to the axillary nodes. 30/84 patients had also an isotopic captation in another lymph node group (internal mammary)., Conclusion: This study confirms that lymphatic mapping is technically possible in the patients with T0-T1 breast cancer and that the histological characteristics of the sentinel node probably reflect the histological characteristics of the rest of the axillary lymph nodes, but do not provide any information about the other lymph node sites.