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Purpose: The recently released EANM/SNMMI guideline, endorsed by several important clinical and imaging societies in the field of breast cancer (BC) care (ACR, ESSO, ESTRO, EUSOBI/ESR, EUSOMA), emphasized the role of [ 18 F]FDG PET/CT in management of patients with no special type (NST) BC. This review identifies and summarizes similarities, discrepancies and novelties of the EANM/SNMMI guideline compared to NCCN, ESMO and ABC recommendations., Methods: The EANM/SNMMI guideline was based on a systematic literature search and the AGREE tool. The level of evidence was determined according to NICE criteria, and 85 % agreement or higher was reached regarding each statement. Comparisons with NCCN, ESMO and ABC guidelines were examined for specific clinical scenarios in patients with early stage through advanced and metastatic BC., Results: Regarding initial staging of patients with NST BC, [ 18 F]FDG PET/CT is the preferred modality in the EANM-SNMMI guideline, showing superiority as a single modality to a combination of contrast-enhanced CT of thorax-abdomen-pelvis plus bone scan in head-to-head comparisons and a randomized study. Its use is recommended in patients with clinical stage IIB or higher and may be useful in certain stage IIA cases of NST BC. In NCCN, ESMO, and ABC guidelines, [ 18 F]FDG PET/CT is instead recommended as complementary to conventional imaging to solve inconclusive findings, although ESMO and ABC also suggest [ 18 F]FDG PET/CT can replace conventional imaging for staging patients with high-risk and metastatic NST BC. During follow up, NCCN and ESMO only recommend diagnostic imaging if there is suspicion of recurrence. Similarly, EANM-SNMMI states that [ 18 F]FDG PET/CT is useful to detect the site and extent of recurrence only when there is clinical or laboratory suspicion of recurrence, or when conventional imaging methods are equivocal. The EANM-SNMMI guideline is the first to emphasize a role of [ 18 F]FDG PET/CT for assessing early metabolic response to primary systemic therapy, particularly for HER2+ BC and TNBC. In the metastatic setting, EANM-SNMMI state that [ 18 F]FDG PET/CT may help evaluate bone metastases and determine early response to treatment, in agreement with guidelines from ESMO., Conclusions: The recently released EANM/SNMMI guideline reinforces the role of [ 18 F]FDG PET/CT in the management of patients with NST BC supported by extensive evidence of its utility in several clinical scenarios., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Clinical axillary lymph node management in early breast cancer has evolved from being merely an aspect of surgical management and now includes the entire multidisciplinary team. The second edition of the "Lucerne Toolbox", a multidisciplinary consortium of European cancer societies and patient representatives, addresses the challenges of clinical axillary lymph node management, from diagnosis to local therapy of the axilla. Five working packages were developed, following the patients' journey and addressing specific clinical scenarios. Panellists voted on 72 statements, reaching consensus (agreement of 75% or more) in 52.8%, majority (51%-74% agreement) in 43.1%, and no decision in 4.2%. Based on the votes, targeted imaging and standardized pathology of lymph nodes should be a prerequisite to planning local and systemic therapy, axillary lymph node dissection can be replaced by sentinel lymph node biopsy ( ± targeted approaches) in a majority of scenarios; and positive patient outcomes should be driven by both low recurrence risks and low rates of lymphoedema., Competing Interests: Ana Bosch: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Roche, Novartis; Support for attending meetings and/or travel from Roche; Participation on a Data Safety Monitoring Board or Advisory; Giuseppe Curigliano: Consulting fees from BMS, Roche, Pfizer, Novartis, Lilly, Astra Zeneca, Daichii Sankyo, Merck, Seagen, Ellipsis, Gilead; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Pfizer, Relay; Support for attending meetings and/or travel from Daichii Sankyo; Jana De Boniface: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca; Carsten Denkert: Grants from Myriad, Roche, BMBF, European Commission, GBG Foundation; consulting fees from MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly; Peter Dubsky: Honoraria for presentations and Advisory from Roche and Astra Zeneca to Hirslanden Klinik St. Anna; Michael Knauer: Grants or contracts Agendia BV; Consulting fees from Myriad, Exact Sciences; Thorsten Kühn: Consulting fees from Merit Medical, Endomag, Hologic, Sirius Medical; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GILEAD, MSD, Pfizer, Exact Sciences; Support for attending meetings and/or travel from Gilead, MSD; Sibylle Loibl: Grants or contracts from Abbvie, AZ, BMS/Celgene, DAichi Synkyo, Gilead, Molecular Health, Novartis, Pfizer, Roche; Royalties or licenses for Ki 67 Analyser, VM SCOPE; Consulting fees from AZ, Amgen, Abbvie, BMS, Celgene, Daichi Sankyo Eirgenix, Gilead, Lilly, Merck, MSD, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Incyte, Roche, Sanofi, Seagen; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Gilead, Roche, Seagen, MSD, Pierre Fabre, MEDSCAPE; Patents planned, issued or pending EP14153692.0; EP21152186.9; EP15702464.7; EP15702464.7; Participation on a Data; Safety Monitoring Board or Advisory Board from Daichi Sankyo; Receipt of equipment, materials, drugs, medical writing, gifts or other services Daichiy Sankyo, Gilead, Novartis, AstraZeneca, Roche, Seagen; Icro Meattini: Consulting fees from Novartis, Pfizer, Eli Lilly, Seagen, Gilead; Katja Pinker: Consulting fees from Genentech, Inc., Merantix Healthcare, AURA Health Technologies GmbH; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: European Society of Breast Imaging (active), Bayer (active), Siemens Healthineers (ended), DKD 2019 (ended), Olea Medical (ended), Roche (ended); Trine Tramm: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Roche; Support for attending meetings and/or travel from Roche and Novartis; Jong Han Yu: Consulting fees from Gencurix; Walter Paul Weber: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD; all other others have no conflicts of interest to declare., (© 2023 The Author(s).)

The aims of this Oncoplastic Breast Consortium and European Breast Cancer Research Association of Surgical Trialists initiative were to identify uncertainties and controversies in axillary management of early breast cancer and to recommend appropriate strategies to address them. By use of Delphi methods, 15 questions were prioritized by more than 250 breast surgeons, patient advocates and radiation oncologists from 60 countries. Subsequently, a global virtual consensus panel considered available data, ongoing studies and resource utilization. It agreed that research should no longer be prioritized for standardization of axillary imaging, de-escalation of axillary surgery in node-positive cancer and risk evaluation of modern surgery and radiotherapy. Instead, expert consensus recommendations for clinical practice should be based on current evidence and updated once results from ongoing studies become available. Research on de-escalation of radiotherapy and identification of the most relevant endpoints in axillary management should encompass a meta-analysis to identify knowledge gaps, followed by a Delphi process to prioritize and a consensus conference to refine recommendations for specific trial designs. Finally, treatment of residual nodal disease after surgery was recommended to be assessed in a prospective register., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: Demand for nipple- and skin- sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario., Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology., Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recommendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR., Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: For oncological care, there is a clear tendency towards centralisation and collaboration aimed at improving patient outcomes. However, in market-based healthcare systems, this trend is related to the potential trade-off between hospital volume and hospital competition. We analyse the association between hospital volume, competition from neighbouring hospitals and outcomes for patients who underwent surgery for invasive breast cancer (IBC)., Outcome Measures: Surgical margins, 90 days re-excision, overall survival., Design, Setting, Participants: In this population-based study, we use data from the Netherlands Cancer Registry. Our study sample consists of 136 958 patients who underwent surgery for IBC between 2004 and 2014 in the Netherlands., Results: Our findings show that treatment types as well as patient and tumour characteristics explain most of the variation in all outcomes. After adjusting for confounding variables and intrahospital correlation in multivariate logistic regressions, hospital volume and competition from neighbouring hospitals did not show significant associations with surgical margins and re-excision rates. For patients who underwent surgery in hospitals annually performing 250 surgeries or more, multilevel Cox proportional hazard models show that survival was somewhat higher (HR 0.94). Survival in hospitals with four or more (potential) competitors within 30 km was slightly higher (HR 0.97). However, this effect did not hold after changing this proxy for hospital competition., Conclusions: Based on the selection of patient outcomes, hospital volume and regional competition appear to play only a limited role in the explanation of variation in IBC outcomes across Dutch hospitals. Further research into hospital variation for high-volume tumours like the one studied here is recommended to (i) use consistently measured quality indicators that better reflect multidisciplinary clinical practice and patient and provider decision-making, (ii) include more sophisticated measures for hospital competition and (iii) assess the entire process of care within the hospital, as well as care provided by other providers in cancer networks., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a transition from wire-guided localization (WGL) of non-palpable breast cancer to other localization techniques. Multiple prospective studies have sought to establish superior clinical outcomes for radioactive-seed localization (RSL), but consistent and congruent evidence is missing., Methods: In this study, female patients with breast cancer operated with breast-conserving surgery after tumour localization of a non-palpable breast cancer or ductal carcinoma in situ (DCIS) were included. The cohort was identified from the nationwide Netherlands Breast Cancer Audit conducted between 2013 and 2018. Trends in localization techniques were analysed. Univariable and multivariable analyses were performed to assess the association between the localization technique and the probability of a reoperation., Results: A total of 28 370 patients were included in the study cohort. The use of RSL increased from 15.7 to 61.1 per cent during the study years, while WGL decreased from 75.4 to 31.6 per cent. The localization technique used (RSL versus WGL) was not significantly associated with the odds of a reoperation, regardless of whether the lesion was DCIS (odds ratio 0.96 (95 per cent c.i. 0.89 to 1.03; P = 0.281)) or invasive breast cancer (OR 1.02 (95 per cent c.i. 0.96 to 1.10; P = 0.518))., Conclusion: RSL is rapidly replacing WGL as the preoperative localization technique in breast surgery. This large nationwide registry study found no association between the type of localization technique and the odds of having a reoperation, thus confirming the results of previous prospective cohort studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It is well known nowadays that radioactivity can destroy the living cells it interacts with. It is therefore unsurprising that radioactive sources, such as iodine-125, were historically developed for treatment purposes within radiation oncology with the goal of damaging malignant cells. However, since then, new techniques have been invented that make creative use of the same radioactivity properties of these sources for medical applications. Here, we review two distinct kinds of therapeutic uses of radioactive sources with applications to prostate, cervical, and breast cancer: brachytherapy and radioactive seed localization. In brachytherapy (BT), the radioactive sources are used for internal radiation treatment. Current approaches make use of real-time image guidance, for instance by means of magnetic resonance imaging, ultrasound, computed tomography, and sometimes positron emission tomography, depending on clinical availability and cancer type. Such image-guided BT for prostate and cervical cancer presents a promising alternative and/or addition to external beam radiation treatments or surgical resections. Radioactive sources can also be used for radio-guided tumor localization during surgery, for which the example of iodine-125 seed use in breast cancer is given. Radioactive seed localization (RSL) is increasingly popular as an alternative tumor localization technique during breast cancer surgery. Advantages of applying RSL include added flexibility in the clinical scheduling logistics, an increase in tumor localization accuracy, and higher patient satisfaction; safety measures do however have to be employed. We exemply the implementation of RSL in a clinic through our experiences at the Netherlands Cancer Institute.

In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about 'response-adjusted' surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?, (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The rate of breast-conserving surgery (BCS) is used as an esthetic outcome parameter, while other treatments contribute also, such as neoadjuvant chemotherapy (NAC) enabling BCS or immediate breast reconstruction (IBR). This study explores these efforts to preserve the patient's breast contour., Patients and Methods: All patients who underwent surgery for invasive breast cancer in The Netherlands between January 2011 and December 2015 were selected from the Dutch national breast cancer audit (n = 61,309). The breast-contour-preserving procedures (BCPP) rate was defined as the rate of primary BCS, BCS after NAC, or mastectomy with IBR. BCPP rates were calculated and compared by year of diagnosis, age categories, and individual hospitals., Results: The rate of primary BCS remained stable (53%) while the BCPP rate increased from 63% in 2011 to 71% in 2015 due to an increase in patients receiving BCS after NAC and mastectomy with IBR. Primary BCS rates increased with age (from 17% in patients aged < 30 years to 63% in patients aged 60-69 years), while the proportion of patients undergoing mastectomy with IBR decreased from 44% in patients < 30 years to 1% in patients ≥ 70 years. The BCPP rate was similar for all age groups except for patients > 70 years. BCPP rates varied between the different hospitals in The Netherlands, ranging from 47 to 88%., Conclusions: The chance of preserving the breast contour for patients with breast cancer has increased substantially over recent years. BCPP provides a comprehensive parameter of esthetic outcome of breast cancer surgery.

Background: Mammographic screening has led to the identification of more women with nonpalpable breast cancer, many of them to be treated with breast-preserving surgery. To accomplish radical tumor excision, adequate localization techniques such as radioactive seed localization (RSL) are required. For RSL, a radioactive I-seed is implanted central in the tumor to enable intraoperative localization using a γ-probe. In case of extensive tumor or multifocal carcinoma, multiple I-seeds can be used to delineate the involved area. Preoperative imaging is performed different from surgical positioning; therefore, exact I-seed depth remains unknown during surgery., Patients and Methods: Twenty patients (mean age, 56.8 years) with 25 implanted I-seeds scheduled for RSL were included. Sixteen patients had 1 I-seed implanted in the primary lesion, 3 patients had 2 I-seeds, and 1 patient had 3 I-seeds. Freehand SPECT localized I-seeds by measuring γ-counts from different directions, all registered by an optical tracking system. A reconstruction and visualization algorithm enabled 3-dimensional (3D) navigation toward the I-seeds., Results: Freehand SPECT visualized all I-seeds in primary tumors and provided preincision depth information. The deviation, mean (SD), between the freehand SPECT depth and the surgical depth estimation was 1.9 (2.1) mm (range, 0-7 mm). Three-dimensional freehand SPECT was especially useful identifying multiple implanted I-seeds because the conventional γ-probe has more difficulty discriminating I-seeds transcutaneous., Conclusions: Freehand SPECT with 3D navigation is a valuable tool in RSL for both single and multiple implanted I-seeds in breast-preserving cancer surgery. Freehand SPECT provides continuous updating 3D imaging with information about depth and location of the I-seeds contributing to adequate excision of nonpalpable breast cancer.

Purpose: To prospectively compare prone and supine acquired 18F-FDG PET/CT for visualization of primary tumors and regional lymph nodes in stage II/III breast cancer patients., Materials and Methods: One hundred ninety-eight patients were included consecutively from August 2010 to April 2012. One hour after administration of 180-240 MBq 18F-FDG, PET/CT images of the thorax were firstly acquired in prone position. Subsequently, a standard PET/CT in supine position from skull base to thighs was made. Both sets of images were tested in a univariate and a multivariate analysis for the number of lesions per breast or lymph node (LN) region and anatomical mismatch between PET and CT images., Results: Images in prone position showed less compression of breast tissue, more primary tumor (PT) multifocality (P < 0.001) and more avid axillary LNs (P < 0.001) compared with supine position. Anatomical mismatch of the axillary LN metastases was found more often on supine PET/CT images compared with prone (P = 0.004). Prone images showed a smaller PT functional volume compared with supine position (P < 0.001)., Conclusions: Prone position PET/CT improved the visualization of PT multifocality and the number of detected axillary lymph nodes. Therefore, it is a valuable addition to standard supine PET/CT in the protocol for locoregional assessment in stage II/III breast cancer patients.

The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure. The NRI was evaluated in an independent consecutive series of patients to validate the previous findings. Univariable and multivariable analyses were done to assess the predictive value of clinical parameters and of the NRI for RFS. We combined the original and validation series of patients to build a multivariable predictive model for RFS after neoadjuvant chemotherapy in TN breast cancer. The validation set (N = 108) confirmed that patients with a higher-than-median NRI (>0.7) had excellent RFS (P = 0.002), similar to that of patients who had achieved a pCR. Multivariable analysis in 191 patients showed that the NRI was a strong independent predictor of RFS (P = 0.0002), with N-stage (P = 0.001) and T-stage (P = 0.014) ranking second and third, respectively. Importantly, among patients who did not achieve a pCR (NRI values below 1), higher NRI values were still associated with better RFS. The NRI is a simple method and a practical tool to predict RFS in TN breast cancer patients treated with neoadjuvant chemotherapy. It adds prognostic information to the presence or absence of pCR and could be useful to compare the efficacies of different chemotherapy regimens.

Background: Radioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL., Methods: We retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen., Results: Pre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6-21)., Conclusion: Margin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast-conserving therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Wire-guided localization is the most commonly used technique for intraoperative localization of non-palpable breast cancer. Radioactive seed localization (RSL) is becoming more popular and seems to be a reliable alternative for intraoperative lesion localization. The purpose of the present meta-analysis was to evaluate the use of RSL. Primary study outcomes were irradicality and re-excision rates. In total 3168 patients were included. The clinical adaptation shows growing confidence in RSL and further growth is expected., (© 2014 Wiley Periodicals, Inc.)

Objective: The MARI procedure [marking the axillary lymph node with radioactive iodine (I) seeds] is a new minimal invasive method to assess the pathological response of nodal metastases after neoadjuvant systemic treatment (NST) in patients with breast cancer. This method allows axilla-conserving surgery in patients responding well to NST., Methods: Prior to NST, proven tumor-positive axillary lymph nodes were marked with a I seed. This marked lymph node is the so-called MARI-node. After NST, the MARI node was selectively removed using a γ-detection probe. A complementary axillary lymph node dissection was performed in all patients to assess whether pathological response in the MARI node was indicative for the pathological response in the additional lymph nodes., Results: A tumor-positive axillary lymph node was marked with a I seed in 100 patients. The MARI node was successfully identified in 97 of these 100 patients (identification rate 97%). Two patients did not undergo subsequent axillary lymph node dissection, leaving 95 patients for further analysis. The MARI node contained residual tumor cells in 65 of these 95 patients. In the other 30 patients, the MARI node was free of tumor, but additional positive lymph nodes were found in 5 patients. Thus, the MARI procedure correctly identified 65 of 70 patients with residual axillary tumor activity (false negative rate 5/70 = 7%)., Conclusions: This study shows that marking and selectively removing metastatic lymph nodes after neoadjuvant systemic treatment has a high identification rate and a low false negative rate. The tumor response in the marked lymph node may be used to tailor further axillary treatment after NST.

Purpose: Radioactive seed localization (RSL) uses an iodine-125 ((125)I) seed as a marker for tumour location. The (125)I seed is implanted into the tumour and enables intraoperative localization with a conventional gamma probe. However, specimen margins in relation to the (125)I seed are estimated on the basis of gamma-probe readings only. A novel device, freehand SPECT, is capable of measuring the distance from the resection plane to the (125)I seed. The aim of this feasibility study was to establish the accuracy of this device in predicting resection margins in ex-vivo tumour specimens excised with RSL guidance., Patients and Methods: In this feasibility study 10 patients with nonpalpable breast cancer scheduled for wide local excision with RSL were included. After surgery, the specimens containing the breast tumour and the (125)I seed were scanned using freehand SPECT. Measurements from five directions were taken and compared with distances measured by means of an ex-vivo computed tomographic (CT) scan and related to the pathology report., Results: The difference between freehand SPECT and CT measurements was 2.9±2.7 mm (mean±SD). One patient had a positive margin based on freehand SPECT. This specimen contained a focal irradical resection ventral of the tumour based on the pathology report. The smallest distance to the (125)I seed was 4 mm for the freehand SPECT and 5 mm for the CT scan., Conclusion: Accurate ex-vivo measurements of the tumour resection margins using (125)I seeds and freehand SPECT are feasible in patients undergoing breast-conserving surgery. Incorporation of the freehand-SPECT device in RSL protocols may enable a real-time estimation of resection margins, which may be useful for surgeons to adjust resection planes.

Purpose: To explore the potential complementary value of PET/CT and dynamic contrast-enhanced MRI in predicting pathological response to neoadjuvant chemotherapy (NAC) of breast cancer and the dependency on breast cancer subtype., Methods: We performed (18)F-FDG PET/CT and MRI examinations before and during NAC. The imaging features evaluated on both examinations included baseline and changes in (18)F-FDG maximum standardized uptake value (SUVmax) on PET/CT, and tumour morphology and contrast uptake kinetics on MRI. The outcome measure was a (near) pathological complete response ((near-)pCR) after surgery. Receiver operating characteristic curves with area under the curve (AUC) were used to evaluate the relationships between patient, tumour and imaging characteristics and tumour responses., Results: Of 93 patients, 43 achieved a (near-)pCR. The responses varied among the different breast cancer subtypes. On univariate analysis the following variables were significantly associated with (near-)pCR: age (p = 0.033), breast cancer subtype (p < 0.001), relative change in SUVmax on PET/CT (p < 0.001) and relative change in largest tumour diameter on MRI (p < 0.001). The AUC for the relative reduction in SUVmax on PET/CT was 0.78 (95% CI 0.68-0.88), and for the relative reduction in tumour diameter at late enhancement on MRI was 0.79 (95% CI 0.70-0.89). The AUC increased to 0.90 (95% CI 0.83-0.96) in the final multivariate model with PET/CT, MRI and breast cancer subtype combined (p = 0.012)., Conclusion: PET/CT and MRI showed comparable value for monitoring response during NAC. Combined use of PET/CT and MRI had complementary potential. Research with more patients is required to further elucidate the dependency on breast cancer subtype.

Background: The aim of this study was to assess the accuracy of 18F-FDG PET/CT in T1 breast cancer regarding visualization of the primary tumor and the detection of locoregional and distant metastases., Methods: Sixty-two women with invasive T1 breast cancer underwent a PET/CT. Image acquisition of the thorax was done in prone position with hanging breasts, followed by whole-body scanning in supine position. Primary tumor FDG uptake was evaluated and compared with clinical and histopathological characteristics. Presence of locoregional and distant metastases was assessed and compared with conventional imaging procedures., Results: The primary tumor was visible with PET/CT in 54 (87%) of 62 patients, increasing from 59% (10/17) in tumors ≤ 10 mm to 98% (44/45) in tumors over 10 mm. All triple negative and HER2-positive tumors and 40/48 (83%) ER-positive/HER2-negative tumors were visualized. Sensitivity and specificity of PET/CT in the detection of axillary metastases were 73% and 100%, respectively. PET/CT depicted periclavicular nodes in two patients. Of 12 distant lesions, one was confirmed to be a lung metastasis, three were false positive, and eight were new primary proliferative lesions., Conclusion: Using optimal imaging acquisition, the majority of T1 breast carcinomas can be visualized with PET/CT. Specificity in the detection of axillary metastases is excellent, but sensitivity appears to be limited. Additional whole body imaging has a low yield in this specific patient group.

Purpose: To investigate the value of response monitoring in both the primary tumour and axillary nodes on sequential PET/CT scans during neoadjuvant chemotherapy (NAC) for predicting complete pathological response (pCR), taking the breast cancer subtype into account., Methods: In 107 consecutive patients 290 PET/CT scans were performed at baseline (PET/CT1, 107 patients), after 2 - 3 weeks of chemotherapy (PET/CT2, 85 patients), and after 6 - 8 weeks (PET/CT3, 98 patients). The relative changes in SUVmax (from baseline) of the tumour and the lymph nodes and in both combined (after logistic regression), and the changes in the highest SUVmax between scans (either tumour or lymph node) were determined and their associations with pCR of the tumour and lymph nodes after completion of NAC were assessed using receiver operating characteristic (ROC) analysis., Results: A pCR was seen in 17 HER2-positive tumours (65 %), 1 ER-positive/HER2-negative tumour (2 %), and 16 triple-negative tumours (52 %). The areas under the ROC curves (ROC-AUC) for the prediction of pCR in HER2-positive tumours after 3 weeks were 0.61 for the relative change in tumours, 0.67 for the combined change in tumour and nodes, and 0.72 for the changes in the highest SUVmax between scans. After 8 weeks equivalent values were 0.59, 0.42 and 0.64, respectively. In triple-negative tumours the ROC-AUCs were 0.76, 0.84 and 0.76 after 2 weeks, and 0.87, 0.93 and 0.88 after 6 weeks, respectively., Conclusion: In triple-negative tumours a PET/CT scan after 6 weeks (three cycles) appears to be optimally predictive of pCR. In HER2-positive tumours neither a PET/CT scan after 3 weeks nor after 8 weeks seems to be useful. The changes in SUVmax of both the tumour and axillary nodes combined correlates best with pCR.

Background: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half., Methods: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an 'unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival., Results: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%., Conclusion: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.

Purpose: To define the correlation between the core biopsy location and the area with highest metabolic activity on 18F-FDG PET/CT in stage II-III breast cancer patients before neoadjuvant chemotherapy. Also, we would like to select a subgroup of patients in which PET/CT information may optimize tumor sampling., Methods: A PET/CT in prone position was acquired in 199 patients with 203 tumors. The distance and relative difference in standardized uptake value (SUV) between core biopsy localization (indicated by a marker) and area with highest degree of FDG uptake were evaluated. A distance ≥ 2 cm and a relative difference in SUV ≥ 25% were considered clinically relevant and a combination of both was defined as non-correspondence. Non-correspondence for different tumor characteristics (TNM stage, lesion morphology on MRI and PET/CT, histology, subtype, grade, and Ki-67) was assessed., Results: Non-correspondence was found in 28 (14%) of 203 tumors. Non-correspondence was significantly associated with T-stage, lesion morphology on MRI and PET/CT, tumor diameter, and histologic type. It was more often seen in tumors with a higher T-stage (p = 0.028), diffuse (non-mass) and multifocal tumors on MRI (p = 0.001), diffuse and multifocal tumors on PET/CT (p<0.001), tumors >3 cm (p<0.001), and lobular carcinomas (p<0.001). No association was found with other features., Conclusion: Non-correspondence between the core biopsy location and area with highest FDG uptake is regularly seen in stage II-III breast cancer patients. PET/CT information and possibly FDG-guided biopsies are most likely to improve pretreatment tumor sampling in tumors >3 cm, lobular carcinomas, and diffuse and multifocal tumors., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Response monitoring with MRI during neoadjuvant chemotherapy (NAC) in breast cancer is promising, but knowledge of breast cancer subtype is essential. The aim of the present study was to evaluate the relevance of breast cancer subtypes for monitoring of therapy response during NAC with 18F-FDG PET/CT., Methods: Evaluation included 98 women with stages II and III breast cancer. PET/CTs were performed before and after six or eight weeks of NAC. FDG uptake was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes: HER2-positive, ER-positive/HER2-negative, and triple negative. Tumor response at surgery was assessed dichotomously (presence or absence of residual disease) and ordinally (breast response index, representing relative change in tumor stage). Multivariate regression and receiver operating characteristic (ROC) analyses were employed to determine associations with pathological response., Results: A (near) complete pathological response was seen in 19 (76%) of 25 HER2-positive, 7 (16%) of 45 ER-positive/HER2-negative, and 20 (71%) of 28 triple negative tumors. Multivariate regression of pathological response indicated a significant interaction between change in FDG uptake and breast cancer subtype. The area under the ROC curve was 0.35 (0.12-0.64) for HER2-positive, 0.90 (0.76-1.00) for ER-positive/HER2-negative, and 0.96 (0.86-1.00) for triple negative tumors. We found no association between age, stage, histology, or baseline SUVmax and pathological response., Conclusion: Response monitoring with PET/CT during NAC in breast cancer seems feasible, but is dependent on the breast cancer subtype. PET/CT may predict response in ER-positive/HER2-negative and triple negative tumors, but seems less accurate in HER2-positive tumors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In breast cancer patients treated with neoadjuvant chemotherapy (NAC) the number of tumor-positive nodes can no longer reliably be determined. Furthermore, ultrasound (US) seems suboptimal for the detection of N3-disease. Therefore we assessed the proportion of breast cancer patients treated with NAC in which pre-chemotherapy 18F-FDG PET/CT detected ≥4 axillary nodes or occult N3-disease, upstaging nodal status and changing risk estimation for locoregional recurrence (LRR). Conventional regional staging consisted of US with fine needle aspiration and/or sentinel lymph node biopsy. Patients were classified as low-risk (cT2N0), intermediate-risk (cT0N1, cT1N1, cT2N1, cT3N0), or high-risk (cT3N1, cT4, cN2-3) for LRR. The presence and number of FDG-avid nodes were evaluated and the proportion of patients that would be upstaged by PET/CT, based on detection of ≥4 FDG-avid axillary nodes defined as cN2(4+) or occult N3-disease, was calculated. In total, 87 of 278 patients were considered high-risk based on conventional staging. PET/CT detected occult N3-disease in 5 (11 %) of 47 low-risk patients. In 144 intermediate-risk patients, PET/CT detected ≥4 FDG-avid nodes in 24 (17 %) patients and occult N3-disease in 22 (15 %) patients, thereby finally upstaging 38 (26 %) of intermediate-risk patients. Of 43 (23 %) upstaged patients, 18 were ypN0, 12 were ypN1, and 13 were ypN2-3. Pre-chemotherapy PET/CT is valuable for selection of breast cancer patients at high risk for LRR. In our population, 23 % of patients treated with NAC were upstaged to the high-risk group based on PET/CT information, potentially benefiting from regional radiotherapy.

Background: Radioguided occult lesion localization (ROLL) with technetium-99 m colloid (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with nonpalpable breast tumors. Radioactive seed localization is a relatively new technique that localizes the tumor with a radioactive iodine-125 ((125)I) seed. The feasibility and outcome of these techniques after neoadjuvant systemic treatment has not been widely investigated., Methods: All patients treated with neoadjuvant systemic treatment between 2007 and 2010 in the Netherlands Cancer Institute who underwent breast-conserving surgery with the ROLL-(99m)Tc technique (n = 83) or with (125)I seed localization (n = 71) were analyzed. The weight of the resected specimen, the margins, and the percentage of patients requiring a second surgical intervention as a result of positive margins were assessed., Results: Patient and tumor characteristics and systemic treatment regimens were comparable between both groups. The median weight of the resected specimen (53 vs. 48 g), the median smallest margin (3.5 vs. 3.0 mm), and the risk for additional surgery for incomplete resections (7 vs. 8 %) did not differ significantly between patients treated with the ROLL-(99m)Tc technique and (125)I seed localization., Conclusions: The ROLL-(99m)Tc technique and (125)I seed localization demonstrate comparable results when used to perform breast-conserving surgery after neoadjuvant systemic treatment. Because (125)I seed localization does not require additional radiological localization shortly before surgery, it simplifies surgery scheduling. Therefore, we prefer (125)I seed localization to perform breast-conserving surgery after neoadjuvant systemic treatment.

Background: If all initially node-positive patients undergo axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC), overtreatment may occur in patients with complete response. Positron emission tomography-computed tomography (PET/CT) during NAC may predict axillary response and select patients appropriate for less invasive treatment after NAC. We evaluated the value of sequential (18)F fluorodeoxyglucose (FDG) PET/CTs during NAC for axillary response monitoring in stage II-III breast cancer., Methods: A total of 219 PET/CTs were performed in 80 patients with cytology-proven, node-positive disease at baseline (PET/CT1, n = 80) and twice during NAC (PET/CT2 n = 62, PET/CT3, n = 77). The relative changes in maximum standardized uptake value (SUVmax) of axillary nodes were examined for their ability to assess pathological response. All patients underwent ALND after chemotherapy, and complete axillary response (pCR), defined as absence of isolated tumor cells and of micro- and macrometastases, served as the reference standard., Results: A total of 32 (40 %) patients experienced axillary pCR. The relative decrease in SUVmax was significantly higher in patients with pCR than in those without, both on PET/CT2 (p < 0.001) and PET/CT3 (p = 0.025). The area under the receiver operating characteristic curve values for PET/CT2 and PET/CT3 were 0.80 (95 % confidence interval 0.68-0.92) and 0.65 (95 % confidence interval 0.52-0.79), respectively. A relative decrease of ≥60 % on PET/CT2 had an excellent specificity (35 of 37, 95 %), a high positive predictive value (12 of 14, 86 %), and a sensitivity of 48 %-that is, it accurately identified histologic pCR in 12 of 25 patients with disease that responded to therapy., Conclusions: (18)F-FDG PET/CT early during NAC is useful for axillary response monitoring in cytology-proven node-positive breast cancer because it identifies pathological response, thus permitting ALND to be spared.

To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m(2) , carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node-positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty-seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin-paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2-positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines., (© 2013 Wiley Periodicals, Inc.)

Aim: Recently, a high-resolution dedicated PET system for hanging breast imaging (MAMMI PET) has been developed to improve primary tumor detection and characterization. The aim of this pilot study was to assess its feasibility for tumor detection and FDG uptake measurements in patients with stage II and III breast cancer., Methods: Thirty-two patients with invasive breast cancer (26 ductal, 4 lobular, 2 other), prior to and/or during neoadjuvant chemotherapy, underwent both conventional PET/CT and MAMMI PET in prone position with hanging breasts. Conventional PET/CT and MAMMI PET were performed 60±10 min and 110±10 min after injection of 180-240 MBq of FDG, respectively. Primary tumor detection was assessed and FDG uptake, expressed as maximum standardized uptake value (SUVmax), was calculated., Results: Both MAMMI PET and conventional PET/CT visualized the primary tumor in 31 patients (97%). The mean distance from the tumor to the pectoral muscle was 26.4mm (smallest distance 3.3mm). Agreement in FDG uptake between PET/CT and MAMMI PET was high (r=0.86, 95% CI 0.69-0.94). However, SUVmax as assessed with MAMMI PET was consistently higher than with PET/CT in all patients with an average ratio of 2.7., Conclusion: The dedicated high-resolution breast PET with hanging breast technique is able to visualize approximately all breast tumors in stage II and III breast cancer patients, including tumors in the vicinity of the thoracic wall. This may enable its sequential use in the assessment of response in breast cancer patients receiving neoadjuvant systemic therapy, although SUVmax values are not directly comparable to standard PET/CT.

Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies ("NKI dataset"). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10(-6)). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.

Purpose: The aim of this study was to evaluate the association of primary tumour (18)F-fluorodeoxyglucose (FDG) uptake with clinical, histopathological and molecular characteristics of breast cancer patients scheduled for neoadjuvant chemotherapy. Second, we wished to establish for which patients pretreatment positron emission tomography (PET)/CT could safely be omitted because of low FDG uptake., Methods: PET/CT was performed in 214 primary stage II or III breast cancer patients in the prone position with hanging breasts. Tumour FDG uptake was qualitatively evaluated to determine the possibility of response monitoring with PET/CT and was quantitatively assessed using maximum standardized uptake values (SUV(max)). FDG uptake was compared with age, TNM stage, histology, hormone and human epidermal growth factor receptor 2 status, grade, Ki-67 and molecular subtype in univariable and multivariable analyses., Results: In 203 tumours (95 %) FDG uptake was considered sufficient for response monitoring. No subgroup of patients with consistently low tumour FDG uptake could be identified. In a univariable analysis, SUV(max) was significantly higher in patients with distant metastases at staging examination, non-lobular carcinomas, tumours with negative hormone receptors, triple negative tumours, grade 3 tumours, and in tumours with a high proliferation index (Ki-67 expression). After multiple linear regression analysis, triple negative and grade 3 tumours were significantly associated with a higher SUV(max)., Conclusion: Primary tumour FDG uptake in breast cancer patients scheduled for neoadjuvant chemotherapy is significantly higher in tumours with prognostically unfavourable characteristics. Based on tumour characteristics associated with low tumour FDG uptake, this study was unable to identify a subgroup of patients unlikely to benefit from pretreatment PET/CT.

Background: An important benefit of neoadjuvant chemotherapy, as compared to adjuvant chemotherapy, in breast cancer patients is down staging of the primary tumour, which allows for more breast-conserving surgery. When a tumour becomes non-palpable after this down staging, precise localisation of the original tumour bed is crucial to be able to perform breast-conserving surgery. Radioguided Occult Lesion Localisation with (99m)Technetium (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with non-palpable breast tumours. We modified this technique to use it in the neoadjuvant setting. The present analysis was performed to assess its feasibility and analyse the number of patients in which a mastectomy was correctly withheld using this technique., Methods: A retrospective analysis was performed for all patients who were treated with neoadjuvant chemotherapy between 2007 and 2010 in our institute and underwent breast-conserving surgery with the ROLL-(99m)Tc technique afterwards. The status of the margins and the weight of the resected specimen were assessed., Results: The median weight of the resected specimen in these 83 patients was 53 g (range: 11-204 g). Eleven of the 58 patients with residual disease revealed positive margins at pathological examination. However, in only 5 of those 11 patients a secondary mastectomy was indicated. This means that in 94% of all included patients a mastectomy was correctly withheld., Conclusion: The ROLL-(99m)Tc technique is a feasible technique that can be used to perform breast-conserving surgery after neoadjuvant chemotherapy in a carefully selected group of patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Invasive lobular carcinoma (ILC) has been reported to be less responsive to neoadjuvant chemotherapy (NAC) than invasive ductal carcinoma (IDC). We sought to determine whether ILC histology indeed predicts poor response to NAC by analyzing tumor characteristics such as protein expression, gene expression, and imaging features, and by comparing NAC response rates to those seen in IDC after adjustment for these factors. We combined datasets from two large prospective NAC trials, including in total 676 patients, of which 75 were of lobular histology. Eligible patients had tumors ≥3 cm in diameter or pathologic documentation of positive nodes, and underwent serial biopsies, expression microarray analysis, and MRI imaging. We compared pathologic complete response (pCR) rates and breast conservation surgery (BCS) rates between ILC and IDC, adjusted for clinicopathologic factors. On univariate analysis, ILCs were significantly less likely to have a pCR after NAC than IDCs (11 vs. 25 %, p = 0.01). However, the known differences in tumor characteristics between the two histologic types, including hormone receptor (HR) status, HER2 status, histological grade, and p53 expression, accounted for this difference with the lowest pCR rates among HR+/HER2- tumors in both ILC and IDC (7 and 5 %, respectively). ILC which were HR- and/or HER2+ had a pCR rate of 25 %. Expression subtyping, particularly the NKI 70-gene signature, was correlated with pCR, although the small numbers of ILC in each group precluded significant associations. BCS rate did not differ between IDC and ILC after adjusting for molecular characteristics. We conclude that ILC represents a heterogeneous group of tumors which are less responsive to NAC than IDC. However, this difference is explained by differences in molecular characteristics, particularly HR and HER2, and independent of lobular histology.

The optimal method for locoregional staging in patients treated with neoadjuvant chemotherapy (NAC), usually ultrasound (US) and pre- or post-chemotherapy sentinel lymph node biopsy (SLNB), remains subject of debate. The aim of this study was to assess the value of 18F-FDG PET/CT for detecting locoregional lymph node metastases in primary breast cancer patients scheduled for NAC. 311 breast cancer patients, scheduled for NAC, underwent PET/CT of the thorax in prone position with hanging breasts. A panel of four experienced reviewers examined PET/CT images, blinded for other diagnostic procedures. FDG uptake in locoregional nodes was determined qualitatively using a 4-point scale (0 = negative, 1 = questionable, 2 = moderately intense, and 3 = very intense). Results were compared with pathology obtained by US-guided fine needle aspiration or SLNB prior to NAC. All FDG-avid extra-axillary nodes were considered metastatic, based on the previously reported high positive predictive value of the technique. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG-avid nodes for the detection of axillary metastases (score 2 or 3) were 82, 92, 98, 53, and 84 %, respectively. Of 28 patients with questionable axillary FDG uptake (score 1), 23 (82 %) were node-positive. Occult lymph node metastases in the internal mammary chain and periclavicular area were detected in 26 (8 %) and 32 (10 %) patients, respectively, resulting in changed regional radiotherapy planning in 50 (16 %) patients. In breast cancer patients scheduled for NAC, PET/CT renders pre-chemotherapy SLNB unnecessary in case of an FDG-avid axillary node, enables axillary response monitoring during or after NAC, and leads to changes in radiotherapy for a substantial number of patients because of detection of occult N3-disease. Based on these results, we recommend a PET/CT as a standard staging procedure in breast cancer patients scheduled for NAC.

The aim of the present study was to investigate if 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) outperforms conventional imaging techniques for excluding distant metastases prior to neoadjuvant chemotherapy (NAC) treatment in patients with stage II and III breast cancer. Second, we assessed the clinical importance of false positive findings. One hundred and fifty four patients with stage II or III breast cancer, scheduled to receive NAC, underwent an 18F-FDG PET/CT scan and conventional imaging, consisting of bone scintigraphy, ultrasound of the liver, and chest radiography. Suspect additional lesions at staging examination were confirmed by biopsy and histopathology and/or additional imaging. Metastases that were detected within 6 months after the PET/CT scan were considered evidence of occult metastasis, missed by staging examination. Forty-two additional distant lesions were seen in 25 patients with PET/CT and could be confirmed in 20 (13%) of 154 patients. PET/CT was false positive for 8 additional lesions (19%) and misclassified the presence of metastatic disease in 5 (3%) of 154 patients. In 16 (80%) of 20 patients, additional lesions were exclusively seen with PET/CT, leading to a change in treatment in 13 (8%) of 154 patients. In 129 patients with a negative staging PET/CT, no metastases developed during the follow-up of 9.0 months. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT in the detection of additional distant lesions in patients with stage II or III breast cancer are 100, 96, 80, 100, and 97%, respectively. FDG PET/CT is superior to conventional imaging techniques in the detection of distant metastases in patients with untreated stage II or III breast cancer and is associated with a low false positive rate. PET/CT may be of additional value in the staging of breast cancer prior to NAC.

Distant metastases from breast cancer most frequently occur in the skeleton. Although 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), with or without computed tomography (CT), is superior to bone scintigraphy for the detection of osteolytic bone metastases, it has been reported that sclerotic bone metastases frequently show no or only a low degree of FDG uptake on PET and PET/CT. Since both lytic and sclerotic metastases can occur in breast cancer patients, bone scintigraphy may remain of additional value in these patients. In this case series, we describe four breast cancer patients in whom FDG PET/CT has clearly visualized sclerotic bone metastases because of increased FDG uptake. Not so much the type of metastasis (sclerotic or lytic), but possibly the characteristics of the primary tumor or treatments prior to the FDG PET/CT scan might influence the degree of FDG uptake of bone metastases. The ability to detect sclerotic bone metastases based on increased FDG uptake supports the use of FDG PET/CT as a staging procedure in breast cancer patients, but knowledge of factors determining the visibility of bone metastases with FDG PET/CT is crucial.

On average, 250 skin-sparing mastectomies with immediate prosthetic reconstruction are performed in the Dutch Antoni van Leeuwenhoek Hospital each year. We report on two breast cancer patients (46 and 53 years old) who each developed a local recurrence at the entry site of the core needle biopsy after skin-sparing mastectomy with immediate prosthetic reconstruction. In hindsight, the most likely cause for these recurrences was the fact that one of the entry sites for the core needle biopsies was not marked preoperatively, and thus not excised during surgery. These examples emphasise the need for accurate documentation of the locations of these entry sites, followed by their excision, in patients undergoing skin-sparing mastectomy for invasive breast cancer.

Background: Neoadjuvant chemotherapy is gaining acceptance as an option for breast cancer treatment, particularly in young women. These women may seek immediate breast reconstruction after mastectomy even though it is not known whether such preoperative chemotherapy may be detrimental to post-reconstruction wound healing. Therefore, we set out to assess the influence of neoadjuvant chemotherapy for invasive breast cancer on the short-term complications after skin sparing mastectomy and immediate prosthetic reconstruction., Methodology: The short-term surgical outcome of 48 immediate breast reconstructions in 37 women treated with neoadjuvant chemotherapy from 2006 through 2009 was prospectively compared to that of 215 immediate reconstructions in 176 women who were operated in the same period without neoadjuvant chemotherapy., Results: The overall rate of short-term postoperative complications was significantly less among neoadjuvantly treated women (15% vs. 29%; p = 0.042) but this did not result in a reduction of loss of prostheses (8% vs. 11%; p = 0.566)., Conclusion: Because neoadjuvant chemotherapy is not associated with an increase in short-term complications after skin sparing mastectomy and immediate prosthetic reconstruction in patients with invasive breast cancer, such combined surgical therapy may be offered as treatment option for this particular group of patients also., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Positron emission tomography (PET), with or without integrated computed tomography (CT), using 18F-fluorodeoxyglucose (FDG) is based on the principle of elevated glucose metabolism in malignant tumors, and its use in breast cancer patients is frequently being investigated. It has been shown useful for classification, staging, and response monitoring, both in primary and recurrent disease. However, because of the partial volume effect and limited resolution of most whole-body PET scanners, sensitivity for the visualization of small tumors is generally low. To improve the detection and quantification of primary breast tumors with FDG PET, several dedicated breast PET devices have been developed. In this nonsystematic review, we shortly summarize the value of whole-body PET/CT in breast cancer and provide an overview of currently available dedicated breast PETs.

Preoperative localization is important to optimize the surgical treatment of breast lesions, especially in nonpalpable lesions. Radioactive seed localization (RSL) using iodine-125 is a relatively new approach. To provide accurate guidance to surgery, it is important that the seeds do not migrate after placement. The aim of this study was to assess short-term and long-term seed migration after RSL of breast lesions. In 45 patients, 48 RSL procedures were performed under ultrasound or stereotactic guidance. In the first 12 patients, the lesion was localized with two markers: an iodine-125 seed and a reference marker. In 33 patients, 36 RSL procedures were performed using a single iodine-125 seed. All patients received control mammograms after seed placement and prior to surgery. In the patients with two markers, migration was defined as the difference in the largest distance between the markers observed in the mammograms. For single-marked lesions, migration was assessed by comparing distances between anatomical landmarks in the mammograms. RSL was successful in all patients. Seeds were in-situ for 59.5 days on average (3-136 days). The detection rate during surgery was 100%. Overall, an average seed migration of 0.9 mm (standard deviation 1.0 mm) was observed. Neither differences in lesion type, nor days in situ, type of surgery or radiologic localization method were found to have impact on seed migration. RSL is an accurate preoperative localization method for breast lesions with negligible seed migration, independent of time in-situ., (© 2011 Wiley Periodicals, Inc.)

Purpose: To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC)., Patients and Methods: MRI examinations were performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index [BRI], representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations., Results: Residual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve [AUC], 0.84; P < .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearson's r = 0.465; P < .001). In subset analysis, this was only significant for triple-negative tumors (P < .001) and HER2-positive tumors (P < .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P < .001). No associations were found for ER-positive/HER2-negative tumors., Conclusion: MRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.

Introduction: Lymphatic drainage patterns from the breast have been described in the past. Drainage may change after treatment of a breast or axilla, and this may have implications for lymphatic mapping. The aim of this study was to determine the lymphatic drainage patterns in breast cancer patients with a previously treated ipsilateral breast., Methods: Between January 1999 and November 2008, 115 sentinel node procedures were performed in breast cancer patients who had undergone treatment of the ipsilateral breast in the past. Lymphatic drainage patterns were analyzed based on preoperative lymphoscintigraphy and sentinel lymph node biopsy. Patients were divided into subgroups according to their previous treatment., Results: Sentinel nodes were found in 84% of the patients: in 81 patients (70%) in the axilla, 43 patients (37%) had drainage to more than one site, and in 18 patients (16%) no drainage was detected. The percentage of drainage outside the axilla was higher than in a series of untreated breast cancer patients from our institution (51% versus 33%, P = 0.01). The 16% nonidentification rate was also higher than the 3.1% in patients without previous treatment (P = 0.003). Four patients (3.5%) had lymphatic drainage to the contralateral axilla. Twelve patients (10%) had involved sentinel nodes; these were harvested from the contralateral axilla in two of them. No lymph node recurrences were observed during a median follow-up time of 39 months., Conclusion: Lymphatic mapping yields a lymph node in 84% of breast cancer patients who have undergone previous treatment of the breast. Nonidentification and extra-axillary nodes are more frequently encountered than in patients without treatment of the breast in the past. The finding of involved nodes suggests that sentinel node biopsy improves staging. Long-term follow-up will determine the sensitivity of the procedure in this specific situation.

Objective: The aim of this study was to establish an magnetic resonance imaging (MRI)-based interpretation model to facilitate the selection of breast-conserving surgery (BCS) after neoadjuvant chemotherapy (NAC)., Summary of Background Data: Although MRI is the most reliable method to assess tumor size after NAC, criteria for the correct selection of surgery remain unclear., Methods: In 208 patients, dynamic contrast-enhanced MRI was performed before and after NAC. Imaging was correlated with pathology. Differences <20 mm in tumor extent were considered to accurately indicate disease extent. Multivariate analysis with cross-validation was performed to analyze features affecting the potential of MRI to correctly indicate BCS (ie, residual tumor size <30 mm on pathology)., Results: The accuracy of MRI to detect residual disease was 76% (158/208). The positive and negative predictive value of MRI were 90% (130/144) and 44% (28/64), respectively. In 35 patients (17%), MRI underestimated the tumor size by >20 mm and in 27 patients (13%) this would have lead to incorrect indication of BCS. The features most predictive of indicating feasibility of BCS in tumors <30 mm on preoperative MRI were the largest diameter at the baseline MRI, the reduction in diameter and the tumor subtype based on hormone-, and human epidermal growth factor receptor 2-status (area under the curve: 0.78)., Conclusions: Optimal selection of patients for BCS after NAC based on MRI should take into account (1) the tumor size at baseline (2) the reduction in tumor size, and (3) the subtype based on hormone-, and human epidermal growth factor receptor 2-status.

The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions. The aim of this study was to assess its value to predict chemosensitivity in the neoadjuvant setting. We obtained the 70-gene profile of stage II-III patients prior to neoadjuvant chemotherapy and classified the prognosis-signatures. Pathological complete remission (pCR) was used to measure chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%) a good prognosis-signature. None of the good prognosis-signature patients achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38) had a poor prognosis-signature. Within the non triple-negative subgroup, the response of the primary tumor remained associated with the classification of the prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy.

ER, PR and HER2 status in breast cancer are important markers for the selection of drug therapy. By immunohistochemistry (IHC), three major breast cancer subtypes can be distinguished: Triple negative (TN(IHC)), HER2+(IHC) and Luminal(IHC) (ER+(IHC)/HER2-(IHC)). By using the intrinsic gene set defined by Hu et al. five molecular subtypes (Basal(mRNA), HER2+(mRNA), Luminal A(mRNA), Luminal B(mRNA) and Normal-like(mRNA)) can be defined. We studied the concordance between analogous subtypes and their prediction of response to neoadjuvant chemotherapy. We classified 195 breast tumors by both IHC and mRNA expression analysis of patients who received neoadjuvant treatment at the Netherlands Cancer institute for Stage II-III breast cancer between 2000 and 2007. The pathological complete remission (pCR) rate was used to assess chemotherapy response. The IHC and molecular subtypes showed high concordance with the exception of the HER2+(IHC) group. 60% of the HER2+(IHC) tumors were not classified as HER2+(mRNA). The HER2+(IHC)/Luminal A or B(mRNA) group had a low response rate to a trastuzumab-chemotherapy combination with a pCR rate of 8%, while the HER2+(mRNA) group had a pCR rate of 54%. The Luminal A(mRNA) and Luminal B(mRNA) groups showed similar degrees of response to chemotherapy. Neither the PR status nor the endocrine responsiveness index subdivided the ER+(IHC) tumors accurately into Luminal A(mRNA) and Luminal B(mRNA) groups. Molecular subtyping suggests the existence of a HER2+(IHC)/Luminal(mRNA) group that responds poorly to trastuzumab-based chemotherapy. For Luminal(IHC) and triple negative(IHC) tumors, further subdivision into molecular subgroups does not offer a clear advantage in treatment selection.

Background: The aims of this study were to determine which consent procedure patients prefer for use of stored tissue for research purposes and what the effects of consent procedures on actual consenting behaviour are., Methods: We offered 264 cancer patients three different consent procedures: 'one-time general consent' (asked written informed consent), 'opt-out plus' (had the opportunity to opt out by a form), or the standard hospital procedure (control group). The two intervention groups received a specific leaflet about research with residual tissue and verbal information. The control group only received a general hospital leaflet including opt-out information, which is the procedure currently in use. Subsequently, all patients received a questionnaire to examine their preferences for consent procedures., Results: In all, 99% of patients consented to research with their residual tissue. In the 'one-time consent' group 85% sent back their consent form. Patients preferred 'opt-out plus' (43%) above 'one-time consent' (34%) or 'opt-out' (16%), whereas 8% indicated that they did not need to receive information about research with residual tissues or be given the opportunity to make a choice., Conclusions: The 'opt-out plus' procedure, which places fewer demands on administrative resources than 'one-time consent', can also address the information needs of patients.

Background: Recently, lower axillary lymph node retrieval after neoadjuvant chemotherapy was reported. We did not have this experience, and retrospectively analyzed our axillary lymph node dissections (ALNDs)., Methods: One hundred ninety-one patients who had ALND after neoadjuvant chemotherapy were compared with 192 patients with primary ALND after a positive sentinel node biopsy., Results: There were no differences in the mean number of nodes retrieved between the neoadjuvant group and the primary surgery group: 16.3 (range 4-38) and 15.8 (range 6-33), respectively (P = .4); or in the retrieval of fewer than 10 lymph nodes: 13/191 (7%) and 11/192 (6%) (P = .7). The number of cases with retrieval of more than 20 lymph nodes was higher in the neoadjuvant group: 42/191 (22%) versus 26/192 (13%) (P = .03). In the neoadjuvant group, 150/191 (79%) patients had residual lymph node metastasis after neoadjuvant chemotherapy., Conclusion: Our results show the feasibility and need to remove enough lymph nodes to provide precise prognostic information and adequate local control.

Purpose: The recently introduced hybrid single-photon emission computed tomography camera with integrated CT (SPECT/CT) fuses tomographic lymphoscintigrams with anatomical data from CT. The purpose of this study was to explore this sophisticated technique in lymphatic mapping in breast cancer patients., Methods: We studied 134 patients who underwent SPECT/CT immediately after late planar imaging when these images showed an unusual drainage pattern (85 patients), a pattern that was difficult to interpret (27 patients), or nonvisualization (22 patients)., Results: Planar imaging suggested 271 sentinel nodes in 112 of the 134 patients (84%). SPECT/CT showed 269 of these same nodes and indicated that two sites of radioactivity were caused by skin contamination. SPECT/CT visualized 19 additional sentinel nodes in 15 patients, of whom 11 had non-visualization on planar images. One or more tumour-positive sentinel nodes were seen in 27 patients, and in 4 of these patients (15%), these were visualized only by SPECT/CT. SPECT/CT had no additional value for the surgical approach in 11 patients with persisting nonvisualization (8%), and was of questionable value in 67 other patients (50%). Based on the SPECT/CT images, a more precise incision was made in 48 patients (36%), an extra incision was made in 6 (4%), and an incision was omitted in 2 (1.5%)., Conclusion: SPECT/CT detected additional sentinel nodes and showed the exact anatomical location of sentinel nodes in breast cancer patients with inconclusive planar images. SPECT/CT was able to visualize drainage in patients whose planar images did not reveal a sentinel node. Therefore, SPECT/CT facilitates surgical exploration in difficult cases and may improve staging.

It is unknown whether there are any clinically relevant differences between volume-controlled (<30-50 ml/24h across trials) vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery on outcomes such as seroma formation, wound infection or length of hospital stay. Randomised controlled trials comparing volume-controlled drainage vs no or short-term drainage after axillary lymph node dissection in breast cancer surgery were identified systematically using Pubmed, EMBASE and The Cochrane library. Trial data were reviewed and extracted independently by two reviewers in a standardised unblinded manner. Six randomised controlled trials which included a total of 561 patients fulfilled our inclusion criteria. Patients randomised to volume-controlled drainage were less likely to develop clinically relevant seromas compared to patients randomised to no/short-term drainage. There was, however, no difference in wound infections between patients treated with volume-controlled drainage and patients with no or short-term drainage. Patients randomised to volume-controlled drainage stayed significantly longer in hospital than patients randomised to no/short-term drainage. Based on available evidence, clinically relevant seromas occur more frequently in patients treated with no/short-term drainage. However, no/short-term drainage after axillary lymph node dissection does not lead to an increase in wound infections and is associated with shorter hospital stay.

Background: Axillary lymph node dissection (ALND) is a standard procedure in the treatment of breast cancer. Current practice following ALND involves several days of drainage of the axilla to reduce the formation of seroma. The aim of this study is to investigate the feasibility of 24 h drainage., Study Design: A prospective randomized trial was performed comparing 24 h drainage to long-term drainage. The primary outcome measure was duration of hospital stay. Formation of seroma and wound related complications were secondary outcome measures., Results: Fifty patients were randomised to the 24 h drainage group and 50 patients to the long-term drainage group. 24 h drainage was associated with a shorter hospital stay (2.5 versus 4.6 days, p < 0.001). Seroma aspiration was required in 76% of the patients after 24 h drainage and in 64% after long-term drainage (p = 0.19). The number of wound related complications was higher after long-term drainage (13 versus 9, p = 0.33). Infectious complications were seen in 11 patients after long-term drainage versus 6 after 24 h drainage (p = 0.18)., Conclusion: These results indicate that 24 h drainage following ALND is feasible and facilitates early hospital discharge. Furthermore, 24 h drainage is not associated with excess wound related complications compared to long-term drainage.