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In this Personal View, we outline proposals for uniform collection of biospecimens obtained in neoadjuvant breast cancer trials undertaken by the Breast International Group (BIG) and the National Cancer Institute-sponsored North American Breast Cancer Group (NABCG). These proposals aim to standardise collection of high-quality specimens, with respect to both type and timing, to enhance and allow integration of results obtained from neoadjuvant trials done by several groups. They should be considered in parallel with recommendations for tissue-specimen collection and handling previously developed by BIG and NABCG. We propose that tumour tissue (formalin-fixed, paraffin-embedded and samples dedicated for molecular studies) should be taken at baseline, 1-3 weeks after the start of treatment, and at definitive surgery, with clear prioritisation in the study protocol of number, order, and preservation of samples to be gathered. This step should be accompanied by blood collection (plasma, serum, and whole blood) whenever possible. We advocate strongly a move towards one diagnostic and research biopsy procedure in all women with breast cancers potentially suitable for neoadjuvant treatment. If possible, patients should be referred at the outset to specialised centres to give them the opportunity to participate in neoadjuvant clinical trials, thereby avoiding several biopsy procedures., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In patients with positive lymph nodes (cN+) prior to neoadjuvant treatment (NAT), which convert to a clinically negative axilla (cN0) after treatment, the use of sentinel node biopsy (SNB) is still debatable, since the false-negative rate (FNR) is significantly high (12.6–14.2%). The objective of this retrospective mono-institutional study, with a long follow-up, aimed to evaluate the outcome in patients undergoing NAT who remained or converted to cN0 and received SNB independent of target axillary dissection (TAD) or the removal of at least 3 sentinel nodes (SNs). This study analyzed 688 consecutive cT1-3, cN0/1/2 patients, operated at the European Institute of Oncology, Milan, from 2000 to 2015 who became or remained cN0 after NAT and underwent SNB with a least one SN found. Axillary dissection (AD) was not performed if the SN was negative. Nodal radiotherapy (RT) was not mandatory. Axillary failure occurred in 1.8% of the initially cN1/2 patients and in 1.5% of the initially cN0 patients. After a median follow-up of 9.2 years (IQR 5.3–12.3), the 5- and 10-year overall survival (OS) were 91.3% (95% CI, 88.8–93.2) and 81.0% (95% CI, 77.2–84.2) in the whole cohort, 92.0% (95% CI, 89.0–94.2) and 81.5% (95% CI, 76.9–85.2) in those initially cN0, 89.8% (95% CI, 85.0–93.2) and 80.1% (95% CI, 72.8–85.7) in those initially cN1/2. The 10-year follow-up confirmed our preliminary data that the use of standard SNB is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome. [ABSTRACT FROM AUTHOR]

Abstract: Background: Biopsy of metastatic site of disease can influence treatment decisions, but its impact on survival remains uncertain. Patients and methods: One-hundred patients with first metachronous liver metastases (LM) from breast cancer (BC) who underwent liver biopsy between 1999 and 2009 were identified. One-hundred matched control patients with LM from BC and no biopsy were selected. Results: Liver biopsy had no statistically significant impact on survival when comparing biopsied patients to controls [HR 0.82 (95% CI 0.58–1.16)]. Patients with early metastasis (within 3 years) undergoing liver biopsy had a better survival [HR 0.60 (95% CI 0.38–0.97)] compared to those who did not. Liver biopsy had no statistically significant impact on survival in patients with late LM (after 3 years) [HR 1.09 (95% CI 0.69–1.74)]. We observed that 18 out of 100 biopsied patients (18.0%) had a conversion of predictive factors which allowed adjusting for therapy, specifically new expression of ER (n =5), overexpression of HER2 (n =12) or both (n =1). Fourteen out of 18 (77.8%) received anti-HER2 treatment for the first time at the time of metastasis and 3 others (16.7%) received hormone therapy. Those 18 patients showed a better survival compared to the other 82 biopsied patients [HR 0.55 (95% CI 0.28–1.10)] and compared to the 13 biopsied patients with disappearance of features which predicted responsiveness to a given treatment [HR 0.19 (95% CI 0.06–0.62)]. Conclusions: Liver biopsy can impact survival of patients with early metastases from BC. Discordance between primary and distant lesions can offer the patients new treatment options. [Copyright &y& Elsevier]

Introduction. In recent decades, a steady improvement in imaging diagnostics has been observed together with a rising adherence to regular clinical breast examinations. As a result, the detection of small clinically occult (nonpalpable) lesions has progressively increased. At present in our institution some 20% of the cases are treated when nonpalpable. The aim of the present study is to analyze the characteristics and prognosis of such tumors treated in a single institution. Methods. The analysis focused on 1,258 women who presented at the European Institute of Oncology with a primary clinically occult carcinoma between 2000 and 2006. All patients underwent radioguided occult lesion localization (ROLL), axillary dissection when appropriate, whole breast radiotherapy, or partial breast intraoperative irradiation and received tailored adjuvant systemic treatment. Results. Median age was 56 years. Imaging showed a breast nodule in half of the cases and a breast nodule accompanied by microcalcifications in 9%. Microcalcifications alone were present in 17.1% of the cases, whereas suspicious opacity, distortion, or thickening represented the remaining 24.6%. Most tumors were characterized by low proliferative rates (68.9%), positive estrogen receptors (92.3%), and non-overexpressed Her2/neu (91.3%). After a median follow-up of 60 months, we observed 19 local events (1.5%), 12 regional events (1%), and 20 distant metastases (1.6%). Five-year overall survival was 98.6%. Conclusions. Clinically occult (nonpalpable) carcinomas show very favorable prognostic features and high survival rates, showing the important role of modern imaging techniques. [ABSTRACT FROM AUTHOR]

Discordance in estrogen receptor and human epidermal growth factor receptor 2 receptor status between the primary tumor and recurrence is frequently reported in the literature. This is frequently interpreted as evidence for a change in the biology of breast cancer during the course of the disease. This commentary discusses some of the caveats of this interpretation. Discordant receptor results can be caused by any of 3 factors: (a) a genuine switch in the biology of the disease, (b) sampling error in focally receptor-positive cancers, and (c) limited accuracy and reproducibility of receptor assays. The relative contribution of each of these factors to discordant results is unknown. A switch in molecular class between primary and recurrent cancer (or residual cancer after therapy) appears to be a rare event based on the available limited molecular profiling data. Small pockets of strongly focally receptor-positive tumor nests in a larger receptor-negative cancer are also relatively infrequently seen. Discordance resulting from inherent limitations in assay reproducibility is evident from the frequently discordant receptor results even when the same samples are assessed in different laboratories (e.g., central versus local laboratory). A repeat tumor biopsy is clearly justified when it is suspected, on clinical grounds, that the original receptor results may have been false negative or when the diagnosis of metastatic disease is in question. However, routine repeat biopsy for receptor re-evaluation does not necessarily improve diagnostic accuracy and have a potential to harm through a false-negative result. For patients with clinical courses consistent with hormone responsiveness, or with prior positive hormone receptor results, a course of endocrine therapy is reasonable regardless of the most recent hormone receptor assay result. [ABSTRACT FROM AUTHOR]

Sentinel lymph node biopsy (SLNB) is currently not recommended in pregnant patients with breast cancer due to radiation concerns. Twelve pregnant patients with breast cancer received low-dose (10 MBq on average) lymphoscintigraphy using 99mTc human serum albumin nanocolloids. The sentinel lymph node (SLN) was identified in all patients. Of the 12 patients, 10 had pathologically negative SLN. One patient had micrometastasis in one of four SLN. One patient had metastasis in the SLN and underwent axillary clearance. From the 12 pregnancies, 11 healthy babies were born with no malformations and normal weight. One baby, whose mother underwent lymphatic mapping during the 26th week of gestation, was operated on at the age of 3 months for a ventricular septal defect and at 43 months was in good health. This malformation was suspected at the morphological US examination during week 21, well before lymphoscintigraphy, and was confirmed a posteriori by a different observer based on videotaped material. No overt axillary recurrence appeared in the patients with negative SLNs after a median follow-up of 32 months. Our experience supports the safety of SLNB in pregnant patients with breast cancer, when performed with a low-dose lymphoscintigraphic technique. [ABSTRACT FROM AUTHOR]

Summary: Sentinel lymph node biopsy (SLNB) is a staging technique with a significant impact on patients’ quality of life: the oncological effectiveness in a large number of patients affected by breast carcinoma has been already demonstrated, and the clinical research is now focusing on new indication for the biopsy and widespread adoption of the technique. At the European Institute of Oncology we are applying SLNB under local anesthesia: our aim is to improve the management of the disease with low costs for the structure and patients, and to improve patients’ acceptance of breast cancer treatments. We are now discussing the impact of the SLNB under local anesthesia on the activity of a breast surgery department. We also present an update of our experience. [Copyright &y& Elsevier]

Hypothesis: A sentinel lymph node (SLN) biopsy should not be considered a standard procedure in the treatment of all patients with ductal carcinoma in situ (DCIS) of the breast if the lesion is completely excised by radical surgery and there are free margins of resection. Design: Prospective case series. Setting: Department of breast surgery of a comprehensive cancer center. Patients: From January 1, 1998, to December 1, 2001, 223 unselected consecutive patients affected by pure DCIS of the breast underwent an SLN biopsy. Results: Metastases in the SLN were detected in 7 (3.1%) of the 223 patients, and complete axillary dissection was subsequently performed in all these patients but 1. Of these 7 patients, 5 had only micrometastases in the SLNs; and in the 6 patients treated with complete axillary dissection, the SLN was the only positive node. Conclusions: Because of the low prevalence of metastases, an SLN biopsy should not be considered a standard procedure in all patients with DCIS. In patients with pure DCIS in whom the lesion is completely excised by radical surgery, an SLN biopsy could be avoided. It could be considered in patients with DCIS undergoing mastectomy, in whom there exists a higher risk of harboring an invasive component using definitive histologic features, like large solid tumors or diffuse or multicentric microcalcifications; in these patients, an SLN biopsy cannot be performed at a later operation. Complete axillary dissection may not be mandatory if the SLN is micrometastatic. [ABSTRACT FROM AUTHOR]

Hypothesis: Sentinel lymph node (SN) biopsy performed with local anesthesia has a positive effect on patients' quality of life and on treatment management for early-stage breast carcinoma. This method represents an interesting development in breast-conserving surgery. Design: We performed SN biopsy with local anesthesia in selected patients to test the feasibility of the technique and its impact on our organization and on patients' quality of life. Patients and Methods: From September 2000 to December 2001, we studied 115 patients with a palpable breast tumor (maximum diameter, 2.5 cm). The axilla was clinically negative for metastasis in all cases. Results: Forty-eight patients (41.7%) had SNs that were positive for metastasis. In 20 cases (17.4%), the SN was macrometastatic and in 28 cases (24.3%), it was micrometastatic (diameter <2 mm). The SN was negative for metastasis in 66 cases (57.4%). In 1 case, the histologic examination revealed the presence of a non-Hodgkin B-cell lymphoma. The complete axillary dissection performed in the subgroup of patients with macrometastatic SNs showed that in 9 cases (45%), the SN was the only positive node. In another 9 cases (45%), patients had fewer than 4 positive axillary lymph nodes; more than 4 axillary nodes were metastatic in 2 cases (10%). Among the 28 patients with SN micrometastasis, 21 received complete axillary dissection: 15 patients (53.6%) had no other metastasis to the axillary nodes and 6 patients (21.4%) had cancer cells in other axillary nodes. In case of micrometastasis, we suggested that patients enter the International Breast Cancer Study Group 2301 trial (15 of them accepted and signed the informed consent), which compared completion of axillary dissection with no further surgical treatment of the axilla. Based on randomization, 7 patients (25%) in the group with micrometastasis to the SN received no axillary dissection. Patients' tolerance to this kind of treatment was excellent. Conclusion: Our... [ABSTRACT FROM AUTHOR]

Background: Axillary lymph node dissection is an established component of the surgical treatment of breast cancer, and is an important procedure in cancer staging; however, it is associated with unpleasant side effects. We have investigated a radioactive tracer-guided procedure that facilitates identification, removal, and pathologic examination of the sentinel lymph node (i.e., the lymph node first receiving lymphatic fluid from the area of the breast containing the tumor) to predict the status of the axilla and to assess the safety of foregoing axillary dissection if the sentinel lymph node shows no involvement.Methods: We injected 5-10 MBq of 99mTc-labeled colloidal particles of human albumin peritumorally in 376 consecutive patients with breast cancer who were enrolled at the European Institute of Oncology during the period from March 1996 through March 1998. The sentinel lymph node in each case was visualized by lymphoscintigraphy, and its general location was marked on the overlying skin. During breast surgery, the sentinel lymph node was identified for removal by monitoring the acoustic signal from a hand-held gamma ray-detecting probe. Total axillary dissection was then carried out. The pathologic status of the sentinel lymph node was compared with that of the whole axilla.Results: The sentinel lymph node was identified in 371 (98.7%) of the 376 patients and accurately predicted the state of the axilla in 359 (95.5%) of the patients, with 12 false-negative findings (6.7%; 95% confidence interval = 3.5%-11.4%) among a total of 180 patients with positive axillary lymph nodes.Conclusions: Sentinel lymph node biopsy using a gamma ray-detecting probe allows staging of the axilla with high accuracy in patients with primary breast cancer. A randomized trial is necessary to determine whether axillary dissection may be avoided in those patients with an uninvolved sentinel lymph node. [ABSTRACT FROM AUTHOR]

Replies to questions related sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Exlusion of the minimal lymph node involvement from the node-positive category in order to avoid overstaging; Percentage of patients with isolated tumor cell in their SLN had axillary metastases; Distinction between isolated tumor cell and true micrometastases; Detection of tumor cell emboli within lymphovascular channels.

Abstract: One of the most important lessons learned from trials of neoadjuvant chemotherapy (NACT) is that achievement of pathological complete response (pCR) is a powerful prognostic predictor of long-term outcome, with significantly better disease-free and overall survival for patients achieving pCR, as compared with patients having residual tumour after NACT. The pathologists' role in the neoadjuvant setting is: (i) to ensure an accurate assessment of pCR, and (ii) to evaluate burden and biological characteristics of residual tumour if pCR has not been achieved. A conversion of receptor status from the core biopsy to the post-NACT surgical specimen may cause uncertainty in the choice of the post-surgical systemic treatment for the patients. It is therefore imperative to ensure accuracy in the assessment of ER, PgR and HER2, and to double check any apparent conversion by re-staining the previous core biopsy and the residual tumour in the same run, thus minimizing the technical artifacts, and to use both immunohistochemical and in situ hybridization assays to evaluate HER2 status. It is essential that protocols for evaluation of tumour response and for assessment of prognostic/predictive parameters of residual disease after NACT be eventually harmonized. [Copyright &y& Elsevier]

The concept of sentinel lymph node biopsy in breast cancer surgery is based on the fact that the tumour drains in a logical way via the lymphatic system, from the first to upper levels. Since axillary node dissection does not improve the prognosis of patients with breast cancer, sentinel lymph node biopsy might replace complete axillary dissection for staging of the axilla in clinically N0 patients. Sentinel lymph node biopsy would represent a significant advantage as a minimally invasive procedure, considering that about 70% of patients are found to be free from metastatic disease, yet axillary node dissection can lead to significant morbidity. Subdermal or peritumoural injection of small aliquots (and very low activity) of radiotracer is preferred to intratumoural administration, and 99mTc-labelled colloids with most of the particles in the 100–200 nm size range would be ideal for radioguided sentinel node biopsy in breast cancer. The success rate of radioguidance in localising the sentinel lymph node in breast cancer surgery is about 97% in institutions where a high number of procedures are performed, and the success rate of lymphoscintigraphy in sentinel node detection is about 100%. The sentinel lymph node should be processed for intraoperative frozen section examination in its entirety, based on conventional histopathology and, when necessary, immune staining with anti-cytokeratin antibody. Nowadays, lymphoscintigraphy is a useful procedure in patients with different clinical evidence of breast cancer. [ABSTRACT FROM AUTHOR]

Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications. We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour. 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21–0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19–0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours. HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression. • HER2-low expression is emerging as an actionable biomarker in breast cancer. • HER2 IHC score increased from primary to metastatic tumour in 44% of the patients. • HER2-low to HER2-zero evolution was observed in 22% of the patients. • HER2-low expression is dynamic and may be enriched in the advanced-stage setting. [ABSTRACT FROM AUTHOR]

Abstract: Premises: Sentinel node biopsy (SNB) in patients with breast carcinoma accurately predicts the axillary node status. However, in some 4–7% of patients with negative sentinel nodes, the remaining axillary nodes harbour cancer cells. Objective: Our purpose was the long-term observation of a large number of patients who did not receive axillary dissection after a negative sentinel node biopsy, in order to evaluate the incidence of overt axillary metastases. Methods: Patients (3548) treated from 1996 to 2004, with negative sentinel nodes not submitted to axillary dissection, were followed up to 11 years with a median follow-up of 48 months. Results: Three hundred and sixteen unfavourable events occurred among the 3548 patients, 196 of which (5.5%) related to primary breast carcinoma. Thirty one cases of overt axillary metastases were found (0.9%): they received total axillary dissection and 27 of them are at present alive and well. The 5-year overall survival rate of the whole series was 98%. Conclusions: Patients with negative sentinel node biopsy not submitted to axillary dissection show, at follow-up, a rate of overt axillary metastases lower than expected. [Copyright &y& Elsevier]

Background: Although numerous studies have shown that the status of the sentinel node is an accurate predictor of the status of the axillary nodes in breast cancer, the efficacy and safety of sentinel-node biopsy require validation. Methods: From March 1998 to December 1999, we randomly assigned 516 patients with primary breast cancer in whom the tumor was less than or equal to 2 cm in diameter either to sentinel-node biopsy and total axillary dissection (the axillary-dissection group) or to sentinel-node biopsy followed by axillary dissection only if the sentinel node contained metastases (the sentinel-node group). Results: The number of sentinel nodes found was the same in the two groups. A sentinel node was positive in 83 of the 257 patients in the axillary-dissection group (32.3 percent), and in 92 of the 259 patients in the sentinel-node group (35.5 percent). In the axillary-dissection group, the overall accuracy of the sentinel-node status was 96.9 percent, the sensitivity 91.2 percent, and the specificity 100 percent. There was less pain and better arm mobility in the patients who underwent sentinel-node biopsy only than in those who also underwent axillary dissection. There were 15 events associated with breast cancer in the axillary-dissection group and 10 such events in the sentinel-node group. Among the 167 patients who did not undergo axillary dissection, there were no cases of overt axillary metastasis during follow-up. Conclusions: Sentinel-node biopsy is a safe and accurate method of screening the axillary nodes for metastasis in women with a small breast cancer. N Engl J Med 2003;349:546-53. [ABSTRACT FROM AUTHOR]