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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 © 2013 Elsevier Ltd. All rights reserved.)

Background: For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm., Methods: In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293., Findings: Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection., Interpretation: Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival., Funding: None., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes., Patients and Methods: We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years., Results: There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018)., Conclusion: In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.

There is considerable interest in foregoing axillary dissection (AD) when the sentinel node (SN) is positive in early breast cancer, particularly when involvement is minimal (micrometastases or isolated tumor cells). To address this issue we analyzed outcomes in patients with a single micrometastatic SN who did not receive AD. We selected 377 consecutive patients treated at the European Institute of Oncology between 1999 and 2007 for invasive breast cancer. Classical and competing risks survival analyses were performed to estimate prognostic factors for axillary recurrence, first events and overall survival. Median age was 53 years (range 26-80); median follow-up was 5 years (range 1-9). Most (91.8%) patients received conservative surgery; 209 (55.4%) had only one SN (range 1-8). Five-year overall survival was 97.3%. There were 10 local events, 2 simultaneous local and axillary events, 6 axillary recurrences and 12 distant events. The cumulative incidence of axillary recurrence was 1.6% (95% CI 0.7-3.3). By multivariable analysis, tumor size and grade were significantly associated with axillary recurrence. The high five-year survival and low cumulative incidence of axillary recurrence in this cohort provide justification for the increasingly common practice of foregoing AD in women with minimal SN involvement, and suggest in particular that AD can safely be avoided in women with small, low-grade tumors. Nevertheless, a subset of patients might be at high risk of developing overt axillary disease and efforts should be made to identify such patients by ancillary analyses of the results of ongoing or recently published clinical trials.

Purpose: Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents., Patients and Methods: Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present., Results: Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease)., Conclusion: The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

Purpose: Sentinel lymph node biopsy (SLNB) is currently not recommended in pregnant patients with breast cancer due to radiation concerns., Methods: Twelve pregnant patients with breast cancer received low-dose (10 MBq on average) lymphoscintigraphy using (99m)Tc human serum albumin nanocolloids., Results: 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., Conclusion: Our experience supports the safety of SLNB in pregnant patients with breast cancer, when performed with a low-dose lymphoscintigraphic technique.

Objective: The aim of this study is to assess the role of sentinel lymph node (SLN) biopsy in patients with pure ductal carcinoma in situ of the breast (DCIS) as a rationale for recommending the best managing option for the treatment of such patients in daily practice., Summary Background Data: DCIS cannot give rise to axillary metastases by definition. Axillary dissection is therefore not indicated. The role of SLN biopsy in the management of DCIS has not yet been established., Methods: From March 1996 to September 2006, 854 patients with pure DCIS underwent SLN biopsy at the European Institute of Oncology. Clinical and pathologic data were prospectively collected. When previous surgery or stereotactic biopsy had been performed elsewhere, all the histopathological preparations were reviewed. Patients with microinvasion were excluded from this investigation. Lymphatic mapping was performed using a radiocolloid technique., Results: SLN metastases were detected in 12 (1.4%) DCIS patients. In 7 cases, only micrometastases (<2 mm) were diagnosed and in 5 cases macrometastases. In addition, isolated tumoral cells (ITC) (<0.2 mm) were identified in 4 additional patients. Eleven patients underwent complete axillary dissection. None of these patients had additional positive axillary lymph nodes., Conclusions: Because of the low prevalence of metastatic involvement, SLN biopsy should not be considered a standard procedure in the treatment of all patients with DCIS. The sole criteria for proposing SLN biopsy in DCIS should be when there exists any uncertainty regarding the presence of invasive foci at definitive histology.

Objective: To assess the accuracy of a commercially available real-time reverse-transcription-polymerase chain reaction assay for mammaglobin and cytokeratin 19 mRNAs [GeneSearch Breast Lymph Node (BLN) Assay, Veridex LLC, Warren, NJ] in the detection of axillary sentinel lymph nodes (SLNs) metastases in patients with breast carcinoma., Summary Background Data: Because of the lack of standardized and widely accepted protocols for a truly accurate histopathologic examination of SLN, the relative merits of alternative assays based on the identification of tumor specific mRNA markers deserve further assessment., Methods: : A prospective series of 293 consecutive SLNs from 293 patients was evaluated. The BLN assay results were compared with those of an extensive histopathologic examination of the entire SLNs performed on serial frozen sections cut at 40 to 50 microm intervals., Results: The BLN assay correctly identified 51 of 52 macrometastatic and 5 of 20 micrometastatic SLNs, with a sensitivity of 98.1% to detect metastases larger than 2 mm, 94.7% for metastases larger than 1 mm, and 77.8% for metastases larger than 0.2 mm. The overall concordance with histopathology was 90.8%, with specificity of 95.0%, positive predictive value of 83.6%, and negative predictive value of 92.9%. When the results were evaluated according to the occurrence of additional metastases to non-SLN in patients with histologically positive SLNs, the assay was positive in 33 (91.7%) of the 36 patients with additional metastases and in 22 (66.6%) of the 33 patients without further echelon involvement., Conclusions: The sensitivity of the reverse-transcription -polymerase chain reaction assay is comparable to that of the histopathologic examination of the entire SLN by serial sectioning at 1.5 to 2 mm.

Background: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up., Methods: Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival., Findings: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1)., Interpretation: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

Unlabelled: Lymphnodes status in cervical carcinoma is important in therapeutic planning, and the role of Computed Tomography (CT) and Magnetic Resonance (MR) is controversial: this paper aims to evaluate their accuracy in diagnosing nodal metastases in patients with cervical carcinoma. We reviewed, retrospectively and blindly, CT and MR of 62 patients, before surgical lymphnode resection: 45 of these patients had pre-surgical chemotherapy. Lymphnodes were defined metastatic by CT and MRI when larger than 1 cm short axis. Both diagnoses by the original routine reports and by a second blind expert were compared with pathological reports., Results: combining the reading results of both observers CT showed a sensitivity of 64.6% and specificity of 93.3%; MRI a sensitivity of 72.9% and specificity of 93.1%. Positive Predictive Value was 50.8% for CT and 53% for MR, while Negative Predictive Value was 96% both for CT and MR. The expert Radiologist reviewing the films obtained better results. Inter-observer variability in the lower quadrants was high for each imaging technique (kappa for CT: 0.71; kappa for MRI: 0.84). Both imaging techniques showed similar screening accuracy in identifying nodal metastases. The radiologist's experience is important in determining the performance of the imaging technique. Anyway, CT and MRI are only moderately sensitive for detection of nodal metastases and the clinical impact of their results in patient's management is limited.

Background: Sentinel lymph node biopsy (SLNB) is a safe and accurate axillary staging procedure for patients with primary operable breast cancer. An increasing proportion of these patients undergo breast-conserving surgery, and 5% to 15% will develop local relapses that necessitate reoperation. Although a previous SLNB is often considered a contraindication for a subsequent SLNB, few data support this concern., Methods: Between January 2000 and June 2004, 79 patients who were previously treated at our institution with breast-conserving surgery and who had a negative SLNB for early breast cancer developed, during follow-up, local recurrence that was amenable to reoperation. Eighteen of these patients were offered a second SLNB because of a clinically negative axillary status an average of 26.1 months after the primary event., Results: In all 18 patients (7 with ductal carcinoma-in-situ and 11 with invasive recurrences), preoperative lymphoscintigraphy showed an axillary sentinel lymph node, with a preoperative identification rate of 100%, and 1 or more SLNs (an average of 1.3 per patient) were surgically removed. Sentinel lymph node metastases were detected in two patients with invasive recurrence, and a complete axillary dissection followed. At a median follow up of 12.7 months, no axillary recurrences have occurred in patients who did not undergo axillary dissection., Conclusions: Second SLNB after previous SLNB is technically feasible and likely effective in selected breast cancer patients. A larger population and longer follow-up are necessary to confirm these preliminary data.

Background: Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain., Patients and Methods: We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000., Results: Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases)., Conclusion: Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.

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 (99m)Tc-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.

The axillary sentinel lymph node biopsy (SLNB) has gained increasing popularity as a novel surgical approach for staging patients with breast carcinoma and for guiding the choice of adjuvant therapy with minimal morbidity. Patients with negative SLNB represent a subset of breast carcinoma patients with definitely better prognosis, because their pN0 status is based on a very thorough examination of the sentinel lymph nodes (SLNs), with a very low risk of missing even small micrometastatic deposits, as compared with routine examination of the 20 or 30 lymph nodes obtained by the traditional axillary clearing. The histopathologic examination of the SLNs may be performed after fixation and embedding in paraffin, or intraoperatively on frozen sections. Whatever is the preferred tracing technique and surgical procedure, the histopathologic examination of each SLN must be particularly accurate, to avoid a false-negative diagnosis. Unfortunately, because of the lack of standardised guidelines or protocols for SLN examination, different institutions still adopt their own working protocols, which differ substantially in the number of sections cut and examined, in the cutting intervals (ranging from 50 to more than 250 microm), and in the more or less extensive use of immunohistochemical assays for the detection of micrometastatic disease. Herein, a very stringent protocol for the examination of the axillary SLN is reported, which is applied either to frozen SLN for the intraoperative diagnosis, and to fixed and embedded SLN as well., (Copyright 2004 Wiley-Liss, Inc.)

Objective: Male breast cancer is a rare disease and axillary status is the most important prognostic indicator. Lymphoscintigraphy associated with gamma-probe guided surgery has been proved to reliably detect sentinel nodes in female patients with breast cancer. This study evaluates the feasibility of the surgical identification of sentinel node by using lymphoscintigraphy and a gamma-detecting probe in male patients, in order to select subjects who would be suitable for complete axillary lymphadenectomy., Methods: Colloid human albumin labelled with 99Tc was administered to 18 male patients with breast cancer and clinically negative axillary lymph nodes. Lymphoscintigraphy was performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery., Results: Lymphoscintigraphy and biopsy of the sentinel node were successful in all cases. A total of 20 sentinel nodes were removed. Pathological examinations showed 11 infiltrating ductal carcinomas, two intraductal carcinomas and five intracystic papillary carcinomas. Six patients (33%) had positive sentinel node (micrometastases were found in three patients). These patients underwent axillary dissection; in five of them (83%) the sentinel node was the only positive node. Twelve patients (67%) showed negative sentinel nodes; in all of them no further surgical treatments were planned., Conclusions: As in women, lymphoscintigraphy and sentinel node biopsy under the guidance of a gamma-detecting probe proved to be an easy method for the detection of sentinel nodes in male breast carcinoma. In male patients with early stage cancer, sentinel node biopsy might represent the standard surgical procedure in order to avoid unnecessary morbidity after surgery, preserving accurate staging of the disease in the axilla.

Background: Ductal carcinoma in situ with microinvasion (DCISM) is a separate pathological entity, distinct from pure ductal carcinoma in situ (DCIS). DCISM is a true invasive breast carcinoma with a well-known metastatic potential. Currently, there is controversy regarding the indication for complete axillary dissection (CAD) to stage the axilla in patients with DCISM. The role of CAD is questioned given its morbidity and reported low incidence of axillary involvement. Sentinel lymph node biopsy (SLNB) may obviate the need for CAD in these patients without compromising the staging of the axilla and the important prognostic information., Methods: From March 1996 to December 2002, 4602 consecutive patients with invasive breast carcinoma underwent SLN biopsy. Of these, 41 patients with DCISM were selected., Results: Metastasis in the SLN were detected in 4 of 41 (9.7%) patients. Two of the 4 patients had only micrometastasis in the SLN. In three patients, the SLN was the only positive node after CAD., Conclusions: SLN biopsy should be considered as a standard procedure in DCISM patients. SLNB can detect nodal micrometastasis and accurately stage the axilla avoiding the morbidity of a CAD. Complete AD may not be mandatory if only the SLN contains micrometastatic disease. Informed consent is very important in the decision not to undergo CAD.

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]

Background: Invasive lobular carcinomas (ILCs) account for 10-15% of all breast cancers. They are characterized by an elevated endocrine responsiveness and by a long lasting risk of relapse over time. Here we report for the first time an analysis of clinical and pathological features associated with the risk of late distant recurrence in ILCs.Patients and Methods: We retrospectively analyzed all consecutive patients with hormone receptor-positive ILC operated at the European Institute of Oncology (EIO) between June 1994 and December 2010 and scheduled to receive at least 5 years of endocrine treatment. The aim was to identify clinical and pathological variables that provide prognostic information in the period beginning 5 years after definitive surgery. The cumulative incidence of distant metastases (CI-DM) from 5 years after surgery was the prospectively defined primary endpoint.Results: One thousand eight hundred seventy-two patients fulfilled the inclusion criteria. The median follow-up was 8.7 years. Increased tumor size and positive nodal status were significantly associated with higher risk of late distant recurrence, but nodal status had a significant lower prognostic value in late follow-up period (DM-HR, 3.21; 95% CI, 2.06-5.01) as compared with the first 5 years of follow-up (DM-HR, 9.55; 95% CI, 5.64-16.2; heterogeneity p value 0.002). Elevated Ki-67 labeling index (LI) retained a significant and independent prognostic value even after the first 5 years from surgery (DM-HR, 1.81; 95% CI 1.19-2.75), and it also stratified the prognosis of ILC patients subgrouped according to lymph node status. A combined score, obtained integrating the previously validated Clinical Treatment Score post 5 years (CTS5) and Ki-67 LI, had a strong association with the risk of late distant recurrence of ILCs.Conclusion: We identified factors associated with the risk of late distant recurrence in ER-positive ILCs and developed a simple prognostic score, based on data that are readily available, which warrants further validation. [ABSTRACT FROM AUTHOR]

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC.Methods: We considered two patient series with TIL data: a multicentric retrospective series (n = 614) and the BIG 02-98 study (n = 149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n = 159) and IDC (n = 468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n = 98) and IDC (n = 388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided.Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P < .001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8+ were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition.Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. [ABSTRACT FROM AUTHOR]

Aims To ascertain the prognostic relevance of micropapillary carcinoma, a specific type of breast tumour. Methods and results We interrogated the clinical records of a series of 49 pure micropapillary carcinoma patients and 13 487 invasive ductal carcinoma patients, diagnosed and treated consecutively in our institution over a 9-year time-frame. Compared with invasive ductal carcinoma, patients with micropapillary carcinoma more frequently had moderately differentiated tumours ( P = 0.02) with extensive peritumoral vascular invasion ( P < 0.0001), associated with a significantly higher rate of axillary lymph node involvement ( P < 0.0001). Survival data obtained by comparing 49 micropapillary carcinoma patients with a set of 98 invasive ductal carcinoma patients matched for age, tumour size and grade, peritumoral vascular invasion, immunohistochemically defined molecular subtype, number of positive lymph nodes and year of surgery showed that the micropapillary histotype did not add any independent information to the risk of locoregional ( P = 0.48) or distant ( P = 0.79) relapse, or overall survival ( P = 0.60). Conclusions Our data reinforce the notion that micropapillary carcinoma usually arises as a locally advanced disease, and provide evidence that micropapillary histology does not add any additional information on clinical outcome independent of clinicopathological characteristics such as lymph node status and immunohistochemically defined molecular subtype. [ABSTRACT FROM AUTHOR]

The TNMUICC classification of breast cancer categorizes tumor size, regional lymph node involvement, and distant metastases. Treatment is influenced by these characteristics, but requires knowledge of several other factors. In fact, effective treatment is dependent on disease extent, hormone receptor status, and other biologic characteristics of the cancer. We propose a new classification [tumor node metastasis (TNM)] that not only includes relevant biologic characteristics and can expand to include others as they are validated but also specifies tumor size exactly (T2.3 indicates a cancer of maximum diameter 2.3 cm), provides more information on regional lymph node involvement, and specifies the site(s) of distant metastases. We also propose abolishing the term “carcinoma” for non-invasive neoplastic conditions and the term “infiltrating” for carcinomas. The new classification is sufficiently similar to the TNMUICC classification to permit valid comparison of patients classified by both systems, but is more logical, provides information useful for guiding therapy, and is flexible enough to satisfy present and future clinical and research needs. [ABSTRACT FROM AUTHOR]

The article discusses a study on the prognostic implications of invasive lobular carcinoma (ILC) of the breast. A retrospective analysis of 530 patients with ILC revealed some prognostic factors of the disease to be tumor size, lymph node metastatic involvement and hormonal status. It is concluded that the clinicopathologic features of ILC is useful as prognostic parameters of ILC.

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]

Summary: Current classification for solid tumors is based upon characteristics of their extent. Size of the primary tumor, presence of metastatic regional lymph nodes and/or of distant metastases are the key elements for their categorization. Treatment decision-making may depend upon defined extent of disease, but it requires the knowledge of several other factors. Furthermore, effective therapeutics is less dependent upon extent of disease, biological features being increasingly instrumental for treatment choice. A new classification that integrates both requisites is proposed. The scope of this proposal is to transform the current rigid and gross categorization into a more analytical and fine tuned listing including biological variables, making staging allocation more flexible and functional for proper clinical and research needs in the present and for the future. The significant changes we propose are: [•] Abolishing the term of carcinoma for non-invasive cancer [•] Complete metric description of all parameters, rather than categorization [•] Assessment of biological features as predictive of response. [Copyright &y& Elsevier]

Summary: Major efforts have been recently devoted to a better definition of intraductal proliferative lesions with atypia. The new WHO classification of tumors of the breast highlights the morphological features of flat epithelial atypia (DIN 1A) and atypical duct hyperplasia (DIN 1B). Flat epithelial atypia now encompasses lesions previously designated as clinging carcinoma (monomorphous type) and atypical columnar changes. Atypical ductal hyperplasia (ADH) is characterized by the same cytological changes as low-grade DCIS, involving a very small portion of the ductal tree. Minimal lymph node involvement includes true micrometastases (from 0.2 to 2mm in size) and isolated tumor cells (ITC). ITC have been defined as individual tumor cells or small clusters of cells, not more than 0.2mm in size, that do not typically show evidence of metastatic activity or penetration of vascular or lymphatic sinus walls. The biological and clinical implications of ITC remain to be elucidated. [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]

Formalin-fixed, paraffin-embedded tumors (FFPETs) are a valuable source of DNA for genotype association studies and are often the only germline DNA resource from cancer clinical trials. The anti-estrogen tamoxifen is metabolized into endoxifen by CYP2D6, leading to the hypothesis that patients with certain CYP2D6 genotypes may not receive benefit because of their inability to activate the drug. Studies testing this hypothesis using FFPETs have provided conflicting results. It has been postulated that CYP2D6 genotype determined using FFPET may not be accurate because of somatic tumor alterations. In this study, we determined the concordance between CYP2D6 genotypes generated using 3 tissue sources (FFPETs; formalin-fixed, paraffin- embedded unaffected lymph nodes [FFPELNs]; and whole blood cells [WBCs]) from 122 breast cancer patients. Compared with WBCs, FFPET and FFPELN genotypes were highly concordant (>94%), as were the predicted CYP2D6 metabolic phenotypes (>97%). We conclude that CYP2D6 genotypes obtained from FFPETs accurately represent the patient's CYP2D6 metabolic phenotype. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with ERBB2 (HER2)-positive breast cancer experience high pathologic complete response (pCR) rates after standard neoadjuvant anti-HER2 systemic therapy. We examined axillary pathologic nodal response to neoadjuvant dual HER2-targeted therapy alone, based on breast pathologic response, in a multi-institution clinical trial. STUDY DESIGN: Patients with HER2-positive breast cancer were enrolled to a phase II single-arm trial, which administered 6 cycles of neoadjuvant trastuzumab emtansine (T-DM1) plus pertuzumab. Rates of pathologic nodal disease (ypN) in patients who were clinically node-negative (cN0) and node-positive (cN1) were analyzed, by residual breast disease (pCR and residual cancer burden [RCB] I to III). RESULTS: One hundred fifty-eight patients completed preoperative treatment and proceeded to surgery. Of 92 patients who were cN0, 48 (52.2%) and 10 (10.9%) experienced breast pCR and RCB I, respectively. Of these, 100% were ypN0. Of 34 with RCB II to III, 26 (76.5%) were ypN0. Of 30 patients who were cN1 with breast pCR, 100% were ypN0; of the 12 patients who were cN1 with RCB I, 66.7% were ypN0; and of the 24 patients who were cN1 with RCB II to III, 25% were ypN0. ypN0 rates were significantly different between patients who did and did not experience a pCR, in both cN0 (p = 0.002) and cN1 (p < 0.001) subgroups. CONCLUSIONS: Patients with HER2-positive breast cancer treated with dual HER2-targeted therapy who experienced a breast pCR or RCB I response were frequently ypN0. These findings support future trials considering omission of axillary surgical staging for patients with HER2- positive breast cancer in neoadjuvant trials of active HER2-targeted regimens, particularly if they experience breast pCR or RCB I. (J Am Coll Surg 2024;238:303-311. © 2023 by the American College of Surgeons. [ABSTRACT FROM AUTHOR]