Third national surgical consensus conference of the Italian Association of Breast Surgeons (ANISC) on management after neoadjuvant chemotherapy: The difficulty in reaching a consensus.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) has a profound impact on surgical management of breast cancer. For this reason, the Italian Association of Breast Surgeons (ANISC) promoted the third national Consensus Conference on this subject, open to multidisciplinary specialists. MATERIALS AND METHODS: The Consensus Conference was held on-line in November 2022, and after an introductory session with five core-team experts, participants were asked to vote on eleven controversial issues, while results were collected in real-time with a polling system. RESULTS: A total of 164 dedicated specialists from 74 Breast Centers participated. Consensus was reached for only three of the eleven issues, including: 1) the indication to assess the response with Magnetic Resonance Imaging (79 %); 2) the need to re-assess the biological factors of the residual tumor if present (96 %); 3) the possibility of omitting a formal axillary node dissection for cN1 patients if a pathologic Complete Response (pCR) was confirmed with analysis of one or more sentinel lymph nodes (82 %). The majority voted in favor of mapping both the breast and nodal lesions pre-NAC (59 %), and against the omission of sentinel lymph node biopsy in cN0 patients in the case of pathologic or clinical Complete Response (69 %). In cases of cT3/cN1+ tumors with pCR, only 8 % of participants considered appropriate the omission of Post-Mastectomy Radiation Therapy. CONCLUSION: There is still a wide variability in surgical approaches after NAC in the "real world". As NAC is increasingly used, multidisciplinary teams should be attuned to conforming their procedures to the rapid advances in this field.

Is routine axillary lymph node dissection needed to tailor systemic treatments for breast cancer patients in the era of molecular oncology? A position paper of the Italian National Association of Breast Surgeons (ANISC).

BACKGROUND: De-escalation of axillary surgery in breast cancer (BC) management began when sentinel lymph node biopsy (SLNB) replaced axillary lymph node dissection (ALND) as standard of care in patients with node-negative BC. The second step consolidated ALND omission in selected subgroups of BC patients with up to two macrometastases and recognized BC molecular and genomic implication in predicting prognosis and planning adjuvant treatment. Outcomes from the recent RxPONDER and monarchE trials have come to challenge the previous cut-off of two SLN in order to inform decisions on systemic therapies for hormone receptor-positive (HR+), human epidermal growth factor receptor type-2 (HER2) negative BC, as the criteria included a cut-off of respectively three and four SLNs. In view of the controversy that this may lift in surgical practice, the Italian National Association of Breast Surgeons (Associazione Nazionale Italiana Senologi Chirurghi, ANISC) reviewed data regarding the latest trials on this topic and proposes an implementation in clinical practice. MATERIAL AND METHODS: We reviewed the available literature offering data on the pathological nodal status of cN0 breast cancer patients. RESULTS: The rates of pN2 status in cN0 patients ranges from 3.5 % to 16 %; pre-surgical diagnostic definition of axillary lymph node status in cN0 patients by ultrasound could be useful to inform about a possible involvement of ≥4 lymph nodes in this specific sub-groups of women. CONCLUSIONS: The Italian National Association of Breast Surgeons (ANISC) considers that for HR + HER2-/cN0-pN1(sn) BC patients undergoing breast conserving treatment the preoperative workup should be optimized for a more detailed assessment of the axilla and the technique of SLNB should be optimized, if considered appropriate by the surgeon, not considering routine ALND always indicated to determine treatment recommendations according to criteria of eligibility to RxPONDER and monarch-E trials.

Prognostic Role of p53 Immunohistochemical Status in invasive Breast Cancer. A Retrospective Review of 1387 Cases With Luminal-Like/Her2 Negative Breast Tumors.

PURPOSE: The aim of this study was to evaluate the prognostic role of p53 immunohistochemical (IHC) expression in a large cohort of patients with hormone receptors (HR)-positive/Her2-negative primary invasive breast cancer. METHODS: Retrospective review of consecutive cases treated at our Breast Unit between 2003 and 2013. Patients were divided into 3 subgroups based on p53 IHC expression: null (0%), low (0.1%-49%), and high (≥50%) p53 expression. RESULTS: A total of 1387 patients were included in the study with a median follow-up of 86 months. After adjusting for age, size, node status, lymphovascular invasion, progesterone, and Ki67 expression, only null p53 immunophenotype was associated with worse disease-free survival (DFS) (OR 1.74, 95% IC, 1.11-2.71, P = .015) and distant recurrence-free survival (DRFS) (OR 1.73, 95% IC, 1.04-2.90, P = .036). Null p53 impacted significantly DFS and DRFS also in patients with early breast cancer. CONCLUSIONS: p53 IHC expression affects survival and, thus can be a valuable tool in the management of patients with HR-positive/Her2-negative breast cancer.

Liquid Biopsy in the Management of Breast Cancer Patients: Where Are We Now and Where Are We Going.

Liquid biopsy (LB) is an emerging diagnostic tool that analyzes biomarkers in the blood (and possibly in other body fluids) to provide information about tumor genetics and response to therapy. This review article provides an overview of LB applications in human cancer with a focus on breast cancer patients. LB methods include circulating tumor cells and cell-free tumor products, such as circulating tumor DNA. LB has shown potential in detecting cancer at an early stage, monitoring tumor progression and recurrence, and predicting patient response to therapy. Several studies have demonstrated its clinical utility in breast cancer patients. However, there are limitations to LB, including the lack of standardized assays and the need for further validation. Future potential applications of LB include identifying the minimal residual disease, early detection of recurrence, and monitoring treatment response in various cancer types. LB represents a promising non-invasive diagnostic tool with potential applications in breast cancer diagnosis, treatment, and management. Further research is necessary to fully understand its clinical utility and overcome its current limitations.

Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence.

BACKGROUND: Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. In humans, its defective function is associated with cancer development and induces specific post-transcriptional alterations of gene expression. In this study, we seek to unbiasedly identify mRNAs regulated by dyskerin in human breast cancer-derived cells. RESULTS: We find that dyskerin depletion affects the expression and the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin in the cytoplasm in the form of shorter 3' snoRT fragments. We then characterize the whole cytoplasmic dyskerin RNA interactome and find both H/ACA box snoRTs and protein-coding transcripts which may be targeted by the snoRTs' guide properties. Since a fraction of these protein-coding transcripts is involved in the nuclear hormone receptor binding, we test to see if this specific activity is affected by dyskerin. Obtained results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer cells. These results are paralleled by consistent observations on the outcome of primary breast cancer patients stratified according to their tumor hormonal status. Accordingly, experiments in nude mice show that the reduction of dyskerin levels in estrogen-dependent cells favors xenograft development in the absence of estrogen supplementation. CONCLUSIONS: Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions.

Successful Pregnancies, Births, and Children Development Following Oocyte Cryostorage in Female Cancer Patients During 25 Years of Fertility Preservation.

The preservation of fertility in cancer patients is a crucial aspect of modern reproductive medicine. Amenorrhea and infertility often occur after cancer therapy, worsening the quality of life. Cryopreservation of oocytes in young cancer patients is a therapeutic option for preserving fertility. A prospective study was conducted on 508 cancer patients who underwent oocyte cryopreservation to preserve fertility between 1996 and 2021 including the COVID-19 pandemic period. Patients underwent ovarian stimulation, followed by egg retrieval, and oocytes were cryopreserved by slow freezing or vitrification. Sixty-four thawing/warming cycles were performed. Survival, fertilization, pregnancy, and birth rate over the thawing/warming cycles were obtained. The data were compared with those from a group of 1042 nononcological patients who cryopreserved supernumerary oocytes. An average of 8.8 ± 6.9 oocytes were retrieved per cycle, and 6.1 ± 4.2 oocytes were cryopreserved. With their own stored oocytes, 44 patients returned to attempt pregnancy. From a total of 194 thawed/warmed oocytes, 157 survived (80%). In total, 100 embryos were transferred in 57 transfer/cycles, and 18 pregnancies were achieved. The pregnancy rate per transfer and pregnancy rate per patient were 31% and 41%, respectively. No statistically significant differences were observed between oncological patients and nononcological patients. A total of 15 babies were born from oncological patients. Children born showed normal growth and development. One minor malformation was detected.

First Surgical National Consensus Conference of the Italian Breast Surgeons association (ANISC) on breast cancer management in neoadjuvant setting: Results and summary.

RATIONALE: On October 15th, 2020, the first Surgical National Consensus Conference on neoadjuvant chemotherapy (NACT) was promoted by the Italian Association of Breast Surgeons (ANISC). METHOD: The Consensus Conference was entirely held online due to anti-Covid-19 restrictions and after an introductory four lectures held by national and international experts in the field, a total of nine questions were presented and a digital "real-time" voting system was obtained. A consensus was reached if 75% or more of all panelists agreed on a given question. RESULTS: A total of 202 physicians, from 76 different Italian Breast Centers homogeneously distributed throughout the Italian country, participated to the Conference. Most participants were surgeons (75%). Consensus was reached for seven out of the nine considered topics, including management of margins and lymph nodes at surgery, and there was good correspondence between the 32 "Expert Panelists" and the "Participants" to the Conference. Consensus was not achieved regarding the indications to NACT for high-grade luminal-like breast tumors, and the need to perform an axillary lymph node dissection in case of micrometastases in the sentinel lymph node after NACT. CONCLUSIONS: NACT is a topic of major interest among surgeons, and there is need to develop shared guidelines. While a Consensus was obtained for most issues presented at this Conference, controversies still exist regarding indications to NACT in luminal B-like tumors and management of lymph node micrometastases. There is need for clinical studies and analysis of large databases to improve our knowledge on this subject.

Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft.

We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.

Pre-analytics, a national survey of Senonetwork Italia breast centers: Much still to do ahead.

INTRODUCTION: Pre-analytics involves handling and processing of microbiopsy and surgical specimen. It is critical for the preservation of morphology and the integrity of molecular markers, which are paramount as prognostic and predictive factors in breast cancer. Although pre-analytical variables in breast cancer are codified by national and international guidelines, there is currently no data on their actual endorsement in clinical practice among Breast Units (BU). MATERIALS AND METHODS: An anonymous questionnaire was sent by e-mail by Senonetwork Italia, a no-profit organization representing the multidisciplinary network of BU in Italy. The questionnaire involved twenty-four questions concerning critical issues related to the average time and transport temperature of the samples, monitoring of warm and cold ischemia, average fixation time for biopsies and surgical specimens, inking of the margins, and radiography of the operating sample. RESULTS: Forty-nine of 113 affiliated BU (43%), involved in the management of 44% of all breast cancer treated every year in Italy, answered the questionnaire. More than 90% of the BU reported a biopsy/VABB fixation time between 6 and 24 h. Only 41% of the Centers received the fresh operative sample to be sectioned immediately, 20% used the vacuum method and the sample arrived in the laboratory within 24-72 h. Delay in sectioning the sample was reported in as many as 40% of BU, while hot and cold ischemia time was monitored in only 4.2% and 6.2% of BU, respectively. CONCLUSION: Critical issues on pre-analytics are reported by the majority of dedicated BU in Italy. This represents a major challenge regarding quality of care, and improvements are needed in order to obtain valid and reproducible results of prognostic and predictive factors.

Mitochondrial DNA analysis efficiently contributes to the identification of metastatic contralateral breast cancers.

PURPOSE: In daily practice, a contralateral breast cancer (CBC) is usually considered as a new independent tumor despite the indications of several studies showing that the second neoplasia may be a metastatic spread of the primary tumor. Recognition of clonal masses in the context of multiple synchronous or metachronous tumors is crucial for correct prognosis, therapeutic choice, and patient management. Mitochondrial DNA (mtDNA) sequencing shows high informative potential in the diagnosis of synchronous neoplasms, based on the fact that somatic mtDNA mutations are non-recurrent events, whereas tumors sharing them have a common origin. We here applied this technique to reveal clonality of the CBC with respect to the first tumor. METHODS: We analyzed 30 sample pairs of primary breast cancers and synchronous or metachronous CBCs with detailed clinical information available and compared standard clinico-pathological criteria with mtDNA sequencing to reveal the metastatic nature of CBCs. RESULTS: MtDNA analysis was informative in 23% of the cases, for which it confirmed a clonal origin of the second tumor. In addition, it allowed to solve two ambiguous cases where histopathological criteria had failed to be conclusive and to suggest a clonal origin for two additional cases that had been classified as independent by pathologists. CONCLUSION: Overall, the mtDNA-based classification showed a more accurate predictive power than standard histopathology in identifying cases of metastatic rather than bilateral breast cancers in our cohort, suggesting that mtDNA sequencing may be a more precise and easy-to-use method to be introduced in daily routine to support and improve histopathological diagnoses.

HLA-J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer.

The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA-G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA-J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a "pseudogene" by in silico sequence interpretation. HLA-J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA-J and frequently increased HLA-J mRNA levels after NACT. HLA-J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA-J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA-J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.

A regional population-based hereditary breast cancer screening tool in Italy: First 5-year results.

BACKGROUND: Up to 10% of individuals with breast cancer (BC) belong to families with hereditary syndromes. The aim of this study was to develop an instrument to identify individuals/families at high-hereditary risk for BC and offer dedicated surveillance programs according to different risks. METHODS: The instrument consisted of a primary questionnaire collecting history of BC and ovarian cancer (OC). This questionnaire was applied to women enrolled in the Emilia-Romagna Breast Cancer Screening Program. General practitioners (GPs) and specialists could propose the same questionnaire too. Women with a score of ≥ 2, were invited to complete an oncogenetic counseling. According to the Tyrer-Cuzick evaluation, women considered at high risk were invited to involve the most representative alive individual of the family affected with BC/OC for BRCA1/2 genetic testing. RESULTS: Since January 2012 and December 2016, 660 040 women were evaluated by the regional screening program, of which 22 289 (3.5%) were invited to the Spoke evaluation, but only 5615 accepted (25.2%). Totally, also considering women sent by GPs and specialists, 11 667 were assessed and 5554 were sent to the Hub evaluation. Finally, 2342 (42.8%) women fulfilled the criteria for genetic testing, and 544 (23.2%) resulted BRCA1/2 mutation carriers. CONCLUSIONS: To our knowledge, this is the first regional population-based multistep model that is aimed to identify individuals with BRCA1/2 mutations and to offer an intensive surveillance program for hereditary-high risk women. This tool is feasible and effective, even if more efforts must be performed to increase the acceptance of multiple assessments by the study population.

HPV DNA Associates With Breast Cancer Malignancy and It Is Transferred to Breast Cancer Stromal Cells by Extracellular Vesicles.

A causal link between Human Papillomavirus (HPV) and breast cancer (BC) remains controversial. In spite of this, the observation that HPV DNA is over-represented in the Triple Negative (TN) BC has been reported. Here we remark the high prevalence of HPV DNA (44.4%) in aggressive BC subtypes (TN and HER2+) in a population of 273 Italian women and we convey the presence of HPV DNA in the epithelial and stromal compartments by in situ hybridization. As previously reported, we also found that serum derived-extracellular vesicles (EVs) from BC affected patients contain HPV DNA. Interestingly, in one TNBC patient, the same HPV DNA type was detected in the serum-derived EVs, cervical and BC tissue samples. Then, we report that HPV DNA can be transferred by EVs to recipient BC stromal cells that show an activated phenotype (e.g., CD44, IL6 expression) and an enhanced capability to sustain mammospheres (MS) formation. These data suggest that HPV DNA vehiculated by EVs is a potential trigger for BC niche aggressiveness.

Hereditary breast cancer: screening and risk reducing surgery.

BACKGROUND: The screening modalities for women at high risk for breast cancer has received an increasing role during the last years. The aim of this study was to evaluate the performance of our screening program comparing the diagnostic sensitivity of clinical breast examination, mammography, ultrasonography (US) and magnetic resonance imaging (MRI). METHODS: Clinical Breast examination, mammography, US and MRI for each patient with BRCA1 and BRCA2 mutation who underwent breast surgery in our Institution from October 2008 to April 2016 were retrospectively evaluated. The diagnostic accuracy for MRI and for the other surveillance tests in identifying early breast cancer were assessed. RESULTS: Twenty-six female patients with genetic mutation underwent breast surgery. Twenty-two out of 26 (85%) developed cancer during the dedicated screening protocol whereas 4 women who underwent surgery did not have cancer. Imaging was able to detect cancer in all 22 patients (per patient sensibility of 100%), identifying all 35 neoplastic lesions (per lesion sensibility of 100%). The combination of Clinical Breast Examination, US and mammography aided the cancer diagnosis in 14 (64%) of patients with a sensitivity of 64% and specificity of 100%. MRI identified all the cancers, with sensibility and specificity of 100%. Moreover, in 8 (36%) of the 22 patients who developed breast cancers, the cancers were detected only by MRI, revealing a significant superiority respect to the other surveillance modalities (P<0.05). CONCLUSIONS: MRI demonstrated to be the best imaging modality in detection of breast cancer even for lesion <1 cm. Prophylactic mastectomy is the most effective risk reduction strategy in women at high risk, contributing to the reduction of anxiety related to the condition of a carrier.

A simple immunohistochemical bio-profile incorporating Bcl2 curbs those cases of invasive breast carcinoma for which an Oncotype Dx characterization is needed.

AIM: Our goal has been to evaluate the importance that the incorporation of Bcl2 in the ER/PGR/Her2/Ki67 bio-profile can have as predictor of the Oncotype Dx categories. MATERIAL AND METHODS: 156 consecutive cases of HR+/Her2- pN0/1 primary breast carcinoma were sent to the Oncotype Dx test. Immunohistochemical determination of Bcl2/ER/PGR/Ki67/Her2 expression was evaluated for each case. After the selection of the appropriate cut-off values for PGR and Ki67, explorative as well as confirmative statistical analyses were performed to build and validate predictive risk-of-recurrence immunohistochemical only bio-profiles. RESULTS: The predictive capacity of these immunohistochemical profiles was compared with both traditional and TAILORx Oncotype Dx risk class classification. This comparison showed that immunohistochemical bio-profiles select those cases not associated with high risk-of-recurrence of disease (luminal-A/B and luminal A/B Bcl2) and those that are instead at high risk and therefore worthy of chemotherapy (luminal-B ki67 and luminal-B Bcl2/Ki67), strongly suggesting to only submit PGR-positive/Bcl2-Ki67 altered cases to Oncotype Dx, thus reducing the number of cases to be tested. CONCLUSIONS: Our results indicate that the addition of Bcl2 to an immunohistochemical bio-profile definitely improves its predictive capacity to correctly select which cases to send to the Oncotype Dx test. We have also suggested that institutions with a significant number of breast carcinomas sent to the Oncotype Dx test can use these latter to derive their own PGR and Ki67 cut-off values, overcoming the drawbacks of sharing common inter-laboratory values. Validation of these bio-profiles as predictors of the Oncotype Dx categories is ongoing in a prospective series of new cases.

Granular cell tumour of the breast: A rare presentation of a breast mass in an elderly female with a subsequent breast cancer diagnosis.

A 74-year-old female patient presented with a hard breast mass and dimpling with a clinical suspicion of a carcinoma. Histological evaluation revealed a granular cell tumour. Granular cell tumour is a rare neoplasm, mostly benign in origin that may arise in every body site, 5%-15% of cases occur in the breast. It is strongly suggested that granular cell tumours origin is Schwann cells. Clinically, granular cell tumours presentation may mimic mammary carcinoma and their similar features on mammography and ultrasound make it difficult to differentiate between them.

Microinvasive breast carcinoma: An analysis from ten Senonetwork Italia breast centres.

BACKGROUND AND OBJECTIVES: We studied a large series of ductal carcinoma in situ with microinvasion (MIDC) an infrequent disease whose diagnosis and management are not well defined. METHODS: 17,431 cases of breast carcinoma were treated between 2011 and 2016 by ten Italian Breast Units. Our analysis included diagnostic and clinic-pathological characteristics, surgical management, and the use of adjuvant therapies. RESULTS: 15,091 cases (86.6%) were infiltrating carcinomas (IC), 2107 (12.1%) ductal carcinoma in situ (DCIS), and 233 (1.3%) MIDC. Age at diagnosis did not differ between DCIS and MIDC. MIDC were usually larger and expressed more frequently biologically aggressive features (higher Ki67 values, hormone receptor negativity and HER2/neu over-expression) (p < 0.01). Axillary lymph nodes were involved in 25 MIDC cases (12%), but >3 lymph nodes were involved in two cases only (1%). At multivariable analysis, only lymphovascular invasion (LVI) was associated with lymph node status (p < 0.01). Hormone therapy was prescribed in 388/1462 DCIS cases (26.5%), in 84/200 MIDC cases (42%), and in 11,086/14,188 IC cases (84.7%) (p < 0.01). Chemotherapy was administered in 28/190 MIDC cases (14.7%), and in 4080/11,548 IC cases (35.3%) (p < 0.001). CONCLUSIONS: This is one of the largest studies of MIDC reported in the literature. Approximately 10% of DCIS harbor one or more foci of MIDC, and the latter often expresses aggressive biological features. LVI is a predictor of axillary node involvement, but this is infrequent and usually limited. Conservative surgery is performed less often than in DCIS, and adjuvant chemotherapy is less frequently utilized compared to IC.

Axillary dissection versus no axillary dissection in patients with breast cancer and sentinel-node micrometastases (IBCSG 23-01): 10-year follow-up of a randomised, controlled phase 3 trial.

BACKGROUND: We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8-12·7). METHODS: In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. FINDINGS: Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5-81·0) in the no axillary dissection group, compared with 74·9% (70·5-79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65-1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae. INTERPRETATION: The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8-12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. FUNDING: International Breast Cancer Study Group.

Reducing harms from treatment. Sixteen years of surgery of the axilla for screen-detected breast cancers in Italy.

OBJECTIVES: Available evidence on axillary surgery has accumulated dramatically in the last two decades in favor of less invasive care. The aim of this paper is to study 16-years trends in the surgical management of the axilla in a large population-based data set of screen-detected breast cancers in Italy and to document at what extent recommendations have been adopted in actual clinical care. MATERIAL AND METHODS: This is a retrospective cohort study documenting the surgical management of the axilla in primary breast cancer patients over time. We retrieved from the Italian database of screen-detected cancers 41213 cases diagnosed in women aged 50-69 between years 2000 and 2015 in twelve Italian Regions. RESULTS: In pN0 cases, an increasing trend (p < 0.001) in the number of patients who received sentinel lymph node biopsy (SLNB) as the only axillary staging procedure was observed. In pN + cases SLNB was the only staging procedure in an increasing number of patients (p < 0.001) especially since the publication of the ACOSOG-Z0011 paper. In ductal carcinoma in situ (DCIS) SLNB was more frequent in mastectomies and in high grade and large lesions. However, 45% of low grade, small DCIS over the whole time period had some form of axillary surgery. CONCLUSION: This large series of screen-detected cases documents a strong time trend in the direction of reducing axillary surgery and hence potential harms from treatment. The continuing practice of SLNB in low risk DCIS is of concern in an era of increasing awareness towards overdiagnosis and overtreatment.