Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Breast cancer highlights from 2023: Knowledge to guide practice and future research.

This narrative work highlights a selection of published work from 2023 with potential implications for breast cancer practice. We feature publications that have provided new knowledge immediately relevant to patient care or for future research. We also highlight guidelines that have reported evidence-based or consensus recommendations to support practice and evaluation in breast cancer diagnosis and treatment. The scope of selected highlights represents various domains and disciplines in cancer control, from prevention to treatment of early and advanced breast cancer.

Evaluating the ability of an artificial-intelligence cloud-based platform designed to provide information prior to locoregional therapy for breast cancer in improving patient's satisfaction with therapy: The CINDERELLA trial.

BACKGROUND: Breast cancer therapy improved significantly, allowing for different surgical approaches for the same disease stage, therefore offering patients different aesthetic outcomes with similar locoregional control. The purpose of the CINDERELLA trial is to evaluate an artificial-intelligence (AI) cloud-based platform (CINDERELLA platform) vs the standard approach for patient education prior to therapy. METHODS: A prospective randomized international multicentre trial comparing two methods for patient education prior to therapy. After institutional ethics approval and a written informed consent, patients planned for locoregional treatment will be randomized to the intervention (CINDERELLA platform) or controls. The patients in the intervention arm will use the newly designed web-application (CINDERELLA platform, CINDERELLA APProach) to access the information related to surgery and/or radiotherapy. Using an AI system, the platform will provide the patient with a picture of her own aesthetic outcome resulting from the surgical procedure she chooses, and an objective evaluation of this aesthetic outcome (e.g., good/fair). The control group will have access to the standard approach. The primary objectives of the trial will be i) to examine the differences between the treatment arms with regards to patients' pre-treatment expectations and the final aesthetic outcomes and ii) in the experimental arm only, the agreement of the pre-treatment AI-evaluation (output) and patient's post-therapy self-evaluation. DISCUSSION: The project aims to develop an easy-to-use cost-effective AI-powered tool that improves shared decision-making processes. We assume that the CINDERELLA APProach will lead to higher satisfaction, better psychosocial status, and wellbeing of breast cancer patients, and reduce the need for additional surgeries to improve aesthetic outcome.

Micrometastases in the sentinel node after neoadjuvant therapy. Is axillary dissection still required?

The present review intends to discuss the controversies and strengths in clinically node-positive patients with axillary nodal status ypN i+ / mi after neoadjuvant chemotherapy. Over the past 20 years, a de-escalation approach toward axillary surgery has been observed in patients with breast cancer. The worldwide use of sentinel node biopsy in the upfront setting and after primary systemic therapy substantially reduced surgical complications or late sequelae and eventually improving quality of life of patients. However, the role of axillary dissection is still unclear in patients with low residual disease post-chemotherapy, namely those with micrometastases in the sentinel node, and its prognostic role is still not very clear. The aim of the present narrative review is to report the available evidence on this topic, discussing the pros and cons of performing axillary lymph node dissection in the infrequent finding of micrometastases in the sentinel node after neoadjuvant chemotherapy. We will also describe the ongoing prospective studies which are expected to shed light and guide future decisions.

Axillary surgery after neoadjuvant therapy in initially node-positive breast cancer: international EUBREAST survey.

BACKGROUND: There is no consensus on axillary management after neoadjuvant therapy (NAT) in patients with clinically node-positive (cN+) breast cancer. To investigate current clinical practice, an international survey was conducted among breast surgeons and radiation oncologists. The aim of the first part of the survey was to provide a snapshot of international discrepancies regarding axillary surgery in this context. METHODS: The European Breast Cancer Research Association of Surgical Trialists (EUBREAST) developed a web-based survey containing 39 questions describing clinical scenarios in the setting of axillary management in patients with cN1 disease converting to ycN0 after NAT. The survey was then distributed to breast surgeons and radiation oncologists via 14 breast cancer societies between April and October 2021. RESULTS: Responses from 349 physicians in 45 countries were recorded. The most common post-NAT axillary surgery in patients with cN1 disease converting to ycN0 was targeted axillary dissection (54.2 per cent), followed by sentinel lymph node biopsy (SLNB) alone (20.9 per cent), level 1-2 axillary lymph node dissection (ALND) (18.4 per cent), level 1-3 ALND (4 per cent), and targeted lymph node biopsy (2.5 per cent). For SLNB alone, dual tracers were most commonly used (62.3 per cent). Management varied widely in patients with ambiguous axillary status before initiation of treatment or a residual metastatic burden in the axilla after NAT. In patients with ycN+ tumours, ALND was the preferred surgical approach for 66.8 per cent of respondents. CONCLUSION: These results highlight the wide heterogeneity in surgical approaches to the axilla after NAT. To standardize the guidelines, further data from clinical research are urgently needed, which underlines the importance of the ongoing AXSANA (EUBREAST-3) study.

Ovarian reserve of women with and without BRCA pathogenic variants: A systematic review and meta-analysis.

INTRODUCTION: Preliminary clinical evidence suggests a detrimental effect of pathogenic variants of BRCA1 and 2 genes on fertility outcome. This meta-analysis evaluates whether women carrying BRCA mutations (BRCAm) have decreased ovarian reserve, in terms of Anti-Muellerian Hormone (AMH), compared to women without BRCAm (wild-type). MATERIAL AND METHODS: Systematic searches of PubMed, Medline, Scopus, Embase, Science Direct and the Cochrane Library from inception until July 2020 were conducted. All studies comparing AMH level in fertile age women, with and without BRCA pathogenic variants were considered. Sub-analyses were performed according to age, presence of breast cancer, and type of mutation. RESULTS: Among 64 studies, 10 series were included. For the entire cohort, a trend of reduced AMH level were found between BRCAm carriers and women without pathogenic variants. BRCAm carriers aged 41-years or younger had lower AMH levels compared to 41-years or younger wild type women (OR: 0.73 [95%CI-1.12;-0.35]; p = 0.0002). This finding was confirmed for BRCA1m carriers (OR: 1 [95%CI-1.96;-0.05]; p = 0.004) whereas no difference was observed between BRCA2m carriers and wild type women. The same analysis on breast cancer patients with and without BRCAm achieved the same results. CONCLUSION: Young BRCA1m carriers seem to have lower AMH level compared with wild type women and therefore a potential decreased ovarian reserve.

Fibrin Sealants and Axillary Lymphatic Morbidity: A Systematic Review and Meta-Analysis of 23 Clinical Randomized Trials.

BACKGROUND: use of fibrin sealants following pelvic, paraaortic, and inguinal lymphadenectomy may reduce lymphatic morbidity. The aim of this meta-analysis is to evaluate if this finding applies to the axillary lymphadenectomy. METHODS: randomized trials evaluating the efficacy of fibrin sealants in reducing axillary lymphatic complications were included. Lymphocele, drainage output, surgical-site complications, and hospital stay were considered as outcomes. RESULTS: twenty-three randomized studies, including patients undergoing axillary lymphadenectomy for breast cancer, melanoma, and Hodgkin's disease, were included. Fibrin sealants did not affect axillary lymphocele incidence nor the surgical site complications. Drainage output, days with drainage, and hospital stay were reduced when fibrin sealants were applied (p < 0.0001, p < 0.005, p = 0.008). CONCLUSION: fibrin sealants after axillary dissection reduce the total axillary drainage output, the duration of drainage, and the hospital stay. No effects on the incidence of postoperative lymphocele and surgical site complications rate are found.

Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized?

AIM: We report molecular subtype impact on 1325 early breast cancer (BCa) patients treated with whole breast hypofractionated (WBH) adjuvant forward-planned intensity modulated radiotherapy (F-IMRT) without boost. METHODS AND MATERIALS: From 02/2009-05/2017 1325 patients with pTis-pT3, pNx-N1aM0 BCa who underwent breast conservation surgery were treated with WBHF-IMRT in our institute, to a total dose of 40 Gy/15 fractions, without boost. Median age: 62 (interquartile range-IQR-:51.14-70.53) years. HISTOLOGY: 8% in situ carcinoma (ISC), 92% invasive tumors. Molecular subtypes (invasive tumors): 49.9% Luminal A, 33.1% Luminal B Her2 negative (-), 6.2% Luminal B Her2 positive (+), 3.6% Hormone Receptor (HR)- Her2+, 7.1% Triple negative (TNBC), and 0.2% HR+. Chemotherapy (CT) was prescribed in 28% of patients, hormonal therapy in 80.3%, monoclonal antibodies (MAb) in 86.8% of Luminal B Her2+ and 97.7% of HR- Her2+ patients. RESULTS: Median follow up was 72.43 (IQR: 44.63-104.13) months. The 5-year Kaplan-Meier estimates of local relapse-free survival (LRFS) was 97.8%, regional-(RRFS) 98.6%, loco-regional- (LRRFS) 96.9%, distant- (DRFS) 96.6%, disease-free survival (DFS) 94.8% and overall survival (OS) 95.5%. Considering molecular subtypes, 5-year LRFS was: 99.8% for Luminal A, 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 87.9% for HR- Her2+, 95.1% for TNBC and 99.1% for in situ carcinoma. CONCLUSION: While the overall estimated probability of LR within 5 years after WBHF-IMRT without boost is good (2.2%), molecular subtypes have a strong impact, despite MAb therapy in Her2+ patients, and CT for TNBC patients, and could be used as a parameter in deciding the boost prescription.

Axillary observation alone versus sentinel node biopsy: past, present and future perspectives.

The evolution of axillary surgery in breast cancer has led from complete axillary dissection (AD) to sentinel node biopsy (SNB). It has not stopped yet but continues with a progressive de-escalation of surgical procedures aiming at axillary conservation. In parallel, the meaning of axillary surgery has changed as well. Over time, the dual role of both a therapeutic and a staging procedure has decreased leaving room to other modalities to treat and stage breast cancer. Although, the gold standard for axillary staging in early breast cancer remains SNB, the idea that axillary surgery could be even omitted has been proposed. The concept of abandoning axillary surgery is revolutionary but not new. Historical literature provides interesting data on patients who did not receive any axillary treatment at all with no impact on their survival. Starting from this, several ongoing trials are working to demonstrate that in selected breast cancer cohorts the information deriving from axillary surgery is superfluous and "axillary observation" alone is as effective as SNB. Whilst surgery has been de-escalated to less invasive procedures, systemic treatment, radiotherapy, multigene assays and advanced imaging modalities have gained ground in the management of breast cancer. New research is expected to help select the subgroups of patients for whom axillary surgery is not necessary anymore. This is a qualitative review reporting the most relevant literature data from historical trials on the omission of axillary surgery to the most recent and ongoing ones.

Risk-Reducing Bilateral Salpingo-Oophorectomy for BRCA Mutation Carriers and Hormonal Replacement Therapy: If It Should Rain, Better a Drizzle than a Storm.

Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer. The most effective strategy to reduce this risk is the bilateral salpingo-oophorectomy, with or without additional risk-reducing mastectomy. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended between age 35 and 40 and between age 40 and 45 years for women carriers of BRCA1 and BRCA2 mutations, respectively. Consequently, most BRCA mutation carriers undergo this procedure prior to a natural menopause and develop an anticipated lack of hormones. This condition has a detrimental impact on various systems, affecting both the quality of life and longevity; in particular, women carrying BRCA1 mutation, who are likely to have surgery earlier as compared to BRCA2. Hormonal replacement therapy (HRT) is the only effective strategy able to significantly compensate the hormonal deprivation and counteract menopausal symptoms, both in spontaneous and surgical menopause. Although recent evidence suggests that HRT does not diminish the protective effect of RRBSO in BRCA mutation carriers, concerns regarding the safety of estrogen and progesterone intake reduce the use in this setting. Furthermore, there is strong data demonstrating that the use of estrogen alone after RRBSO does not increase the risk of breast cancer among women with a BRCA1 mutation. The additional progesterone intake, mandatory for the protection of the endometrium during HRT, warrants further studies. However, when hysterectomy is performed at the time of RRBSO, the indication of progesterone addition decays and consequently its potential effect on breast cancer risk. Similarly, in patients conserving the uterus but undergoing risk-reducing mastectomy, the addition of progesterone should not raise significant concerns for breast cancer risk anymore. Therefore, BRCA mutation carriers require careful counselling about the scenarios following their RRBSO, menopausal symptoms or the fear associated with HRT use.

Sentinel node biopsy after primary systemic therapy in node positive breast cancer patients: Time trend, imaging staging power and nodal downstaging according to molecular subtype.

BACKGROUND: The management of axilla after Primary Systemic Therapy (PST) for breast cancer is a highly debated field. Despite the proven axillary downstaging occurring after PST, there is still some degree of reluctance in applying sentinel node biopsy (SNB) in the neoadjuvant setting. PATIENTS AND METHODS: We performed a retrospective analysis on 181 PST patients with axillary positive nodes at presentation treated between 2005 and 2017 at San Raffaele Hospital in Milan. The aim was to observe the application time trend of SNB, to determine the imaging staging power and the axillary downstaging according to molecular subtypes. RESULTS: Median follow-up after surgery was 32.5(IQR: 12-59) months. After PST, 119 (65.7%) patients had no clinically palpable nodes, 72 (39.7%) converted to N0 on final imaging and 34 (18.8%) underwent SNB with an increasing application trend. Axillary-US showed the highest accuracy (69.3%) in re-staging axilla after PST. Staging power of preoperative testing varied with tumour biology: Positive Predictive Value was higher in Luminal A (80% for clinical examination and 100% for axillary-US) and Luminal B (72% and 70.5%) tumours, whilst Negative Predictive Value was higher in HER2 positive (100% and 93.3%), and triple negative (71.4% and 93.3%) tumours. Ninety five (52.5%) patients experienced axillary downstaging after PST, by molecular subtype 15% (3/20) in Luminal A, 46.4% (45/97) in Luminal B, 90.9% (20/22) in HER2+ and 70.3% (26/37) in triple negative breast tumours. CONCLUSION: SNB application after PST for breast cancer in node positive patients at presentation is increasing. Pre-operative axillary imaging and tumour biology help identify patients who might be candidates for SNB as a single staging procedure.

Sentinel node biopsy in early breast cancer. A review on recent and ongoing randomized trials.

INTRODUCTION: Sentinel Lymph Node Biopsy (SLNB) is regarded as the standard procedure for nodal staging in patients with early breast cancer. In the last decade several randomized trials have been evaluating its role and indications. MATERIALS AND METHODS: This article reviews recent and ongoing randomized trials on SLNB. RESULTS: Four randomized controlled trials have recently shown evidence that SLNB either alone or followed by radiation therapy is effective for the management in patients with low axillary tumor burden in early breast cancer. Nine randomized controlled trials on SLNB are ongoing: four assessing its role in case of positive sentinel node, three evaluating whether SLNB itself can be omitted when the preoperative nodal imaging is negative, two are studying SLNB in the neoadjuvant setting. DISCUSSION AND CONCLUSION: SLNB either alone or with axillary radiotherapy has been shown to be non-inferior to complete axillary dissection in terms of local recurrence, disease-free survival and overall survival in early breast cancer with minimally metastatic axilla. So far, results from ongoing trials are going to confirm the appropriate treatment in patients with limited axillary nodal involvement, the role and the timing of SLNB within the neoadjuvant setting and to define whether surgery can be avoided in the axilla in early stage breast cancer patients with negative preoperative imaging.

Less is more. Breast conservation might be even better than mastectomy in early breast cancer patients.

During the recent years an increase of mastectomy rates in early breast cancer patients has been observed. Nevertheless, several large population-based studies reported a possible improved outcome after breast conserving therapy compared to radical surgery, after all the adjustments. We hereby summarize our opinion on this topic suggesting that these robust and consistent data might challenge the statement that breast conserving therapy is merely not inferior to radical surgery.

Breast-conserving surgery in BRCA1/2 mutation carriers: are we approaching an answer?

BACKGROUND: Approximately 10% of patients with breast cancer who are treated with breast-conserving surgery (BCS) develop an ipsilateral-breast tumor recurrence (IBTR). The optimal local therapy for women with BRCA-associated breast carcinoma remains controversial. We report the outcome of BCS in BRCA mutation carriers followed at a single institution. METHODS: A total of 54 women with BRCA1/2-associated breast cancer treated with BCS and whole breast radiotherapy were matched for age, tumor size, and time of surgery with 162 patients with sporadic breast cancer who had the same treatment between February 1994 and October 2007. Primary end points were cumulative incidence of IBTR and contralateral breast cancer (CBC). Median follow-up was 4 years for both groups. RESULTS: Median age was 36 and 37 years for mutation carriers and controls, respectively; mean tumor size was 1.8 cm in carriers and 1.9 cm in controls. Ten-year cumulative incidence of IBTR was 27% for mutation carriers and 4% for sporadic controls (hazard ratio 3.9; 95% confidence interval 1.1-13.8; P = 0.03). Ten-year cumulative incidence of CBC was 25% for mutation carriers and 1% for sporadic controls (P = 0.03). CONCLUSIONS: Our data suggest that IBTR risk after BCS in BRCA1/2 mutation carriers is increased compared with patients who have sporadic breast cancer. Likewise, the risk of CBC seems to be increased in this group. These risks and the likelihood of developing new primary tumors should be discussed with carriers interested in breast conservation as well as when choosing risk-reducing strategies.

When sentinel lymph node is intramammary.

INTRODUCTION: Sentinel lymph node biopsy is an accepted standard of care for staging the axilla in patients with early-stage breast cancer. Little attention has been placed to the presence of intramammary sentinel lymph nodes (intraMSLNs) on preoperative lymphoscintigraphy. METHODS: Between December 2001 and September 2006, in 9632 breast cancer patients with clinically uninvolved axillary nodes, lymphoscintigraphy was performed at the European Institute of Oncology (EIO). An axillary SLN (axSLN) was identified in 99.4% of cases. An intraMSLN was identified in association with the axillary sentinel lymph node in 22 patients (0.2%). In 15 cases both the axSLN and the intraMSLN were excised. RESULTS: The intraMSLN was positive in six patients (micrometastatic in three cases). The axSLNs were negative in all 15 cases. Two patients with positive intraMSLNs and one patient with a negative intraMSLN underwent axillary dissection; all three cases had negative axillary nodes. At a median follow-up of 24 months, no locoregional or systemic recurrences were observed. CONCLUSIONS: Positive intraMSLNs can improve disease staging but do not necessarily portend axillary lymph node metastasis. When intraMSLNs and axSLNs are present, we advocate biopsy of both sites and that management of the axilla should rely on axSLN status. In cases with intraMSLNs as the only draining site on lymphoscintigraphy, decisions on axillary management should be made on individualized basis.