Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).

PURPOSE: Ki67 assessed at diagnosis (Ki67baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki672week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki672week) with recurrence-free survival. The aim was to define the association between Ki67baseline and after aromatase inhibitor (AI) exposure ∆Ki672week and Ki672week with key prognostic and biologic factors utilising data from the POETIC study. PATIENTS AND METHODS: In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression. RESULTS: Established associations of Ki67baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67baseline. In control group Ki672week was 18% lower than Ki67baseline (p < 0.001) when Ki672week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki672week) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type. CONCLUSIONS: The magnitude of this study allowed characterisation of relationships between Ki67baseline, ∆Ki672week and Ki672week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki672week or Ki672week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies.

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ.

BACKGROUND: Oestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision. METHODS: In total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate. RESULTS: ER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence). CONCLUSION: The strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Correction: The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lung cancer screening: does pulmonary nodule detection affect a range of smoking behaviours?

BACKGROUND: Lung cancer screening can reduce lung cancer mortality by 20%. Screen-detected abnormalities may provide teachable moments for smoking cessation. This study assesses impact of pulmonary nodule detection on smoking behaviours within the first UK trial of a novel auto-antibody test, followed by chest x-ray and serial CT scanning for early detection of lung cancer (Early Cancer Detection Test-Lung Cancer Scotland Study). METHODS: Test-positive participants completed questionnaires on smoking behaviours at baseline, 1, 3 and 6 months. Logistic regression compared outcomes between nodule (n = 95) and normal CT groups (n = 174) at 3 and 6 months follow-up. RESULTS: No significant differences were found between the nodule and normal CT groups for any smoking behaviours and odds ratios comparing the nodule and normal CT groups did not vary significantly between 3 and 6 months. There was some evidence the nodule group were more likely to report significant others wanted them to stop smoking than the normal CT group (OR across 3- and 6-month time points: 3.04, 95% CI: 0.95, 9.73; P = 0.06). CONCLUSION: Pulmonary nodule detection during lung cancer screening has little impact on smoking behaviours. Further work should explore whether lung cancer screening can impact on perceived social pressure and promote smoking cessation.

Determinants of motivation to quit in smokers screened for the early detection of lung cancer: a qualitative study.

BACKGROUND: The promotion of smoking cessation within lung cancer screening could lead to benefits for smoking-related disease and improve cost-effectiveness of screening. Little is known about how smokers respond to lung cancer screening and how this impacts smoking behaviour. We aimed to understand how lung cancer screening influences individual motivations about smoking, including in those who have stopped smoking since screening. METHODS: Thirty one long-term smokers aged 51-74 took part in semi-structured interviews about smoking. They had been screened with the EarlyCDT-Lung Test (13 positive result; 18 negative) as part of the Early Cancer Detection Test Lung Cancer Scotland Study. They were purposively sampled for interview based on their self-reported post-screening smoking behaviour. Eleven participants had stopped smoking since screening. Verbatim interview transcripts were analysed using thematic analysis. RESULTS: Two key overarching themes were interpretations of screening test results and emotional responses to those interpretations. Participants' understanding of the risk implied by their test result was often inaccurate, for example a negative result interpreted as an 'all-clear' from lung cancer and a positive result as meaning lung cancer would definitely develop. Those interpretations led to emotional responses (fear, shock, worry, relief, indifference) influencing motivations about smoking. Other themes included a wake-up call causing changes in perceived risk of smoking-related disease, a feeling that now is the time to stop smoking and family influences. There was no clear pattern in smoking motivations in those who received positive or negative test results. Of those who had stopped smoking, some cited screening experiences as the sole motivation, some cited screening along with other coinciding factors, and others cited non-screening reasons. Cues to change were experienced at different stages of the screening process. Some participants indicated they underwent screening to try and stop smoking, while others expressed little or no desire to stop. CONCLUSIONS: We observed complex and individualised motivations about smoking following lung cancer screening. To be most effective, smoking cessation support in this context should explore understanding of screening test results and may need to be highly tailored to individual emotional responses to screening.

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.

BACKGROUND: Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. METHODS: In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0-2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. FINDINGS: Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637-0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83-20·99) in the fulvestrant group versus 13·8 months (11·99-16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. INTERPRETATION: Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. FUNDING: AstraZeneca.

Breast conservation in ductal carcinoma in situ (DCIS): what defines optimal margins?

The introduction of mammographic screening has resulted in a rise in the detection rate of ductal carcinoma in situ (DCIS), currently accounting for one-fifth of screen-detected breast cancers. Although 60-70% of DCIS are treated with breast-conserving surgery (BCS) with or without radiotherapy, the frequency of subsequent surgery to re-excise positive margins in order to reduce the probability of recurrences remains high. DCIS recurrence is associated not only with financial, health and psychological implications; approximately half these recurrences are invasive disease. An appropriate margin width for patients undergoing BCS for invasive breast cancer has been largely agreed. Although there is a perception that such recommendations may be applicable to DCIS, major differences exist which may affect this application. Importantly, DCIS patients often do not receive systemic adjuvant (endocrine) therapy and not all receive radiotherapy in routine practice. There is evidence that wide margins (i.e. >10 mm) confer better protection against recurrence than positive (i.e. 0 mm) margins; however, there remains a debate concerning the optimum margin width between 0 and 10 mm. Previous studies have demonstrated that radiation therapy may not compensate for lack of re-excision in those patients with positive or close margins, while wide margins will inevitably compromise cosmesis and patients' body image perception. This review aims to address the clinical question of the minimal margin width in DCIS treated with BCS that is associated with the lowest recurrence rate and when, therefore, further surgical intervention for re-excision can be safely avoided. A range of clinical circumstances that might affect this are considered.

Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies.

We report the first study of the biological effect of fulvestrant on ER positive clinical breast cancer using sequential biopsies through to progression. Thirty-two locally/systemically advanced breast cancers treated with first-line fulvestrant (250 mg/month) were biopsied at therapy initiation, 6 weeks, 6 months and progression and immunohistochemically-analyzed for Ki67, ER, EGFR and HER2 expression/signaling activity. This series showed good fulvestrant responses (duration of response [DoR] = 25.8 months; clinical benefit = 81%). Ki67 fell (p < 0.001) in 79% of tumours by 6 months and lower Ki67 at all preprogression time-points predicted for longer DoR. ER and PR significantly decreased in all tumours by 6 months (p < 0.001), with some declines in ER (serine 118) phosphorylation and Bcl-2 (p = 0.007). There were modest HER2 increases (p = 0.034, 29% tumours) and loss of any detectable EGFR phosphorylation (p = 0.024, 50% tumours) and MAP kinase (ERK1/2) phosphorylation (p = 0.019, 65% tumours) by 6 months. While ER remained low, there was some recovery of Ki67, Bcl-2 and (weakly) EGFR/MAPK activity in 45-67% patients at progression. Fulvestrant's anti-proliferative impact is related to DoR, but while commonly downregulating ER and indicators of its signaling and depleting EGFR/MAPK signaling in some patients, additional elements must determine response duration. Residual ER at fulvestrant relapse explains reported sensitivity to further endocrine therapies. Occasional modest treatment-induced HER2 and weakly detectable EGFR/HER2/MAPK signaling at relapse suggests targeting of such activity might have value alongside fulvestrant in some patients. However, unknown pathways must drive relapse in most. Ki67 has biomarker potential to predict fulvestrant outcome and as a quantitative measure of response.

Personalization of loco-regional care for primary breast cancer patients (part 1).

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

Personalization of loco-regional care for primary breast cancer patients (part 2).

Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer.

INTRODUCTION: Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer. METHODS: In this double-blind, multicenter trial, 121 patients received fulvestrant 500 mg on Day 1 plus anastrozole 1 mg/day for 14 to 21 days (F + A); fulvestrant plus anastrozole placebo (F); or fulvestrant placebo plus anastrozole (A), 2 to 3 weeks before surgery. ER, progesterone-receptor (PgR) and Ki67 expression were determined from tumor biopsies before treatment and at surgery. RESULTS: A total of 103 paired samples were available (F, n = 35; F+A, n = 31; A, n = 37). All treatments significantly reduced mean ER expression from baseline (F: -41%, P = 0.0001; F + A: -39%, P = 0.0001; A: -13%, P = 0.0034). F and F + A led to greater reductions in ER versus A (both P = 0.0001); F + A did not lead to additional reductions versus F. PgR and Ki67 expression were significantly reduced with all treatments (means were -34% to -45%, and -75% to -85%, respectively; all P = 0.0001), with no differences between groups. CONCLUSIONS: In this short-term study, all treatments reduced ER expression, although F and F + A showed greater reductions than A. No significant differences were detected between the treatment groups in terms of PgR and Ki67 expression. No additional reduction in tumor biomarkers with combination treatment was observed, suggesting that F + A is unlikely to have further clinical benefit over F alone. TRIAL REGISTRATION: Clinicaltrials.gov NCT00259090.

Molecular classification of hormone receptor-positive HER2-negative breast cancer.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR+/HER2- breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR+/HER2- breast cancer.

Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized 'FIRST' study.

Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. At data cut-off, only 36 % of patients had progressed and the median time to progression (TTP) had not been reached for fulvestrant. Here, we report follow-up data for TTP for fulvestrant 500 mg versus anastrozole 1 mg. Key inclusion criteria were postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy. Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug. Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1; anastrozole was administered 1 mg/day. TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis, and investigator opinion after data cut-off. Best overall response to subsequent therapy and serious adverse events are also reported. In total, 205 patients received fulvestrant 500 mg (n = 102) or anastrozole (n = 103). Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment. Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole; a 34 % reduction in risk of progression (hazard ratio 0.66; 95 % confidence interval: 0.47, 0.92; P = 0.01). Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups. No new safety concerns for fulvestrant 500 mg were documented. These longer-term, follow-up results confirm efficacy benefit for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP, and, importantly, show similar best overall response rates to subsequent endocrine therapy.

Preoperative systemic therapy in locoregional management of early breast cancer: highlights from the Kyoto Breast Cancer Consensus Conference.

Data reviewed at the Kyoto Breast Cancer Consensus Conference (KBCCC) showed that preoperative systemic therapy (PST) could optimize surgery through the utilization of information relating to pre- and post-PST tumor stage, therapeutic sensitivity, and treatment-induced changes in the biological characteristics of the tumor. As such, it was noted that the biological characteristics of the tumor, such as hormone receptors, human epidermal growth factor receptor-2, histological grade, cell proliferative activity, mainly defined by the Ki67 labeling index, and the tumor's multi-gene signature, should be considered in the planning of both systemic and local therapy. Furthermore, the timing of axillary sentinel lymph node diagnosis (i.e., before or after the PST) was also noted to be critical in that it may influence the likelihood of axillary preservation, even in node positive cases. In addition, axillary diagnosis with ultrasound and concomitant fine needle aspiration cytology or core needle biopsy (CNB) was reported to contribute to the construction of a treatment algorithm for patient-specific or individualized axillary surgery. Following PST, planning for breast surgery should therefore be based on tumor subtype, tumor volume and extent, therapeutic response to PST, and patient preference. Nomograms for predicting nodal status and drug sensitivity were also recognized as a tool to support decision-making in the selection of surgical treatment. Overall, review of data at the KBCCC showed that PST increases the likelihood of patients receiving localized surgery and individualized treatment regimens.

EarlyCDT®-Lung test: improved clinical utility through additional autoantibody assays.

Tumor-associated autoantibodies (AAbs) have been described in patients with lung cancer, and the EarlyCDT®-Lung test that measures such AAbs is available as an aid for the early detection of lung cancer in high-risk populations. Improvements in specificity would improve its cost-effectiveness, as well as reduce anxiety associated with false positive tests. Samples from 235 patients with newly diagnosed lung cancer and matched controls were measured for the presence of AAbs to a panel of six (p53, NY-ESO-1, CAGE, GBU4-5, Annexin I, and SOX2) or seven (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, and MAGE A4) antigens. Data were assessed in relation to cancer type and stage. The sensitivity and specificity of these two panels were also compared in two prospective consecutive series of 776 and 836 individuals at an increased risk of developing lung cancer. The six-AAb panel gave a sensitivity of 39% with a specificity of 89 %, while the seven-AAb panel gave a sensitivity of 41 % with a specificity of 91 % which, once adjusted for occult cancers in the population, resulted in a specificity of 93 %. Analysis of these AAb assays in the at-risk population confirmed that the seven-AAb panel resulted in a significant increase in the specificity of the test from 82 to 90 %, with no significant change in sensitivity. The change from a six- to a seven-AAb assay can improve the specificity of the test and would result in a PPV of 1 in 8 and an overall accuracy of 92 %.

Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor-positive Breast Cancers.

PURPOSE: Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor-positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs. EXPERIMENTAL DESIGN: Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors. RESULTS: The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study. CONCLUSIONS: Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.

Identifying gaps in the locoregional management of early breast cancer: highlights from the Kyoto Consensus Conference.

A consensus conference was held to investigate issues related to the local management of early breast cancer. Here, we highlight the major topics discussed at the conference and propose ideas for future studies. Regarding axillary management, we examined three major issues. First, we discussed whether the use of axillary reverse mapping could clarify the lymphatic system of breast and whether the ipsilateral arm might help avoid lymphedema. Second, the use of an indocyanine green fluorescent navigation system was discussed for intraoperative lymphatic mapping. These new issues should be examined further in practice. Finally, some agreement was reached on the importance of "four-node diagnosis" to aid in the diagnostic accuracy of sentinel nodes. Regarding breast treatment, there was general agreement that the clinical value of surgical margins in predicting local failure was dependent on the tumor's intrinsic biology and subtypes. For patients treated with preoperative chemotherapy, less extensive excision may be feasible in those who respond to systemic therapy in an acceptable manner. Most trials of preoperative chemotherapy lack outcome data on local recurrence. Therefore, there is a need for such data for overview analysis. We also agreed that radiation after mastectomy may be beneficial in node-positive cases where more than four nodes are involved. Throughout the discussions for both invasive and noninvasive disease, the investigation of nomograms was justified for major issues in the decision-making process, such as the presence or absence of microinvasion and the involvement of nonsentinel nodes in sentinel node-positive patients.