No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS]: protocol of a prospective randomized clinical trial.

BACKGROUND: Following sentinel lymph node biopsy (SLNB), the axillary recurrence rate is very low although SLNB has a false-negative rate of 5-10%. In the ACOSOG Z0011 trial, non-sentinel positive-lymph nodes were found in more than 20% of the axillary dissection group; the SLNB only group did not have a higher axillary recurrence rate. These findings raised questions about the direct therapeutic effect of the SLNB. SLNB has post-surgical complications including lymphedema. Considering advances in imaging modalities and adjuvant therapies, the role of SLNB in early breast cancer needs to be re-evaluated. METHODS: The NAUTILUS trial is a prospective multicenter randomized controlled trial involving clinical stage T1-2 and N0 breast cancer patients receiving breast-conserving surgery. Axillary ultrasound is mandatory before surgery with predefined imaging criteria for inclusion. Ultrasound-guided core needle biopsy or needle aspiration of a suspicious node is allowed. Patients will be randomized (1:1) into the no-SLNB (test) and SLNB (control) groups. A total of 1734 patients are needed, considering a 5% non-inferiority margin, 5% significance level, 80% statistical power, and 10% dropout rate. All patients in the two groups will receive ipsilateral whole-breast radiation according to a predefined protocol. The primary endpoint of this trial is the 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. DISCUSSION: This trial will provide important evidence on the oncological safety of the omission of SLNB for early breast cancer patients undergoing breast-conserving surgery and receiving whole-breast radiation, especially when the axillary lymph node is not suspicious during preoperative axillary ultrasound. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04303715 . Registered on March 11, 2020.

Retrospective Cohort Study on the Long-term Oncologic Outcomes of Sentinel Lymph Node Mapping Methods (Dye-Only versus Dye and Radioisotope Mapping) in Early Breast Cancer: A Propensity Score-Matched Analysis.

PURPOSE: In sentinel lymph node (SLN) biopsy (SLNB) during breast cancer surgery, SLN mapping using dye and isotope (DUAL) may have lower false-negative rates than the dye-only (DYE) method. However, the long-term outcomes of either method are unclear. We aimed to compare long-term oncological outcomes of DYE and DUAL for SLNB in early breast cancer. Materials and Methods: This retrospective single-institution cohort study included 5,795 patients (DYE, 2,323; DUAL, 3,472) with clinically node-negative breast cancer who underwent SLNB and no neoadjuvant therapy. Indigo carmine was used for the dye method and Tc99m-antimony trisulfate for the isotope. To compare long-term outcomes, pathologic N0 patients were selected from both groups, and propensity score matching (PSM), considering age, pT category, breast surgery, and adjuvant treatment, was performed (1,441 patients in each group). RESULTS: The median follow-up duration was 8.7 years. The median number of harvested sentinel nodes was 3.21 and 3.12 in the DYE and DUAL groups, respectively (p=0.112). The lymph node-positive rate was not significantly different between the two groups in subgroups of similar tumor sizes (p > 0.05). Multivariate logistic regression revealed that the mapping method was not significantly associated with the lymph node-positive rate (p=0.758). After PSM, the 5-year axillary recurrence rate (DYE 0.8% vs. DUAL 0.6%, p=0.096), and 5-year disease-free survival (DYE 93.9% vs. DUAL 93.7%, p=0.402) were similar between the two groups. CONCLUSION: Dye alone for SLNB was not inferior to dual mapping regarding long-term oncological outcomes in early breast cancer.

The percentage of unnecessary mastectomy due to false size prediction using preoperative ultrasonography and MRI in breast cancer patients who underwent neoadjuvant chemotherapy: a prospective cohort study.

BACKGROUND: Imaging-estimated tumour extent after neoadjuvant chemotherapy tends to be discordant with the pathological extent. The authors aimed to prospectively determine the proportion of decisions regarding total mastectomy for potential breast-conserving surgery candidates owing to false size prediction with imaging in neoadjuvant chemotherapy and non-neoadjuvant chemotherapy patients. MATERIALS AND METHODS: The authors prospectively enroled clinical stage II or III breast cancer patients who are scheduled for total mastectomy between 2018 and 2021. This study was conducted at Seoul National University Hospital at South Korea. Before surgery, each surgeon recorded the hypothetical maximum tumour size at which the surgeon would have been able to attempt breast-conserving surgery if the patient had actually less than the size of the tumour at that location in the breast. After surgery, the hypothetical maximum tumour size was compared with the final pathologic total extent of the tumour, including invasive and in situ cancers. RESULTS: Among the 360 enroled patients, 130 underwent neoadjuvant chemotherapy, and 230 did not undergo neoadjuvant chemotherapy. Of the total of each group, 47.7% in the neoadjuvant chemotherapy group and 21.3% in the non-neoadjuvant chemotherapy group had a smaller pathologic tumour extent than the pre-recorded hypothetical maximum tumour size (P<0.001). Further analyses were conducted for the neoadjuvant chemotherapy group. The proportions of total mastectomy with false size prediction were higher in HER2-positive (63.3%) and triple-negative (57.6%) patients compared with ER-positive/HER2-negative (25.0%) patients (P<0.001). Both magnetic resonance imaging-pathology and ultrasonography-pathology size discrepancies were significantly associated with false decisions for total mastectomy (both P<0.001). Without magnetic resonance imaging, the false decision may be reduced by 21.5%. CONCLUSION: A total of 47.7% of patients who received total mastectomy after neoadjuvant chemotherapy were breast-conserving surgery eligible, which was significantly higher than that of non-neoadjuvant chemotherapy patients. Magnetic resonance imaging contributed the most to false size predictions.

Comparison of Quality of Life and Cosmetic Outcome of Latissimus Dorsi Mini-Flap With Breast Conservation Surgery Without Reconstruction.

PURPOSE: Latissimus dorsi mini-flap (LDMF) reconstruction after breast-conserving surgery (BCS) is a useful volume replacement technique when a large tumor is located in the upper or outer portion of the breast. However, few studies have reported the impact of LDMF on patients' quality of life (QoL) and cosmesis compared with conventional BCS. METHODS: We identified patients who underwent BCS with or without LDMF between 2010 and 2020 at a single center. At least 1 year after surgery, we prospectively administered the BREAST-Q to assess QoL and obtained the patients' breast photographs. The cosmetic outcome was assessed using four panels composed of physicians and the BCCT.core software. RESULTS: A total of 120 patients were enrolled, of whom 62 and 58 underwent LDMF or BCS only, respectively. The LDMF group had significantly larger tumors, shorter nipple-to-tumor distances in preoperative examinations, and larger resected breast volumes than did the BCS-only group (p < 0.001). The questionnaires revealed that QoL was poorer in the LDMF group, particularly in terms of the physical well-being score (40.9 vs. 20.1, p < 0.001). Notably, the level of patients' cosmetic satisfaction with their breasts was comparable, and the cosmetic evaluation was assessed by panels and the BCCT.core software showed no differences between the groups. CONCLUSION: Our results showed that cosmetic outcomes of performing LDMF are comparable to those of BCS alone while having the advantage of resecting larger volumes of breast tissue. Therefore, for those who strongly wish to preserve the cosmesis of their breasts, LDMF can be considered a favorable surgical option after the patient is oriented toward the potential for physical dysfunction after surgery.

Triple-Negative Breast Cancer-Derived Extracellular Vesicles Promote a Hepatic Premetastatic Niche via a Cascade of Microenvironment Remodeling.

Patients with triple-negative breast cancer (TNBC) often develop metastases in visceral organs including the liver, but the detailed molecular mechanisms of TNBC liver metastasis is not clearly understood. In this study, we tried to dissect the process of premetastatic niche formation in the liver by using patient-derived xenograft (PDX) models of TNBC with different metastatic propensity. RNA sequencing of TNBC PDX models that successfully metastasized to liver showed upregulation of the Cx3cr1 gene in the liver microenvironment. In syngeneic breast cancer models, the Cx3cr1 upregulation in liver preceded the development of cancer cell metastasis and was the result of recruitment of CX3CR1-expressing macrophages. The recruitment was induced by the CX3CL1 production from the liver endothelial cells and this CX3CL1-CX3CR1 signaling in the premetastatic niche resulted in upregulation of MMP9 that promoted macrophage migration and cancer cell invasion. In addition, our data suggest that the extracellular vesicles derived from the breast cancer cells induced the TNFα expression in liver, which leads to the CX3CL1 upregulation. Lastly, the plasma CX3CL1 levels in 155 patients with breast cancer were significantly associated with development of liver metastasis. IMPLICATIONS: Our data provides previously unknown cascades regarding the molecular education of premetastatic niche in liver for TNBC.

Targeting CLK4 inhibits the metastasis and progression of breast cancer by inactivating TGF-ß pathway.

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer that is highly resistant to current therapeutic options. According to the public databases Oncomine and KM plotter, the CLK4 expression is correlated with poor patient survival in TNBC, especially in mesenchymal-like TNBC (MES-TNBC) that has strong metastatic potential. Therefore, we investigated the potential involvement of CLK4 in the metastasis and progression of MES-TNBC. In the MES-TNBC cell lines, the CLK4 expression was elevated. Notably, the RNAi-mediated silencing of CLK4 reduced the expression of multiple epithelial-mesenchymal transition (EMT) genes that mediate metastasis. Furthermore, CLK4 silencing reduced both the invasive behaviors of the cultured cells and tumor metastasis in the mouse xenograft model. It is also noteworthy that CLK4 silencing repressed the invasive and cancer stem cell (CSC) properties that are induced by the TGF-ß signaling. Importantly, the pharmacological inhibition of CLK4 potently repressed the invasion and proliferation of MES-TNBC cell lines and patient-derived cells, which demonstrates its clinical applicability. Collectively, our results suggest that CLK4 plays a crucial role in invasion and proliferation of MES-TNBC, especially in the processes that are induced by TGF-ß. Also, this study characterizes CLK4 as a novel therapeutic target in breast cancer.

Impact of Trastuzumab on Ipsilateral Breast Tumor Recurrence for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer after Breast-Conserving Surgery.

PURPOSE: Trastuzumab is effective in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, few studies have reported the effect of trastuzumab on ipsilateral breast tumor recurrence (IBTR), whose incidence is higher in the HER2-positive subtype than in other subtypes. METHODS: We retrospectively investigated 959 patients who underwent breast-conserving surgery (BCS), chemotherapy, and radiotherapy for HER2-positive breast cancer between 2000 and 2017. IBTR was compared between the patients who received neoadjuvant or adjuvant trastuzumab (Tmab group) for a total duration of 1 year and those who received no trastuzumab (N-Tmab group). RESULTS: Propensity score matching designated 426 and 142 patients in the Tmab and N-Tmab groups, respectively. The median follow-up period for all patients after matching was 73.79 months. The IBTR-free survival rate was significantly higher in the Tmab group than in the N-Tmab group (10-year IBTR-free survival rate, 92.9% vs. 87.3%; p = 0.002). The multivariate analysis showed a significant association between the N-Tmab and Tmab group (hazard ratio, 3.03; 95% confidence interval, 1.07-8.59) and IBTR in addition to close or positive resection margin and hormone receptor (HR) positivity. The subgroup analysis showed that adjuvant treatment with trastuzumab significantly reduced IBTR among the patients with HR-negative or lymph node-negative breast cancer. CONCLUSION: Significantly reduced IBTR after BCS was observed in the patients who received 1 year of adjuvant/neoadjuvant trastuzumab treatment for HER2-positive breast cancer.

Comparison of Long-Term Oncological Outcomes in Oncoplastic Breast Surgery and Conventional Breast-Conserving Surgery for Breast Cancer: A Propensity Score-Matched Analysis.

PURPOSE: The oncoplastic breast-conserving surgery (OPS) technique, combined with the principles of oncological safety and plastic surgery, results in complete tumor resection while preserving the natural appearance of the breast. The purpose of this study was to evaluate the long-term oncological results after OPS compared with conventional breast-conserving surgery (BCS) for early breast cancer. METHODS: The medical records of patients who underwent breast cancer surgery and adjuvant radiation therapy at Seoul National University Hospital between 2011 and 2014 were reviewed. Ipsilateral breast tumor recurrence (IBTR)-free survival rate and recurrence-free survival (RFS) rates were compared between the OPS and BCS groups. RESULTS: One-to-one propensity score matching was conducted, yielding 371 patients in each group. The mean tumor distance from the nipple was shorter, and the mean retrieved specimen size and pathologic tumor size, including ductal carcinoma in situ, were larger in the OPS group than in the conventional BCS group (p < 0.001). Surgical margin positivity was not significantly different between the two groups (p = 0.777). The surgical technique was not significantly associated with IBTR (OPS versus conventional BCS, 5-year survival rate, 96.9% vs. 98.6%; p = 0.355) and RFS (5-year survival rate, 92.9% vs. 94.5%; p = 0.357) on the log-rank test. Multivariate analysis revealed that OPS versus conventional BCS was not significantly associated with survival outcomes. CONCLUSION: We observed no significant differences in long-term IBTR and RFS between the OPS and conventional BCS groups in this retrospective analysis. OPS can be an oncologically and surgically safe alternative option for conventional BCS for early breast cancer.

JAK2 regulates paclitaxel resistance in triple negative breast cancers.

We investigated the molecular mechanisms of paclitaxel resistance in TNBC using seven patient-derived xenograft (PDX) models and TNBC cell lines. Among the seven PDX models, four models showed resistance to paclitaxel. Dysregulation of JAK/STAT pathways and JAK2 copy number gains were observed in the four paclitaxel-resistant PDX tumors. In TNBC cell lines, silencing the JAK2 gene showed a significant but mild synergistic effect when combined with paclitaxel in vitro. However, JAK1/2 inhibitor treatment resulted in restoration of paclitaxel sensitivity in two out of four paclitaxel-resistant PDX models and JAK1/2 inhibitor alone significantly suppressed the tumor growth in one out of the two remaining PDX models. Transcriptome data derived from the murine microenvironmental cells revealed an enrichment of genes involved in the cell cycle processes among the four paclitaxel-resistant PDX tumors. Histologic examination of those PDX tumor tissues showed increased Ki67-positive fibroblasts in the tumor microenvironment. Among the four different cancer-associated fibroblast (CAF) subtypes, cycling CAF exhibiting features of active cell cycle was enriched in the paclitaxel-resistant PDX tumors. Additionally, fibroblasts treated with the conditioned media from the JAK2-silenced breast cancer cells showed downregulation of cell cycle-related genes. Our data suggest that the JAK2 gene may play a critical role in determining responses of TNBC to paclitaxel by modulating the intrinsic susceptibility of cancer cells against paclitaxel and also by eliciting functional transitions of CAF subtypes in the tumor microenvironment. KEY MESSAGES : We investigated the molecular mechanisms of paclitaxel resistance in TNBC. JAK2 signaling was associated with paclitaxel resistance in TNBC PDX models. Paclitaxel-resistant PDX tumors were enriched with microenvironment cCAF subpopulation. JAK2 regulated paclitaxel-resistant CAF phenotype transition.

Effects of tamoxifen and aromatase inhibitors on the risk of acute coronary syndrome in elderly breast cancer patients: An analysis of nationwide data.

BACKGROUND: Aromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen. METHODS: We analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE. RESULTS: We included 47,569 women for the final analysis. Patients were classified into 'No hormonal treatment (n = 18,807), 'Switch (n = 2097)', 'Tamoxifen (n = 7081)' and 'AI (n = 19,584)'. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74-0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84-1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47-0.84). CONCLUSIONS: Our results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE.