MRI-based radiomic models to predict surgical margin status and infer tumor immune microenvironment in breast cancer patients with breast-conserving surgery: a multicenter validation study.

OBJECTIVES: Accurate preoperative estimation of the risk of breast-conserving surgery (BCS) resection margin positivity would be beneficial to surgical planning. In this multicenter validation study, we developed an MRI-based radiomic model to predict the surgical margin status. METHODS: We retrospectively collected preoperative breast MRI of patients undergoing BCS from three hospitals (SYMH, n = 296; SYSUCC, n = 131; TSPH, n = 143). Radiomic-based model for risk prediction of the margin positivity was trained on the SYMH patients (7:3 ratio split for the training and testing cohorts), and externally validated in the SYSUCC and TSPH cohorts. The model was able to stratify patients into different subgroups with varied risk of margin positivity. Moreover, we used the immune-radiomic models and epithelial-mesenchymal transition (EMT) signature to infer the distribution patterns of immune cells and tumor cell EMT status under different marginal status. RESULTS: The AUCs of the radiomic-based model were 0.78 (0.66-0.90), 0.88 (0.79-0.96), and 0.76 (0.68-0.84) in the testing cohort and two external validation cohorts, respectively. The actual margin positivity rates ranged between 0-10% and 27.3-87.2% in low-risk and high-risk subgroups, respectively. Positive surgical margin was associated with higher levels of EMT and B cell infiltration in the tumor area, as well as the enrichment of B cells, immature dendritic cells, and neutrophil infiltration in the peritumoral area. CONCLUSIONS: This MRI-based predictive model can be used as a reliable tool to predict the risk of margin positivity of BCS. Tumor immune-microenvironment alteration was associated with surgical margin status. CLINICAL RELEVANCE STATEMENT: This study can assist the pre-operative planning of BCS. Further research on the tumor immune microenvironment of different resection margin states is expected to develop new margin evaluation indicators and decipher the internal mechanism. KEY POINTS: • The MRI-based radiomic prediction model (CSS model) incorporating features extracted from multiple sequences and segments could estimate the margin positivity risk of breast-conserving surgery. • The radiomic score of the CSS model allows risk stratification of patients undergoing breast-conserving surgery, which could assist in surgical planning. • With the help of MRI-based radiomics to estimate the components of the immune microenvironment, for the first time, it is found that the margin status of breast-conserving surgery is associated with the infiltration of immune cells in the microenvironment and the EMT status of breast tumor cells.

The learning curve of the MS-TRAM/DIEP breast reconstruction by dual-trained breast surgeons.

BACKGROUND: Breast cancer surgeries involving MS-TRAM/DIEP breast reconstruction has traditionally been collaborative efforts between breast surgeons and plastic surgeons. However, in our institution, this procedure is performed by dual-trained breast surgeons who are proficient in both breast surgery and MS-TRAM/DIEP breast reconstruction. This study aims to provide insights into the learning curve associated with this surgical approach. MATERIALS AND METHODS: We included eligible breast cancer patients who underwent MS-TRAM/DIEP breast reconstruction by dual-trained breast surgeons between 2015 and 2020 at our institution. We present the learning curve of this surgical approach, with a focus on determining factors affecting flap harvesting time, surgery time, and ischemic time. Additionally, we assessed the surgical complication rates. RESULTS: A total of 147 eligible patients were enrolled in this study. Notably, after 30 cases, a statistically significant reduction of 1.7 h in surgery time and 21 min in ischemic time was achieved, signifying the attainment of a plateau in the learning curve. And the major and minor complications were comparable between the early and after 30 cases. CONCLUSION: This study explores the learning curve and feasibility experienced by dual-trained breast surgeons in performing MS-TRAM/DIEP breast reconstruction. TRIAL REGISTRATION: NCT05560633.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase II single-arm study.

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin (PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (BC). Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD (30-35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 90-100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, rate of breast-conserving surgery (BCS), and safety (with a focus on cardiotoxicity). Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42 (53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval (95% CI), 48.5%-71.2%] patients achieved tpCR, and 49 (62.8%) achieved bpCR. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine (11.5%) patients experienced asymptomatic left ventricular ejection fraction (LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP (NT-proBNP), troponin I, or high-sensitivity troponin. Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile, especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Circumferential Shaving of the Cavity in Breast-Conserving Surgery: A Randomized Controlled Trial.

BACKGROUND: This randomized controlled trial aimed to investigate the effects of circumferential shaving on reducing the intraoperative margin positivity rate (MPR) during breast-conserving surgery (BCS). METHODS: Eligible breast cancer patients were randomly assigned into no-shave and shave groups. In the no-shave group, the cavity margins were collected for assessment after the tumor resection, whereas in the shave group, a circumferential shaving was performed before collecting the cavity margins. The primary outcome was the intraoperative MPR by frozen section analysis. RESULTS: A total of 181 patients, with a median age of 49 years, were randomized. Patient characteristics at baseline were well-balanced between the two groups. The intraoperative MPRs (12.1% vs. 7.8%, p = 0.38), postoperative MPRs (16.5% vs. 7.8%, p = 0.073), intraoperative re-excision rates (26.4% vs. 23.3%, p = 0.64), second operation rates (4.4% vs. 1.1%, p = 0.34), and successful BCS rate (93.4% vs. 94.4%, p = 0.94) were all similar between the no-shave and the shave groups. The volume of the shaved tissues was significantly increased in patients with larger breast volume (p < 0.01). In patients with C-E cup breasts, the no-shave and shave groups had 16.7% and 0% (p = 0.03) intraoperative MPRs, and 22.0% and 0% (p = 0.01) postoperative MPRs, respectively. In patients with A-B cup breasts, the MPRs were similar between the two groups. The presence of the ductal carcinoma in situ component is the only determinant of margin positivity. CONCLUSIONS: Circumferential shaving did not significantly reduce the MPR in BCS. Its benefit depends on the volume of the shaved tissues and the breast. Trial registration This trial was registered at ClinicalTrials.gov (NCT02648802).

Ductal Lavage for Patients With Nonlactational Mastitis: A Single-Arm, Proof-of-Concept Trial.

BACKGROUND: Surgery, steroids, and/or observations alone have been proposed for patients with nonlactational mastitis (NLM), but most of these studies were retrospective. The optimal treatment for these patients remains unclear. This prospective, single-arm, proof-of-concept trial aimed to evaluate the feasibility and safety of ductal lavage as a novel treatment for patients with NLM. METHODS: Eligible patients with NLM received an intraductal infusion of corticosteroids and antimicrobial agents and returned the next day for a breast massage. This cycle was repeated for 2 wk, and we followed up these patients for 1 y. Patients did not receive surgery or steroids after ductal lavage. The primary endpoint was the time to complete response (CR). RESULTS: This trial included 32 patients with a median (range) age of 32 (20-53). Skin erythema and tenderness were the major symptoms. The median (range) visual analog score was 5 (0-9). There were 21 (65.6%), 4 (12.5%), and 7 (21.9%) patients diagnosed as idiopathic granulomatous mastitis, periductal mastitis, and unspecific NLM, respectively. During the ductal lavage, the median (range) number of cannulated ducts at first attempt was 5 (3-8). Ductal lavage significantly reduced the visual analog score and mastitis score (M-score) (P < 0.01). Within a median follow-up of 15.6 mo, 93.8% (30/32) of patients achieved CR. The median (range) time to CR was 6 (0.5-21) mo. Three patients (10.0%) relapsed. No adverse events associated with ductal lavage were observed. CONCLUSIONS: Ductal lavage for patients with NLM is feasible and safe, and a definitive randomized controlled trial for further investigation is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02794688.

Development of nomograms to predict axillary lymph node status in breast cancer patients.

BACKGROUND: Prediction of axillary lymph node (ALN) status preoperatively is critical in the management of breast cancer patients. This study aims to develop a new set of nomograms to accurately predict ALN status. METHODS: We searched the National Cancer Database to identify eligible female breast cancer patients with profiles containing critical information. Patients diagnosed in 2010-2011 and 2012-2013 were designated the training (n = 99,618) and validation (n = 101,834) cohorts, respectively. We used binary logistic regression to investigate risk factors for ALN status and to develop a new set of nomograms to determine the probability of having any positive ALNs and N2-3 disease. We used ROC analysis and calibration plots to assess the discriminative ability and accuracy of the nomograms, respectively. RESULTS: In the training cohort, we identified age, quadrant of the tumor, tumor size, histology, ER, PR, HER2, tumor grade and lymphovascular invasion as significant predictors of ALNs status. Nomogram-A was developed to predict the probability of having any positive ALNs (P_any) in the full population with a C-index of 0.788 and 0.786 in the training and validation cohorts, respectively. In patients with positive ALNs, Nomogram-B was developed to predict the conditional probability of having N2-3 disease (P_con) with a C-index of 0.680 and 0.677 in the training and validation cohorts, respectively. The absolute probability of having N2-3 disease can be estimated by P_any*P_con. Both of the nomograms were well-calibrated. CONCLUSIONS: We developed a set of nomograms to predict the ALN status in breast cancer patients.

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. METHODS: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). RESULTS: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). CONCLUSION: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.

Benign Phyllodes Tumor of the Breast Diagnosed After Ultrasound-Guided Vacuum-Assisted Biopsy: Surgical Excision or Wait-and-Watch?

BACKGROUND: The role of tumor-free resection in the treatment of benign phyllodes tumors (PTs) is still unknown. Ultrasound-guided vacuum-assisted biopsy (UGVAB) has been used for complete removal of benign breast lesions. This retrospective study aimed to compare the risk of relapse between patients with benign PT who undergo UGVAB and those who receive surgical excision (SE). METHODS: Benign PT patients with a pathology diagnosis who had received treatment between 2005 and 2013 at the authors' hospital were identified. The patients who received UGVAB did not receive any SE. In the SE group, wide local excision or mastectomy was performed when appropriate. The Kaplan-Meier curve and Cox proportional hazards regression were used to analyze and compare the relapse-free survival (RFS) between the patients in the two groups. RESULTS: The study enrolled 225 female patients with benign PT. The patients in the UGVAB group (n = 108) had significantly smaller tumors, more fibroadenoma, a higher body mass index (BMI), and a lower Breast Imaging-Reporting and Data System classification than the patients in the SE group (n = 117). The 5-year cumulative RFS was 81.6 and 88.7 % (p = 0.11) respectively for the patients receiving UGVAB and SE during a median follow-up period of 35.5 months. After adjustment for age, tumor size, BMI, or presence of fibroadenoma, treatment (UGVAB vs. SE) was not associated with increased risk for relapse events (hazard ratio 0.34; 95 % confidence interval 0.08-1.43; p = 0.14). No distant metastasis or death events occurred. CONCLUSIONS: The patients with benign PT who received UGVAB alone did not have a significantly more compromised RFS than those who underwent SE. A prospective, randomized study is needed to confirm this observation.

What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis.

To evaluate the incidence of chemotherapy-induced amenorrhea (CIA) and its therapeutic impact in premenopausal breast cancer patients. A systematic search was performed to identify clinical studies that compared the incidence of CIA with different chemotherapy regimens and oncological outcomes with and without CIA. The fixed-effects and random-effects models were used to assess the pooled estimates. Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. A total of 15,916 premenopausal breast cancer patients from 46 studies were included. The cyclophosphamide-based regimens, taxane-based regimens, and anthracycline/epirubicin-based regimens all increased the incidence of CIA with pooled odds ratios of 2.25 (95 % CI 1.26-4.03, P = 0.006), 1.26 (95 % CI 1.11-1.43, P = 0.0003) and 1.39 (95 % CI 1.15-1.70, P = 0.0008), respectively. The three-drug combination regimens of cyclophosphamide,anthracycline/epirubicin, and taxanes (CAT/CET) caused the highest rate of CIA compared with the other three drug combinations (OR 1.41, 95 % CI 1.16-1.73, P = 0.0008). Tamoxifen therapy was also correlated with a higher incidence of CIA, with an OR of 1.48. Patients with CIA were found to exhibit better disease-free survival (DFS) and overall survival (OS) compared with patients without CIA. With respect to molecular subtype, this DFS advantage remained significant in hormone-sensitive patients (HR 0.61, 95 % CI 0.52-0.72, P < 0.00001). The current meta-analysis has demonstrated that anthracycline/epirubicin, taxanes, cyclophosphamide, and tamoxifen all contributed to elevated rates of CIA, and CIA was not merely a side effect of chemotherapy but was a better prognostic marker, particularly for ER-positive premenopausal early-stage breast cancer patients. However, this topic merits further randomized control studies to detect the associations between CIA and patient prognosis after adjusting for age, ER status, and other influential factors.

HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy.

BACKGROUND: The effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery. METHODS: We studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A χ2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated. RESULTS: A total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P < 0.001), LVI (P = 0.026), pN stage (N1 vs. N0: P = 0.018; N3 vs. N0: P < 0.001), and luminal B (P = 0.001) and HER-2 (P < 0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P < 0.001), pN stage (P = 0.003), and HER-2 subtype (P < 0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P = 0.031). CONCLUSIONS: The HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.

Distinct ER and PR expression patterns significantly affect the clinical outcomes of early HER2-positive breast cancer: A real-world analysis of 871 patients treated with neoadjuvant therapy.

INTRODUCTION: The impact of distinct estrogen receptor (ER) and progesterone receptor (PR) expression patterns on tumor behavior and treatment outcomes within HER2-positive breast cancer is not fully explored. This study aimed to comprehensively examine the clinical differences among patients with HER2-positive breast cancer harboring distinct ER and PR expression patterns in the neoadjuvant setting. METHODS: This retrospective analysis included 871 HER2-positive breast patients treated with neoadjuvant therapy at our hospital between 2011 and 2022. Comparisons were performed across the three hormone receptor (HR)-specific subtypes, namely the ER-negative/PR-negative/HER2-positive (ER-/PR-/HER2+), the single HR-positive (HR+)/HER2+, and the triple-positive breast cancer (TPBC) subtypes. RESULTS: Of 871 patients, 21.0% had ER-/PR-/HER2+ tumors, 33.6% had single HR+/HER2+ disease, and 45.4% had TPBC. Individuals with single HR+/HER2+ tumors and TPBC cases demonstrated significantly lower pathological complete response (pCR) rates compared to those with ER-/PR-/HER2+ tumors (36.9% vs. 24.3% vs. 49.2%, p < 0.001). Multivariate analysis confirmed TPBC as significantly associated with decreased pCR likelihood (OR = 0.42, 95%CI 0.28-0.63, p < 0.001). Survival outcomes, including disease-free survival (DFS) and overall survival (OS), showed no significant differences across HR-specific subtypes in the overall patient population. However, within patients without anti-HER2 therapy, TPBC was linked to improved DFS and a trend towards better OS. CONCLUSIONS: HER2-positive breast cancer exhibited three distinct HR-specific subtypes with varying clinical manifestations and treatment responses. These findings suggest personalized treatment strategies considering ER and PR expression patterns, emphasizing the need for further investigations to unravel molecular traits underlying HER2-positive breast cancer with distinct HR expression patterns.

Which nomogram is best for predicting non-sentinel lymph node metastasis in breast cancer patients? A meta-analysis.

To present a systematic [corrected] review and meta-analysis to evaluate the nomograms developed to predict non-sentinel lymph node (NSLN) metastasis in breast cancer patients. We focused on the six nomograms (Cambridge, MSKCC, Mayo, MDA, Tenon, and Stanford) that are the most widely validated. The AUCs were converted to odds ratios for the meta-analysis. In total, the Cambridge, Mayo, MDA, MSKCC, Stanford, and Tenon models were validated in 2,156, 2,431, 843, 8,143, 3,700, and 3,648 patients, respectively. The pooled AUCs for the Cambridge, MDA, MSKCC, Mayo, Tenon, and Stanford models were 0.721, 0.706, 0.715, 0.728, 0.720, and 0.688, respectively. Subgroup analysis revealed that in populations with a higher micrometastasis rate in the SLNs, the Tenon and Stanford models had a significantly higher predictive accuracy. A meta-regression analysis revealed that the SLN micrometastasis rate, but not the NSLN-positivity rate, was associated with improved predictive accuracy in the Tenon and Stanford models. The performance of the MSKCC and Cambridge models was not influenced by these two factors. All of these prediction models perform better than random chance. The Stanford model seems to be relatively inferior to the other models. The accuracy of the Tenon and Stanford models is influenced by the tumor burden in the SLNs.

CCL18 signaling from tumor-associated macrophages activates fibroblasts to adopt a chemoresistance-inducing phenotype.

The heterogeneity of cancer-associated fibroblasts (CAFs) might be ascribed to differences in origin. CD10 and GPR77 have been reported to identify a chemoresistance-inducing CAF subset in breast cancer. However, the precise mechanism for the formation of the CD10+GPR77+ CAFs remains unknown. In this study, we found that CCL18 expression was positively correlated with the density of CD10+GPR77+ CAFs in breast cancer and associated with a poor response to chemotherapy. Moreover, CCL18 secreted by tumor-associated macrophages (TAMs) activated a CD10+GPR77+ CAF phenotype in normal breast-resident fibroblasts (NBFs), which could then enrich cancer stem cells (CSCs) and induce chemoresistance in breast cancer cells. Mechanistically, CCL18 activated NF-κB signaling via PITPNM3 and thus enhanced the production of IL-6 and IL-8. Furthermore, intratumoral CCL18 injection significantly induced the activation of NBFs and the chemoresistance of xenografts in vivo. In addition, targeting CCL18 by anti-CCL18 antibody could inhibit the formation of CD10+GPR77+ CAFs and recover the chemosensitivity in vivo, leading to effective tumor control. Collectively, these findings reveal that inflammatory signaling crosstalk between TAMs and fibroblasts is responsible for the formation of the CD10+GPR77+ CAFs, suggesting CCL18-PITPNM3 signaling is a potential therapeutic target to block the activation of this specific CAF subtype and tumor chemoresistance.

A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study.

BACKGROUND: In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. METHODS: Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. RESULTS: Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. CONCLUSION: Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.

Cavity margins and lumpectomy margins for pathological assessment: which is superior in breast-conserving surgery?

PURPOSE: This prospective cohort study aimed to compare the efficacy of cavity margins (CMs) and lumpectomy margins (LMs) for pathological assessment in breast-conserving surgery. METHODS: We assessed the CMs and LMs of 163 breast cancer patients during breast-conserving surgery. We compared and analyzed the positivity rates of CM and LM. RESULTS: The positivity rate of CM at the case level and individual margin level was 30.7% and 8.0%, respectively. The positivity rate of LM was 12.3%, 33.1%, and 45.4% at the case level and 1.8%, 6.2%, and 9.1% at the individual margin level, when we used the National Surgical Adjuvant Breast and Bowel Project criteria (ink-free), 1 mm-free criteria and 2 mm-free criteria, respectively. The positivity rate of LM with 1 mm-free criteria was similar to that of CM. Delivery of neoadjuvant chemotherapy increased the positivity rate of CM (50.0% versus 25.2%; P < 0.01) but not LM (41.6% versus 30.7%; P > 0.05) at the case level, whereas the positivity rate of CM and LM both increased after neoadjuvant chemotherapy at the margin level (CMs: 15.5% versus 5.6%, P < 0.001; and LMs: 10.7% versus 4.9%, P < 0.001). In univariate and multivariate analysis, delivery of neoadjuvant chemotherapy, higher node-positive stage, and presence of ductal carcinoma in situ component were correlated with positive CM, whereas positive human epidermal growth factor receptor 2 status and higher node-positive stage were associated with positive LM. CONCLUSIONS: Ink-free criteria may be insufficient for LM assessment in breast-conserving surgery, and at least 1 mm width LM is suggested. After the delivery of neoadjuvant chemotherapy, CM assessment should be routinely performed in addition to LM assessment.

CD16+ fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition.

The leukocyte Fcγ receptor (FcγR)-mediated response is important for the efficacy of therapeutic antibodies; however, little is known about the role of FcγRs in other cell types. Here we identify a subset of fibroblasts in human breast cancer that express CD16 (FcγRIII). An abundance of these cells in HER2+ breast cancer patients is associated with poor prognosis and response to trastuzumab. Functionally, upon trastuzumab stimulation, CD16+ fibroblasts reduce drug delivery by enhancing extracellular matrix stiffness. Interaction between trastuzumab and CD16 activates the intracellular SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway, leading to elevated contractile force and matrix production. Targeting of a Rho family guanine nucleotide exchange factor, VAV2, which is indispensable for the function of CD16 in fibroblasts rather than leukocytes, reverses desmoplasia provoked by CD16+ fibroblasts. Collectively, our study reveals a role for the fibroblast FcγR in drug resistance, and suggests that VAV2 is an attractive target to augment the effects of antibody treatments.

A single-center, prospective and randomized controlled study: Can the prophylactic use of lamivudine prevent hepatitis B virus reactivation in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy?

Over the past four decades, chemotherapy has played an important role in prolonging survival in breast cancer patients. However, it may also result in undesirable side effects such as hepatitis B virus (HBV) reactivation seen in this study. With the increasing use of chemotherapy paralleling the rise in breast cancer incidence, the occurrence of HBV reactivation is likely to further increase. Several strategies use lamivudine to deal with this problem. Initially, lamivudine had been used to treat patients who developed alanine transaminase elevation attributable to HBV reactivation during chemotherapy. However, using this strategy, fatal reactivation has also been reported. Later studies have suggested that prophylactic lamivudine significantly reduces HBV reactivation and its associated morbidity. However, these studies were based mainly on patients with lymphoma, whereas studies on breast cancer patients were few. Moreover, these studies were retrospective. Recently, a prospective study has recommended that deferred preemptive lamivudine could be a comparable alternative to the prophylactic strategy. However, it was not a randomized controlled study. In this study, it was examined the efficacy of the prophylactic strategy in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy using a prospective, randomized controlled study. Two groups were studied. One group consisted of 21 patients who were treated with prophylactic lamivudine, the other group consisted of 21 patients who were not treated with prophylactic lamivudine. The results showed that the prophylactic lamivudine strategy significantly decreased the incidence of HBV reactivation (0 vs. 28.6%, P = 0.021). It was conclude that the prophylactic lamivudine strategy significantly reduces the incidence of HBV reactivation for hepatitis B s-antigen seropositive breast cancer undergoing chemotherapy.

Risk factors associated with loss to follow-up of breast cancer patients: A retrospective analysis.

BACKGROUND: Loss to follow-up (LTFU) during post-operative surveillance of breast cancer patients is detrimental. The pattern of LTFU and its risk factors in Chinese breast cancer patients remains unknown. METHOD: Eligible non-metastatic breast cancer patients who underwent surgery at our institution between 2009 and 2012 were included. The clinicopathological features, as well as the LTFU status, were retrieved from the REDCap database. LTFU was defined as the absence of patients for at least 12 months since her last contact. 5-year LTFU was defined as the LTFU status of each patients at 5 years after surgery. The incidence and potential risk factors of LTFU were analyzed. A LTFU-risk score was developed to quantify the risk of LTFU. RESULTS: A total of 1536 patients with breast cancer were included, and 411(26.8%) patients were 5-year LTFU. 198 patients were LTFU in the first year. Univariate and multivariate analysis revealed that age (younger and older), a lack of medical insurance, longer distance from residence to the hospital, pathology (DCIS/Paget's/Phyllodes), lymph node metastasis, the absence of endocrine therapy and fewer than five contact numbers were significantly and independently associated with the risk of LTFU. A LTFU-risk score was developed and was predictive of LTFU. CONCLUSIONS: A series of risk factors were significantly associated with post-operative LTFU of breast cancer patients. Patients with different risks of LTFU could possibly be identified, and surveillance plans could be individualized for different patients, so as to effectively reduce the overall LTFU rate, and optimize the allocation of medical resources.

Multicentre, randomised, open-label, non-inferiority trial comparing the effectiveness and safety of ductal lavage versus oral corticosteroids for idiopathic granulomatous mastitis: a study protocol.

INTRODUCTION: The ideal treatment for idiopathic granulomatous mastitis (IGM) remains unclear. In a prospective, single-centre, pilot study, we reported that ductal lavage treatment for non-lactational mastitis patients had a 1-year clinical complete response (cCR) rate of >90%, without any significant adverse events. Thus, in this multicentre, randomised, open-label, non-inferiority trial, we will aim to compare the effectiveness and safety of ductal lavage vs oral corticosteroids as the first-line treatment for patients with IGM. METHODS AND ANALYSIS: The trial will be conducted at the Breast Tumor Center of Sun Yat-sen Memorial Hospital in China and at least at one participating regional centre. We plan to recruit 140 eligible IGM patients who will be randomised into the ductal lavage group or oral corticosteroid group with a 1:1 ratio. The patients in the oral corticosteroid group will receive meprednisone or prednisone for 6 months. The patients in the ductal lavage group will receive ductal lavage and breast massage, as previously reported. All the participants will be followed up at the clinic for 1 year post randomisation. The primary endpoint of this trial will be the 1-year cCR rate, and the secondary endpoints will include the time to cCR, treatment failure rate, relapse rate and protocol compliance rate. The trial was designed to determine whether ductal lavage is non-inferior to oral corticosteroids (1-year cCR rate assumed to be 90%), with a non-inferiority margin of 15%. ETHICS AND DISSEMINATION: The ethics committee of Sun Yat-sen Memorial Hospital at Sun Yat-sen University approved the study (2018-Lun-Shen-Yan-No. 30). The results of the trial will be communicated to the participating primary care practices, published in international journals and presented at international clinical and scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03724903); Pre-results.

lncRNA CISAL Inhibits BRCA1 Transcription by Forming a Tertiary Structure at Its Promoter.

Cisplatin-based neoadjuvant chemotherapy has been shown to improve survival in patients with squamous cell carcinoma (SCC), but clinical biomarkers to predict chemosensitivity remain elusive. Here, we show the long noncoding RNA (lncRNA) LINC01011, which we termed cisplatin-sensitivity-associated lncRNA (CISAL), controls mitochondrial fission and cisplatin sensitivity by inhibiting BRCA1 transcription in tongue SCC (TSCC) models. Mechanistically, we found CISAL directly binds the BRCA1 promoter and forms an RNA-DNA triplex structure, sequestering BRCA1 transcription factor-GABPA away from the downstream regulatory binding region. Importantly, the clinical relevance of these findings is suggested by the significant association of CISAL and BRCA1 expression levels in TSCC tumors with neoadjuvant chemosensitivity and overall survival. We propose a new model where lncRNAs are tethered at gene promoter by RNA-DNA triplex formation, spatially sequestering transcription factors away from DNA-binding sites. Our study uncovers the potential of CISAL-BRCA1 signaling as a potential target to predict or improve chemosensitivity.