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For patients with breast cancer who receive docetaxel chemotherapy, taxane-associated acute pain syndrome (T-APS), considered a form of neural pathology, is a significant clinical problem. We evaluated the effect of prophylactic etoricoxib on T-APS in patients with breast cancer.We conducted a phase II randomised trial including 144 patients with breast cancer receiving four cycles of docetaxel-based chemotherapy. Patients were randomised in the ratio 1:1 to receive prophylactic etoricoxib (60 mg, Day 1 to Day 8) or no prophylactic treatment. The primary end-point was the overall incidence of T-APS across all cycles. Secondary end-points included the incidence of severe pain (greater than 5 on a scale 0-10); severity and duration of T-APS; Functional Assessment of Cancer Therapy-Breast subscale; chronic sensory and motor neurotoxicity and adverse events.The overall incidence of T-APS across all cycles of chemotherapy in the etoricoxib group was 57.1%, while that in the control group was 91.5% (P 0.001). The incidences of severe T-APS were 11.4% and 54.9% for the etoricoxib and control groups, respectively (P 0.001). The mean Functional Assessment of Cancer Therapy-Breast subscale score of the etoricoxib group (103.79-107.24) was significantly higher than that of the control group (93.88-96.71) (P = 0.001 at cycle 1 and P 0.001 at cycles 2-4). After four cycles of docetaxel chemotherapy, the etoricoxib group demonstrated a significantly higher mean Functional Assessment of Cancer Treatment Neurotoxicity subscale score than the control group (38.46, 95% CI: 37.63-39.29; 34.59, 95% CI: 33.73-35.45, respectively; P 0.001). Electromyography showed that most peripheral sensory nerves in the etoricoxib group had significantly improved action potential amplitudes and conduction velocities compared with those in the control group.Prophylactic use of etoricoxib could significantly reduce the incidence and severity of docetaxel-induced acute pain syndrome and potentially decrease docetaxel-induced peripheral neuropathy.ClinicalTrials.gov, NCT04565600.

Background Acute-on-chronic liver failure (ACLF) is characterized by the development of a syndrome associated with a high risk of short-term death in patients with acute decompensated cirrhosis, and better indicators are needed to predict such outcomes. Sarcopenia, a common complication of cirrhosis, is closely associated with poor prognosis and increased mortality. In this study, the skeletal muscle index of ACLF patients was measured to determine whether sarcopenia combined with clinical parameters can aid in identifying those at high risk of progression. Methods A total of 433 hospitalized patients with ACLF according to the APASL criteria were included and allocated into two groups: transplantation-free survival (n = 293) or progression (n = 140, 107 died; 33 underwent liver transplantation) within 90 days. Muscle mass was assessed based on the skeletal muscle index. The optimal cut-off value of the AMPAS1 model (age, MELD score, platelet count, alpha-fetoprotein level, sarcopenia, and more than one complication combination) for progression prediction was identified using receiver-operating characteristic (ROC) analysis. Results Sarcopenia was an independent risk factor for progression in the ACLF population (HR 3.771 95% CI 2.114–6.727, p Conclusion We demonstrate that sarcopenia is a simple and objective indicator for predicting short-term prognosis in patients with ACLF. Moreover, compared to conventional prognostic scores, AMPAS1 is a better model for predicting 90 day adverse outcomes in ACLF patients.

Background: Recent studies have explored the potential role of homologous recombination deficiency (HRD) as a biomarker and shown that the HRD status may be related to the pCR rate. However, does HRD specifically predict the efficacy of platinum chemotherapy, or only predict the benefit of the pCR, irrespective of the treatment regimen? Is there any difference in the efficacy of platinum supplementation between gBRCA1/2 carriers and HRD tumors without gBRCA mutations? Does the addition of platinum to neoadjuvant chemotherapy for patients without HRD bring no curative effects but only increase adverse reactions? We developed this meta-analysis and included all qualified relevant clinical trials to answer these research questions. Materials and methods: Eligible studies were systematically searched from inception to June 1, 2021, in the PubMed, Embase, Medline, Web of Science, and Cochrane databases, and in the abstracts of the European Society for Medical Oncology Congress and the American Society of Clinical Oncology Annual Meeting. The primary outcome was the pathological complete response (pCR, defined as ypT0/is ypN0) after neoadjuvant chemotherapy. Secondary outcomes included clinical response rates and grade 3 or higher adverse events. Classic forest plots were generated using standard techniques to present the meta-analysis results. Results: A total of 1404 patients were included in the present meta-analysis, of which the HRD status was measurable in 1142 (81.3%) patients, and 723 (51.5%) were confirmed to have HRD. Regardless of the HRD status, platinum-based neoadjuvant treatment was statistically associated with better pCR rates than platinum-free neoadjuvant regimens (51.3% vs. 37.6%, OR 1.93, 95% CI 1.13 - 3.30, p = 0.02). The pCR was higher in HRD patients receiving platinum than those without platinum exposure (56.7% vs. 39.4%, OR 1.95, 95% CI 1.17 - 3.23, p = 0.01), while no significant differences were identified between the platinum and control groups in non-HRD patients (36.5% vs. 20.5%, OR 1.82, 95% CI 0.61 - 5.40, p = 0.28). Irrespective of the treatment arm, the odds ratio of achieving the pCR was 3.35 times higher in patients with HRD than in non-HRD patients (51.6% vs. 27.4%, OR 3.35, 95% CI 1.93 - 5.81, p < 0.01). Moreover, among patients on platinum-based regimens, HRD patients had a significant pCR benefit compared to the non-HRD group (58.3% vs. 33.3%, OR 3.40, 95% CI 1.86 - 6.24, p < 0.01). For those without platinum exposure, the results revealed no difference in pCR rates, irrespective of the HRD status (34.3% vs. 20.5%, OR 1.89, 95% CI 0.81 - 4.43, p = 0.14). Among patients with HRD who received platinum-containing therapy, pooled results demonstrated no statistically significant difference between patients with BRCA mutations and those with BRCA wild-type (70.4% vs. 57.8%, OR 1.84, 95% CI 0.84 - 4.02, p = 0.12). With respect to clinical response rates, while more benefit was observed with the use of platinum in HRD and non-HRD patients, the difference was not statistically significant in the forest plot (85.1% vs. 76.1%, OR 1.97, 95% CI 0.91 - 4.27, p = 0.08). Additionally, our results revealed that grade 3 or higher adverse events were more frequently observed in patients on platinum-based regimens. Conclusion: Platinum-based neoadjuvant chemotherapy is associated with significantly higher pCR rates in early-stage triple-negative breast cancer patients with HRD, irrespective of BRCA status. Adding platinum to neoadjuvant treatment in the non-HRD population increases adverse reactions rather than improving the therapeutic effect. Citation Format: Yuanqi Chen, Liulu Zhang, Minyi Cheng, Xiaosheng Zhuang, Ci-Qiu Yang, Fei Ji, Hong-Fei Gao, Mei Yang, Teng Zhu, Jieqing Li, Kun Wang. Homologous recombination deficiency predicts the response to platinum-based neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-32.

PURPOSE Pathologic complete response (pCR) rates of patients with triple-negative breast cancer who were administered docetaxel plus carboplatin were significantly higher than those of patients administered epirubicin/cyclophosphamide followed by docetaxel in the neoadjuvant NeoCART trial. Here, we performed a preplanned secondary analysis of the homologous recombination deficiency (HRD) score as a predictor of the pCR in patients with triple-negative breast cancer from the NeoCART cohort. METHODS Pretherapeutic tumor tissues were assessed retrospectively by DNA extraction and sequencing. BRCA1/2 mutations were evaluated in both somatic and germline forms. HRD scores were calculated from genome-wide allele-specific copy number results and comprised telomeric allelic imbalance, loss of heterozygosity, and large-scale state transitions. High HRD scores were defined as ≥ 38, and HRD was defined as either a high HRD score or a deleterious BRCA1/2 mutation. RESULTS HRD testing was completed for 43 (79.6%) of 54 NeoCART cohort patients. Thirty of 43 (69.8%) tumors had high HRD scores, and eight patients had BRCA-mutated tumors. No significant association between BRCA1/2 mutation status and pCR was observed either in the general population or in the two treatment arms. Docetaxel plus carboplatin group patients who achieved pCR had higher HRD scores than non-pCR patients, and this difference approached significance (61.69 ± 24.26 v 39.44 ± 22.83, P = .061). No significant correlations between HRD scores and pCR (61.29 ± 24.02 v 53.21 ± 24.31, P = .480) or residual cancer burden 0/1 (62.50 ± 22.50 v 51.85 ± 24.74, P = .324) were observed in the epirubicin/cyclophosphamide followed by docetaxel group. CONCLUSION HRD is a potential predictive biomarker for clinical benefit from neoadjuvant carboplatin–based chemotherapy and provides a possibility for screening the optimum chemotherapy backbone to combine with immunotherapy.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC), and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane- and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase 2 trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for 6 cycles group (DCb group) or an epirubicin plus cyclophosphamide for 4 cycles followed by docetaxel for 4 cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between September 1, 2016, and December 31, 2019, 93 patients were randomly assigned, and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0) (odds ratio 2.52, 95% CI 2.4-43.1; p noninferiority = 0.004). Noninferiority was met, and the DCb regimen was confirmed to be superior to the EC-D regimen (P = 0.044, superiority margin of 5%). At the end of the 37-month median follow-up period, OS and EFS rates were equivalent in both groups. This article is protected by copyright. All rights reserved.

Background The benefit of adjuvant cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) in hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) early breast cancer (EBC) is uncertain. Hence, we performed a meta-analysis to determine the efficacy and safety of adjuvant CDK4/6 inhibitors plus ET and to identify potential preferred subpopulations for this regimen. Methods A literature search was conducted in PubMed, Embase, Cochrane databases up to Jan 15, 2021. Hazard ratios (HRs) for invasive disease-free survival (IDFS) and risk ratios (RRs) for grade 3/4 adverse events (AEs) and treatment discontinuation were extracted. Analysis with predefined subgroup variables was done. Trial sequential analysis (TSA) was performed to assess the conclusiveness of survival outcomes. Results Three trials were eligible (N = 12647). Compared with ET, adjuvant CDK4/6 inhibitors with ET prolonged IDFS in patients with HR+/HER2- EBC (HR 0.87, 95% CI 0.76–0.98, p = 0.03, I2 = 19%), with positive therapeutic responses observed in patients with N2/N3 nodal status (HR 0.83, 95% CI 0.71–0.97, p = 0.02, I2 = 0%). None of the cumulative z-curves crossed the trial monitoring boundaries in TSA, and no reliable conclusion could be drawn. The combination treatment carried a higher risk of grade 3/4 AEs (RR 4.14, 95% CI 3.33–5.15, p, Highlights • Primary results from clinical trials investigating adjuvant CDK4/6 inhibitors were inconsistent. • The meta-analysis demonstrated potential IDFS benefit of adjuvant CDK4/6 inhibitors with endocrine therapy in HR+/HER2-early breast cancer patients. • A statistically significantly improved IDFS was observed in patients with N2/N3 nodal status. • Overall evidence favoring the use of adjuvant CDK4/6 inhibitors remained inadequate.

Background Previous studies revealed that patients with early-stage metaplastic breast cancer (MBC) underwent mastectomy more often than breast-conserving therapy (BCT) mainly due to the larger tumor size. This study was performed to compare the survival outcomes following BCT versus mastectomy for patients with early-stage MBC. Methods Surveillance, Epidemiology, and End Results (SEER) database was used to identify women diagnosed with early-stage MBC (T1-3N0-3M0) between 2001 and 2016, who were treated with either BCT or mastectomy. We assessed overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and hazard ratios using Cox proportional hazards models. Results A total of 2412 MBC patients were identified, 881 (36.5%) of whom underwent BCT and 1531(63.5%) underwent mastectomy. The median follow-up time was 73 months. Most of patients had older age (≥50 years old), larger tumor size, higher American Joint Committee on Cancer (AJCC) stage and hormone receptor negativity. After adjustment for confounding variables, patients who underwent BCT had significantly improved OS (5-year OS: 84.3% vs 62.5%; 10-year OS: 73.0% vs 52.1%; adjusted HR = 0.76, 95%CI: 0.59–0.97, p = 0.028) and BCSS (5-year BCSS: 89.1% vs 70.8%; 10-year BCSS: 83.9% vs 67.5%; adjusted HR = 0.72, 95%CI: 0.53–0.96, p = 0.026) than those who underwent mastectomy, and this improvement remained significant for all T and N stages of MBC except for N2-3 stage. Conclusion BCT conferred improved OS and BCSS compared with mastectomy for patients with early-stage MBC, and the improvement persisted in almost all of the subgroups of different T and N stages., Highlights • Breast conservation benefits patients with early-stage metaplastic breast cancer. • Breast conservation has better survival than mastectomy for breast cancer patients. • It provides evidence of surgical options for patients with metaplastic breast cancer.

Background Immune infiltration of breast cancer is associated with clinical outcome. A growing number of research suggests the immune response were composed by variously functionally distinct immune cell. But it’s not clear which kinds of cell play the important role. The aim of this study was to determine whether differences in the cellular composition of the immune infiltrate in breast cancer influence survival and treatment response, and construct a stromal immunotype which could predict the response of neoadjuvant therapy and survival. Patients and Methods A total of 1502 ER negative breast cancers from TCGA and METABRIC cohort were used to infer the proportions of 22 subsets of immune cells, Another 320 ER negative breast cancer patients from Guangdong Provincial People’s Hospital in the validation cohort were also included in the study. Immune cell infiltration was evaluated by immunohistochemical staining or CIBERSORT method, Five immune features were selected out of 22 immune features to construct immunotype based on LASSO Cox regression model. ResultOf the cell subsets investigated, CD8+ T cells (hazard ratio [HR] = 0.064, 95% CI 0.018-0.234; p < 0.001), CD4+ T cells (HR 0.072, 95% CI 0.013-0.382; p = 0.002), B cells (HR 0.04, 95% CI 0.005-0.340; p = 0.003) , M1 macrophages(HR 0.09, 95% CI 0.016-0.502; p = 0.006) were associated with favourable outcome. T regulatory cells(HR 10.791, 95% CI 2.059-58.444; p = 0.005) emerged as the most strongly associated with poor outcome. Using the LASSO model, we classified ER negative breast cancer patients into stromal immunotype A subgroup (CD8+T cellshigh CD4+T cellshigh B cellhigh M1 macrophageshigh Treglow) and stromal immunotype B subgroup (CD8+T cellslow CD4+T cellslow B celllow M1 macrophageslow Treg high). Significant differences were found between immunotype A and immunotype B in the combined cohort with 10-year overall survival (66.2% vs. 49.8%; P Citation Format: Fei Ji, Ciqiu Yang, Liulu Zhang, Mei Yang, Jieqing Li, Hongfei Gao, Teng Zhu, Minyi Cheng, Kun Wang. Identification and validation of stromal immunotype predict survival and benefit from neoadjuvant chemotherapy in patients of breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-11.

Background: Pathogenic factors embedded in the germline genome are widely recognized as being crucial to breast cancer development. However, current knowledge is either concentrated on the pathogenic variants of a few individual genes or SNPs distributed sparsely across the genome in non-coding regions. Methods: We developed a multi-layered framework, DAGG, which converts somatic mutations or germline rare coding variants (gRCVs) into a functional spectrum of dozens of cellular functions and signaling pathways to identify potential pathogenic factors.Findings: We analyzed whole-exome sequencing (WES) data of 726 germline DNA samples and 169 breast tumor DNA samples from breast cancer patients with various pathological types and cancer-free female subjects, we found that germline pathogens of breast cancers were (1) mainly distributed in HER2-negative subtypes, and (2) involved Her2 signaling pathway activation and immune suppression. These computational discoveries were experimentally validated and can provide digital features to explain the germline differences between diseased and healthy genome (AUC = 0.76). Furthermore, an individual’s risk for breast cancer can be estimated by calculating the combined effects of these identified germline pathogens. Carriers of BRCA1/2 pathogenic variants were found to have a significantly higher average risk (p = 0.02). Interpretation: The results demonstrated that the identified pathogenic mechanisms by DAGG were compatible with our current understanding of the causes of breast cancer. Moreover, DAGG provides improved performance over currently used polygenic risk score method of measuring complex disease risks. Our framework promises possible future applications for the prevention, diagnosis, and treatment of breast cancer. Citation Format: Mei Yang, Yanhui Fan, Zhi-Yong Wu, Zhendong Feng, Qiangzu Zhang, Shunhua Han, Zhonghai Zhang, Xu Li, Yiqing Xue, Xiaoling Li, Meixia Hu, Jieqing Li, Weiping Li, Hongfei Gao, Ciqiu Yang, Chunming Zhang, Liulu Zhang, Teng Zhu, Minyi Cheng, Fei Ji, Juntao Xu, Hening Cui, Guangming Tan, Michael Q Zhang, Changhong Liang, Zaiyi Liu, You-Qiang Song, Gang Niu, Kun Wang. Rare variants in the germline genome holistically determine receptor-independent Her2 signaling pathway activation and immune suppression, shaping pathological type and risk of HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-29.

Background Appropriate tracing methods for sentinel lymph node biopsy (SLNB) play a key role in accurate axillary staging. This prospective, non-inferiority, phase III RCT compared the feasibility and diagnostic performance of ultrasound-assisted carbon nanoparticle suspension (CNS) mapping with dual tracer-guided SLNB in patients with early breast cancer. Methods Eligible patients had primary breast cancer without nodal involvement (cN0), or had clinically positive lymph nodes (cN1) that were downstaged to cN0 after neoadjuvant chemotherapy. Patients were randomly assigned (1 : 1) to undergo either ultrasound-assisted CNS sentinel lymph node (SLN) mapping (UC group) or dual tracer-guided mapping with CNS plus indocyanine green (ICG) (GC group). The primary endpoint was the SLN identification rate. Results Between 1 December 2019 and 30 April 2021, 330 patients were assigned randomly to the UC (163 patients) or GC (167 patients) group. The SLN identification rate was 94.5 (95 per cent c.i. 90.9 to 98.0) per cent in the UC group and 95.8 (92.7 to 98.9) per cent in the GC group. The observed difference of –1.3 (–5.9 to 3.3) per cent was lower than the prespecified non-inferiority margin of 6 per cent (Pnon–inferiority = 0.024). No significant difference was observed in metastatic node rate (30.5 versus 24.4 per cent; P = 0.222), median number of SLNs harvested (3 (range 1–7) versus 3 (1–8); P = 0.181), or duration of surgery (mean(s.d.) 7.53(2.77) versus 7.63(3.27) min; P = 0.316) between the groups. Among the subgroup of patients who had undergone neoadjuvant treatment, the SLN identification rate was 91.7 (82.2 to 100) per cent in the UC group and 90.7 (81.7 to 99.7) per cent in the GC group. Conclusion The diagnostic performance of ultrasound-assisted CNS mapping was non-inferior to that of dual tracer-guided SLN mapping with CNS plus ICG in patients with early breast cancer. Registration number NCT04951245 (http://www.clinicaltrials.gov).

Background and objectives This study mainly explored the factors that influence non-sentinel lymph node (NSLN) metastasis in patients with breast cancer (BC) whose axillary lymph nodal status changed from clinically node positive (cN+) to clinically node negative (cN0) after neoadjuvant chemotherapy (NAC). Methods We retrospectively analyzed the clinicopathological factors affecting NSLN metastasis in a total of 179 patients with cN+ BC downstaged to cN0 (120 in the training set and 59 in the validation set) who underwent both sentinel lymph node (SLN) biopsy and axillary lymph node dissection following NAC. Results Among 179 patients enrolled, the overall NSLN metastatic rate was 24.0% (95% confidence interval [CI]: 17.7%-30.3%). In multivariate logistic regression analysis, the number of positive SLNs achieving a pathological complete remission of the breast and clinical node staging was independent predictors of NSLN metastasis. A nomogram was established based on these factors and displayed a good discriminatory capability, with an area under the curve of 0.919 (95% CI: 0.865-0.973) for the training set and 0.900 (95% CI: 0.812-0.988) for the validation set and its clinical utility was confirmed by the decision curve analysis. Conclusions The nomogram established showed the ability to predict NSLN metastases in patients with initial cN+ BC that downstaged to cN0 after NAC.

The overall risk of developing a second primary cancer is increasing. The purpose of this study was to analyze the survival of patients with breast cancer diagnosed after a prior cancer and identify risk factors of breast cancer death in this population. Using the SEER database, we identified 1,310 woman diagnosed with breast cancer between 2010 and 2015 after a prior cancer as the primary cohort. Clinicopathological characteristics were compared using the Student t-test and chi-square test. Fine and Gray’s regression was used to evaluate the effect of treatments on breast cancer death. After propensity score matching (PSM), 9,845 pairs of patients with breast cancer as the prior or second cancer diagnosed between 2010 and 2011 were included as a second cohort. PSM-adjusted Kaplan-Meier and Cox hazards models were used to evaluate the impact of prior cancer on survival. The results showed that survivors of gynecologic cancers (e.g., ovarian cancer) had a higher risk of developing breast cancer than survivors of gastrointestinal and urinary tract cancers. More patients died of breast cancer than of prior urinary cancer (53.3% vs. 40%, P < 0.05) and melanoma (66.7% vs. 33.3%, P < 0.05). The ratio of breast cancer deaths to prior cancer deaths was significantly higher in patients with diagnoses interval ≥ 3 years than in those with the interval < 3 years (2.67 vs. 0.69, P < 0.001). Breast cancer-specific survival and overall survival rates were significantly lower in women with breast cancer as the second primary cancer than in those with breast cancer as the prior cancer, especially among hormone receptor-positive women. However, breast cancer treatment decreased the risk of breast cancer -specific death (hazard ratio = 0.695, 95% confidence interval: 0.586–0.725, P < 0.001). Breast cancer patients with prior cancers must be carefully considered for clinical trials.

Background Acute-on-chronic liver failure (ACLF) is characterized by the development of a syndrome associated with a high risk of short-term death in patients with acute decompensated cirrhosis, and better biomarkers are needed to predict such outcomes. Sarcopenia, a common complication of cirrhosis, is tightly associated with poor prognosis and increased mortality. In this study, the skeletal muscle index of ACLF patients was measured to determine whether sarcopenia combined with clinical parameters helps in identifying those at high risk of progression. Methods A total of 314 hospitalized ACLF patients were included and allocated into groups of transplantation-free survival (n = 214) or progression (n = 100) within 90 days. Muscle mass was assessed based on the skeletal muscle index. The optimal cutoff value of the AMPAS1 model (age, MELD score, platelet count, alpha-fetoprotein level, sarcopenia and more than one complication combination) for progressive prediction was identified using receiver operating characteristic (ROC) analysis. Results Sarcopenia was an independent risk factor for progression in the ACLF population (HR 3.705 95%CI 2.131-6.441, P

Immune response which involves distinct immune cells is associated with prognosis of breast cancer. Nonetheless, less study have determined the associations of different types of immune cells with patient survival and treatment response. In this study, A total of 1,502 estrogen receptor(ER)-negative breast cancers from public databases were used to infer the proportions of 22 subsets of immune cells. Another 320 ER-negative breast cancer patients from Guangdong Provincial People’s Hospital were also included and divided into the testing and validation cohorts. CD8+ T cells, CD4+ T cells, B cells, and M1 macrophages were associated with favourable outcome (all p p = 0.005). Using the LASSO model, we classified patients into the stromal immunotype A and B subgroups according to immunoscores. The 10 years OS and DFS rates were significantly higher in the immunotype A subgroup than immunotype B subgroup. Stromal immunotype was identified as an independent prognostic indicator in multivariate analysis in all cohorts and was also related to pathological complete response(pCR) after neoadjuvant chemotherapy. The nomogram that integrated the immunotype and clinicopathologic features showed good predictive accuracy for pCR and discriminatory power. The stromal immunotype A subgroup had higher expression levels of immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) and cytokines (IL-2, INF-γ, and TGF-β). In addition, patients with immunotype A and B diseases had distinct mutation signatures. Therefore, The stromal immunotypes could predict survival and responses of ER-negative breast cancer patients to neoadjuvant chemotherapy.

Peritoneal metastases from invasive lobular carcinoma (ILC) of breast are uncommon and usually related to poor prognosis due to difficulty of detection in clinical practice and drug resistance. Therefore, recognizing the entities of peritoneal metastases of ILC and the potential mechanism of drug resistance is of great significance for early detection and providing accurate management. We herein report a case of a 60-year-old female who presented with nausea and vomiting as the first manifestation after treated with abemaciclib (a CDK4/6 inhibitor) plus fulvestrant for 23 months due to bone metastasis of ILC. Exploratory laparotomy found multiple nodules in the peritoneum and omentum, and immunohistochemistry confirmed that the peritoneal metastatic lesions were consistent with ILC. Palliative therapy was initiated, but the patient died two months later due to disease progression with malignant ascites. Whole exome sequencing (WES) was used to detect the tumor samples and showed the peritoneal metastatic lesions had acquired ESR1 and PI3KCA mutations, potentially explaining the mechanism of endocrine therapy resistance. We argue that early diagnosis of peritoneal metastasis from breast cancer is crucial for prompt and adequate treatment and WES might be an effective supplementary technique for detection of potential gene mutations and providing accurate treatment for metastatic breast cancer patients.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC) and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane-based and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase II trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for six cycles group (DCb group) or an epirubicin plus cyclophosphamide for four cycles followed by docetaxel for four cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between 1 September 2016 and 31 December 2019, 93 patients were randomly assigned and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0; odds ratio 2.52, 95% CI 2.4-43.1; P

BACKGROUND: At present, most histological evaluations of microcalcifications without a mass are performed using X-ray guided hook wire localization or vacuum-assisted stereotactic biopsy (VASB), but there are still several limitations to these techniques. Therefore, we designed a visualization positioning technique based on three directions of mammography to accurately locate suspected microcalcifications to guide the biopsy. METHODS: We retrospectively analyzed consecutive patients with suspicious microcalcifications who underwent visualization positioning-guided biopsy (VPB) from June 1, 2016, to June 1, 2021. The visualization positioning technique was performed using an electronic ruler to measure the vertical distance from the microcalcification core to the vertical lines on mammography. RESULTS: A total of 133 patients (median age 46 years; range, 22–87 years) who underwent VPB were included in our study. Among the 133 cases of microcalcifications based on pathological results, 104 were benign, 14 were high risk, and 15 were malignant. In 124 (93.2%) patients, microcalcification was confirmed during the first round of VPB specimen analysis. Only 6 (4.5%) and 3 (2.3%) patients underwent second and third extended resections, respectively, as the resected specimens did not contain microcalcifications. Four patients (3.0%) with malignant biopsy results underwent a subsequent operation. Two patients with DCIS underwent mastectomy and sentinel lymph node biopsy because of diffuse calcification. One patient had no residual cancer, and the other was upgraded to invasive ductal carcinoma (IDC). Two patients with IDC underwent breast-conserving surgery and mastectomy with sentinel lymph node biopsy. CONCLUSIONS: VPB can be used to evaluate breast microcalcifications when a mass is not present, making it an effective diagnostic technique.

Background Nipple-sparing mastectomy (NSM) is becoming increasingly accepted as a treatment for breast disease; however, nipple-areolar complex (NAC) necrosis, a frequent severe postoperative complication, inhibits the popularity of this procedure. This study reports the technical aspects and short-term postoperative outcomes of NSM. Methods A single-center, retrospective review of 110 patients treated with NSM at our institution from November 2015 to September 2018 was performed. The primary outcome was the incidence of NAC necrosis. Results A total of 130 NSMs performed on 110 patients were included in our study. Median patient age was 42 years. We performed a sharp dissection by using a scalpel, raising 3-5 mm thick flaps, and continuing onto the undersurface of the NAC. None of the 110 patients appeared to have NAC necrosis or mastectomy skin flap necrosis. However, discoloration or ischemia of the NAC with eschar formation presented between postoperative days 3 and 7 in six nipples; four nipples were ischemic, and two were discolored. No infection was detected in any of the 110 patients. All NACs were intact after an average follow-up of 30 months, and no local or systemic recurrence was detected in those breast cancer cases. Conclusion NSM can be safely performed in properly selected patients. Nipple necrosis was avoided using a special surgical technique, and other complications occurred at an acceptable rate.

Background Tumor location in the breast varies, with the highest frequency in the upper outer quadrant and lowest frequency in the lower inner quadrant. Nevertheless, tumors in the central and nipple portion (TCNP) are poorly studied types of breast cancer; therefore, we aimed to clarify the clinicopathological characteristics and prognostic features of TCNP. Methods Using the Surveillance, Epidemiology, and End Results database, we identifed 105,037 patients diagnosed with tumor in the breast peripheral quadrant (TBPQ) (n=97,046) or TCNP (n=7,991). The chi-squared test was used to compare categorical variables across TCNP and TBPQ. Cox proportional hazard models with hazard ratios were applied to estimate the factors associated with prognosis. Results The median follow-up was over 43 months. Compared with TBPQ, TCNP patients were signifcantly older (age ≥66 years: 40.4% vs 34.1%, P 20 mm size: 46.9% vs 37.3%, P

Background: Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy regimens improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane- and anthracycline-based regimens.Methods: The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase 2 trial to assess the efficacy and safety of docetaxel combined with carboplatin with taxane- and anthracycline-based neoadjuvant chemotherapy in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to the experimental DCb group (docetaxel plus carboplatin for six cycles) or the EC-D group (epirubicin plus cyclophosphamide followed by docetaxel). In both groups, pCR (ypT0/is ypN0) was evaluated as the primary outcome.Results: Between September 1, 2016, and December 31, 2019, 93 patients from 6 participating centers were randomly assigned, and 88 patients were evaluated for the primary end-point (44 patients in the DCb group and 44 patients in the EC-D group). In the primary end point analysis, 27 patients in the DCb group achieved a pCR (61.4%, 95% CI 47.0-75.8), and 17 patients in the EC-D group achieved a pCR (38·6%, 95% CI 24.3-53.0); with a difference of 22.8% (odds ratio 2.52, 95% CI 2.4-43.1; p non-inferiority=0.004), non-inferiority was met, and the DCb regimen was confirmed as superior to the EC-D regimen (p=0.044, superiority margin of 5%). At the end of the 37-month median follow-up period, overall survival and event-free rates were equivalent in both groups. The grade 3/4 adverse events in the DCb group included anemia (4.5%), thrombocytopenia (2.3%), neutropenia (2.3%) and an increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio (2.3%).Conclusions: Compared with the taxane- and anthracycline-based regimen, the pCR rate of DCb was higher in TNBC patients.Trial registration: ClinicalTrials.gov, NCT03154749. Registered 12 May 2017 - Retrospectively registered, https://clinicaltrials.gov/

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate. It has been reported that circular RNA hsa_circ_0091579 (circ_0091579) is involved in HCC progression. Nevertheless, the molecular mechanism by which circ_0091579 modulates HCC advancement is indistinct. The expression of circ_0091579, microRNA (miR)-624, and H3 histone family member 3B (H3F3B) mRNA was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of HCC cells were analyzed using an extracellular flux analyzer. Adenosine triphosphate (ATP) level was evaluated using a commercial kit. Cell migration, invasion, and apoptosis were assessed by wound-healing, transwell, or flow cytometry assay. The relationship between miR-624 and circ_0091579 or H3F3B was verified using luciferase reporter assay and/or RNA immunoprecipitation (RIP) assay. H3F3B protein level was detected by western blotting. Circ_0091579 was upregulated in HCC tissues and cells. Circ_0091579 inhibition decreased xenograft tumor growth in vivo and repressed Warburg effect, migration, invasion, and induced apoptosis of HCC cells in vitro. MiR-624 was downregulated, while H3F3B was upregulated in HCC tissues and cells. Circ_0091579 acted as a miR-624 sponge and regulated H3F3B expression by adsorbing miR-624. MiR-624 inhibitor reversed circ_0091579 downregulation-mediated effects on the Warburg effect and malignant behaviors of HCC cells. H3F3B overexpression reversed the repressive impact of miR-624 mimic on the Warburg effect and malignancy of HCC cells. Circ_0091579 accelerated Warburg effect and tumor growth via upregulating H3F3B via adsorbing miR-624 in HCC, providing evidence to support the involvement of circ_0091579 in the progression of HCC.

BackgroundBreast cancers can be divided into HER2-negative and HER2-positive subtypes according to the status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to accurately assess its potential risk and to understand the potential mechanisms.MethodsWe developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs).FindingsWe characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed the HER2 signalling pathway was up-regulated in the germline of HER2-negative patients, and those with high APSP risk scores had suppressed immunity. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk of developing HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations.InterpretationThe DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer.FundingThis work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW)Research in contextEvidence before this studyThe majority of hereditary breast cancers are caused by BRCA1/2 mutations, and the presence of these mutations is strongly associated with an increased risk of breast cancer. Meanwhile, BRCA1/2 gene mutations are rarely found in sporadic breast cancers and only account for a modest percentage of all breast cancer patients. Polygenic risk score (PRS), a widely-used approach for stratifying individuals according to their risk of a certain kind of complex disease, has been used to predict subjects at high risk for breast cancer. However, relying on SNPs from genome-wide association studies (GWAS) without including gene expressions or pathway activities, PRS is not very suitable for cross-population prediction and describes disease risk in terms of genomic mutations without alluding to the underlying pathogenic mechanism(s). Therefore, there is still an urgent need for a population-independent comprehensive method to accurately assess the risk of breast cancer and to gain insights on potential mechanism(s).Added value of this studyWhen subjecting germline rare coding mutations (gRCMs) to DAGM framework, which results in the corresponding APSP and APSP risk score. Both APSP and APSP risk score can identify HER2-negative from HER2-positive breast cancers. These findings suggest HER2-negative breast cancer does not develop accidentally, but rather is defined by a genomic evolutionary strategy. Furthermore, this study also revealed the up-regulation of HER2 signalling pathway in germlines of HER2-negative breast cancers and the immune suppression in subjects with high APSP risk score, shedding new light on the potential mechanisms of developing HER2-negative breast cancer. Moreover, our APSP risk score was able to relatively accurately evaluate the risk of developing HER2-negative breast cancer for each female, including not only BRCA1/2 carriers, but also non-carriers.Implications of all the available evidenceThe present study suggests that HER2 signalling pathway activity, as an aggressive factor, contribute to the development of different types of breast cancers, either via the combined effects of multiple germline mutations in HER2-negative germlines or via amplifying the gene itself in HER2-positive tumour cells. This provides a theoretical basis for the prevention, diagnosis, and treatment of breast cancers. At the same time, the study provides preliminary methods for assessing the relative risk of HER2-negative breast cancer for females with or without BRCA1/2 mutations. Finally, our findings provide a new perspective and theoretical basis for identifying high-risk female subjects, based on the high APSP risk score, for early screening and prevention of HER2-negative breast cancer.

Background: Recent studies showed homologous recombination deficiency (HRD) status may correlate with pathological complete response (pCR) rate. However, whether HRD specifically predicts platinum chemotherapy efficacy or predicts pCR benefit irrespective of treatment regimen remains unclear. Methods: This meta-analysis aimed to determine the predictive value of HRD on pCR in patients with triple-negative breast cancer (TNBC) receiving platinum-based neoadjuvant chemotherapy (NCT). Published articles were searched on PubMed, Embase, Medline, Web of Science, and Cochrane database up to June 1, 2021 and studies reporting pCR rate for HRD carriers on platinum-based NCT selected. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined for pCR, clinical response rates and grade 3 or higher adverse events (AEs) using the random-effects model. Bias risk was evaluated using Cochrane Collaboration’s tool. Findings: Seven studies were eligible. Results showed that HRD carriers had higher pCR rates than non-HRD carriers across all treatment arms (OR 3.35, 95% CI 1.93 – 5.81, p < 0.01). In HRD carriers, pCR rate was higher in patients on platinum-based NCT relative to those without platinum exposure (OR 1.95, 95% CI 1.17 – 3.23, p = 0.01). We did not observe marked pCR improvements in non-HRD carriers. PCR rates in breast cancer susceptibility gene (BRCA) mutant relative to the BRCA wild-type group did not differ significantly in HRD carriers on platinum-based NCT (OR 1.84, 95% CI 0.84 – 4.02, p = 0.12). Interpretation: HRD carriers correlated with higher pCR in TNBC patients on platinum-based NCT irrespective of BRCA status. In non-HRD carriers, adding platinum to NCT was associated with elevated AEs rather than improved therapeutic effect. Registration Information: PROSPERO, registration number CRD420212498740. Funding Information: This study was supported by grants from National Natural Science Foundation of China (82171898)，Science and Technology Planning Project of Guangzhou City (202002030236), Beijing Medical Award Foundation(YXJL-2020-0941-0758), Science and Technology Special Fund of Guangdong Provincial People's Hospital (No.Y012018218), CSCO-Hengrui Cancer Research Fund (Y-HR2016-067), Medical Scientific Research Foundation of Guangdong Province (B2021406), and Guangdong Provincial Department of Education Characteristic Innovation Project（2015KTSCX080. Declaration of Interests: We declare no competing interests.

In this paper, 16 commercial banks listed on Shanghai and Shenzhen A-shares are selected as research samples and data from 2010 to 2019 are adopted. According to their mechanism of operation, scale of asset and etc, the research samples are divided into three groups. They are 16 listed commercial banks as a whole, 5 large state-owned listed commercial banks and 11 other medium and large listed commercial banks. The study makes an empirical analysis on the factors affecting the liquidity risk of listed commercial banks. Firstly, the factors affecting liquidity risk of listed commercial banks are divided into external and internal levels, and then descriptive analysis carried out on the factors at two levels. Then the stability of data is tested. After the data is tested, the panel data models applicable to 16 listed commercial banks as a whole, 5 large state-owned listed commercial banks and 11 other medium and large listed commercial banks are established through Hausman test and F test. The regression analysis of groups are conducted. Finally, according to regression analysis results, some reasonable recommendations are put forward.

e12606 Background: We recently performed the NeoCART trial to compare six cycles of docetaxel plus carboplatin (DCb) with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel (EC-D) in the neoadjuvant setting of triple-negative breast cancer (TNBC). The present study assessed the homologous recombination deficiency (HRD) score, stromal tumor-infiltrating lymphocytes (TILs), and Ki67 as predictors of pathological complete response (pCR) in the NeoCART trial cohort. Methods: Participants in the NeoCART trial (NCT03154749) were randomly assigned, at a 1:1 ratio, to an experimental DCb for 6 cycles (DCb group) or an EC for 4 cycles followed by docetaxel for 4 cycles group (EC-D group). Pretherapeutic formalin-fixed, paraffin-embedded tumor tissues were assessed retrospectively for DNA extraction and sequencing. Sequencing was performed using the Illumina HiSeq4000 platform. The HRD score was calculated based on the genome-wide allele-specific copy number result, and it was composed of three parts: 1) loss of heterozygosity (LOH): the number of segments >=15 Mb in length (but not covering the entire chromosome), mCN =0 and tCN > 0; 2) telomeric allelic imbalance (TAI): the number of segments with allelic imbalances (mCN!= tCN - mCN) extending to the telomeric end of a chromosome; 3) large-scale state transitions (LST), the number of chromosomal breaks between adjacent segments of at least 10 Mb, with a distance between them not larger than 3 Mb. Results: The primary and secondary endpoints, including pCR, event-free survival, overall survival, breast-conserving surgery rates, and treatment-related toxicities, were published previously. HRD testing was attempted on baseline FFPE tumor samples for 54 patients in the NeoCART cohort and was successfully completed for 43 patients (79.6%). It was unavailable for 11 patients due to inadequate tissue or the quality filter. Patients with HRD measurable tumors received DCb in 22 cases and EC-D in 21 cases. TP53 (93.0%), PIK3CA (27.9%), PTEN (11.6%), ATRX (9.3%), NF1 (9.3%), PIK3R1 (9.3%) and PKHD1 (9.3%) were the most frequently mutated genes. No significant association between BRCA1/2 mutation status and pCR was observed in the general population or the two treatment arms. Patients in the DCb group who achieved pCR had a higher HRD score (p =0.04), higher stromal TILs (p =0.02), and a higher Ki67 index (p =0.04) than non-pCR patients. RCB 0/1 was associated with higher stromal TILs (P =0.05) and a higher Ki67 index (P =0.008). However, no correlation between HRD score and pCR was observed in the EC-D group. Conclusions: PCR in TNBC patients correlated with a higher HRD score, higher stromal TILs, and a higher Ki67 index on carboplatin-based neoadjuvant chemotherapy regardless of BRCA status. Clinical trial information: NCT03154749.

ObjectiveInvasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) account for most breast cancers. However, the overall survival (OS) differences between ILC and IDC remain controversial. This study aimed to compare nonmetastatic ILC to IDC in terms of survival and prognostic factors for ILC.MethodsThis retrospective cohort study used data from the Surveillance, Epidemiology and End Results (SEER) Cancer Database (www.seer.cancer.gov). Women diagnosed with nonmetastatic ILC and IDC between 2006 and 2016 were included. A propensity score matching (PSM) method was used in our analysis to reduce baseline differences in clinicopathological characteristics and survival outcomes. Kaplan-Meier curves and log-rank test were used for survival analysis.ResultsCompared to IDC patients, ILC patients were diagnosed later in life with poorly differentiated and larger lesions, as well as increased expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). A lower rate of radiation therapy and chemotherapy was observed in ILC. After PSM, ILC, and IDC patients exhibited similar OS (HR=1.017, p=0.409, 95% CI: 0.967–1.069). In subgroup analysis of HR-negative, AJCC stage III, N2/N3 stage patients, or those who received radiotherapy, ILC patients exhibited worse OS compared to IDC patients. Furthermore, multivariate analysis revealed a 47% survival benefit for IDC compared to ILC in HR-negative patients who received chemotherapy (HR=1.47, p=0.01, 95% CI: 1.09–1.97).ConclusionsOur results demonstrated that ILC and IDC patients had similar OS after PSM. However, ILC patients with high risk indicators had worse OS compared to IDC patients by subgroup analysis.

Objectives Breast cancers show different regression patterns after neoadjuvant chemotherapy. Certain regression patterns are associated with more reliable margins in breast-conserving surgery. Our study aims to establish a nomogram based on radiomic features and clinicopathological factors to predict regression patterns in breast cancer patients. Methods We retrospectively reviewed 144 breast cancer patients who received neoadjuvant chemotherapy and underwent definitive surgery in our center from January 2016 to December 2019. Tumor regression patterns were categorized as type 1 (concentric regression + pCR) and type 2 (multifocal residues + SD + PD) based on pathological results. We extracted 1158 multidimensional features from 2 sequences of MRI images. After feature selection, machine learning was applied to construct a radiomic signature. Clinical characteristics were selected by backward stepwise selection. The combined prediction model was built based on both the radiomic signature and clinical factors. The predictive performance of the combined prediction model was evaluated. Results Two radiomic features were selected for constructing the radiomic signature. Combined with two significant clinical characteristics, the combined prediction model showed excellent prediction performance, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval 0.8343–0.9701) in the primary cohort and 0.826 (95% confidence interval 0.6774–0.9753) in the validation cohort. Conclusions Our study established a unique model combining a radiomic signature and clinicopathological factors to predict tumor regression patterns prior to the initiation of NAC. The early prediction of type 2 regression offers the opportunity to modify preoperative treatments or aids in determining surgical options.

Purpose The aim of this study was to explore the value of adjuvant chemotherapy in patients with early-stage ER/PR-positive mucinous carcinoma. Methods We identified early-stage ER/PR-positive mucinous carcinoma patients in the Surveillance, Epidemiology, and End Results (SEER) database. We used propensity-score matching (PSM) analysis to eliminate selection bias and differences in baseline characteristics. Univariate and multivariate analyses were performed to identify significant prognostic factors. The primary outcomes were overall survival (OS) and breast cancer-specific survival (BCSS), which were evaluated with the Kaplan-Meier method. Results After propensity score matching, 805 pairs were selected. Patients with early-stage ER/PR-positive mucinous adenocarcinoma in the chemotherapy group had a better OS, but not BCSS, than those in the nonchemotherapy group after PSM (OS: p, Highlights • Propensity-score matching was used to narrow selection bias. • Chemotherapy benefits patients with negative nodes and tumors larger than 3 cm. • Chemotherapy benefits patients with positive nodes and tumors larger than 1 cm. • Randomized controlled trials are expected in the future.

Introduction Our previous research has confirmed that a carbon nanoparticle suspension (CNS) tracer for sentinel lymph node biopsy (SLNB) has a satisfactory identification rate. The aim of this randomized study was to compare the performance of ultrasound-assisted carbon nanoparticle suspension with that of a dual-tracer method using CNS plus indocyanine green (ICG) for sentinel lymph node (SLN) mapping in patients with early breast cancer (BC). Methods This was a prospective, randomized, controlled phase III clinical study. We included patients with primary lymph node-negative (cN0) BC or with initial cN1 BC that downstaged to cN0 after neoadjuvant chemotherapy (NAC). SLNB was performed in all enrolled patients by certified breast surgeons who were well trained in SLNB. The dual method using the CNS and ICG was standardized for SLNB in our study. All patients were randomized 1:1 to receive the CNS assisted by preoperative ultrasound positioning (CNS group) or the CNS plus ICG (CG group) for SLN mapping. The node to which black-stained or fluorescent lymph vessels flowed first was defined as the first sentinel lymph node. If there were other fluorescent or black-stained lymph nodes, they were removed as the second and later SLNs. Resected LNs that contained fluorescent ICG and/or black staining were defined as true sentinel lymph nodes. The remaining palpable and axillary enlarged LNs (not blue stained or without fluorescence) were removed as suspicious SLNs.The primary end point was the SLN identification rate in the CNS group compared with that in the CG group. Secondary end points, including the metastatic SLN rate, SLN counts, metastatic SLN counts, time to the first SLN and adverse events, were compared between the two groups. Results Overall, 340 patients were enrolled and randomized 1:1 to the CNS group and the CNS+ICG group between December 2019 and April 2021. There were 330 evaluable patients, 163 in the CNS group and 167 in the CG group; 10 patients were excluded from the analysis due to incomplete data. Parameters such as average age, tumor stage, and molecular type were comparable between the two groups.The SLN identification rate was 94.5% (154/163) in the CNS group and 95.8% (160/167) in the CG group (P=0.57). The rate of metastatic SLNs in the CNS group was identical to that in the CG group (30.7% vs. 25.1%, P =0.26). No significant differences were observed between the CNS and CG groups in SLN counts (4.6±2.25 vs. 5.07±2.43, P > 0.05), positive metastatic SLN counts (0.53±1.27 vs. 0.43±1.09, P > 0.05), and time to the first SLN (7.75 min±3.08 min vs. 7.60 min±3.29 min, P > 0.05).In the NAC subgroups, the SLN identification rate was 88.9% (32/36) in the CNS group and 90.7% (39/43) in the CG group (P=0.54). The rate of metastatic SLNs in the CNS group was identical to that in the CG group (52.8% vs. 23.3%, P =0.06). No significant differences were observed between the CNS and CG groups in SLN counts (4.67±2.17 vs. 5.62±3.13, P =0.24), positive metastatic SLN counts (0.97±1.38 vs. 0.38±1.09, P > 0.05), and time to the first SLN (7.64 min±3.15 min vs. 7.93 min±4.01 min, P > 0.05). The proportion of patients with cN1 BC was 77.8% (28/36) in the CNS group and 58.1% (25/43) in the CG group. The SLN identification rate was 85.7% (24/28) in the CNS group and 84.0% (21/25) in the CG group for patients with cN1 BC after NAC (P=0.58). The SLN identification rate was 100% in both groups for cN0 patients after NAC.During and after the operation, no complications, including allergic reactions or skin necrosis, occurred in either group. Conclusions The ultrasound-assisted CNS was comparable to the ICG plus CNS technique for SLN mapping in patients with early breast cancer and also has potential application value in SLNB after NAC. Citation Format: Minyi Cheng, Liulu Zhang, Yuanqi Chen, Xiaosheng Zhuang, Ciqiu Yang, Fei Ji, Hongfei Gao, Mei Yang, Teng Zhu, Jieqing Li. Feasibility and diagnostic performance of ultrasound assisted carbon nanoparticle suspension versus dual-tracer-guided sentinel lymph node mapping in patients with early breast cancer: A prospective, randomized controlled, phase III clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-03.

Background: Breast cancers can be divided into HER2-negative and HER2-positive subtypes according to different status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to obtain accurate risk assessment and to understand the potential underlying mechanisms. Methods: We developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs). Findings: We characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed that HER2 signalling pathway was up-regulated in germline of HER2-negative patients, and those with high APSP risk scores had exhibited immune suppression. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk for HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations. Interpretation: The DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer. Funding: This work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); Shenzhen Science and Technology Planning Project (grant no. JCYJ20170817095211560 574 to YN); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW and S2013010012048 to MY); Hefei National Laboratory for Physical Sciences at the Microscale (grant no. KF2020009 to GN); and RGC General Research Fund (grant no. 17114519 to YQS).

// Teng Zhu 1, * , Fangping Xu 2, * , Liulu Zhang 1 , Yifang Zhang 1 , Ciqiu Yang 1 , Minyi Cheng 1 , Fulong Chen 1 and Kun Wang 1 1 Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China 2 Department of Pathology, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China * These authors have contributed equally to this work Correspondence to: Kun Wang, email: gzwangkun@126.com Keywords: dose-dense; paclitaxel; carboplatin; ER-positive; biomarkers Received: February 18, 2017 Accepted: June 05, 2017 Published: July 28, 2017 ABSTRACT The aim of this study was to determine the predictive value of the clinical and histopathological characteristics of estrogen receptor (ER)-positive patients treated with dose-dense paclitaxel/carboplatin neoadjuvant chemotherapy (NCT). Pathological complete response (pCR) and the change in tumor size between pre- and post-NCT were used to evaluate the tumor response.85 ER-positive breast cancer patients who were treated with dose-dense (biweekly) paclitaxel/carboplatin NCT were analyzed with respect to the expression of progesterone receptor (PgR), Tau, Ki67, human epidermal growth factor receptor 2 (HER2), and Bcl-2 by immunohistochemistry (IHC). These data were used to determine whether these biomarkers could predict the tumor response. A univariate analysis showed that the patients who tested positive for HER2 expression (56.00% vs 11.67%, p

Purpose Tau is a microtubule-associated protein that can be found in both normal and abnormal breast cells. Whether the expression of Tau protein can predict the response to neoadjuvant chemotherapy (NACT) is still unclear. In this study, we assessed the role of Tau protein expression in predicting a pathological complete response (pCR) to NACT for different subtypes of breast cancer. Methods Four hundred and sixty-eight eligible patients were retrospectively recruited in our study. The relationship between clinicopathologic factors, including Tau protein expression, and pCR in different subtypes was evaluated using logistic regression analysis. Correlation between Tau and disease-free survival (DFS) and overall survival (OS) was performed using Kaplan–Meier analysis. Results The expression of Tau protein was negatively correlated with pCR, especially in triple-negative breast cancer (TNBC). No significant difference was observed in the luminal human epidermal growth factor receptor-2 (HER2)-negative subtype and HER2-positive subtype. Patients with pCR were associated with better DFS and OS (p < 0.05). However, Tau protein expression had no association with either DFS or OS (p > 0.05). Conclusion Tau protein expression can predict pCR before NACT in TNBC, but there was no correlation between Tau expression and DFS or OS.

To evaluate the value of multiparametric magnetic resonance imaging (MRI) in pretreatment prediction of breast cancers insensitive to neoadjuvant chemotherapy (NAC). A total of 125 breast cancer patients (63 in the primary cohort and 62 in the validation cohort) who underwent MRI before receiving NAC were enrolled. All patients received surgical resection, and Miller–Payne grading system was applied to assess the response to NAC. Grade 1–2 cases were classified as insensitive to NAC. We extracted 1941 features in the primary cohort. After feature selection, the optimal feature set was used to construct a radiomic signature using machine learning. We built a combined prediction model incorporating the radiomic signature and independent clinical risk factors selected by multivariable logistic regression. The performance of the combined model was assessed with the results of independent validation. Four features were selected for the construction of the radiomic signature based on the primary cohort. Combining with independent clinical factors, the combined prediction model for identifying the Grade 1–2 group reached a better discrimination power than the radiomic signature, with an area under the receiver operating characteristic curve of 0.935 (95% confidence interval 0.848–1) in the validation cohort, and its clinical utility was confirmed by the decision curve analysis. The combined model based on radiomics and clinical variables has potential in predicting drug-insensitive breast cancers.

Background: Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade. Methods: Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0). Results: From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8–50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3–67.9) in the TCH group ( p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group ( p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group ( p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group ( p = 0.006). Conclusion: For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy. Trial registration: This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

586 Background: Taxane- and anthracycline-based neoadjuvant regimens have become a standard treatment for triple-negative breast cancer (TNBC). Previous studies have shown that adding carboplatin to neoadjuvant chemotherapy regimens significantly improved pCR rate in TNBC patients. The NeoCART study was designed to compare the efficacy and safety of docetaxel plus carboplatin with standard neoadjuvant chemotherapy in TNBC. Methods: NeoCART was designed as a multicenter, randomized controlled, open-label, phase 2 trial. The patients enrolled were at least 18 years old with previously untreated stage II-III (T1cN1-2 or T2-4N0-2) invasive TNBC who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All eligible patients were randomly assigned, in a 1:1 ratio, to the experimental arm (docetaxel (75 mg/m2) plus carboplatin (AUC 6) for six cycles) or the standard treatment arm (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 four cycles, followed by docetaxel 100 mg/m2 for four cycles). The primary end point was the pCR rate (ypT0/is and ypN0). Secondary endpoints included event-free survival, frequency of breast-conserving surgery, and safety. Results: Between September 1, 2016, and December 31, 2019, 88 patients from 6 participating centers were included and randomized (44 patients to the DCb arm and 44 to the EC-D arm). In the primary end point analysis, 27 patients (61.4%, 95% CI 47.0 - 75.8) in the DCb group achieved a pCR compared with 17 patients (38·6%, 95% CI 24.3 - 53.0) in the EC-D group (odds ratio 2.52, 95% CI 2.4 - 43.1; p = 0.033). In different stage disease, the pCR rates of the DCb and the EC-D groups were 73.3% (22/30) vs 48.4% (15/31) in stage II (p = 0.046), and 35.7% (5/14) vs 15.4% (2/13) in stage III (p = 0.384). In patients with axillary lymph node involvement, the pCR rates were 45.8% (11/24) vs 30.8% (8/26) (p = 0.273); and 80.0% (16/20) vs 50.0% (9/18) with lymph node negative disease (p = 0.052). The frequency of breast-conserving surgery in the DCb and EC-D groups was 36.4% and 37.2%, respectively (p = 0·935). The grade 3/4 adverse events include anemia (4.5%), thrombocytopenia (2.3%), neutropenia (2.3%) and ALT/AST increased (2.3%) in the DCb group. Conclusions: Compared with the standard neoadjuvant regimen, docetaxel combined with carboplatin showed a higher pCR rate in TNBC. The higher pCR rate was more significant in patients with earlier disease stage and negative lymph node. Clinical trial information: NCT03154749 .

585 Background: The optimal neoadjuvant treatment for HER2-positive breast cancer is unknown. We wanted to compare the efficacy and safety of the anthracycline regimen EC-TH versus nonanthracycline regimen TCH in neoadjuvant setting for HER2-positive breast cancer. Methods: Patients with stage II or III HER2-positive breast cancer were randomly assigned to either four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel and trastuzumab (EC-TH) every 3 weeks during all chemotherapy cycles, or six cycles of docetaxel and carboplatin plus trastuzumab (TCH) every 3 weeks. The primary endpoint was pathological complete response (defined as the absence of invasive tumour cells in breast and axilla, ypT0/is ypN0). This trial is registered with ClinicalTrials.gov, number NCT03140553. Results: From September 2016 to November 2019, 140 patients were randomly assigned, and 131 were evaluable for the primary end-point. The pathological complete response was recorded in 25 (38.5%, 95% confidence interval [CI] 26.6–50.2) of 65 patients in the EC-TH group and in 37 (56.1%, 44.1–68.0) of 66 in the TCH group (p=0.044). In the EC-TH group, 15 (23.1%) of 65 patients underwent breast-conserving surgery. In the TCH group, 21 (31.8%) of 66 patients underwent breast-conserving surgery. There was no difference in the proportions of patients undergoing breast-conserving surgery between the two treatment groups (p=0·262). The most common adverse events were neutropenia (in 23 [35.4%] of 65 patients in the EC-TH group vs 27 [40.9%] of 66 in the TCH group), anemia(in 33 [50.8%] of 65 patients in the EC-TH group vs 34 [51.5%] of 66 in the TCH group) and thrombocytopenia (in 5 [7.7%] of 65 patient in the EC-TH group vs 17 [25.8%] of 66 in the TCH group). Conclusion: This is the first multicenter prospective randomised phase II trial compare EC-TH with TCH for neoadjuvant therapy in HER2-positive breast cancer. There was a similar incidence of AEs but a higher pCR rate in TCH arm compared with the EC-TH arm. TCH regimen might be a preferred approach in patients with HER2-positive breast cancer. Long-term follow-up is required to confirm these results. Clinical trial information: NCT03140553 .

e15261 Background: Immune infiltration of breast cancer is associated with clinical outcome. A growing number of research suggests the diversity of functionally distinct cell types that make up the immune response. The aim of this study was to determine whether differences in the cellular composition of the immune infiltrate in breast cancer influence survival and treatment response, and construct the stromal immunotype which could improve prediction of neoadjuvant therapy and survival. Methods: A total of 1502 ER negative breast cancers from TCGA and METABRIC cohort were used to infer the proportions of 22 subsets of immune cells, Another 200 ER negative breast cancer patients from Guangdong Provincial People’s Hospital in the validation cohort were also included in the study. Immune cell infiltration was evaluated by immunohistochemical staining or CIBERSORT method, Five immune features were selected out of 22 immune features to construct immunotype based on LASSO Cox regression model. Results: Of the cell subsets investigated, CD8+ T cells (p < 0.001), CD4+ T cells (p = 0.002), B cells (p = 0.003), M1 macrophages(p = 0.006) were associated with favourable outcome. T regulatory cells(p = 0.005) emerged as the most strongly associated with poor outcome. T regulatory cells were associated with pathological complete response to neoadjuvant chemotherapy (p = 0.012). Using the LASSO model, we classified ER negative breast cancer patients into stromal immunotype A subgroup (CD8+Thigh CD4+Thigh B cellhigh M1 macrophagehigh Treglow) and stromal immunotype B subgroup (CD8+Tlow CD4+Tlow B celllow M1 macrophagelow Treg high). Significant differences were found between immunotype A and immunotype B in the combined cohort with 10-year overall survival (66.2% vs. 49.8%; P < 0.001) and 10-year disease-free survival (63.8% vs. 44.4%; P < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately, and also showed to be related to pCR in neoadjuvant chemotherapy. Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, CTLA-4) expression and three important cytokines expression profiles (IL-2, INF-γ and TGF-β). Conclusions: The stromal immunotypes could predict survival and recurrence of ER negative breast cancer patients effectively. Furthermore, the immunotypes might be a practical predictive tool for immunotherapy.