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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: 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.

Occult breast cancer, commonly presenting with axillary lymphadenopathy, is an extremely rare entity of breast cancer. Metastasis to the spleen as a single site is rarely seen and has been little reported in literature. Herein we described a case of a 60-year-old patient who presented with an asymptomatic solitary splenic mass 19 months after axillary lymph node dissection, regional radiotherapy, and systemic therapy. Laparoscopic splenectomy was performed, and histopathological examination confirmed metastasis from occult breast cancer. Then, the patient was administered with oral vinorelbine and dual-targeted treatment. With over 10 months of follow-up, there is no evidence of recurrence or metastasis of malignancy. To our knowledge, this study reports the first case of solitary splenic metastasis from occult breast cancer and highlights the importance of considering splenic metastasis as the only site of recurrence during follow-up of primary cancer, regardless of its rarity. If possible, splenectomy may be a therapeutic strategy.

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.

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.

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.

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.

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.

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.

Human epithelial growth factor receptor 2 (HER2) is over-expressed in several malignancies and represents an important therapeutic target. Aptamers are oligonucleotides that may potentially serve as tumor-homing ligand with excellent affinity and specificity for targeted cancer therapy. However, aptamers need to have nuclease resistance in order to function in vivo. The aim of this study was to generate a novel HER2 thioaptamer with enhanced nuclease resistance.The HER2 thioaptamer is selected in an evolutionary process called systematic evolution of ligands by exponential enrichment.The thioaptamer could bind to the extracellular domain of HER2 with a K d of 172 nM and had minimal cross reactivity to trypsin or IgG. Moreover, the thioaptamer was found capable of binding with the HER2-positive breast cancer cells SK-BR-3 and MDA-MB-453, but not the HER2-negative cells MDA-MB-231. Notably, the thioaptamer HY6 largely maintained its structural integrity facing the nucleases in serum, while regular DNA aptamers were mostly digested. Additionally, the thioaptamer retained the capability of binding with the HER2-positive cells in the presence of serum, whereas non-thionated HER2 aptamer lost the binding function.The results indicated that the selected thioaptamer was more resistant to nuclease than regular DNA aptamers and might potentially function as a HER2-targeting ligand in complicated environment.

Introduction The prognostic value of the mesenchymal–epithelial transition (MET) in triple-negative breast cancers (TNBCs) remains controversial. A meta-analysis of the impact of MET in TNBCs was performed by searching published data. Methods PubMed and Embase databases were searched for eligible literature. The principal outcome measures were hazard ratios (HRs) for recurrence-free survival or overall survival according to MET expression. Combined HRs were calculated using fixed- or random-effects models according to heterogeneity. Results Six studies involving 785 patients met our selection criteria. The meta-analysis results showed that MET overexpression was associated with a 1.29-fold increased risk of recurrence (combined HR 1.29; 95% confidence interval, 1.04-1.60; P = .020) in the TNBCs. Three studies provided the related overall survival data (488 cases). The results showed that MET overexpression was associated with a 1.38-fold increased risk of mortality (HR, 1.38; 95% confidence interval, 1.08-1.76; P = .009). Conclusion MET is an adverse prognostic marker for TNBCs. The results strengthen the rationale for targeted therapy of TNBCs using MET inhibitors in future clinical trials.

e13055 Background: To establish and validate a radiomics-based imaging diagnostic model to predict Breast Imaging Reporting and Data System (BI-RADS) category 4 calcification of breast with mammographic images before biopsy and assess its value. Methods: A total of 212 BI-RADS category 4 pathology-proven mammographic calcifications without obvious mass on mammography were retrospectively enrolled (159 in primary cohort and 53 in validation cohort). All patients received ultrasound inspection and the results were available. 8286 radiomic features were extracted from each mammography images. We utilized machine learning to build a radiomic signature based on optimal features. Independent clinical factors were selected by multivariable logistic regression analysis, and we incorporated the radiomic signatures and risk clinical factors to build a radiomic nomogram. The performance of the radiomic nomogram were assessed by the area under the receiver-operating characteristic curve (AUC). Results: Six features were selected to develop the radiomic signatures based on the primary cohort. Combining with menopausal states, the individualized radiomic nomogram reached an AUC of 0.803 in the validation cohorts, and its clinical utility was confirmed by the decision curve analysis. The difference was significant between the AUC value of differentiating results of the radiomic nomogram compared with ultrasound, mammography and combined modality respectively(p < 0.05 in all three groups). Especially, for patients with MG+/US- calcifications, radiomics nomogram can be screen out benign calcifications. Conclusions: Based on mammographic radiomics, we developed a method for prediction of pathological classification in BI-RADS IV calcification, which has a certain predictive effect.

Background: Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of HR+ (ER+ and PR+) and HER2- breast cancer patient, either alone or in combination with CDK4/6 inhibitors such as palbociclib or abemaciclib. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft model and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Trial Design: D-0502 is currently being evaluated in a phase 1 trial of women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). This is a multicenter, open-label phase I study of D-0502 single agent and D-0502 in combination with standard dose of palbociclib. The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objective is to evaluate the PK properties and the preliminary anti-tumor activities. Patients will receive D-0502 orally every day and treatment will be administered as 28-day cycles. The study has two parts: Dose Escalation (phase 1a) and Dose Expansion and Combination (phase 1b). In phase Ia, patients will be enrolled using a conventional dose-escalation algorithm (3+3 subjects per dose level) with 4 sequential dose cohorts to identify the MTD and RDE (recommended dose for expansion) in phase 1b) which will be at or below MTD. In phase 1b, there will be 2 cohorts, one is D-0502 single agent administered at RDE and the other is D-0502 in combination with standard dose of palbociclib, each with approximately 12 patients. Key Eligibility Criteria: Eligible patients included women with confirmed HR+, HER2- MBC who have previously received no more than 2 prior chemotherapies for MBC; ECOG 0-1; evaluable (phase 1a) or measurable (phase 1b) disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. Current Status and Contact Information: At the time of abstract submission, the first cohort of 50 mg patients have started the study treatment. For inquiry of the study, please contact ling.zhang@inventisbio.com. Citation Format: Zhang L, Dai D, Shi Z, Jiang J, Wang Y. Phase 1 study of D-0502, an orally bioavailable SERD with optimized pharmacological and PK/PD property for ER-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-04.

e12638Background: To evaluate the efficacy and safety of carboplatin-based neoadjuvant chemotherapy in triple-negative breast cancer patients (TNBC). Methods: PubMed, EMBASE, the Web of Science, th...

Purpose The use of oncoplastic reconstruction for breast-conserving surgery (BCS) extends benefits beyond merely minimizing poor cosmetic results. However, the feasibility and oncological safety of oncoplastic surgery (OPS) are controversial. Methods This meta-analysis aimed to compare the short-term and long-term oncological outcomes of BCS alone and BCS plus OPS. Relevant studies published before July 2017 in the Embase, the Cochrane Library, PubMed, and Web of Science databases were screened and collected. The meta-analysis was performed using STATA software (Stata Corp.). Results A total of 3,789 patients from 11 studies were included, with 2,691 patients in the BCS-alone group and 1,098 patients in the BCS plus OPS group. The demographics were similar between both groups, and no significant difference was observed in pathological T and N stages between the two groups. Re-excision was less common (relative risk [RR], 0.66; p=0.009) and the positive-margin rate was lower, but not significantly (RR, 0.83; p=0.191), in the BCS plus OPS group than in the BCS-alone group. The local and distal recurrence rates were similar in both groups. Both disease-free survival (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.96-1.49; p=0.112) and overall survival (HR, 1.14; 95% CI, 0.76-1.69; p=0.527) did not differ between the two groups. Conclusion A combination of BCS and OPS is preferred over BCS alone for decreasing re-excisions and provides similar long-term survival as BCS alone in patients with breast cancer.

e12125 Background: Neoadjuvant endocrine therapy (NET)is effective in postmenopausal patients with breast cancers expressing oestrogen receptor. However, the therapeutic benefit of NET in premenopausal population is not fully characterized. We aimed to assess the efficacy and safety of endocrine therapy between the postmenopausal and premenopausal patients with highly endocrine responsiveoperable breast cancer for primary systemic therapy. Methods: Previously untreated patients with operable breast cancer and highly endocrine responsive breast cancer (ER/PR≥50% and Her2-) were recruited. Patients were assigned to receive letrozole 2.5mg daily (combined with triptorelin in premenopausal patients) for a period of at least 6 months. The primary end point of the study was the objective response rate (ORR) measured by breast ultrasound. Secondary end points included safety, pathologically complete response (pCR) rate, breast conservative surgery (BCS) rate. Results: Between September 2012 and December 2016, 41 patients were enrolled in the study (16 postmenopausal, 25 premenopausal ). The total ORR of this study was 73.2% (30 of 41). No significant differences were seen in the ORR, 76.0% (19 of 25 premenopausal patients) and 68.8% (11 of 16 postmenopausal patients) (P = 0.723). The pCR rate was 8% (2 of 25) for the premenopausal and 0%(0 of 16) for the postmenopausal (p=0.512). The BCS rate was 40% (10 of 25) for the premenopausal and 37.5%(6 of 16) for the postmenopausal (P = 0.873). No treatment-related grade 3/4 adverse events were recorded in both groups. Conclusions: Letrozole shows a high activity and excellent tolerability as neoadjuvant therapy in both postmenopausal and premenopausal patients with highly endocrine responsive operable breast cancer.

Background:Axillary lymph node metastasis is one of the most important prognostic determinants for patients with breast cancer. It’s a big progress from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB), however, SLNB also has some limitations, including the detection failure rate, false negative rate, tracer allergies et al. Since about 70% of early breast cancer patients have negative SLNs, surgery maybe overtreatment for these patients and noninvasive assessment of axillary staging seems to be a better choice. It’s not easy to detect and mapping metastasis lymph nodes in vivo non-invasively because we don’t have specific cancer markers, but what we know is that most breast cancer cells come from epithelial origin and should have epithelial markers, and this kind of markers should not show up in lymph system. EpCam is a surface epithelial marker and expressed in 80-100% breast cancer patients. The aim of this study was to evaluate the value of EpCAM antibody in detecting breast cancer lymph node metastases non-invasively.Methods:VX2 rabbit model which is an epithelial tumor model with lymph node metastasis was used in this experiment. Anti-EpCAM was labeled with a near infra-red (NIR) fluorescence imaging agent Cy7 and selected as metastasis tracer. New Zealand white rabbits were assigned to study group and control group at random. Twelve rabbits in the study group received VX2 tumor injection to bilateral mammary glands and 12 rabbits in the control group were tumor free. Twenty four cases of axillary lymph nodes metastasis were investigated in each group because of bilateral experiments. Anti-EpCAM/Cy7 was subcutaneously injected around the tumors in study group or in mammary gland in control group at a dosage of 0.1ml (10umol/L). After 30 hours of screening by a NIR fluorescence detection machine, all the axillary lymph nodes in both groups were removed for pathological examination and the fluorescence status of each node was recorded. Result:The fluorescence signal could be detected 2 hours after injection in 24 cases in the control group and 23 cases in the study group. Thirty hours later, fluorescence disappeared in all cases in the control group and all the lymph nodes resected were pathological negative. While in study group, fluorescence signal could be detected continuously in 14 cases and 13 were proven to be pathological metastasis. The case failed to have fluorescence image from the beginning finally proved to be vascular invasion and cancerous node formation. The sensitivity, specificity rate of anti-EpCAM/Cy7 to detect axillary lymph node metastasis was 92.8% (13/14) and 90.0% (9/10). Conclusion:The NIR dye labeled EpCAM antibody (anti-EpCAM/Cy7) has a high accuracy in evaluating the axillary lymph node status of breast cancer in the animal experiment. Our tiny preclinical experiment showed the value of using EpCAM antibody as a new method for noninvasive lymph node evaluation for breast cancer and potentially extended in a lot of other epithelial originated cancers. Citation Format: Shu Wang, Jiajia Guo, Liulu Zhang, Houpu Yang. Noninvasive assessment of axillary lymph node metastases in breast cancer using EpCAM antibody [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-15.

e19541 Background: A retrospective study showed that bone metastatic NSCLC patients with high uNTX levels at diagnosis had a higher skeletal related event (SRE) and an increased death risk than tha...

e18016 Background: For adenocarcinoma of lung, anti-folate drug like pemetrexed was active, however, the role of XEL, pro-drug of 5≂J-DFUR, has yet to be defined. Preclinical studies showed a stron...