Comparison of neoadjuvant chemotherapy response and prognosis between HR-low/HER2-negative BC and TNBC: an exploratory real-world multicentre cohort study.

Objective: Hormone receptor (HR)-low/HER2-negative breast cancers (BCs) are more likely to be basal-like BCs, with similar molecular features and gene expression profiles to HR-negative (estrogen receptor <1% or negative and progesterone receptor <1% or negative) BCs. Recently, with the clinical application of adjuvant intensive therapy for triple-negative breast cancer (TNBC), the prognosis of TNBC patients without pathological complete response (pCR) has significantly improved. Therefore, it is necessary to reanalyse the prognostic characteristics of clinically high-risk HR-low/HER2-negative BC. Methods: According to the inclusion and exclusion standards, 288 patients with HR-low/HER2-negative BC and TNBC who received NAC and were followed up between 2015 and 2022 at three breast centres in Hunan Province, China, were enrolled. Inverse probability of treatment weighting (IPTW) was utilized to mitigate imbalances in baseline characteristics between the HR-low/HER2-negative BC group and TNBC group regarding event-free survival (EFS) and overall survival (OS). The primary clinical endpoints were pCR and EFS, while the secondary endpoints included OS, objective response rate (ORR), and clinical benefit rate (CBR). Results: The pCR rate (27.1% vs. 28.0%, P = 1.000), ORR rate (76.9% vs. 78.3%, P = 0.827) and CBR rate (89.7% vs. 96.5%, P = 0.113) after NAC were similar between the HR-low/HER2-negative BC and the TNBC group. EFS in patients with non-pCR from the 2 groups was significantly inferior in comparison to patients with pCR (P = 0.001), and the 3-year EFS was 94.74% (95% CI = 85.21% to 100.00%) and 57.39% (95% CI =43.81% to 75.19%) in patients with pCR and non-pCR from the HR-low/HER2-negative BC group, respectively, and 89.70% (95% CI = 82.20% to 97.90%) and 69.73% (95% CI = 62.51% to 77.77%) in the TNBC patients with pCR and non-pCR, respectively. Conclusions: In the real world, the therapeutic effects of NAC for HR-low/HER2-negative BCs and TNBCs were similar. EFS of patients with non-pCR in the HR-low/HER2-negative BC group was inferior to that of the TNBC group with non-pCR, suggesting that it is necessary to explore new adjuvant intensive therapy strategies for these patients.

Research progress on the multi-omics and survival status of circulating tumor cells.

In the dynamic process of metastasis, circulating tumor cells (CTCs) emanate from the primary solid tumor and subsequently acquire the capacity to disengage from the basement membrane, facilitating their infiltration into the vascular system via the interstitial tissue. Given the pivotal role of CTCs in the intricate hematogenous metastasis, they have emerged as an essential resource for a deeper comprehension of cancer metastasis while also serving as a cornerstone for the development of new indicators for early cancer screening and new therapeutic targets. In the epoch of precision medicine, as CTC enrichment and separation technologies continually advance and reach full fruition, the domain of CTC research has transcended the mere straightforward detection and quantification. The rapid advancement of CTC analysis platforms has presented a compelling opportunity for in-depth exploration of CTCs within the bloodstream. Here, we provide an overview of the current status and research significance of multi-omics studies on CTCs, including genomics, transcriptomics, proteomics, and metabolomics. These studies have contributed to uncovering the unique heterogeneity of CTCs and identifying potential metastatic targets as well as specific recognition sites. We also review the impact of various states of CTCs in the bloodstream on their metastatic potential, such as clustered CTCs, interactions with other blood components, and the phenotypic states of CTCs after undergoing epithelial-mesenchymal transition (EMT). Within this context, we also discuss the therapeutic implications and potential of CTCs.

Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial.

PURPOSE: This study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab. EXPERIMENTAL DESIGN: Data from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: The baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07-1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12-1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20-1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively). CONCLUSIONS: A low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.

A pilot study on pyroptosis related genes in peripheral blood mononuclear cells of non-small cell lung cancer patients.

OBJECTIVE: To investigate the GSDMD, CASP1, CASP4 and CASP5 expression in peripheral blood mononuclear cells of non-small cell lung cancer patients and analyze their clinical significance. METHODS: 71 non-small cell lung cancer patients were selected as the study group and 50 healthy individuals as the control group. The GSDMD, CASP1, CASP4 and CASP5 expression in peripheral blood mononuclear cells of the two groups were detected by real-time fluorescence quantitative PCR. The GSDMD, CASP1, CASP4, CASP5 expression and their relationship with the clinical characteristics of the patients were analyzed. RESULTS: Compared with the control group, the GSDMD, CASP4 and CASP5 expression in PBMCs of lung cancer patients was significantly higher(P < 0.05). Lymph node metastasis had significant difference with the CASP4 and GSDMD expression (P < 0.05); tumor volume had significant difference with CASP1 and CASP5 expression (P < 0.05). The areas under predictive ROC curve of the GSDMD, CASP1, CASP4, and CASP5 mRNA expression were 0.629(P < 0.05), 0.574(p > 0.05), 0.701(P < 0.05) and 0.628(P < 0.05), the sensitivity values were 84.5%, 67.6% 43.7%, and 84.3%;the specificity values were 42%, 52%, 84% and 64%, respectively. CONCLUSION: GSDMD, CASP1, CASP4 and CASP5 gene expression are highly increased in PBMCs of non-small cell lung cancer patients and their expression are closely related to the clinical characteristics of patients. The early enhanced pyroptosis-related gene expression may be potential molecular markers for early diagnosis of non-small cell lung cancer.

METTL3-mediated m6A modification of lnc KCNQ1OT1 promotes doxorubicin resistance in breast cancer by regulating miR-103a-3p/MDR1 axis.

Doxorubicin (DOX) resistance in breast cancer (BC) poses a huge challenge for the therapeutic effect on BC. Lnc KCNQ1OT1 play crucial roles in chemotherapy resistance. However, the role and mechanism of lnc KCNQ1OT1 in DOX resistance BC have not been investigated, which merits further exploration. Based on MCF-7 and MDA-MB-231 cells, MCF-7/DOX and MDA-MB-231/DOX cells were established using gradient concentrations of DOX. IC50 values and cell viability were determined using MTT. Cell proliferation was investigated by colony formation. Flow cytometry was performed to examine cell apoptosis and cell cycle. Gene expression was examined using qRT-PCR and western blot. The interactions among METTL3, lnc KCNQ1OT1, miR-103a-3p, and MDR1 were validated with MeRIP-qPCR, RIP, and dual-luciferase reporter gene assays. The results showed that Lnc KCNQ1OT1 was highly expressed in DOX-resistant BC cells, and lnc KCNQ1OT1 depletion could enhance DOX sensitivity in BC cells and DOX-resistant BC cells. Besides, lnc KCNQ1OT1 was modulated by MELLT3 in the manner of m6A modification. MiR-103a-3p could interact with lnc KCNQ1OT1 and MDR1. Overexpression of MDR1 abolished the impacts of lnc KCNQ1OT1 depletion on DOX resistance in BC. In conclusion, our results unveiled that in BC cells and DOX-resistant BC cells, lnc KCNQ1OT1 could be mediated by METTL3 through m6A modification to elevate and stabilize its expression, further inhibiting miR-103a-3p/MDR1 axis to promote DOX resistance, which might provide novel thought to overcome DOX resistance in BC.

Validation of reference genes for the normalization of the RT-qPCR in peripheral blood mononuclear cells of septic patients.

Objective: To screen and validate reference genes suitable for gene mRNA expression study in peripheral blood mononuclear cells (PBMCs) between septic patients and healthy controls (HC). Methods: Total RNA in PBMCs was extracted and RT-qPCR was used to determine the mRNA expression profiles of 9 candidate genes, including ACTB, B2M, GAPDH, GUSB, HPRT1, PGK1, RPL13A, SDHA and YWHAZ. The genes expression stabilities were assessed by both geNorm and NormFinder software. Results: YWHAZ was the most stable gene among the 9 candidate genes evaluated by both geNorm and NormFinder in mixed and sepsis groups. The most stable gene combination in mixed group analyzed by geNorm was the combination of GAPDH, PKG1 and YWHAZ, while that in sepsis group was the combination of ACTB, PKG1 and YWHAZ. Conclusion: Our first systematic analysis of the reference genes in PBMC of septic patients suggested YWHAZ was the best candidate. The combination of ACTB, PKG1 and YWHAZ could improve RT-qPCR accuracy in septic patients. Our results identified the most stable reference genes to standardize RT-qPCR of sepsis patients, which can serve as a useful tool for gene function exploration in the future.

S100A9 promotes glycolytic activity in HER2-positive breast cancer to induce immunosuppression in the tumour microenvironment.

Purpose: The purpose of this study was to investigate the correlation between S100 calcium binding protein A9 (S100A9), tumour glycolysis and tumour infiltrating lymphocytes (TIL) in human epidermal growth factor receptor 2 (HER2) - positive breast cancer (BRCA). Materials and methods: A total of 667 BRCA patients in Xiangya Hospital of Central South University were enrolled in this study. Haematoxylin and eosin (H&E) staining were used to count TIN in tissues. Human breast cancer cell lines (SK-BR-3 cells and BT474 cells) were transfected with S100A9 specific small interfering RNA (siRNA). The expressions of S100A9, glycolytic enzymes and lymphocyte markers were detected by immunohistochemistry (IHC) staining, Western blot and immunofluorescence. Lactate production, glucose consumption and the extracellular acidification rate (ECAR) were detected to assess glycolysis activity. Results: S100A9 was significantly overexpressed in HER2+ cases. The expressions of phosphoglycerol kinase 1 (PGK1), lactate dehydrogenase A (LDHA) and enolase α (ENO1) were significantly up-regulated in S100A9 dominant tissues. The expressions of PGK1, LDHA and ENO1 detected in S100A9 silenced cell lines were significantly down-regulated. Moreover, S100A9 silencing significantly altered lactate production, glucose uptake and ECAR levels in HER2+ cell lines. Co-expression of S100A9 and c-Myc was detected in HER2+ tissues. The absence of S100A9 greatly hindered ß-catenin expression in cell lines, which later induced the phosphorylation of c-Myc.The amount of TILs in cases with abundant S100A9 and LDHA was much greater than in cases with low S100A9 levels and poorer LDHA. TIL deficiency and elevated S100A9 intensity are factors affecting the survival rate of HER2+ BRCA cases. Conclusions: S100A9 overexpression upregulated the glycolysis activity of tumour cells through the c-Myc-related pathway, suppressing lymphocyte infiltration in the tumour stroma, affecting the efficacy of immune regulation and long-term survival of patients.

Stabilization of estrogen receptor α by USP37 contributes to the progression of breast cancer.

Breast cancer is a major cause of cancer-related morbidity and mortality in women. Estrogen receptor-positive breast cancer accounts for roughly 70%-80% of breast tumors, and estrogen receptor alpha (ERα) has been considered as a key driver in promoting breast cancer progression. In the present study, we identified USP37 as a novel modulator in modulating ERα ubiquitination and stability. The expression of USP37 was upregulated in ERα-positive breast cancer and correlated with ERα protein level. High expression of USP37 was associated with unfavorable prognosis. USP37 depletion resulted in significantly decreased ERα protein level, ERα target genes expression as well as the estrogen response element activity in breast cancer cells. Further mechanistic study revealed the interaction between USP37 and ERα: USP37 regulated ERα signaling through modulating protein stability instead of gene expression, in which it stabilized ERα protein via inhibiting the K48-specific polyubiquitination process. Additionally, USP37 depletion led to growth inhibition and cell cycle arrest of ERα-positive breast cancer cells, which could be further rescued by ERα overexpression. Overall, our study proposed a novel post-translational mechanism of ERα in promoting breast cancer progression. Targeting USP37 may be proved to be a promising strategy for patients with ERα-positive breast cancer.

Pamiparib in patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutations: a phase II study.

PURPOSE: To evaluate the efficacy and safety of pamiparib in patients with locally advanced or metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious germline BRCA1/2 mutations (gBRCA1/2 m). METHODS: In this open-label, phase II, multicenter study in China (NCT03575065), patients with triple-negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+/HER2- cohort) and ≤ 2 prior lines of chemotherapy received pamiparib 60 mg orally twice daily in 28-day, continuous cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee. RESULTS: In total, 88 patients were enrolled (TNBC cohort: 62; HR+/HER2- cohort: 26). Median age was 45.5 (range: 27-67) years, and 60 patients (68.2%) had received 1 or 2 prior lines of chemotherapy; 42 patients (47.7%) had previously received platinum chemotherapy. In the TNBC cohort, ORR was 38.2% (95% confidence interval [CI] 25.4-52.3) and median duration of response (DoR) was 7.0 months (95% CI 3.9-not estimable). In the HR+/HER2- cohort, ORR was 61.9% (95% CI 38.4-81.9) and median DoR was 7.5 months (95% CI 5.6-14.8). The most common treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and ≥ Grade 3 TEAEs were hematologic (including anemia, decreased neutrophil count, and decreased white blood cell count). Overall, 64.8% of patients had TEAEs leading to dose reduction and 2.3% had TEAEs leading to treatment discontinuation. CONCLUSION: Pamiparib showed encouraging efficacy and an acceptable safety profile in patients with locally advanced and metastatic HER2- breast cancer with gBRCA1/2 m. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03575065; July 2, 2018.

The prognostic effect of HER2 heterogeneity and YAP1 expression in HER2 positive breast cancer patients: a retrospective study.

Background: This study sought to estimate the prognostic effect of intratumoral heterogeneity (ITH) and Yes-associated protein 1 (YAP1) intensity in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We also investigated individualized adjuvant therapy for YAP1-sufficient patients and HER2 heterogeneous patients. Methods: The relationship between prognostic outcomes and clinicopathological variables in 1,650 retrieved breast cancer patients was evaluated. The HER2 intensity and YAP1 expression in HER2-ITH and non-ITH (NITH) patients were also estimated. All patients were followed-up, regardless of whether or not they received intensive treatment, to explore individualized adjuvant therapy for YAP1-sufficient patients and HER2 heterogeneous patients. Results: Over-expression and nuclear localization of YAP1 were significant in HER2-ITH patients. The over-expression of YAP1 and the presence of ITH affected the prognosis of HER2 positive patients. YAP1 intensity and lymph nodes metastases was more obviously affected the survival of HER2-ITH patients, while the prognosis of NITH patients were correlated with clinical Tumor-Node-Metastasis (cTNM) stage and lymph-vascular space invasion (LVSI) status. HER2-NITH patients and YAP1-insufficient patients benefited from a combination of Trastuzumab and Pertuzumab/Lapatinib, while Capecitabine significantly decreased the relapse risk of ITH patients and YAP1-sufficient patients. Conclusions: YAP1 overexpression and nuclear localization was usually observed in HER2-ITH patients. For HER2-NITH patients, an advanced stage of cTNM and LVSI status increased the recurrent risk, and intensified Pertuzumab or Lapatinib treatment (combination with Trastuzumab) improved their survival. For HER2-ITH patients, the overexpression of YAP1 and pathological lymph nodes (pLN) metastases increased recurrent risk, and intensified Capecitabine treatment improved their survival. YAP1 overexpression contributed to a poor prognostic outcome, especially when HER2 signal intensity was insufficient.

Efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy regimen in Chinese patients with HER2-positive early breast cancer: a real-world retrospective multi-center cohort study.

Background: Pertuzumab plus trastuzumab combined with chemotherapy has become a standard neoadjuvant therapy option for patients with high-risk human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). There is still not enough evidence for the efficacy and safety of neoadjuvant pertuzumab and trastuzumab plus chemotherapy in HER2-positive BC patients in China, both in clinical trials and real-world settings. This study aimed to assess the efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive BC in real-world clinical application. Methods: We retrospectively collected the data from the electronic medical records of HER2-positive patients treated with neoadjuvant trastuzumab and pertuzumab plus chemotherapy from December 2018 to May 2021 at 21 hospitals located in Hunan Province, China, including age, American Joint Committee on Cancer (AJCC) stage, clinical tumor size, clinical lymph node status, pathological characteristics (before neoadjuvant systemic therapy), treatment approach, adverse events to neoadjuvant therapy, and achievement of pathological complete response (pCR). The primary endpoint was the total rate of pCR, and the secondary endpoints were the rate of pCR of each subgroup and the safety of dual anti-HER2 therapy. Results: A total of 188 patients met the inclusion criteria and were included in the analysis. Of the 188 patients, 119 (63.3%) were diagnosed at stage II and 64 (34.0%) at stage III; 163 (86.7%) were cT2-3; 149 patients (79.3%) were ≥ cN1; 84 patients (44.7%) were hormone receptor (HR)-positive. pCR was observed in 88 of 188 patients (46.8%). The pCR rate of HR-negative patients (54.8%) was higher (P=0.014) than that of HR-positive patients (36.9%). Patients with Ki-67 <15% achieved a higher (P=0.033) pCR rate (68.2%) than those with Ki-67 ≥15% (44.0%). Anemia was the most common adverse event (63.4%), and the most common grade 3-4 adverse event was nausea and vomiting (8.5%). Conclusions: Our study confirmed the benefit of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy on pCR with a tolerable safety profile in routine clinical practice in Chinese patients with HER2-positive BC. HR-negativity and Ki-67 <15% were associated with pCR in these patients.

YAP1/MMP7/CXCL16 axis affects efficacy of neoadjuvant chemotherapy via tumor environment immunosuppression in triple-negative breast cancer.

BACKGROUND: To evaluate the association of potential YAP1/MMP7/CXCL16 axis and tumor infiltrating lymphocytes (TILs) related chemo-response in triple-negative breast cancer (TNBC) patients. METHODS: We estimated the messenger RNA (mRNA) expression levels of Yes-associated protein 1 (YAP1), MMP7, and CXCL16 in paired TNBC tumor/para-tumor tissues by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and performed statistical analysis according to neoadjuvant chemotherapy (NAC) response. Based on The Cancer Genome Atlas (TCGA) data, we noticed outstanding expression of MMP7/CXCL16 in TNBC cases, as well as associations between MMP7/CXCL16 and HIPPO-YAP1-relevant kinases. We also performed gene set enrichment analysis (GSEA) between MMP7/CXCL16 and YAP1-associated pathways. Western blotting assay was employed to evaluate YAP1/MMP7/CXCL16 expression in vitro and their modulation sequence. Logistic model stepwise regression analysis was used to assess YAP1, MMP7, CXCL16, and TILs as therapeutic predictors. Residual cancer burden (RCB) score was calculated and statistically analyzed according to intensity of these variables, and receiver operating characteristic (ROC) curve also showed their predictive value in NAC response. Recruitment efficacy for CD4+/CD8+ TIL cells (TCGA data) as well as quantified TIL cells density were both explored according to YAP1, MMP7, and CXCL16 expression level. RESULTS: Up-regulation of YAP1/MMP7 and down-regulation of CXCL16 were both significant in TNBC cases with poor NAC response. Inhibition of YAP1 induced down-regulation of MMP7 and up-regulation of CXCL16, whereas inhibition of MMP7 also induced up-regulation of CXCL16. It was also shown that MMP7/CXCL16 was enriched in the YAP1-related pathway. Activation of the YAP1/MMP7/CXCL16 axis obviously affected RCB of TNBC cases. The ROC curve also supported the predictive value of YAP1/MMP7/CXCL16 axis and TILs density in NAC response prospect. The density of TILs, meanwhile, demonstrated a strong link with the YAP1/MMP7/CXCL16 axis. Over expression of YAP1/MMP7 significantly suppressed recruitment of CD4+/CD8+ TILs, while CXCL16 over expression had a beneficial impact on anti-tumor immune. CONCLUSIONS: Over expression of causes up-regulation of MMP7 and down-regulation of CXCL16, which suppressed CD4+/CD8+ TILs recruitment and indirectly affected NAC response of TNBC patients.

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OBJECTIVES: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a relatively poor prognosis. Neoadjuvant chemotherapy (NAC) is the main treatment method. Due to the heterogeneity of the tumor, the chemotherapy response of TNBC patients is significantly different. Inflammation is closely related to the occurrence and development of cancer. The systemic immune-inflammation index (SII) is an indicator that can comprehensively reflect the state of systemic inflammation. This study aims to explore the association between SII and the NAC efficacy as well as the prognosis in TNBC. METHODS: The data of TNBC patients who underwent NAC and systemic treatment in Xiangya Hospital of Central South University from January 2015 to June 2019 were collected. According to the inclusion and exclusion criteria, 231 TNBC patients were finally included. The pre-NAC SII was calculated according to the blood routine results of the patients at 1 week before chemotherapy, and the patients were divided into a pre-NAC low SII group (SII<412, 115 cases) and a pre-NAC high SII group (SII≥412, 116 cases). The SII after chemotherapy was calculated according to the blood routine results of the patients at 2 to 3 months after the end of chemotherapy, and the patients were divided into a low SII group after chemotherapy (SII<474, 115 cases) and a high SII group after chemotherapy (SII≥474, 116 cases). Pearson's chi-square test was used to analyze the relationship between SII and other clinical characteristics of TNBC patients, and the relationship between the NAC efficacy and clinical characteristics of TNBC patients. Binary logistic regression analysis was used to find independent factors that affect the efficacy of NAC in TNBC patients. Kaplan-Meier curve analysis was used to analyze factors affecting the prognosis of TNBC patients. Cox regression model was used to find independent factors affecting the prognosis of TNBC patients. RESULTS: Before NAC, the differences in SII between groups with different ages and tumor sizes were significant (P=0.007 and P=0.002, respectively); after chemotherapy, there were no significant differences in SII between different ages, tumor sizes, histological grades, lymph node staging, and Ki-67 groups (all P>0.05). There were 115 patients with low SII before NAC, with a pathological complete response (pCR) rate of 15.7%; there were 116 patients with high SII before NAC, with a pCR rate of 6.0%. Patients with low SII before NAC had a higher pCR rate than patients with high SII before NAC, and the difference was statistically significant (P=0.019).There were 156 patients with lymph node staging pN0, with a pCR rate of 14.7%; and there were 75 patients with lymph node staging pN1-pN2, with a pCR rate of 2.7%. Patients with lymph node staging pN0 had a higher pCR rate than those with lymph node staging pN1-pN2, and the difference was significant (P=0.006). During the follow-up, 34 patients had local recurrence or distant metastasis. The Kaplan-Meier survival curve showed that the 3-year disease-free survival (DFS) rates for patients with low SII before NAC and high SII before NAC were 87.8% and 82.8%, respectively, and the former was significantly higher than the latter (P=0.005); the 3-year DFS rates for patients with tumor sizes of T1-T2 and T3 were 89.0% and 67.5%, respectively, and the former was significantly higher than the latter (P=0.001); the 3-year DFS rates for patients with lymph node staging of pN0 and pN1-pN2 were 87.8% and 82.8%, respectively, and the former was significantly higher than the latter (P=0.009). Cox analysis showed that SII before NAC and tumor size were independent influencing factors of patients' DFS (P=0.038, P=0.010, respectively). CONCLUSIONS: SII has important clinical significance in predicting the efficacy and prognosis of NAC in TNBC patients, and it has the potential to be a biomarker.

Prognostic Roles of Neutrophil-to-Lymphocyte Ratio and Stromal Tumor-Infiltrating Lymphocytes and Their Relationship in Locally Advanced Triple-Negative Breast Cancer Treated with Neoadjuvant Chemotherapy.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) and stromal tumor-infiltrating lymphocytes (sTILs) are associated with immunogenicity and prognosis of patients with triple-negative breast cancer (TNBC). OBJECTIVE: To investigated the prognostic roles of NLR and sTILs and their rela-tionship of TNBC patients treated with neoadjuvant chemotherapy (NAC). METHODS: The clinical data of 170 patients with locally advanced TNBC who received NAC from January 2010 to December 2014 were collected. The difference among variables was calculated by χ2 test. The association between essential clinicopathological characteristics, pathological complete response (pCR), NLR, and sTILs with disease-free survival (DFS) was analyzed. Kaplan-Meier and Cox analysis were performed to address the effects of clinical parameters on prognosis. RESULTS: There was a trend that TNBC patients with lower baseline NLR (NLR1) or higher sTILs scoring would obtain a better pCR rate. NLR1 and sTILs were not associated (p > 0.05). Patients with low NLR1 or high sTILs scoring had a significantly improved DFS compared to those with high NLR1 or low sTILs scoring (p = 0.002 and p = 0.001, respectively). The increased lymphocyte count in peripheral blood after NAC was associated with the improved DFS outcome in both high and low NLR1 groups. Cox analysis revealed that NLR1 and sTILs were independent prognostic predictors of DFS outcome (p < 0.001). CONCLUSION: Low NLR1 and high sTILs were associated with better DFS outcome in locally advanced TNBC patients treated with NAC. Further studies are needed to explore the connection between systemic and local inflammatory/immune markers.

The Efficacy of Pyrotinib as a Third- or Higher-Line Treatment in HER2-Positive Metastatic Breast Cancer Patients Exposed to Lapatinib Compared to Lapatinib-Naive Patients: A Real-World Study.

Background: Pyrotinib is a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor. Evidence of the efficacy of pyrotinib-based treatments for HER2-positive metastatic breast cancer (MBC) in patients exposed to lapatinib is limited. Methods: Ninety-four patients who received pyrotinib as a third- or higher-line treatment for HER2-positive MBC were included in this retrospective study. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were implemented to balance important patient characteristics between groups. Results: Thirty (31.9%) patients were pretreated with lapatinib and subsequently received pyrotinib as an anti-HER2 treatment, and 64 (68.1%) patients did not receive this treatment. The OS and PFS indicated a beneficial trend in lapatinib-naive group compared to lapatinib-treated group in either the original cohort (PFS: 9.02 vs 6.36 months, p = 0.05; OS: 20.73 vs 14.35 months, p = 0.08) or the PSM (PFS: 9.02 vs 6.08 months, p = 0.07; OS: 19.07 vs 18.00 months, p = 0.61) or IPTW (PFS: 9.90 vs 6.17 months, p = 0.05; OS: 19.53 vs 15.10 months, p = 0.08) cohorts. Subgroup analyses demonstrated lapatinib treatment-related differences in PFS in the premenopausal subgroup and the no prior trastuzumab treatment subgroup, but no significant differences were observed in OS. Conclusion: Pyrotinib-based therapy demonstrated promising effects in HER2-positive MBC patients in a real-world study, especially in lapatinib-naive patients, and also some activity in lapatinib-treated patients.

Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data.

PURPOSE: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce. EXPERIMENTAL DESIGN: This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed. RESULTS: Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR). CONCLUSIONS: Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

A novel CD74-ROS1 gene fusion in a patient with inflammatory breast cancer: a case report.

BACKGROUND: CD74-ROS1 fusion genes have been detected in non-small cell lung carcinomas (NSCLC), but not in inflammatory breast cancer. CASE PRESENTATION: Herein, we report a CD74-ROS1 fusion gene identified in a 64-year-old Chinese woman with inflammatory breast cancer (IBC). The patient initially presented with a rapidly growing mass in the left breast with diffuse erythema developing over a period of 2 months. Diagnosis of invasive breast carcinoma was made by core needle biopsy. Positron emission tomography-computed tomography (PET/CT) demonstrated multiple organ metastases. Genomic DNA was extracted from tumor tissue and analyzed using next-generation sequencing (NGS). The CD74-ROS1 fusion gene was detected in the genomic DNA. The patient refused crizotinib treatment, and could not tolerate the side effects of palliative chemotherapy. Unfortunately, the patient died 4 months after diagnosis. CONCLUSION: We report the case of a CD74-ROS1 fusion gene in a patient with IBC. This may reveal, for the first time, a possible association between CD74-ROS1 gene fusion and rapid progression of inflammatory breast cancer. Multigene panel testing can be performed when rapidly progressive breast cancer occurs and could reveal potential therapeutic strategies.

Relationship Between the Neutrophil to Lymphocyte Ratio, Stromal Tumor-infiltrating Lymphocytes, and the Prognosis and Response to Neoadjuvant Chemotherapy in Triple-negative Breast Cancer.

INTRODUCTION: Neutrophil to lymphocyte ratio (NLR) and stromal tumor-infiltrating lymphocytes (sTILs) are correlated with triple-negative breast cancer (TNBC) patient prognosis. However, there has been insufficient research regarding the relationship between systemic and local inflammatory states in patients with TNBC, and their effects on neoadjuvant chemotherapy (NAC) efficacy. METHODS: The clinical data of 395 patients with TNBC admitted from January 2010 to December 2018 were collected. The Pearson χ2 test was used to analyze correlations between clinical basic pathological features, NLR, sTILs, and pathological complete response (pCR). Kaplan-Meier and Cox analyses were performed to address which clinical parameters were prognostic factors of disease-free survival (DFS). RESULTS: There was no correlation between NLR1 (baseline NLR) and sTILs (P > .05) in these patients with TNBC. Patients with TNBC with lower NLR3 (baseline NLR of patients receiving NAC) or higher sTILs scores had better pCR rates, but this failed to reach statistical significance (P > .05). Cox analysis showed that NLR1 and sTILs were independent prognostic indicators of DFS outcome in patients with TNBC (P < .01). CONCLUSION: In patients with TNBC, low NLR1 and high sTILs are associated with prolonged DFS. However, the link between systemic and local inflammation markers needs further exploration.

Conventional suture with prolonged timing of drainage is as good as quilting suture in preventing seroma formation at pectoral area after mastectomy.

BACKGROUND: The aim of this study was to compare conventional suture with prolonged timing of drainage with quilting suture on the formation of seroma at pectoral area after mastectomy (ME) with sentinel lymph node biopsy (SLN) or axillary lymph node dissection (ALND) for breast cancer. METHODS: Three hundred and eighty-eight consecutive breast cancer patients were retrospectively analyzed and categorized into three groups. Patients in group 1 were with quilting suture, group 2 with conventional suture and 13-15 days drainage in situ, and group 3 with conventional suture and 20-22 days drainage. The primary outcome was the incidence of grades 2 and 3 seroma at anterior pectoral area within 1 month postoperatively. Cox regression was used for analysis. RESULTS: The incidence of grades 2 and 3 seroma was comparable among groups (9.5% vs. 7.9% vs. 5.3%, p = 0.437), as well as late grades 2 and 3 seroma among groups (4.3% vs. 2.9% vs. 1.5%, p = 0.412). Old age, high body mass index, and hypertension were independent risk factors for grades 2 and 3 seroma. CONCLUSIONS: Prolonged timing of drainage to 13-15 days in conventional suture was long enough to decrease the incidence of grades 2 and 3 seroma as lower as that in quilting suture group at pectoral area within 1 month after mastectomy.

lncRNA MIR503HG inhibits cell proliferation and promotes apoptosis in TNBC cells via the miR-224-5p/HOXA9 axis.

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer. This study investigated the molecular mechanism and influences of MIR503HG, miR-224-5p, and homeobox A9 (HOXA9) on TNBC cell growth and migration. Dual-luciferase reporter gene and RNA immunoprecipitation were performed to examine the regulation of MIR503HG, miR-224-5p, and HOXA9. Cell proliferation, apoptosis, migration, and invasion were evaluated by colony formation, flow cytometry, and Transwell assays. Finally, nude mice were employed to investigate the influence of MIR503HG on TNBC tumor growth. HOXA9 protein levels were detected by immunohistochemical staining. MIR503HG and HOXA9 expression were reduced in TNBC, while miR-224-5p was increased. Overexpression of MIR503HG or HOXA9 reduced the cell migration ability and proliferation and promoted apoptosis, and knockdown of MIR503HG or overexpression of miR-224-5p exhibited the opposite effects. Furthermore, MIR503HG promoted HOXA9 expression by inhibiting miR-224-5p. Overexpression of miR-224-5p reversed the effects of MIR503HG overexpression on TNBC cells, while overexpression of HOXA9 reversed the effect of MIR503HG knockdown. Additionally, an in vivo study proved that MIR503HG inhibited TNBC tumor growth via the miR-224-5p/HOXA9 axis. MIR503HG inhibited cell proliferation and promoted the apoptosis of TNBC cells via the miR-224-5p/HOXA9 axis, which may function as a novel target for the treatment of TNBC.