Targeting regulator of G protein signaling 1 in tumor-specific T cells enhances their trafficking to breast cancer.

Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.

Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages.

Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.

CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness.

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death.

Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (TH1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell-receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and TH1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.

Machine learning radiomics of magnetic resonance imaging predicts recurrence-free survival after surgery and correlation of LncRNAs in patients with breast cancer: a multicenter cohort study.

BACKGROUND: Several studies have indicated that magnetic resonance imaging radiomics can predict survival in patients with breast cancer, but the potential biological underpinning remains indistinct. Herein, we aim to develop an interpretable deep-learning-based network for classifying recurrence risk and revealing the potential biological mechanisms. METHODS: In this multicenter study, 1113 nonmetastatic invasive breast cancer patients were included, and were divided into the training cohort (n = 698), the validation cohort (n = 171), and the testing cohort (n = 244). The Radiomic DeepSurv Net (RDeepNet) model was constructed using the Cox proportional hazards deep neural network DeepSurv for predicting individual recurrence risk. RNA-sequencing was performed to explore the association between radiomics and tumor microenvironment. Correlation and variance analyses were conducted to examine changes of radiomics among patients with different therapeutic responses and after neoadjuvant chemotherapy. The association and quantitative relation of radiomics and epigenetic molecular characteristics were further analyzed to reveal the mechanisms of radiomics. RESULTS: The RDeepNet model showed a significant association with recurrence-free survival (RFS) (HR 0.03, 95% CI 0.02-0.06, P < 0.001) and achieved AUCs of 0.98, 0.94, and 0.92 for 1-, 2-, and 3-year RFS, respectively. In the validation and testing cohorts, the RDeepNet model could also clarify patients into high- and low-risk groups, and demonstrated AUCs of 0.91 and 0.94 for 3-year RFS, respectively. Radiomic features displayed differential expression between the two risk groups. Furthermore, the generalizability of RDeepNet model was confirmed across different molecular subtypes and patient populations with different therapy regimens (All P < 0.001). The study also identified variations in radiomic features among patients with diverse therapeutic responses and after neoadjuvant chemotherapy. Importantly, a significant correlation between radiomics and long non-coding RNAs (lncRNAs) was discovered. A key lncRNA was found to be noninvasively quantified by a deep learning-based radiomics prediction model with AUCs of 0.79 in the training cohort and 0.77 in the testing cohort. CONCLUSIONS: This study demonstrates that machine learning radiomics of MRI can effectively predict RFS after surgery in patients with breast cancer, and highlights the feasibility of non-invasive quantification of lncRNAs using radiomics, which indicates the potential of radiomics in guiding treatment decisions.

Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial.

BACKGROUND: Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer. METHODS: Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers. RESULTS: Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4+ T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET. CONCLUSION: This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings. TRAIL REGISTRATION: A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051 .

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

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

Multiple metastases of bones and sigmoid colon after mastectomy for ductal carcinoma in situ of the breast: a case report.

BACKGROUND: The prognosis of ductal carcinoma in situ (DCIS) is reportedly well. Extremely rare patients with DCIS develop distant breast cancer metastasis without locoregional or contralateral recurrence. This is the first report of multiple bones and sigmoid colon metastases from DCIS after mastectomy. CASE PRESENTATION: A 43-year-old woman was diagnosed with DCIS, and she received mastectomy, followed by endocrine therapy and target therapy. During the following-up, convulsions and pain on the legs were complaint. Therefore, Computed Tomography (CT) on bones and positron emission tomography (PET) for whole body were examined in order. Multiple bones and sigmoid colon were under the suspect of metastases, which were then verified by biopsy in the left ilium and colonoscopy respectively. CONCLUSIONS: This case reveals the heterogeneous behavior and the potential poor outcome of DCIS, regular examination and surveillance are necessary even though the distant metastasis rate in DCIS is low.

Development and validation of a nomogram incorporating axillary lymph node ratio to predict survival in node-positive breast cancer patients after neoadjuvant chemotherapy.

OBJECTIVE: Over the past decade, several studies have highlighted that axillary lymph node ratio (ratio of involved over excised axillary lymph nodes) was a superior predictor for survival outcomes compared with ypN staging. Thus, this study aimed to integrate the prognostic value of axillary lymph node ratio to improve individualized prediction of survival in node-positive breast cancer patients after neoadjuvant chemotherapy. METHODS: A clinical data of 339 node-positive breast cancer patients after neoadjuvant chemotherapy from two independent centers were retrospectively reviewed. A nomogram incorporating axillary lymph node ratio was constructed to predict disease-free survival based on Cox proportional hazards model. The discrimination, calibration ability, and clinical usefulness of the axillary lymph node ratio-based model were evaluated using C-index, calibration curve, risk group stratification and decision curve analysis and were compared with the TNM staging system. RESULTS: Independent prognostic factors for disease-free survival were age, pathological T stage, axillary lymph node ratio, histological grade, estrogen receptor status, Ki67 and lymphovascular invasion, which were entered into the nomogram. The C-index of the axillary lymph node ratio-based nomogram was higher than that of the TNM staging system (0.773 vs 0.610). The calibration plot indicated close agreement between model predictions and actual observations. Based on the risk group stratification of the nomogram, Kaplan-Meier curves demonstrated significant differences between the low-risk and high-risk groups (P < 0.0001). CONCLUSIONS: The axillary lymph node ratio-based nomogram provided more accurate individualized risk prediction of disease-free survival in node-positive breast cancer patients after neoadjuvant chemotherapy. This practical tool may assist oncologists in selecting the high-risk patients who are in need of a specific treatment strategy.

LncRNA NKILA suppresses TGF-ß-induced epithelial-mesenchymal transition by blocking NF-κB signaling in breast cancer.

TGF-ß plays a central role in mediating epithelial-mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF-ß-induced EMT is NF-κB-dependent in various cancer types. However, it is largely unclear if NF-κB mediates TGF-ß-induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF-ß activates the NF-κB pathway. Inhibition of NF-κB signaling markedly abrogates TGF-ß-induced EMT. By studying the regulatory mechanism of TGF-ß-induced NF-κB signaling, we found that lncRNA NKILA was upregulated by TGF-ß and was essential for the negative feedback regulation of the NF-κB pathway. Accordingly, overexpression of NKILA significantly reduced TGF-ß-induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA-mediated negative feedback affects TGF-ß-induced NF-κB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT.

Does patient age affect the PPV3 of ACR BI-RADS Ultrasound categories 4 and 5 in the diagnostic setting?

OBJECTIVES: To calculate the positive predictive value of biopsies performed (PPV3) of the Ultrasound section of the American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS US) atlas categories 4 and 5 in different age groups and to determine whether patient age influences the PPV3 of each category in the diagnosis of breast lesions. METHODS: We identified 2,433 ACR BI-RADS US categories 4 and 5 lesions with a known pathological diagnosis in 2,433 women. The patients were classified into three age groups (<35, 35-50, and >50 years). The age-related PPV3 of each category in the three age groups were calculated based on the pathological diagnoses and compared using the chi-squared test. RESULTS: The overall PPV3 of each category was within the reference range provided by the ACR in 2013. PPV3 gradually increased with increasing age in patients with category 4 lesions. PPV3 in the oldest group with subcategories 4A and 4B lesions were close to or exceeded the reference values. CONCLUSIONS: PPV3 and age were significantly associated in patients with category 4 lesions according to the newest edition of ACR BI-RADS US in the diagnostic setting. Closer attention should be given to older patients when assigning a final assessment category. KEY POINTS: • In patients with category 4 lesions , the likelihood of malignancy is associated with age. • In patients with category 5 lesions, the association is not definite. • Closer attention should be given to older patients in applying the ACR BI-RADS US.

Polymorphisms in homologous recombination repair genes and the risk and survival of breast cancer.

BACKGROUND: Immunoglobulin (Ig)A antibody of Epstein-Barr virus (EBV) was found to associate with breast cancer (BC), whereas IgA positivity was related to a series of genetic markers in the genes of homologous recombination repair system (HRRs). We assessed the associations of the polymorphisms in HRR genes with the risk and survival of BC. METHODS: A case-control study was conducted with 1551 bc cases and 1605 age-matched healthy controls between October 2008 and March 2012 in the Guangzhou Breast Cancer Study (GZBCS), China, and the case population were followed up until 31 January 2016. Five single nucleotide polymorphisms of candidate genes in HRR system were genotyped. Odds ratios (ORs) and hazards ratios (HRs) were calculated using multivariate logistic regression and Cox proportional hazards regression to estimate the risk and prognostic effect, respectively. RESULTS: RFC1 rs6829064 (AA) was associated with an increased BC risk [OR = 1.35; 95% confidence interval (CI) = 1.06-1.73] compared to the wild genotype (GG). NRM rs1075496 (GT/TT versus GG) was associated with a worse progression-free survival (PFS) and the HR was 1.34 (95% CI = 1.01-1.78), particularly among advanced patients. LIG3 rs1052536 (CT/TT versus CC) was associated with a better PFS and the HR was 0.70 (95% CI = 0.53-0.93). However, RAD54L rs1710286 and RPA1 rs11078676 were not observed to be associated with either the risk or survival of BC. CONCLUSIONS: The findings of the present study suggest that the polymorphisms in HRR genes were associated with BC risk (RFC1 rs6829064) and prognosis (NRM rs1075496 and LIG3 rs1052536), whereas RAD54L rs1710286 and RPA1 rs11078676 had null associations with BC.

Allelic expression imbalance polymorphisms in susceptibility chromosome regions and the risk and survival of breast cancer.

Allelic expression imbalance (AEI) has been applied to indicate potential function of genetic variants. Combining earlier results from global differential allele-specific expression analysis and genome wide association studies (GWASs), we select the single nuclear polymorphisms (SNPs) exhibiting AEI phenomenon located in breast cancer susceptibility chromosome regions, and evaluate their associations with breast cancer risk and survival. We examined the genotypes of 10 AEI SNPs in 1551 incident breast cancer cases and 1605 age-frequency matched controls from Guangzhou, China. In total, 1168 cases were followed up. MUC16 rs2591592 (AT/AA vs. TT) was associated with an increased risk of premenopausal breast cancer (OR [95%CI]: 1.30 [1.07, 1.57]); SLAMF1 rs1061217 (CT/TT vs. CC) decreased the risk of breast cancer among overweight women (OR [95%CI]: 0.74 [0.57, 0.96]) but increased the risk among normal-weight women (OR [95%CI]: 1.15 [1.01, 1.39]); ZNF331 rs8109631 (AG/AA vs. GG) and CHRAC1 rs10216653 (GC/GG vs. CC) were associated with progression free survival among breast cancer patients with negative ER/PR status and higher clinical stage (HRs [95%CIs]: 2.39 [1.14, 5.00], 1.85 [1.03, 3.32], and 0.49 [0.30, 0.80], respectively). ZNF331 rs8109631 and CHRAC1 rs10216653 were further found to represent several functional SNPs through bioinformatic analysis. In conclusion, our findings demonstrated suggestive associations of AEI polymorphisms with breast cancer risk (MUC16 rs2591592 and SLAMF1 rs1061217) and prognosis (ZNF331 rs8109631 and CHRAC1 rs10216653). © 2016 Wiley Periodicals, Inc.

Prognostic significance of Ki67 in Chinese women diagnosed with ER+/HER2- breast cancers by the 2015 St. Gallen consensus classification.

BACKGROUND: This study evaluated the distribution pattern of the Ki67-labeling index (LI) among patients at a Chinese breast cancer center, and analyzed its prognostic significance in the 2015 St Gallen consensus breast cancer classification, estrogen receptor-positive and human epidermal growth factor receptor 2-negative(ER+/HER2-)subtype. METHODS: We classified 939 women with ER+/HER2- breast cancer into three groups by Ki67-LI levels, and followed their clinicopathologic characteristics and prognoses. RESULTS: In the 939 eligible subjects, 342 had Ki67-LI ≤10% (Ki67Low), 281 had Ki67-LI between 10 and 30% (Ki67Medium), and 316 had Ki67-LI ≥30% (Ki67High). Although the Ki67High group had less favorable clinicopathologic factors, the Ki67Medium group's factors varied considerably. Kaplan-Meier estimates showed that disease-free survival(DFS) for the Ki67Medium group was significantly shorter than the Ki67Low group but longer than the Ki67High group. Ki67-LI had independent prognostic significance in multivariate analysis. Other diagnostic factors, including tumor size >2 cm, positive lymph nodes, and grade III disease, were significantly associated with poorer disease-free survival only in the Ki67Medium group. CONCLUSIONS: For patients with ER+/HER2- breast cancer, we confirmed three distinct risk patterns by Ki67-LI levels according to the 2015 St Gallen consensus. For patients with clearly low or high Ki67-LI, straightforward clinical decisions could be offered, but for patients with intermediate Ki67-LI, other factors might provide valuable information.

Prospective comparison of Sapylin and Avitene for reducing hydrops after axillary lymphadenectomy in breast cancer patients.

BACKGROUND: This study compared the efficacy of Sapylin and Avitene in reducing postoperative axillary seroma formation and effusion when applied topically after axillary lymphadenectomy. METHODS: A total of 224 patients were randomly divided into a Sapylin treatment group (STG), an Avitene treatment group, and a control group (CG). All patients underwent axillary lymphadenectomy and were treated during surgery with Sapylin, Avitene, or neither according to their group assignment. The duration and amount of postoperative drainage, as well as the occurrence of seromas were recorded. Outcomes were compared by one-way analysis of variance and chi-square tests. RESULTS: Baseline patient data, including age, body mass index, history of neoadjuvant chemotherapy, type of surgery, number of resected lymph nodes, and number of positive metastases did not differ among the three groups. Patients in both the STG and the Avitene treatment group experienced significantly fewer days of drainage than those in the CG; there was no significant difference in drainage tube retention time between the two treated groups. The STG experienced significantly less drainage volume than the CG. Fewer patients in both treatment groups required seroma treatment or experienced complications compared with CG patients. CONCLUSIONS: Both Sapylin and Avitene effectively reduced postoperative subcutaneous fluid accumulation after axillary lymphadenectomy. These treatments may be particularly useful for breast cancer patients at high risk of seroma formation, especially those with hypertension, diabetes mellitus, or a high body mass index who undergo axillary lymphadenectomy.

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

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

Significance of Tumor-Infiltrating Lymphocytes and the Expression of Topoisomerase IIα in the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy.

PURPOSE: The aim of this study was to determine factors able to predict chemotherapeutic responses and clinical outcomes in patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). METHODS: Fifty-two TNBC patients on taxane-anthracycline-based NAC were included. The expression of Ki67, topoisomerase IIα (TOPOIIα), and p53, as well as the presence of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs were evaluated in biopsy specimens by immunohistochemistry. The expression of Ki67, TOPOIIα, and p53, as well as CD4 and CD8 in TILs was calculated according to the pathological response to NAC, disease-free survival (DFS), and overall survival (OS). RESULTS: Fourteen (26.9%) TNBC patients demonstrated a pathological complete response (pCR). According to univariate analyses, significant factors associated with pCR were high infiltration of CD4+ TILs (p = 0.004), high infiltration of CD8+ TILs (p = 0.010), and high expression of topoisomerase IIα (TOPOIIα) (p = 0.006). CD4+ TILs and TOPOIIα were significantly positively correlated with CD8+ TILs. Multivariate analyses indicated that TOPOIIα was an independent predictor of pCR. Although TNBC patients with high infiltration of CD4+ TILs, CD8+ TILs, or with high expression of TOPOIIα exhibited a significantly good 5-year DFS, only TNBC patients with a high infiltration of CD8+ TILs exhibited significantly positive 5-year OS probabilities. CONCLUSION: Our study demonstrated that CD4+ TILs and TOPOIIα in pretreated cancer tissues were significantly correlated with CD8+ TILs. CD4+ TILs, CD8+ TILs, and TOPOIIα expression were predictors of pCR and 5-year DFS of TNBC patients who were treated with NAC, and TOPOIIα was an independent predictor of pCR. CD8+ TILs were a key factor in the prediction of good 5-year OS rates of TNBC patients after taxane-anthracycline-based NAC.

Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy.

Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by suppressing the chemoresistance of CTCs and reducing the risk of cancer metastasis.

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

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

Genetic variants in EBV reactivation-related genes and the risk and survival of breast cancer.

Tumor susceptibility gene 101 (TSG101) and activating transcription factor 2 (ATF2) have been suggested to involve in the reactivation of EBV which has implications in the development and progression of breast cancer. Therefore, the polymorphisms of TSG101 and ATF2 may associate with breast cancer risk and prognosis. A case-control study with 1551 breast cancer cases and 1605 age-matched controls were conducted in Guangzhou, China. We have also successfully followed up 1168 cases until December 31, 2014. The variant allele of TSG101 rs2292179 was associated with a non-significant reduced risk of breast cancer, particularly among women with BMI < 24 (kg/m(2)) (P for interaction <0.05). For ATF2 rs3845744, the variant allele was also associated with a significantly reduced breast cancer risk [odds ratio (OR) (95 % confidence interval (CI)) 0.86 (0.74∼1.00)], and the association occurred among only postmenopausal women [OR (95 % CI) 0.69 (0.54∼0.88)] (P for interaction <0.05). Breast cancer risk was further reduced with the increasing numbers of the variant G alleles of the two polymorphisms (P for trend <0.05). We did not find an overall association of the two loci with breast cancer prognosis, while the hazard ratios of the two loci (AG/GG vs. AA) were significantly higher among postmenopausal women than premenopausal women (P = 0.046, 0.016 for TSG101 rs2292179 and ATF2 rs3845744, respectively). In summary, the variant alleles of TSG101 rs2292179 and ATF2 rs3845744 were associated with a reduced risk of breast cancer, particularly for subjects with BMI <24 (kg/m(2)) and postmenopausal women, respectively. The two SNPs and menopausal status may have a significant interaction on breast cancer progression.