Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer.

PURPOSE: Mammography screening has increased the detection of subcentimeter breast cancers. The prognosis for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative T1a/bN0M0 breast cancers is excellent; however, the necessity of adjuvant endocrine therapy (ET) is uncertain. METHODS: We evaluated the effectiveness of adjuvant ET in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer who underwent surgery from 2008 to 2012. Standard ET was administrated after surgery. The primary endpoint was the cumulative incidence of distant metastasis. All statistical tests were 2-sided. RESULTS: Adjuvant ET was administered to 3991 (83%) of the 4758 eligible patients (1202 T1a [25.3%] and 3556 T1b [74.7%], diseases). The median follow-up period was 9.2 years. The 9-year cumulative incidence of distant metastasis was 1.5% with ET and 2.6% without ET (adjusted subdistribution hazard ratio [sHR], 0.54; 95% CI, 0.32-0.93). In multivariate analysis, the independent risk factors for distant metastasis were no history of ET, mastectomy, high-grade, and lymphatic invasion. The 9-year overall survival was 97.0% and 94.4% with and without ET, respectively (adjusted HR, 0.57; 95% CI, 0.39-0.83). In addition, adjuvant ET reduced the incidence of ipsilateral and contralateral breast cancer (9-year rates; 1.1% vs. 6.9%; sHR, 0.17, and 1.9% vs. 5.2%; sHR, 0.33). CONCLUSIONS: The prognosis was favorable in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer. Furthermore, adjuvant ET reduced the incidence of distant metastasis with minimal absolute risk difference. These findings support considering the omission of adjuvant ET, especially for patients with low-grade and no lymphatic invasion disease.

Quantitative hormone receptor (HR) expression and gene expression analysis in HR+ inflammatory breast cancer (IBC) vs non-IBC.

BACKGROUND: The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior. METHODS: We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical staining and determined the predictive and prognostic role of HR expression on 189 patients with HR+/HER2- IBC and 677 patients with HR+/HER2- stage III non-IBC. Furthermore, we performed gene expression (GE) analyses on 137 patients with HR+/HER2- IBC and 252 patients with HR+/HER2- non-IBC to detect genes that are specifically overexpressed in IBC. RESULTS: The expression of ER% was significantly associated with longer distant disease-free survival and overall survival. However, there was no significant relationship between ER% and neoadjuvant chemotherapy outcome. In the GE study, 84 genes were identified as significantly distinguishing HR+ IBC from non-IBC. Among the top 15 canonical pathways expressed in IBC, the ERK/MAPK, PDGF, insulin receptor, and IL-7 signaling pathways were associated with the ER signaling pathway. Upregulation of the MYC gene was observed in three of these four pathways. Furthermore, HR+/HER2- IBC had significantly higher MYC amplification, and the genetic alteration was associated with poor survival outcome. CONCLUSIONS: Higher ER expression was significantly associated with improved survival in both HR+/HER2- IBC and HR+/HER2- stage III non-IBC patients. HR+/HER2- IBC had several activated pathways with MYC upregulation, and the genetic alteration was associated with poor survival outcome. The results indicate that MYC may be a key gene for understanding the biology of HR+/HER2- IBC.

Lnc RNA H19 is associated with poor prognosis in breast cancer patients and promotes cancer stemness.

PURPOSE: Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC). METHODS: In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19, which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases. RESULTS: Network analysis revealed the existence of five genes related with H19, including miR-103, miR-107, let-7, miR-29b-1, and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p = 0.012, 20.0 vs. 69.2% at 5 years OS, p = 0.016). CONCLUSION: This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancer patients, particularly in triple-negative subtype.

[Diagnosis and Treatment of HBOC Syndrome by a Breast Surgical Oncologist].

Of all breast cancer cases, 5-10% occur because of inherited germline mutation. For hereditary breast and ovarian cancer (HBOC)syndrome, congenital knowledge and strategies for breast cancer treatment and risk reduction are necessary. Regarding the surgical procedure for the cancer site, the ipsilateral breast tumor recurrence rate following breast-conserving surgery in breast cancers with BRCA1/2 mutation is not significantly higher than that in sporadic breast cancers. In addition, prognosis did not differ according to surgical methods. Therefore, breast-conserving surgery for HBOC is not an absolute contraindication, although the risk of developing new primary tumors in the long term should be carefully considered. For the contralateral breast, 3 choices are available, surveillance, chemo-prevention, and risk-reducing mastectomy. Risk-reducing mastectomy is known to decrease the risk of breast cancer by 90%. Genetic counseling is essential for decision making in HBOC treatment. In this review, we reevaluated the current evidence for surgical decision making and systemic therapies for HBOC syndrome.

Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype.

Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2(+) and progesterone/estrogen receptor (HR)(-) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1(+) cancers had significantly shorter disease-free survival (P < 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1(+) cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1(+) breast cancers tended to be aggressive, with poor prognoses. Although ALDH1(+) TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC.

A model to predict upstaging to invasive carcinoma in patients preoperatively diagnosed with ductal carcinoma in situ of the breast.

BACKGROUND: The aims of this study were to determine clinicopathological factors associated with postoperative upstaging to invasive carcinoma in patients preoperatively diagnosed with ductal carcinoma in situ (DCIS) and to develop a model to predict the risk of upstaging. METHODS: Pre- and post-operative pathological diagnoses and radiological findings were assessed for 1,187 consecutive patients. RESULTS: Of the patients, 306 (25.8%) were upstaged on the surgical specimen. In multivariate analysis, the following four factors were significantly associated with upstaging: 1) the presence of sclerosing adenosis on the preoperative biopsy specimen (odds ratio [OR] 0.46, P = 0.013); 2) pleomorphic calcifications on the mammogram (OR 1.68, P = 0.009); 3) a mass suspicious for invasive carcinoma on ultrasonography and/or MRI (OR 2.13, P < 0.001); 4) tumor size ≥2 cm on ultrasonography (OR 1.80, P = 0.032). HER2-positive (OR 1.54, P = 0.062) and comedo necrosis (OR 1.42, P = 0.056) demonstrated a trend towards significance. A prediction model incorporating these variables demonstrated that the risk of upstaging was 5.1% with score 0-2 and was 58.1% with score 10. CONCLUSIONS: The prediction model incorporating clinicopathological features may be used to guide the selection of patients with DCIS for sentinel lymph node biopsy.

A prospective comparison study utilizing patient-reported outcomes of taxane-related peripheral neuropathy between nab-paclitaxel and standard paclitaxel in patients with breast cancer.

BACKGROUND: Characteristics of taxane-induced peripheral neuropathy (PN) could be different between paclitaxel and nab-paclitaxel. The purpose of this prospective observational multicenter cohort study was to compare tri-weekly nab-paclitaxel to weekly standard paclitaxel regarding the severity, onset and recovery of sensory and motor PN in patients with breast cancer. METHODS: Patients with histologically confirmed breast cancer who were scheduled to receive standard weekly paclitaxel (80 mg/m2) or tri-weekly nab-paclitaxel (260 mg/m2) at institutions in our multicenter group were eligible for this study. Sensory and motor PN were evaluated every 3 weeks until PN improved for up to one year using patient-reported outcome. RESULTS: Between February 2011 and April 2013, 115 patients were enrolled, including 57 and 58 in the paclitaxel and nab-paclitaxel groups, respectively. The incidence of moderate or severe sensory PN was not significantly different between the two groups (p = 0.40). The incidence of moderate or higher motor PN was more frequent in the nab-paclitaxel group than in the paclitaxel group (p = 0.048). The median period for demonstrating PN were shorter in the nab-paclitaxel group than in the paclitaxel group (sensory, p = 0.003; motor, p = 0.001). The recovery of motor PN was slower in the nab-paclitaxel group than in the paclitaxel group (p = 0.035), while the recovery period of sensory PN was not statistically different. CONCLUSION: Nab-paclitaxel induced sensory PN sooner than paclitaxel, and no difference was observed in the severity and recovery duration between the two agents. Motor PN was more severe, started sooner, and improved over a longer period in the nab-paclitaxel-treated patients than in the paclitaxel-treated patients.

Maintenance Pembrolizumab Therapy in Patients with Metastatic HER2-negative Breast Cancer with Prior Response to Chemotherapy.

PURPOSE: Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study. PATIENTS AND METHODS: Patients with a complete response, partial response, or stable disease (SD) after at least three cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 years of pembrolizumab exposure. The endpoints included the 4-month disease control rate (DCR), progression-free survival (PFS), overall survival, and response biomarkers in the blood. RESULTS: Of 43 treated patients, 11 had metastatic IBC and 32 non-IBC TNBC. The 4-month DCR was 58.1% [95% confidence interval (CI), 43.4-72.9]. For all patients, the median PFS was 4.8 months (95% CI, 3.0-7.1 months). The toxicity profile was similar to the previous pembrolizumab monotherapy study. Patients with high T-cell clonality at baseline had a longer PFS with pembrolizumab treatment than did those with low T-cell clonality (10.4 vs. 3.6 months, P = 0.04). Patients who achieved SD also demonstrated a significant increase in T-cell clonality during therapy compared with those who did not achieve SD (20% vs. 5.9% mean increase, respectively; P = 0.04). CONCLUSIONS: Pembrolizumab monotherapy achieved durable treatment responses. Patients with a high baseline T-cell clonality had prolonged disease control with pembrolizumab.

The location of unilateral axillary lymphadenopathy after COVID-19 vaccination compared with that of metastasis from breast cancer without vaccination.

PURPOSE: Unilateral axillary lymphadenopathy is known to occur after coronavirus disease (COVID-19) vaccination. Post-vaccination lymphadenopathy may mimic the metastatic lymph nodes in breast cancer, and it is challenging to distinguish between them. This study investigated whether the localization of axillary lymphadenopathy on magnetic resonance imaging (MRI) could be used to distinguish reactive lymphadenopathy after COVID-19 vaccines from metastatic nodes. MATERIALS AND METHODS: We retrospectively examined preoperative MRI images of 684 axillae in 342 patients who underwent breast cancer surgery from June to October 2021. Lymphadenopathy was defined as cortical thickening or short axis ≥ 5 mm. The axilla was divided into ventral and dorsal parts on the axial plane using a perpendicular line extending from the most anterior margin of the muscle group, including the deltoid, latissimus dorsi, or teres major muscles, relative to a line along the lateral chest wall. We recorded the presence or absence of axillary lymphadenopathy in each area and the number of visible lymph nodes. RESULTS: Of 80 axillae, 41 and 39 were included in the vaccine and metastasis groups, respectively. The median time from the last vaccination to MRI was 19 days in the vaccine group. The number of visible axillary lymph nodes was significantly higher in the vaccine group (median, 15 nodes) than in the metastasis group (7 nodes) (P < 0.001). Dorsal lymphadenopathy was observed in 16 (39.0%) and two (5.1%) axillae in the vaccine and metastasis groups, respectively (P < 0.001). If the presence of both ventral and dorsal lymphadenopathy is considered indicative of vaccine-induced reaction, this finding has a sensitivity of 34.1%, specificity of 97.4%, and positive and negative predictive values of 93.3％ and 58.5%, respectively. CONCLUSION: The presence of deep axillary lymphadenopathy may be an important factor for distinguishing post-vaccination lymphadenopathy from metastasis. The number of axillary lymph nodes may also help.

Optimal Supportive Care for Patients With Metastatic Breast Cancer According to Their Disease Progression Phase.

The clinical progression patterns of metastatic breast cancer (MBC) are heterogeneous; patients experience acute and stable phases at different time points. The acute phase consists of rapid progressive symptomatic changes, whereas in the stable phase, patients have relatively low symptom burden. Therefore, personalized interdisciplinary care is essential. The optimal palliative or supportive care in MBC is to provide comprehensive care that is individually prioritized to the patient's disease status. The purpose of this review is to provide a practical guide for oncologists to understand the priorities for supportive care for patients with MBC in the two phases. We note that for better decision making in patient care, performance status should be broadened to consider not only physical status but also psychosocial needs and cognitive condition. We summarize the clinical importance of physical symptom control, psychosocial support, physical activity, nutrition support, and advance care planning. For optimal care, we present palliative or supportive care checklists according to the disease progression phase, combining the limited evidence with expert input. In the acute phase, close monitoring of the patient's status and symptom management take priority. In the stable phase, the focus can shift to maintenance or improvement of physical strength and emotional condition. Finally, we discuss future directions and unmet needs in providing the best supportive care for patients with MBC.

Pathological complete response of adding targeted therapy to neoadjuvant chemotherapy for inflammatory breast cancer: A systematic review.

BACKGROUND: The current use of targeted therapy plus neoadjuvant chemotherapy for inflammatory breast cancer (IBC) is based on data extrapolated from studies in non-IBC. We conducted a systematic review to determine whether neoadjuvant chemotherapy plus targeted therapy results in a higher pathologic complete response (pCR) rate than neoadjuvant chemotherapy alone in patients with IBC. METHOD AND FINDINGS: This systematic review was registered in the PROSPERO register with registration number CRD42018089465. We searched MEDLINE & PubMed, EMBASE, and EBSCO from December 1998 through July 2020. All English-language clinical studies, both randomized and non-randomized, that evaluated neoadjuvant systemic treatment with or without targeted therapy before definitive surgery and reported the pCR results of IBC patients. First reviewer extracted data and assessed the risk of bias using the Risk of Bias In Non-randomized Studies of Interventions tool. Second reviewer confirmed the accuracy. Studies were divided into 3 groups according to systemic treatment: chemotherapy with targeted therapy, chemotherapy alone, and high-dose chemotherapy with hematopoietic stem cell support (HSCS). Of 995 screened studies, 23 with 1,269 IBC patients met the inclusion criteria. For each of the 3 groups of studies, we computed a weighted average of the pCR rates across all studies with confidence interval (CI). The weighted averages (95% CIs) were as follows: chemotherapy with targeted therapy, 31.6% (26.4%-37.3%), chemotherapy alone, 13.0% (10.3%-16.2%), and high-dose chemotherapy with HSCS, 23.0% (18.7%-27.7%). The high pCR by targeted therapy group came from anti-HER2 therapy, 54.4% (44.3%-64.0%). Key limitations of this study included no randomized clinical studies that included only IBC patients. CONCLUSION: Neoadjuvant chemotherapy plus targeted therapy is more effective than neoadjuvant chemotherapy alone for IBC patients. These findings support current IBC standard practice in particular the use of anti-HER2 targeted therapy.

Bromodomain-containing Protein 4 Is a Favourable Prognostic Factor in Breast Cancer Patients.

AIM: To evaluate the association between bromodomain-containing protein 4 (BRD4) expression and clinicopathological factors and prognosis in human breast cancer specimens. PATIENTS AND METHODS: We used tissue microarrays constructed from samples of patients (n=183) who underwent surgery. We validated the association between BRD4 expression and prognosis in solid tumours, including breast cancer, using The Cancer Genome Atlas (TCGA) database. RESULTS: Immunohistochemical staining showed that BRD4 was widely distributed in breast cancer tissues. BRD4 was strongly expressed in 19.7% of patients but BRD4 staining intensity was not correlated with other clinicopathological factors. Most importantly, patients with a strong BRD4 expression had a significantly longer disease-specific survival than those with a weak BRD4 expression (100.0% vs. 91.3% at 5 years, p=0.027). mRNA expression analysis showed similar results (91.2% vs. 80.2% at 6 years, p=0.047). CONCLUSION: Strong BRD4 expression was associated with a significantly better prognosis in breast cancer tumours.

The Prognostic Impact of Body Composition for Locally Advanced Breast Cancer Patients Who Received Neoadjuvant Chemotherapy.

Our previous study indicated that a high amount of visceral adipose tissue was associated with poor survival outcomes in patients with early breast cancer who received neoadjuvant chemotherapy. However, inconsistency was observed in the prognostic role of body composition in breast cancer treatment outcomes. In the present study, we aimed to validate our previous research by performing a comprehensive body composition analysis in patients with a standardized clinical background. We included 198 patients with stage III breast cancer who underwent neoadjuvant chemotherapy between January 2007 and June 2015. The impact of body composition on pathologic complete response and survival outcomes was determined. Body composition measurements had no significant effect on pathologic complete response. Survival analysis showed a low ratio of total visceral adipose tissue to subcutaneous adipose tissue (V/S ratio ≤ 34) was associated with shorter overall survival. A changepoint method determined that a V/S ratio cutoff of 34 maximized the difference in overall survival. Our study indicated the prognostic effect of body composition measurements in patients with locally advanced breast cancer compared to those with early breast cancer. Further investigation will be needed to clarify the biological mechanism underlying the association of V/S ratio with prognosis in locally advanced breast cancer.

Aldehyde Dehydrogenase 1-related Genes in Triple-negative Breast Cancer Investigated Using Network Analysis.

BACKGROUND/AIM: Aldehyde dehydrogenase 1 (ALDH1) is known as a breast cancer stem cell (CSC) marker. This study aimed to identify genes associated with ALDH1. MATERIALS AND METHODS: ALDH1-positive and -negative breast cancer cells were isolated using laser capture microdissection from five tissue samples of ALDH1-positive breast cancer patients. Messenger RNA expression levels were compared between ALDH1-positive and -negative cells. RESULTS: We found 104 differentially expressed genes between ALDH1-positive and -negative cells. Gene ontology and pathway analysis revealed that these genes were correlated with CSC functions and pathways. Network analyses identified 10 genes that were closely associated with ALDH1. We validated these 10 genes utilizing The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium cohort, and found that they were associated with ALDH1 expression and correlated with Wnt pathway signaling. CONCLUSION: The 10 genes we identified could be potential targets for CSC therapy of breast cancer.

Validation of Prognostic Stage and Anatomic Stage in the American Joint Committee on Cancer 8th Edition for Inflammatory Breast Cancer.

The AJCC updated its breast cancer staging system to incorporate biological factors in the "prognostic stage". We undertook this study to validate the prognostic and anatomic stages for inflammatory breast cancer (IBC). We established two cohorts of IBC diagnosed without distant metastasis: (1) patients treated at The University of Texas MD Anderson Cancer Center between 1991 and 2017 (MDA cohort) and (2) patients registered in the national Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 (SEER cohort). For prognostic staging, estrogen receptor (ER)+/progesterone receptor (PR)+/ human epidermal growth factor receptor-2 (HER2)+/grade 1-2 was staged as IIIA; ER+/PR-/HER2-/grade 3, ER-/PR+/HER2-/grade 3, and triple-negative cancers as IIIC; and all others as IIIB. Endpoints were breast cancer-specific survival (BCSS), overall survival (OS), and disease-free survival (DFS). We studied 885 patients in the MDA cohort and 338 in the SEER cohort. In the MDA cohort, the prognostic stage showed significant predictive power for BCSS, OS, and DFS (all p < 0.0001), although the anatomic stage did not. In both cohorts, the Harrell concordance index (C index) was significantly higher in the prognostic stage than the anatomic stage for all endpoints. In conclusion, the prognostic stage provided more accurate prognostication for IBC than the anatomic stage. Our results show that the prognostic staging is applicable in IBC.

EpCAM-independent isolation of circulating tumor cells with epithelial-to-mesenchymal transition and cancer stem cell phenotypes using ApoStream® in patients with breast cancer treated with primary systemic therapy.

BACKGROUND: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR). METHODS: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (ß-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low). RESULTS: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated. CONCLUSIONS: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted.

Anthracycline could be essential for triple-negative breast cancer: A randomised phase II study by the Kanagawa Breast Oncology Group (KBOG) 1101.

BACKGROUND: It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. METHODS: The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. RESULTS: Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). CONCLUSION: TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

Enhancing effect of chlorinated organic solvents on histamine release and inflammatory mediator production.

We investigated the effect of several chlorinated organic solvents on antigen-induced histamine release and inflammatory mediator production. Non-purified rat peritoneal mast cells (NPMC) and rat basophilic leukemia (RBL-2H3) cells were sensitized with anti-dinitrophenol (DNP) monoclonal IgE antibody, and then stimulated with DNP-conjugated bovine serum albumin (DNP-BSA) and several chlorinated organic solvents. Trichloroethylene (TCE) and tetrachloroethylene (PCE) enhanced histamine release from antigen-stimulated NPMC and RBL-2H3 in a dose-dependent manner. In addition, TCE and PCE increased IL-4 and TNF-alpha production from antigen-stimulated RBL-2H3. In an in vivo study, we investigated the effect of TCE and PCE on passive cutaneous anaphylaxis (PCA) reaction. TCE and PCE enhanced PCA reaction markedly. These results suggest that TCE and PCE increase histamine release and inflammatory mediator production from antigen-stimulated mast cells via the modulation of immune responses. In addition, exposure to TCE and PCE may lead to the augmentation of allergic diseases.

Change in sonographic brightness can predict pathological response of triple-negative breast cancer to neoadjuvant chemotherapy.

INTRODUCTION: Ultrasound (US) is conventionally performed to determine effects of neoadjuvant chemotherapy (NAC) on breast cancer. In patients with triple-negative breast cancer (TNBC), higher pathological complete response (pCR) predicts the most favorable survival outcome. We aimed to predict pCR to NAC using echogenicity changes in US region of interest (ROI) in patients with TNBC. METHODS AND MATERIALS: We retrospectively determined clinicopathological characteristics of 52 patients with primary TNBC who underwent NAC. Changes in echogenicity for pCR and non-pCR patients were calculated from ratios of tumor to fat (T/F) in their ROIs, before and after NAC, as [T/F After/T/F Before] and [T/F After - T/F Before]. RESULTS: Of the 52 patients (median age: 52 years; range 26-77 years), 20 (38.5%) achieved pCR, which was significantly associated with change in ROI ratio (P < 0.01). The cut-off values for ROI ratio and ROI difference were 0.8 and 0.3. Sensitivity and specificity were 73.7 and 81.8% for ROI ratio, and 70.0 and 81.3% for ROI difference. Area under the curves (AUCs) for ROI ratio and ROI difference were 0.80 [95% confidence interval (CI) 0.67-0.92] and 0.78 (95% CI 0.64-0.92), respectively. CONCLUSION: Quantification of echogenic changes by converting absolute values of tumor and fat regions can predict pCR and individual differences between tumors after NAC in patients with TNBC.

ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer.

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously, we observed that S1P is exported out of human breast cancer cells by ATP-binding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathologic consequences of these events to breast cancer progression and metastasis have not been elucidated. Here, it is demonstrated that high expression of ABCC1, but not ABCB1, is associated with poor prognosis in breast cancer patients. Overexpression of ABCC1, but not ABCB1, in human MCF7 and murine 4T1 breast cancer cells enhanced S1P secretion, proliferation, and migration of breast cancer cells. Implantation of breast cancer cells overexpressing ABCC1, but not ABCB1, into the mammary fat pad markedly enhanced tumor growth, angiogenesis, and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival of mice. Interestingly, S1P exported via ABCC1 from breast cancer cells upregulated transcription of sphingosine kinase 1 (SPHK1), thus promoting more S1P formation. Finally, patients with breast cancers that express both activated SPHK1 and ABCC1 have significantly shorter disease-free survival. These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.Implication: Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancer worsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression. Mol Cancer Res; 16(6); 1059-70. ©2018 AACR.