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Background: The trastuzumab biosimilar CT-P6 is approved for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), metastatic breast cancer (MBC), and metastatic gastric cancer (MGC). The objective of this post-marketing surveillance (PMS) study was to evaluate the real-world safety and effectiveness of CT-P6 in patients with HER2-positive cancers., Research Design and Methods: This open-label, observational, prospective, PMS study collected data via investigator surveys from 35 centers in the Republic of Korea (5 October 2018-4 October 2022). Eligible patients with HER2-positive EBC, MBC, or MGC started CT-P6 treatment during routine clinical practice, followed by 1-year observation. Evaluations included adverse events (AEs), adverse drug reactions (ADRs), and effectiveness., Results: Safety was analyzed in 642 patients (494 EBC, 94 MBC, 54 MGC). Overall, 325 (50.6%) patients experienced 1316 AEs, and 550 ADRs occurred in 199 (31.0%) patients. Unexpected ADRs occurred in 62 (9.7%) patients. Unexpected ADRs and ADRs of special interest did not raise any new safety signals. Among trastuzumab-naïve patients, 34/106 (32.1%) with EBC achieved pathological complete response; 30/74 (40.5%) MBC and 24/49 (49.0%) MGC patients achieved complete or partial response., Conclusions: In a real-world setting, CT-P6 demonstrated safety and efficacy findings consistent with previous CT-P6 studies.

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population., (© 2024. The Author(s).)

Background: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up., Methods: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized., Results: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline., Conclusion: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer., Competing Interests: Declaration of Competing Interest SMT reports serving as a consulting or advisory role for Novartis, Pfizer, Merck, Eli Lilly and Company, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant (now Sumitovant Biopharma), Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera; and research funding (to institute) from Genentech/Roche, Merck, Exelixis, Pfizer, Eli Lilly and Company, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead, Seattle Genetics, OncoPep, Daiichi Sankyo, outside of the submitted work. VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly and Company, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Exact Sciences, Gilead, GSK Novartis and Zentiva; personal fees for expert testimony for Eli Lilly and Company, outside of the submitted work. JHS reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. JC reports honoraria from Glaxo, AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Eli Lilly and Company, Daichii Sankyo, Gilead, Seagen, MSD, Pierre Fabre, and Pfizer; serves as a consulting or advisory role for AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Eli Lilly and Company, Glaxo, Daichii Sankyo, Gilead, Seagen, Deciphera, and Pfizer; and travel expenses from Novartis, Gilead, Pharmamar, and Daichii-Sankyo, outside of the submitted work. MHA reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. MT reports fees from Eli Lilly and Company for speaker’s bureau, outside of the submitted work. CB reports grants and research support to their institution from Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Eli Lilly and Company, Seagen, Roche, Bristol-Myers Squibb, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, and Servier; ownership or stocks from Tummi and MEDSIR; and serves on the advisory boards and consulting with Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Eli Lilly and Company, Sanofi, and Daiichi, outside of the submitted work. KM reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. RW, MMunoz, BSA, AML are employees and/or stock shareholders of Eli Lilly and Company. MMartin reports research grants from Roche, PUMA and Novartis; consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly and Company, PUMA, Taiho Oncology, Daiichi Sankyo, Menarini/Stemline, and Pfizer; speakers’ honoraria from AstraZeneca, Lilly, Amgen, Roche/Genentech, Novartis, and Pfizer, outside of the submitted work. SRDJ reports grants or contracts from Pfizer, Puma Biotechnology, Eli Lilly and Company, AstraZeneca, Novartis, and Roche–Genentech for research funding to institute for laboratory studies and clinical trials; consulting fees from Eli Lilly and Company, AstraZeneca, Puma Biotechnology, Pfizer, Novartis, and Sanofi Genzyme for consulting or an advisory role; and payment or honoraria from Pfizer, Eisai, AstraZeneca, and Roche–Genentech for speaker's bureau, outside of the submitted work. PKL reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. NH reports honoraria for lectures and/or consulting froom Amgen, AstraZeneca, Daiichi-Sankyo, EPG Communication, Gilead, Eli Lilly and Company, MEDSCAPE, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Springer, Viatris, and Zuelligpharma; ownership interest in Minority ownership as Co-Director West German Study Group (WSG), outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cascade hydroxyl radical generating hydrogel reactor structures including a chemotherapeutic agent are invented for multiple treatment of breast cancer. Glucose oxidase (GOx) and cupric sulfate (Cu) are introduced for transforming accumulated glucose (in cancer cells) to hydroxyl radicals for starvation/chemodynamic therapy. Cu may also suppress cancer cell growth via cuproptosis-mediated cell death. Berberine hydrochloride (BER) is engaged as a chemotherapeutic agent in the hydrogel reactor for combining with starvation/chemodynamic/cuproptosis therapeutic modalities. Moreover, Cu is participated as a gel crosslinker by coordinating with catechol groups in hyaluronic acid-dopamine (HD) polymer. Controlling viscoelasticity of hydrogel reactor can extend the retention time following local injection and provide sustained drug release patterns. Low biodegradation rate of designed HD/BER/GOx/Cu hydrogel can reduce dosing frequency in local cancer therapy and avoid invasiveness-related inconveniences. Especially, it is anticipated that HD/BER/GOx/Cu hydrogel system can be applied for reducing size of breast cancer prior to surgery as well as tumor growth suppression in clinical application., (© 2023 Wiley-VCH GmbH.)

Background: We analyzed the effect of statins in patients with hormone receptor-positive (HR+) metastatic breast cancer treated with everolimus + exemestane (EverX)., Materials and Methods: We conducted a nationwide retrospective cohort study using the National Health Insurance database with patients who received EverX for metastatic breast cancer between 2011 and 2019., Results: Of 224,948 patients diagnosed with breast cancer, 1749 patients who received EverX for at least 30 days were included. Among them, 500 (28.6%) patients were found to take statins with EverX treatment (statin group), and the median duration of this combination was 5.36 months. The median time to treatment duration (TTD) for EverX and the overall survival (OS) were significantly higher in the statin group than in the no-statin group [7.69 vs. 5.06 months, p < 0.001; 45.7 vs. 26.0 months, p < 0.001, respectively]. Multivariable Cox analysis revealed that the use of statins was associated with prolonged TTD [HR = 0.67 (95% CI, 0.59-0.77)] and OS [HR = 0.57 (95% CI, 0.46-0.70)] for EverX even after adjustment for other covariates., Conclusion: Statins may have synergistic effects with endocrine therapy with the mTOR inhibitor everolimus, and improve survival in patients with HR+ metastatic breast cancer., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The expression of major histocompatibility complex class I (MHC I) has previously been reported to be negatively associated with estrogen receptor (ER) expression. Furthermore, MHC I expression, level of tumor-infiltrating lymphocytes (TILs), and expression of interferon (IFN) mediator MxA are positively associated with one another in human breast cancers. This study aimed to investigate the mechanisms of association of MHC I with ER and IFN signaling., Materials and Methods: The human leukocyte antigen (HLA)-ABC protein expression was analyzed in breast cancer cell lines. The expressions of HLA-A and MxA mRNAs were analyzed in MCF-7 cells in Gene Expression Omnibus (GEO) data. ER and HLA-ABC expressions, Ki-67 labeling index and TIL levels in tumor tissue were also analyzed in ER+/ human epidermal growth factor receptor 2 (HER2)- breast cancer patients who randomly received either neoadjuvant chemotherapy or estrogen modulator treatment followed by resection., Results: HLA-ABC protein expression was decreased after β-estradiol treatment or hESR-GFP transfection and increased after fulvestrant or IFN-γ treatment in cell lines. In GEO data, HLA-A and MxA expression was increased after ESR1 shRNA transfection. In patients, ER Allred score was significantly lower and the HLA-ABC expression, TIL levels, and Ki-67 were significantly higher in the estrogen modulator treated group than the chemotherapy treated group., Conclusion: MHC I expression and TIL levels might be affected by ER pathway modulation and IFN treatment. Further studies elucidating the mechanism of MHC I regulation could suggest a way to boost TIL influx in cancer in a clinical setting.

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-β1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-β1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-β1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-β1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors., Competing Interests: Competing Interests Statement S.G. is the recipient of research funding from Eli Lilly and Co which has been used to support a part of this work. S.G. has served as a paid advisory board member for Eli Lilly and Co, G1 Therapeutics, Pfizer, and Novartis. S.G. also conducts laboratory research sponsored by G1 Therapeutics and clinical research sponsored by Eli Lilly and Co and by Novartis. J.J.Z. is founder and board director of Crimson Biotech and Geode Therapeutics. J.M. is a consultant for Oncoheroes Biosciences and Vivid Biosciences. M.B. receives sponsored research support from Novartis. M.B. is a consultant to H3 Biomedicine and serves on the SAB of Kronos Bio and GV20 Therapeutics. C.M. is a consultant for Pfizer, Novartis, Seattle Genetics and Eli Lilly and Co and receives institutional research funding from Pfizer and Puma. I.K. receives institutional research funding and grants from Genentech/Roche and Pfizer. I.K. is an advisory board participant, consultant, and has received honoraria from Daiichi/Sankyo, Macrogenics, and Genentech/Roche. I.K. is an advisory board participant and has received honoraria from Context Therapeutics, Taiho Oncology, and Seattle Genetics. I.K. is a data monitoring board member at Novartis. E.W. is a consultant at and has received honoraria from Carrick Therapeutics, DragonFly, Genentech/Roche, Genomic Health, GSK, Jounce, Eli Lilly and Co, Seattle Genetics, and Merck. E.W. is a scientific advisory board member and has received honoraria from Leap. M.E. has patents and receives royalties from prosigna/Nanostring. O. M.-F. receives institutional research funding from AbbVie, Genentech, Roche, and Pfizer, and has received honoraria from Roche. M.A.D. has been a member of the advisory boards for CTX CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. The Dawson lab receives research funding from CTX CRC. All other authors declare no conflicts of interest.

A higher level of tumor-infiltrating lymphocytes (TILs) is associated with better prognosis in breast cancer patients. Adoptive transfer of lymphocytes coupled with conventional therapies has appealed to many clinicians and investigators as an effective treatment strategy for cancer patients, which necessitates efficient activation and expansion of cytotoxic T lymphocytes precisely targeting cancer cells. To comprehensively understand composition of TILs and to provide a grounding in adoptive T cell therapy, we analyzed the T cell receptor (TCR) repertoires in ex vivo-expanded TILs from nine breast cancer patients via next-generation sequencing. For the three of them, TCR repertoires of TILs gathered after the initial culture during 2 weeks were additionally analyzed and compared to those of TILs that underwent ex vivo rapid expansion procedure (REP). Diversity of TCR repertoire was variable among the patients. V/J segment usage in the clonotypes was similar among patients, with variable distribution of read counts for each V/J segment. The top 50% of most frequently observed VJ combinations was present in > 80% of the total clonotypes. Compared with TCGA data, the samples contained a similar amount of recurrent CDR3 sequences, but clonotype expansion was variable among the samples. In terms of clinicopathologic factor, presence of in vitro reactivity among triple-negative breast cancer cases seemed to be related to lower Shannon's index, but p value was not statistically significant. In addition, the proportion of CD45RO + cells out of CD8 + T cells were negatively correlated with Shannon's diversity index for both TCRα and TCRβ chains (p = 0.010) via Spearman test. In this study, we identified a heterogeneous pattern of expanded T cell clones and stable usage of V/J segments in ex vivo-expanded TILs from breast cancer patients. Further large-scale studies are requisite to elucidate the clinical significance of TCR repertoires.

Aim To compare the efficacy and safety of intermittent every other days 5-dose filgrastim with single pegfilgrastim in patients with breast cancer receiving adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy. Methods In this pilot study, Korean patients who had undergone complete resection for breast cancer and scheduled for adjuvant TAC chemotherapy were enrolled. Patients were randomized to receive either intermittent 5 doses of filgrastim (5 mcg/kg/day) or once-a-cycle pegfilgrastim (6 mg) as primary prophylaxis during the first three cycles of the TAC chemotherapy. Absolute neutrophil count (ANC) was analyzed as well. Results A total of 22 patients were randomly and equally divided into filgrastim or pegfilgrastim arms. Febrile neutropenia (FN) occurred in 1 patient in the pegfilgrastim arm (1 of 33 cycles) and none in the filgrastim arm. G3 neutropenia occurred in 1 patient (1 of 33 cycles) in the filgrastim arm and 2 patients (4 of 33 cycles) in the pegfilgrastim arm (P = 0.476). G4 neutropenia occurred in 11 patients (28 of 33 cycles) in the filgrastim arm and 9 patients (18 of 33 cycles) in the pegfilgrastim arm (P = 0.476). Except for on day 9 in cycle 3, there was no significant difference between the two groups in terms of ANC. Conclusion We observed no significant differences between the two methods of prophylaxis in terms of FN and G3/4 neutropenia incidence in patients receiving adjuvant TAC chemotherapy. Intermittent every other days 5-dose filgrastim may be available alternative to pegfilgrastim.

Importance: Prospective assessment of treatments known to benefit patients in global clinical trials in specific racial groups is essential., Objective: To compare the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer., Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled phase 3 trial enrolled 329 women with ERBB2-positive early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) and primary tumor larger than 2 cm from March 14, 2016, to March 13, 2017. Analysis of the primary end point was performed on an intention-to-treat basis., Interventions: Before surgery, patients received 4 cycles of intravenous pertuzumab (840-mg loading dose and 420-mg maintenance doses), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), and docetaxel (75 mg/m2) or intravenous placebo, trastuzumab, and docetaxel every 3 weeks. After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of the same intravenous anti-ERBB2 therapy (pertuzumab and trastuzumab or placebo and trastuzumab) for up to 1 year., Main Outcomes and Measures: The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by disease category and hormone receptor status, was used to compare rates between treatment groups., Results: In total, 329 female patients were randomized (pertuzumab, 219; and placebo, 110; mean [SD] age, 48.8 [9.5] years). In the intention-to-treat population, total pathologic complete response rates were 39.3% (86 of 219) in the pertuzumab group and 21.8% (24 of 110) in the placebo group (difference, 17.5% [95% CI, 6.9%-28.0%]; P = .001). Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (83 of 218 [38.1%] vs 36 of 110 [32.7%]). Serious adverse events were reported in 10.1% of patients (22 of 218) in the pertuzumab group and 8.2% of patients (9 of 110) in the placebo group., Conclusions and Relevance: Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen., Trial Registration: ClinicalTrials.gov identifier: NCT02586025.

Breast cancer is the most common cancer among women worldwide, and it is a main cause of death in women. As with breast cancer, metabolic components are important risk factors for the development of nonalcoholic fatty liver disease (NAFLD). In this retrospective cohort study, we aimed to determine the prevalence of NAFLD in patients with breast cancer and the impact of NAFLD on the prognosis of breast cancer.Patients with breast cancer were enrolled in the study from January 2007 to June 2017. Hepatic steatosis was evaluated through non-enhanced computed tomography scan by measuring Hounsfield Units in the liver and spleen, respectively; 123 healthy controls who underwent non-enhanced computed tomography scan were also analyzed.The prevalence of NAFLD in patients with breast cancer was 15.8% (251/1587), which was significantly higher than in healthy controls (8.9%, 11/123) (P = .036). Overall survival did not significantly differ between the groups with and without NAFLD (P = .304). However, recurrence-free survival was significantly higher in patients without NAFLD than in those with NAFLD (P = .009). Among breast cancer patients receiving endocrine treatment, the NAFLD group showed a higher cumulative incidence of significant liver injury than the group without NAFLD (P < .001).The prevalence of NAFLD in patients with breast cancer is significantly higher than in healthy controls. Moreover, breast cancer patients with NAFLD showed poorer prognosis in terms of recurrence. Therefore, diagnostic evaluation for NALFD is important in managing patients with breast cancer.

We report the case of a breast cancer patient in whom a two-phase 18 F-sodium-fluoride ( 18 F-NaF) bone PET/CT was useful for detecting hidden bone metastases and assessing treatment response. The patient underwent a two-phase bone PET/CT to evaluate a newly developed lesion found on bone scintigraphy following surgery. In the perfusion and bone phase PET/CT images, focally increased perfusion and bony uptake were found in the sacrum and L5 vertebra, suggesting bone metastases of breast cancer. Therefore, the patient subsequently underwent palliative treatment. In another twoPET/CT studies (each including two-phase bone images) performed after 3and 6months of follow-up, the perfusion phase images showed an improvement of the lesion uptake more clearly than in the bone phase images in the visual and semi-quantitative analyses, and thus the perfusion phase images were more useful for clarifying the treatment response earlier than the bone phase images. This is the first case showing the clinical usefulness of 18 F-NaF bone PET/CT with the perfusion imaging technique for evaluating bone metastases and the therapeutic response of metastatic bone lesions., (Copyright © 2019 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients., Methods: In 451 women of European ancestry who had prospectively enrolled in a longitudinal cohort study for women diagnosed with breast cancer at or under age 40, we genotyped 44 SNPs that were previously associated with breast cancer risk. A control group was comprised of 1142 postmenopausal healthy women from the Nurses' Health Study (NHS). We assessed if the frequencies of the adequately genotyped SNPs differed significantly (p≤0.05) between the cohort of young breast cancer patients and postmenopausal controls, and then we corrected for multiple testing., Results: Genotyping of the controls or cases was inadequate for comparisons between the groups for seven of the 44 SNPs. 9 of the remaining 37 were associated with breast cancer risk in young women with a p-value <0.05: rs10510102, rs1219648, rs13387042, rs1876206, rs2936870, rs2981579, rs3734805, rs3803662 and rs4973768. The directions of these associations were consistent with those in postmenopausal women. However, after correction for multiple testing (Benjamini Hochberg) none of the results remained statistically significant., Conclusion: After correction for multiple testing, none of the alleles for postmenopausal breast cancer were clearly associated with risk of premenopausal breast cancer in this relatively small study., Competing Interests: The authors have declared that no competing interests exist.

On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Insulin receptor substrate 1 (IRS-1) has been known to be an associated factor with breast cancer progression. However, there has been little study with respect to the relationship between the expression of IRS-1 and breast cancer prognosis in clinical practice. In this study, we evaluated the impact of the estrogen receptor (ER) and IRS-1 on the recurrence and survival of breast cancer patients., Methods: We analyzed the pathologic finding of 376 tissue samples from breast cancer patients who received proper treatment between January 1990 and December 2006 using the tissue microarray. We measured the expression of ER and IRS-1 by immunohistochemistry staining and analyzed the difference of recurrence and survival rate in each subgroup of ER and IRS-1., Results: Our results show that there is a significant difference of disease-free survival (DFS) according to ER and IRS-1 subgroups with both univariate and multivariate analyses. Specifically, ER-positive and IRS-1-positive breast cancer samples showed improved DFS compared to ER-positive and IRS-1-negative breast cancer (adjusted hazard ratio: 2.17; 95% confidence interval: 1.15-4.09; P = 0.01). There was a difference of overall survival according to ER and IRS-1 subgroups by univariate analysis (P = 0.01), but not by multivariate analysis (P = 0.36)., Conclusion: ER and IRS-1 subgroups appear to be critical factors for the prediction of breast cancer recurrence. In particular, we suggest that the patients who have ER-positive and IRS-1-negative breast cancer undergo more aggressive treatment because they have poorer prognoses., Competing Interests: There are no conflicts of interest

Currently, the growing population of the elderly is one of biggest problems in terms of increase in geriatric diseases. Lack of data from large prospective studies on geriatric breast cancer patients often makes it difficult for clinicians to make treatments decisions for them. Because both benefit and risk of treatment should be taken into account, treatment is usually determined considering life expectancy or comorbidities in elderly patients. Treatment of breast cancer is differentiated according to histologic classifications, and hormone therapy is even adopted for patients with metastatic breast cancer if tumor tissue expresses hormone receptors. Endocrine therapy can offer great benefit to elderly patients considering its equivalent efficacy to chemotherapy with fewer toxicities if it is appropriately used. Aromatase inhibitors are usually prescribed agents in hormone therapy for elderly breast cancer patients due to their physiology after menopause. Here, endocrine therapy for elderly patients with breast cancer in neoadjuvant, adjuvant, and palliative setting is reviewed along with predictive adverse events resulting from the use of hormone agents.

Although trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the emergence of resistance. Trastuzumab resistance is a multi-factorial phenomenon thought to arise from the presence of cancer stem cells and interactions between truncated p95HER2 and HER family members. Flubendazole (FLU) is a potent anthelmintic agent with an exceptional safety profile. Evidence also suggests that it can act as an anticancer agent in several cancer cell types. We sought to investigate the effect of FLU on apoptosis, HER2/Akt signaling, breast cancer stem cell (BCSC)-like properties and trastuzumab resistance in HER2-positive breast cancer cells. FLU treatment induced apoptosis, associated with a significant downregulation of truncated p95HER2, phospho-HER2, phospho-HER3 and phospho-Akt levels, as well as suppression of HER2/HER3 hetero-dimerization in both trastuzumab-sensitive and -resistant lines. FLU effectively targeted BCSC-like properties including aldehyde dehydrogenase 1 (ALDH1) expression and the CD44 high /CD24 low phenotype, concomitant with a suppression of mammosphere-forming ability. FLU administration also caused significant tumor suppression in trastuzumab-resistant xenografts, coinciding with the downregulation of BCSC-related markers and intracellular HER2. These findings highlight the mechanisms of action of FLU in overcoming trastuzumab resistance in breast cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Licochalcone A (LCA), isolated from the root of Glycyrrhiza inflata, are known to have medicinal effect such as anti-oxidant, anti-bacterial, anti-viral, and anti-cancer. Though, as a pharmacological mechanism regulator, anti-cancer studies on LCA were not investigated in human breast cancer. We investigated the anti-proliferative and apoptotic effect of LCA in human breast cancer cells MCF-7 and MDA-MB-231 through MTS assay, PI staining, Annexin-V/7-AAD assay, mitochondrial membrane potential assay, multi-caspase assay, RT-PCR, Western blot analysis, and anchorage-independent cell transformation assay. Our results showed the little difference between two cells, as MCF-7 cell is both estrogen/progesterone receptor positive, there were only effect on Sp1 protein level, but not in mRNA level. Adversely, estrogen/progesterone/human epidermal growth factor receptor 2 triple negative, MDA-MB-231 showed decreased Sp1 mRNA, and protein levels. To confirm the participation of Sp1 in breast cancer cell viability, siRNA techniques were introduced. Both cells showed dysfunction of mitochondrial membrane potential and mitochondrial ROS production, which reflects it passed intracellular mitochondrial apoptosis pathway. Additionally, LCA showed the anti-proliferative and apoptotic effect in breast cancer cells through regulating Sp1 and apoptosis-related proteins in a dose- and a time-dependent manner. Consequently, LCA might be a potential anti-breast cancer drug substitute. J. Cell. Biochem. 118: 4652-4663, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Purpose: Genexol-PM is a Cremophor EL-free formulation of low-molecular-weight, non-toxic, and biodegradable polymeric micelle-bound paclitaxel. We conducted a phase III study comparing the clinical efficacy and toxicity of Genexol-PM with conventional paclitaxel (Genexol)., Materials and Methods: Patients were randomly assigned (1:1) to receive Genexol-PM 260 mg/m 2 or Genexol 175 mg/m 2 intravenously every 3 weeks. The primary outcome was the objective response rate (ORR)., Results: The study enrolled 212 patients, of whom 105 were allocated to receive Genexol-PM. The mean received dose intensity of Genexol-PM was 246.8±21.3 mg/m 2 (95.0%), and that of Genexol was 168.3±10.6 mg/m 2 (96.2%). After a median follow-up of 24.5 months (range, 0.0 to 48.7 months), the ORR of Genexol-PM was 39.1% (95% confidence interval [CI], 31.2 to 46.9) and the ORR of Genexol was 24.3% (95% CI, 17.5 to 31.1) (p non-inferiority =0.021, p superiority =0.016). The two groups did not differ significantly in overall survival (28.8 months for Genexol-PM vs. 23.8 months for Genexol; p=0.52) or progression-free survival (8.0 months for Genexol-PM vs. 6.7 months for Genexol; p=0.26). In both groups, the most common toxicities were neutropenia, with 68.6% occurrence in the Genexol-PM group versus 40.2% in the Genexol group (p < 0.01). The incidences of peripheral neuropathy of greater than grade 2 did not differ significantly between study treatments., Conclusion: Compared with standard paclitaxel, Genexol-PM demonstrated non-inferior and even superior clinical efficacy with a manageable safety profile in patients with metastatic breast cancer.

Purpose: Eribulin mesilate was approved for the treatment of patients with locally advanced or metastatic breast cancer (MBC), who had received at least two chemotherapeutic regimens, including anthracycline and taxane. On the other hand, the efficacy and safety information of eribulin in Korean patients is limited by the lack of clinical trials., Materials and Methods: In this multicenter, open-label, single-arm, phase IV study, locally advanced or MBC patients were enrolled between June 2013 and April 2014 from 14 centers in Korea. One point four mg/m 2 dose of eribulin was administered on days 1 and 8 of every 21 days. The primary endpoint was the frequency and intensity of the treatment emergent adverse event. The secondary endpoint was the disease control rate, which included the rate of complete responses, partial responses, and stable disease., Results: A total of 101 patients received at least one dose of eribulin and were included in the safety set. The patients received a total of 543 treatment cycles, with a median of three cycles (range, 1 to 31 cycles). The most common adverse event was neutropenia (91.1% of patients, 48.3% of cycles). The frequent non-hematological adverse events included alopecia, decrease in appetite, fatigue/asthenia, and myalgia/arthralgia. The peripheral neuropathy of any grade occurred in 27 patients (26.7%), including grade 3 in two patients. Disease control rate was 52.7% and 51.3% of patients in the full analysis set and per-protocol set, respectively., Conclusion: This study demonstrated the feasible safety profile and activity of eribulin in Korean patients with MBC.

Patients with postpartum breast cancer have been reported to have a poor prognosis. The present study aimed to evaluate the pregnancy-related risk factors of postpartum breast cancer in Korea. We collected patient data from the Korea National Health Insurance (KNHI) Claims Database of the Health Insurance Review and Assessment Service (HIRA) for the 2009-2013 period. We evaluated the pregnancy-related risk factors for postpartum breast cancer in two population groups. For Group 1 (women who had given birth during the 2010-2012 period), data on those who were diagnosed with breast cancer from childbirth to 1-year postpartum were extracted. For Group 2, we extracted the data of women who gave birth in 2010 and traced them until December 31, 2013. In Group 1, 1,384,551 deliveries and 317 postpartum breast cancer patients were recorded in Korea between January 1, 2010, and December 31, 2012. Women aged ≥35 years (Odds Ratio [OR], 2.003; 95% Confidence Interval [CI], 1.567-2.560) and those who gave birth via cesarean delivery (OR, 1.237; 95% CI, 0.986-1.553) were considered to be at a higher risk for breast cancer. Lower risk was noted in primiparous women (OR, 0.737; 95% CI, 0.585-0.928). In Group 2, the data of 457,924 women who gave birth in 2010 were traced until December 31, 2013. Among them, 655 patients were diagnosed with breast cancer, and age ≥35 years and cesarean delivery were associated with an higher risk of breast cancer, whereas primiparous status was associated with a lower risk of breast cancer. In conclusion, older age (≥35 years) and cesarean delivery are significant risk factors for postpartum breast cancer, and primiparous women have a lower risk of developing postpartum breast cancer., Competing Interests: The Health Insurance Review & Assessment Service (HIRA) of Korea is not a commercial company, but a public institution for reviews and assessment of health care costs and healthcare service quality. Thus, HIRA does not affect our study design, methods and results as well as employment, consultancy, patients, products in development, or marketed products. Also, HIRA does not alter our adherence to PLOS ONE policies on sharing data and materials.

HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The angiotensin II type I receptor (AGTR1) has been implicated in diverse aspects of human disease, from the regulation of blood pressure and cardiovascular homeostasis to cancer progression. We sought to investigate the role of AGTR1 in cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, angiogenesis and tumor growth in the breast cancer cell line MCF7. Stable overexpression of AGTR1 was associated with accelerated cell proliferation, concomitant with increased expression of survival factors including poly(ADP-ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP), as well as extracellular signal-regulated kinase (ERK) activation. AGTR1-overexpressing MCF7 cells were more aggressive than their parent line, with significantly increased activity in migration and invasion assays. These observations were associated with changes in EMT markers, including reduced E-cadherin expression and increased p-Smad3, Smad4 and Snail levels. Treatment with the AGTR1 antagonist losartan attenuated these effects. AGTR1 overexpression also accelerated tumor growth and increased Ki-67 expression in a xenograft model. This was associated with increased tumor angiogenesis, as evidenced by a significant increase in microvessels in the intratumoral and peritumoral areas, and enhanced tumor invasion, with the latter response associated with increased EMT marker expression and matrix metallopeptidase 9 (MMP-9) upregulation. In vivo administration of losartan significantly reduced both tumor growth and angiogenesis. Our findings suggest that AGTR1 plays a significant role in tumor aggressiveness, and its inhibition may have therapeutic implications., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This retrospective study was undertaken to assess the incidence of and risk factors for febrile neutropenia (FN) during adjuvant chemotherapy for early-stage breast cancer (ESBC)., Methods: A multicenter survey of three tertiary hospitals was conducted, with data extracted from the records of ESBC patients treated with adjuvant chemotherapy containing AC (doxorubicin, 60 mg/m2 and cyclophosphamide, 600 mg/m2 every 21 days). Assessments included clinical characteristics, chemotherapy dose modifications, and incidence of FN., Results: A total of 610 patients were included for analysis. The incidence of grade 4 neutropenia and FN was 44.6 and 8.5%, respectively. Reduced relative dose intensity (RDI) less than 85% occurred in 11.0% of patients, and there were treatment delays in 12.6% of patients. Multivariate analysis identified several independent predictors for FN, including the presence of grade 4 neutropenia and pretreatment calculated estimated glomerular filtration rate less than 60 ml/min., Conclusion: Patients with ESBC are at substantial risk for FN and reduced RDI when treated with adjuvant AC chemotherapy. Predictive models based on risk factors identified in this study should enable the selective application of supportive measures in an effort to deliver the full dose of chemotherapy., (© 2016 S. Karger AG, Basel.)

Triple-negative breast cancer (TNBC) is an aggressive tumor subtype with an enriched CD44+/CD24- stem-like population. Salinomycin is an antibiotic that has been shown to target cancer stem cells (CSC); however, the mechanisms of action involved have not been well characterized. The objective of the present study was to investigate the effect of salinomycin on cell death, migration, and invasion, as well as CSC-like properties in MDA-MB-231 breast cancer cells. Salinomycin significantly induced anoikis-sensitivity, accompanied by caspase-3 and caspase-8 activation and PARP cleavage, during anchorage-independent growth. Salinomycin treatment also caused a marked suppression of cell migration and invasion with concomitant downregulation of MMP-9 and MMP-2 mRNA levels. Notably, salinomycin inhibited the formation of mammospheres and effectively reduced the CD44+/CD24- stem-like population during anchorage-independent growth. These observations were associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, interleukin-6 (IL-6)-induced STAT3 activation was strongly suppressed by salinomycin challenge. These findings support the notion that salinomycin may be potentially efficacious for targeting breast cancer stem-like cells through the inhibition of STAT3 activation.

Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. In the present study, we sought to investigate the mechanisms responsible for salinomycin's selective targeting of BCSCs and its anti-tumor activity. Salinomycin suppressed cell viability, concomitant with the downregulation of cyclin D1 and increased p27(kip1) nuclear accumulation. Mammosphere formation assays revealed that salinomycin suppresses self-renewal of ALDH1-positive BCSCs and downregulates the transcription factors Nanog, Oct4 and Sox2. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of ALDH1 and CD44 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on BCSCs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the risk factors for central vein stenosis after placement of the totally implantable venous access ports (TIVPs) and the clinical relevance of this condition in breast cancer patients., Materials and Methods: TIVPs were placed in 191 women with breast cancer via the internal jugular vein (IJV) from January 2009 to December 2012 (mean age, 51.42 years) by left-side (n = 102) and right-side (n = 89) approaches. Medical records were retrospectively reviewed. The presence of significant central vein stenosis, tip location of the catheter and retrosternal space were evaluated on chest computed tomography images. Statistical analysis was performed., Results: Central vein stenosis developed in 1 and 14 patients after placement via the right and left IJV, respectively. Differences in the cumulative incidence of central vein stenosis were statistically significant between left- and right-side approach groups (log rank test p-value: 0.009). In Cox regression analysis, the hazard ratio for central vein stenosis was 9.441 (p = 0.031) in the left-side approach. The distance between the sternum and the left innominate vein was found to be significantly and independently related to the development of central vein stenosis (p = 0.026). The hazard ratio of distances between the sternum and left innominate vein lt;16 mm was 10.133 (1.319-77.841)., Conclusions: The incidence of central vein stenosis in breast cancer patients was higher after placement of TIVPs via the left IJV. When left-side TIVP placement is required in a patient with right-side breast cancer, the possibilities of left innominate vein stenosis should be considered.

In breast cancer, neuregulin-1 (NRG1) is known as a ligand for the HER3 receptor, which has no intrinsic tyrosine kinase activity. When activated by NRG1 binding, the HER3 receptor forms a heterodimer with other HER family receptors and mediates downstream signaling pathways, leading to multiple effects including growth, proliferation, decreased apoptosis, cellular migration and angiogenesis. Cancer stem cells (CSCs), a subgroup of cancer cells, are considered to have features of stem cells such as self-renewal ability and pluripotent differentiation into other types of mature cells. This study showed that NRG1 treatment induced CSC characteristics in breast cancer cell lines. Using breast cancer cell lines, MCF-7, SKBr-3 and MDA-MB 468, changes related to CSC characteristics were analyzed. Flow cytometry was used to analyze changes in CSC fractions in multiple cell lines after NRG1 treatment. Western blot analysis and immunofluorescence staining demonstrated the expression of CSC markers. To confirm that NRG1 treatment acts through the HER3 receptor, inhibition studies using small interfering RNA (siRNA) were performed. In MCF-7 and SKBr-3 cells, increases in the CSC fraction and expression of CSC markers were observed after NRG1 treatment. However, MDA-MB 468 cells showed high intrinsic expression of CSC markers and a high cellular fraction of CSCs, and in these cells, NRG1 treatment caused no significant change in CSC characteristics. Inhibition of the HER3 receptor blocked the NRG1-induced CSC characteristics, indicating that NRG1 functions through the HER3 receptor. The results imply the presence of a mechanism by which the HER receptors, activated by NRG1, contribute to the acquisition of CSC-like characteristics in some types of breast cancer.

YKL-40 is a glycoprotein involved in cellular growth, migration, and the inflammatory process. Elevation in serum levels of YKL-40 has been associated with worse prognosis in various cancers, including breast cancer. Given that the clinical significance of YKL-40 expression in breast cancer tissue is unclear, we aimed to determine the prognostic value of YKL-40 expression in breast cancer tissue using immunohistochemistry. We performed tissue microarray (TMA) analysis of 425 breast cancer tissues collected during operation. Immunohistochemical staining was performed to measure expression of YKL-40 and several breast cancer biomarkers, such as aldehyde dehyadrogenase1, TGF-beta, and Gli-1 as well as hormonal receptor and Her-2/neu status. Statistical analysis of the relationship of YKL-40 expression with clinicopathological characteristics was performed for 390 TMA samples. YKL-40 was expressed to varying degrees in 84.9% of breast cancer tissues. YKL-40 expression was correlated with estrogen receptor and progesterone receptor negativity and was positively correlated with TGF-beta and Gli-1 expression. Strong YKL-40 expression was associated with a larger proportion of Her-2/neu-enriched and basal-like tumors. The results of this study demonstrate that YKL-40 expression in breast cancer tissues is associated with hormone receptor negativity and Her-2/neu-enriched molecular subtypes of breast cancer, and therefore could be considered a poor prognostic predictor.

Unlabelled: Aldehyde dehydrogenase 1 (ALDH1) has been regarded as a breast cancer stem cell marker. Several studies have reported that ALDH1 expression is associated with poor prognosis in breast cancer. We aimed, therefore, to determine the prognostic value of ALDH1 expression and its association with several biomarkers in breast cancer tissue using immunohistochemistry. Furthermore, we investigated the characteristics of and differences between cellular and stromal expression of ALDH1. We performed tissue microarray (TMA) analysis of 425 breast cancer tissue samples collected during surgery. Immunohistochemical staining was then performed to measure the expression of ALDH1 and other breast cancer biomarkers. Statistical analysis of the relationship between ALDH1 expression and clinicopathologic characteristics was performed for 390 TMA samples. We found that ALDH1 was expressed in 71 cases (18.2%) in the tumor cells and/or stroma. Of these cases, 38 (9.7%) showed ALDH1 expression in tumor cells and 38 (9.7%) showed ALDH1 expression in the stroma. ALDH1 expression was significantly associated with markers of a poor prognosis, such as young age, estrogen receptor negativity, progesterone receptor negativity, a high histological grade, and a high Ki-67 index. However, ALDH1 expression was not associated with p53, transforming growth factor-beta, Gli-1, YKL-40, or sonic hedgehog expression status. With regard to the expression site, the clinical characteristics did not differ between cases of cellular expression and those of stromal expression. However, ALDH1 expression in tumor cells was correlated with hormone receptor status, histological grade, molecular subtype, epidermal growth factor receptor expression status, and cytokeratin 5/6 expression status while stromal expression of ALDH1 was only correlated with hormone receptor status. Overall, these findings suggest that ALDH1 expression in tumor tissue is associated with a biologically aggressive phenotype., Keywords: ALDH1, biologically aggressive, breast cancer.

Background: It has long been recognized that some human breast cancers are hormone dependent. Preeclampsia is a syndrome of pregnancy defined by the onset of hypertension and proteinuria and characterized by dysfunction of the maternal endothelium. Many hormonal changes occur with preeclampsia, and we hypothesize that these changes may influence the risk of maternal breast cancer. We also analyzed the relation between pregnancy-induced hypertension (PIH) and maternal risk of breast cancer., Methods: Among 13 relevant publications about preeclampsia and six relevant publications about PIH, some studies find preeclampsia associated with a lower risk of breast cancer, but others did not. Therefore, these results are inconclusive. We conducted meta-analysis to evaluate more precisely the relationship between preeclampsia, PIH and maternal risk of breast cancer., Results: The pooled estimate of the hazard ratio (HR) associated with preeclampsia was 0.86 (95% CI 0.73-1.01), and that associated with PIH was 0.83 (0.66-1.06), both based on the random effects model., Conclusion: Some suggestive but not entirely consistent nor conclusive evidence was found on the association between the history of preeclampsia or PIH with the subsequent risk of breast cancer.

Backgrounds: A pegylated form of recombinant granulocyte-colony stimulating factor (G-CSF) was developed for prophylactic use in breast cancer. The aim of this study was to evaluate the efficacy and safety of once-per-cycle DA-3031 in patients receiving chemotherapy for breast cancer., Methods: A total of 61 patients receiving docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy were randomized in cycle 1 to receive daily injections of filgrastim (100 μg/m(2)) or a single subcutaneous injection of pegylated filgrastim DA-3031 at a dose of either 3.6 mg or 6 mg., Results: The mean duration of grade 4 neutropenia in cycle 1 was comparable among the treatment groups (2.48, 2.20, and 2.05 days for filgrastim, DA-3031 3.6 mg and 6 mg, respectively; P=0.275). No statistically significant differences were observed in the incidence of febrile neutropenia between the treatment groups (9.5 %, 15.0 %, and 5.0 % for filgrastim, DA-3031 3.6 mg and 6 mg, respectively; P=0.681) in cycle 1. The incidences of adverse events attributable to G-CSF were similar among the treatment groups., Conclusions: Fixed doses of 3.6 mg or 6 mg DA-3031 have an efficacy comparable to that of daily injections of filgrastim in ameliorating grade 4 neutropenia in patients receiving TAC chemotherapy.

Background: The balance in the immune system between immune surveillance against non-self-antigens and tolerance of self-antigens is known to be associated with the prognosis of breast cancer patients. However, immunologic signals in tumor microenvironment according to biological characteristics of cancer cells have not been clearly elucidated. CD4(+) T cells, CD8(+) T cells, and forkhead box P3-positive (Foxp3) regulatory T cells (Tregs) are the main keys for immune surveillance and tolerance, respectively. We evaluated the correlations between the immunologic balance and tumor characteristics and their impact on recurrence., Patients and Methods: CD8(+) T cells and Foxp3(+) Tregs were detected by immunohistochemistry using the paraffin-embedded tumor samples from the 72 patients with early stage (I to III) breast cancer. Clinicopathologic data including tumor size and grade, lymph node metastasis, stage, patient's age, expression status of estrogen receptor (ER), progesterone receptor, p53, Ki-67, and human epidermal growth factor receptor-2/neu, and recurrence were reviewed., Results: The decreased number of CD8(+) T cells was significantly associated with tumors with lymph node metastasis (P=0.027), higher stage (stage III, P=0.013), and immunopositivity of Ki-67 (P=0.026). In contrast, the increased number of Foxp3(+) Tregs was significantly correlated with tumors with lymph node metastasis (P=0.027), immunopositivity for p53 (P=0.026), and positive for Ki-67 (P<0.001). There were significant correlations between the increased Foxp3(+) Treg/CD4(+) T-cell ratio and lymph node metastasis (P=0.011), the expression of ER (P=0.023), and immunopositivity of p53 (P=0.031) and Ki-67 (P= 0.003). Of note, lower Foxp3(+) Treg/CD4(+) T-cell ratio was significantly associated with triple-negative breast cancer (P=0.004). Disease-free survival of analyzed patients was significantly associated with the number of Foxp3(+) Tregs (dichotomized by a cutoff point of 17, P= 0.014) only. Univariate analysis indicated that tumor grade (P=0.017), the expression of ER (P=0.032), and non-triple-negative breast cancer (P=0.022) were independent prognostic factors for disease-free survival., Conclusions: Our data showed that lymph node metastases, immunopositivity of p53 and Ki67, and non-triple-negative tumors were associated with high regulatory T-cell infiltration. The role of immunologic balance as a prognostic marker for recurrence must be evaluated more clearly in the future study.

Breast cancer genome-wide association studies have pinpointed dozens of variants associated with breast cancer pathogenesis. The majority of risk variants, however, are located outside of known protein-coding regions. Therefore, identifying which genes the risk variants are acting through presents an important challenge. Variants that are associated with mRNA transcript levels are referred to as expression quantitative trait loci (eQTLs). Many studies have demonstrated that eQTL-based strategies provide a direct way to connect a trait-associated locus with its candidate target gene. Performing eQTL-based analyses in human samples is complicated because of the heterogeneous nature of human tissue. We addressed this issue by devising a method to computationally infer the fraction of cell types in normal human breast tissues. We then applied this method to 13 known breast cancer risk loci, which we hypothesized were eQTLs. For each risk locus, we took all known transcripts within a 2 Mb interval and performed an eQTL analysis in 100 reduction mammoplasty cases. A total of 18 significant associations were discovered (eight in the epithelial compartment and 10 in the stromal compartment). This study highlights the ability to perform large-scale eQTL studies in heterogeneous tissues.

Germline determinants of gene expression in tumors are infrequently studied due to the complexity of transcript regulation caused by somatically acquired alterations. We performed expression quantitative trait locus (eQTL)-based analyses using the multi-level information provided in The Cancer Genome Atlas (TCGA). Of the factors we measured, cis-acting eQTLs accounted for 1.2% of the total variation of tumor gene expression, while somatic copy-number alteration and CpG methylation accounted for 7.3% and 3.3%, respectively. eQTL analyses of 15 previously reported breast cancer risk loci resulted in the discovery of three variants that are significantly associated with transcript levels (false discovery rate [FDR] < 0.1). Our trans-based analysis identified an additional three risk loci to act through ESR1, MYC, and KLF4. These findings provide a more comprehensive picture of gene expression determinants in breast cancer as well as insights into the underlying biology of breast cancer risk loci., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Docetaxel is one of the most commonly used chemotherapeutic agents in breast cancer. To avert from significant toxicities with no clinical benefit, identification of predictive markers for response is one of the most important unsolved clinical needs. Therefore, the potential associations of RASSF1A hypermethylation and response to docetaxel-based chemotherapy were evaluated, and the underlying mechanism was studied. The expression of RASSF1A in breast cancer cell lines and tissues of normal breast, ductal carcinoma in situ (DCIS), and breast cancer (n=45) was analyzed by immunohistochemistry and western blot analysis. Immunohistochemical staining showed that the expression of RASSF1A was frequently lost in primary breast cancers and human breast cancer cell lines, while normal breast tissues or DCIS displayed moderate to strong expression. Furthermore, quantitative methylation analysis of the RASSF1A promoter region in 45 primary breast cancers revealed that RASSF1A was frequently methylated in primary breast cancers (≥20% methylation in 53% of the patients), and prospective analysis in patients with locally advanced or recurrent breast cancer showed that the mean level of methylation of RASSF1A was significantly higher in patients who did not respond to docetaxel-based chemotherapy (30.6±8.5%) than patients with partial or complete response (20.1±11.2%, p=0.042). Finally, in vitro studies showed that RASSF1A had cooperative activity in suppression of cancer cell growth and proliferation by enhancing docetaxel-induced cell cycle arrest. Our results suggest that hypermethylated RASSF1A is an important modulating factor for the efficacy of docetaxel-based chemotherapy in breast cancer.

Women who undergo a greater number of menstrual cycles may be at increased risk of breast cancer, possibly due to cumulative exposure to ovarian hormones. Pregnancy reduces the lifetime number of menstrual cycles and also influences the levels of ovarian hormones. Twin pregnancies differ from singleton pregnancies in both hormone levels and perinatal changes. To date, a meta-analysis on the effects of twin birth on the risk of maternal breast cancer has not been conducted. Among 17 relevant publications identified in a systematic search, some suggest that twin births may be associated with lower breast cancer risk but others do not; therefore, the results are inconclusive. Although our pooled results of all 17 published studies did not show a reduced maternal risk of breast cancer for twin births (HR 0.94; 95% CI = 0.87-1.02; P = 0.127), a trend toward reduced maternal risk of breast cancer was identified in a subgroup analysis of cohort studies (HR 0.91; 95% CI = 0.83-1.01; P = 0.068). The results of this meta-analysis suggest that twin pregnancy does not significantly decrease the maternal risk of breast cancer.

Background: Docetaxel and paclitaxel are likely to have different toxicity profiles, dose reduction and delays despite their similar medical results in breast cancer patients., Aims: This study examined retrospectively the incidence and severity of certain toxicities, dose reduction and delay of two taxanes., Materials and Methods: From January 2009 to June 2010, the incidence and severity of toxicities as well as the dose reduction, dose delay, granulocyte colony stimulating factor (G-CSF) in 54 patients with operable lymph node-positive (tumor stage T1, T2, or T3 and nodal stage N1 or N2) and high risk, node-negative (T2 or T3, N0) breast cancer without a distant metastases who received adjuvant chemotherapy - adriamycin, cyclophosphamide, docetaxel (TAC) and adriamycin, cyclophosphamide, paclitaxel (ACP)- were evaluated., Statistical Analysis Used: Mann-Whitney test and Fisher's exact test., Results and Conclusion: The patients in the ACP group experienced more frequent peripheral neuropathy (P=0.025), nausea (P=0.033) than those in the TAC group. Febrile neutropenia was significant in TAC (P=0.001). Increasing age was associated with an increased risk of anemia (P=0.004), fatigue (P=0.009) and pain (P=0.003), and a decreasing body mass index was associated with an increased risk of febrile neutropenia (P=0.009). Dose reduction and delay occurred due to febrile neutropenia and an increase in aspartate aminotransferase (AST)/alanine aminotransferase (ALT). The dose reduction was only significant in the TAC group (P= 0.001). A taxane-based regimen should be chosen for breast cancer patients based on the pharmacokinetics, dosing schedule, clinical activity and toxicity profile that best meet the patient's therapeutic needs and quality of life.

Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We performed a single-institution phase II study to evaluate the efficacy and toxicities of vinorelbine monotherapy in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m² intravenously on days 1, 8, 15 and 22, every four weeks, and responses were assessed after every two cycles of treatment. All of the patients had previously been treated with anthracyclines and taxanes. A total of 26 patients were enrolled in this study between April 2004 and August 2009. The median age of the patients was 47 years (range, 37 to 71 years), and 80.8% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Out of 24 evaluable patients, five partial responses were observed, giving an overall response rate of 20.8%, with a median response duration of 2.8 months. The median time to progression was 3.7 months (range, 0.5 to 22.6 months), and median overall survival duration was 10.4 months (range, 1.3 to 57.6 months). The major toxicities observed were neutropenia, anemia and peripheral neuropathy. Grade 3 or 4 hematologic toxicities included neutropenia in 18 patients (69.2%) and anemia in four patients (15.3%). Grade 1 or 2 peripheral neuropathy was observed in 11 patients (42.3%), however there were no cases of grade 3 or 4 peripheral neuropathy. The results of this study indicate that vinorelbine monotherapy was feasible regimen with manageable toxicities in patients with metastatic breast cancer who were previously exposed to anthracyclines and taxanes.

Although various new agents have been developed for the treatment of patients with metastatic breast cancer (MBC), overall survival rates have changed little in the last half century. We conducted meta-analysis to verify the clinical efficacy of bevacizumab for the salvage treatment of MBC. Event-based hazard ratios (HR) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Four studies, with a total of 2,860 patients, met the inclusion criteria for analysis. The pooled results of clinical efficacies were: HR for progression free survival 0.69 (95% CI, 0.58-0.81, z = 4.54, P <0.001); HR for overall survival 0.92 (95% CI, 0.82-1.03, z =1.44, P = 0.15); and HR for the clinical objective response rate 1.53 (95% CI, 1.37-1.71, z = 7.37, P < 0.001). In terms of overall survival, subgroup analysis demonstrated statistically significant improvement for the bevacizumab combination in the initial therapy subgroup (HR, 0.878; 95% CI, 0.771-0.999, z = 1.98, P = 0.048). Hypertension and proteinura were more common in the bevacizumab combination arm; however, these toxicities were managed with therapy. In conclusion, meta-analysis suggested benefits of a carefully managed bevacizumab-containing salvage regimen for patients with histologically or cytologically confirmed Her-2 negative MBC who have not received previous cytotoxic therapy. This treatment could improve both progression free survival and overall survival rates.

Published studies on the association between the vascular endothelial growth factor (VEGF) gene 936 C/T polymorphism and breast cancer risk are inconclusive, and a meta-analysis is required to verify the association. Nine studies, including a total of 4,973 cases and 5,035 controls, were subjected to meta-analysis. When all eligible subjects were pooled for meta-analysis, the CT + TT genotypes were not associated with a significant decrease in breast cancer risk (odds ratio = 0.87; 95% confidence interval 0.75-1.02; P = 0.087). We also categorized by ethnicity (Caucasian, Asian, or mixed) for subgroup analysis, however, according to this subgroup analysis, we found no significant association between the CT and TT versus CC genotype with breast cancer risk reduction in any of the subgroups. We conclude that the VEGF gene 936 C/T polymorphism does not affect breast cancer risk.

Transforming growth factor-β1 (TGF-β1) is negative regulator of cell proliferation and the cell cycle, and plasma levels of TGF-β1 are twice as high in TGF-β1 -509 T homozygotes as in -509 C homozygotes. Published studies on the association between the TGF-β1 gene -509 C/T polymorphism and breast cancer risk are inconclusive, and a meta-analysis is required to verify the association. We performed a meta-analysis of four studies, including a total of 5,986 cases and 6,829 controls. Our pooled results indicate that the TGF-β1 gene -509 C/T polymorphism is not associated with breast cancer risk in a TT versus CC codominant (OR = 1.08; 95% CI = 0.87-1.34; P = 0.494), in a CT versus CC codominant (OR = 1.02; 95% CI = 0.94-1.10; P = 0.686), recessive (OR = 0.92; 95% CI = 0.83-1.03; P = 0.157), and dominant (OR = 1.03; 95% CI = 0.96-1.11; P = 0.439) models. Conclusively, this meta-analysis suggests that the TGF-β1 gene -509 T allele polymorphism does not decrease breast cancer risk.

Published studies on the association between the progesterone receptor gene +331 G/A polymorphism and breast cancer risk are inconclusive, and meta-analysis is required to verify the association. Six studies, including a total of 6,849 cases and 6,589 controls, were subjected to meta-analysis. When all eligible subjects were pooled for meta-analysis, the AG + AA variant genotype was not associated with a significantly elevated breast cancer risk [odds ratio (OR) = 1.11; 95% confidence interval (95%CI) = 0.99-1.24; P = 0.071]. However, subgroup analysis revealed that the AG + AA variant genotype was associated with an increased risk of breast cancer in American (OR = 1.32; 95%CI = 1.10-1.58; P = 0.003), but not in European or Australian. We could carefully suggest that the progesterone receptor promoter +331 G/A variant polymorphism might increase breast cancer risk, and this effect appeared to be more prominent in Americans than in Europeans and Australians., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: This study evaluated the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) of TAC compared with FAC following primary surgery for node positive breast cancer patients in Korea., Materials and Methods: A cost-effectiveness analysis was performed using the Markov model from the combined view of Korean National Health Insurance and patients. The model allowed assessment from the beginning of the first cycle of adjuvant chemotherapy following primary surgery until death. Relevant clinical data were obtained from the clinical trial BCIRG 001 and data for local treatment patterns and direct medical costs were obtained from three Korean hospitals., Results: Over a life time horizon, the life expectancy of TAC was 0.9 years longer than that of FAC. The ICER was 8,025,879 Korean won (KW, 6,573 euro) per life year gained and the ICUR was 8,885,794 KW (7,277 euro) per QALY gained when the cost and effectiveness were discounted at 5%. The model was most sensitive to the percent patient receiving prophylactic granulocyte colony stimulating factor (G-CSF) in TAC arm and the ICUR was 12,119,561 KW (9,926 euro) when assuming 100%., Conclusions: TAC appears to be cost-effective in the management of early breast cancer in Korea.

Our aim in this paper is to verify the efficacy and safety of a epirubicin and docetaxel salvage regimen for anthracycline sensitive metastatic breast cancer patients who have relapsed after anthracycline-containing adjuvant therapy. Thirty-two metastatic breast cancer patients were treated with epirubicin and docetaxel every 21 days. Of the 31 evaluable patients, there were 13/31 (41.9%) partial responses and no complete responses. Median time to progression was 12 months (95% CI, 4-60 months) and median survival duration was 41 months (95% CI, 1.2-80.8 months). According to the Cox model, ECOG performance and response group were statistically significant variables, and visceral metastasis was a borderline significant variable with regards to overall survival. Although this salvage regimen showed a high rate of hematologic toxicities, it was a relatively active regimen with manageable toxicities and no cardiac dysfunction. We propose that this salvage regimen could be carefully used in anthracycline sensitive metastatic breast cancer patients who have relapsed after anthracycline-containing adjuvant therapy.

Purpose: Clinical trials have reported conflicting results as to whether pre-operative aromatase inhibitors (AIs) improve outcome over pre-operative tamoxifen in postmenopausal women with hormone receptor-positive breast cancer., Methods: We performed a meta-analysis comparing primary and secondary end points of pre-operative AI and pre-operative tamoxifen. The event-based risk ratio (RR) with 95% confidence intervals (95% Cis) were derived, and a test of heterogeneity was applied., Results: Four studies (1,160 patients) met the inclusion criteria for the analysis. Meta-analysis showed that pre-operative AI was more effective than pre-operative tamoxifen. Pooled results of clinical efficacy were as follows: clinical objective response rate (RR, 1.29; 95% CI, 1.14-1.47; P < 0.001), ultrasound objective response rate (RR, 1.29; 95% CI, 1.10-1.51; P = 0.002), and breast conserving surgery (BCS) rate (RR, 1.36; 95% CI, 1.16-1.59; P < 0.001). Hot flashes, nausea, and fatigue were not different between the pre-operative AI and pre-operative tamoxifen groups. Although headache was more frequent in the pre-operative AI group (P = 0.011), it was a manageable toxicity and was not clinically relevant., Conclusion: Pre-operative AI has better BCS rate than tamoxifen and in terms of toxicities, is not inferior to tamoxifen; therefore, we could suggest pre-operative AI instead of tamoxifen for those postmenopausal patients with hormone receptor positive breast cancer, not eligible for chemotherapy.