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The BRCA1/2 pathogenic variant (PV) increases the risk of breast and ovarian cancer; thus, risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) are recommended. We evaluated the effects of the graphical display of cancer risk compared with those of numerical presentation on the decision-making for risk-reducing (RR) surgery. A total of 471 women representing the Korean population were recruited. The lifetime risk of breast/ovarian cancer were given numerically followed by graphically in hypothetical BRCA1/2 PV-positive cases. Subsequently, the study participants were asked for their willingness to undergo RRSO/RRM. When the ovarian cancer risk was shown as 44.0%, the percentage of study participants who chose RRSO was 41.0% after numerical presentation versus 39.9% after graphical display, of which the difference was not significant. When the breast cancer risk was presented as 72.0%, 30.4% of the participants opted for RRM under numerical presentation, whereas this increased to 38.6% under graphical display, of which the difference was significant (p < 0.0075). The average levels of the cancer risk which study participants consider RR surgery were 57.1% for ovarian cancer and 60.6% for breast cancer. This suggests that the impacts of different formats of risk communication on decision about RRSO or RRM may be different by the absolute levels of ovarian or breast cancer., (© 2024. The Author(s).)

Background: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit., Patients and Methods: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted., Results: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs., Conclusions: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human epidermal growth factor receptor 2 (HER2)-low status has recently gained attention because of the potential therapeutic benefits of antibody-drug conjugates (ADCs) in breast cancer patients. We aimed to investigate the concordance of HER2 status between core needle biopsy (CNB) and subsequent surgical resection specimens focusing on the HER2-low status., Methods: This retrospective study was conducted in 1,387 patients with invasive breast cancer whose HER2 status was evaluated in both CNB and surgical resection specimens. The discordance rates between CNB and surgical resection specimens and the clinicopathological features associated with HER2 status discordance were analyzed., Results: The overall concordance rates of HER2 status between CNB and surgical resection specimens were 99.0% (κ = 0.925) for two-group classification (negative vs. positive) and 78.5% (κ = 0.587) for three-group classification (zero vs. low vs. positive). The largest discordance occurred in CNB-HER2-zero cases with 42.8% of them reclassified as HER2-low in surgical resection. HER2 discordance was associated with lower histologic grade, tumor multiplicity, and luminal A subtype. In multivariate analysis, tumor multiplicity and estrogen receptor (ER) positivity were independent predictive factors for HER2-zero to low conversion., Conclusions: Incorporation of HER2-low category in HER2 status interpretation reduces the concordance rate between CNB and surgical resection specimens. Tumor multiplicity and ER positivity are predictive factors for conversion from HER2-zero to HER2-low status. Therefore, HER2 status should be re-evaluated in resection specimens when considering ADCs in tumors exhibiting multiplicity and ER positivity., (© 2024. The Author(s).)

Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC ( n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.

Background: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline., Patients and Methods: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR., Results: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1., Conclusions: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs., Competing Interests: Disclosure SAH reports contracted paid research from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, CytomX, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Orinove, Pieris, PUMA, Radius, Sanofi, Seagen, Zymeworks, and Phoenix Molecular Designs, Ltd; institutional grants from Ambrx and Samumed; research funding as national/international principal investigator from Novartis, Daiichi Sankyo, Seagen, and GNE/Roche; is a steering committee member of Novartis, Lilly, Daiichi Sankyo/AstraZeneca, GNE/Roche, and Sanofi; travel expenses paid for by Lilly (2019); and uncompensated consulting/advisory board memberships with 4DPharma, Ambrx, Amgen, Artios, Arvinas, Daiichi Sankyo, Dantari, Genentech/Roche, Immunomedics, Macrogenics, Eli Lilly, Novartis, NK Max, Pieris, Pyxis, Seagen, and Biotheranostics. SBK reports institutional research grants from Novartis, Sanofi Aventis, and Dongkook Pharmaceutical Company; consulting fees from Novartis, AstraZeneca, Lilly Dae Hwa Pharmaceutical Co, Ltd, IUS Abxis, and Daiichi Sankyo; participation on an advisory board with Lilly Dae Hwa Pharmaceutical Co, Ltd, IUS Abxis, Daiichi Sankyo, and Beigene; leadership or fiduciary role with ESMO Breast 2021-2023; and stocks or stock options from Genopeak and NeoGene TC. WPC reports payment or honoraria for lectures and presentations from Amgen, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Everest Medicine, Foundation Medicine Kyowa Kirin, Novartis, Pfizer, Roche, Sanofi, and Takeda; travel support from Amgen, AstraZeneca, Pfizer, and Roche; participation on data safety monitoring or advisory board with Amgen, AstraZeneca, Daiichi Sankyo, Everest Medicine, Eli Lilly, IMPACT Therapeutics, MSD, Novartis, Pfizer, Roche, and Sanofi. SAI reports grants or contracts from AstraZeneca, Boryung Pharm, Daewoong Pharmaceutical Co. Ltd, Eisai, Pfizer, and Roche; and consulting fees from AstraZeneca, Hanmi, Idience, Lilly, MSD, GSK, Pfizer, Novartis, Roche, and Daiichi Sankyo. YHP reports grants or contracts from AstraZeneca, Roche, Pfizer, Gencurix, and Novartis; consulting fees from Pfizer, AstraZeneca, Roche, MSD, Eisai, Novartis, Daiichi Sankyo, and Lilly; payment or honoraria from Pfizer, Roche, MSD, and Novartis; participation on data safety monitoring or advisory board with Roche, AstraZeneca, Eisai, MSD, Daiichi Sankyo, and Novartis. VP reports payment or honoraria from Daiichi Sankyo, Novartis, Pfizer, and AstraZeneca; travel support from Pfizer, Mundipharma, Daiichi Sankyo, and Lilly; and participation on an advisory board with Daiichi Sankyo. CFC reports participation on a data safety monitoring or advisory board with Roche, Pfizer, and Daiichi Sankyo. HI reports consulting fees from Daichi Sankyo, Chugai, AstraZeneca, Sanofi, Lilly, MSD, Pfizer, and Novartis; and payment or honoraria from Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, and Pfizer. EH reports institutional research and consulting fees for the present manuscript from Daiichi Sankyo and AstraZeneca; other institutional research grants from AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Arvinas AtlasMedX, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Dana Farber Cancer Institute, Deciphera, eFFECTOR Therapeutics, Ellipses Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millenium, Molecular Templates, Myriad Genetic Labs, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks; and consulting fees from Arcus, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, Seagen, and Silverback Therapeutics. GC reports support for the current manuscript from AstraZeneca and Daichii Sankyo; grants or contracts from Merck; consulting fees from Bristol Myers Squibb, Roche, Pfizer, Novartis, Lilly, AstraZeneca, Daichii Sankyo, Merck, Seagen, and Ellipsis; payments or honoraria from Pfizer and Lilly; and travel support from Roche and Lilly. BX reports consulting fees from AstraZeneca and Novartis and payments or honoraria for lectures from AstraZeneca, Pfizer, and Roche. AE reports stocks/stock options from and is an employee of Daiichi Sankyo. YL reports stocks/stock options from and was an employee of Daiichi Sankyo at the time of the study. JC is an employee of Daiichi Sankyo. EB was an employee of Daiichi Sankyo at the time of the study. KT is an employee of Daiichi Sankyo. SV reports stocks/stock options from and is an employee of AstraZeneca. JC reports support for the current work from Daiichi Sankyo and AstraZeneca; consulting fees from AstraZeneca, Athenex, Bioasis, BioInvent, Boehringer Ingelheim, Celgene, Cellestia, Clovis Oncology, Daiichi Sankyo, Ellipses, Erytech, GEMoaB, Gilead, GSK, Hibercell, Leuko, Lilly, Menarini, Merck Sharp & Dohme, Polyphor, Roche, Seagen, Zymeworks; payment or honoraria from Celegene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung Bioepis; travel support from AstraZeneca, Daiichi Sankyo, Eisai, Novartis, Pfizer, and Roche; stocks/stock options from Leuko (relative), MedSIR, and Nektar Pharmaceuticals. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021)., Patients and Methods: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety., Results: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5., Conclusions: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC., Competing Interests: Disclosure CS reports consulting or advisory roles for AstraZeneca, AX’Consulting, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd, ISSECAM, Medical Statistics Consulting, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Seagen, and Zymeworks and a leadership role for SOLTI. SM reports consulting or advisory roles for AstraZeneca, Daiichi Sankyo, Genentech, GlaxoSmithKline, Macrogenics, Novartis, and Seagen; research funding from AstraZeneca (inst) and Daiichi Sankyo (inst); and honoraria from AstraZeneca, Daiichi Sankyo, Genentech, Macrogenics, and Seagen. IK reports consulting or advisory roles for AstraZeneca, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Macrogenics, Merck, Novartis, Roche, Seagen, and Taiho Oncology; research funding from Genentech (inst), Macrogenics (inst), Pfizer (inst), and Roche (inst); honoraria from AstraZeneca; and a leadership role with PureTech. YHP reports consulting or advisory roles for AstraZeneca, Daiichi Sankyo, Eisai, Roche, MSD, Novartis, Pfizer, and Lilly; research funding from AstraZeneca, Gencurix, Novartis, Pfizer, and Roche; and honoraria from Pfizer, Roche, MSD, and Novartis. SBK reports consulting or advisory roles for AstraZeneca, Beigene, Dae Hwa Pharmaceutical Co, Ltd, Daiichi Sankyo, IUS Abxis, Lilly, and Novartis and research funding from DongKook Pharm (inst), Novartis (inst), and Sanofi-Aventis (inst). HI reports consulting or advisory roles for AstraZeneca, Chugai, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, and Sanofi and honoraria from AstraZeneca, Chugai, Daiichi Sankyo, Lilly, MSD, and Pfizer. JT reports consulting or advisory roles for AstraZeneca and Daiichi Sankyo; research funding from Chugai (inst), Daiichi Sankyo (inst), Eisai (inst), Lilly (inst), Nihon Kayaku (inst), and Taiho (inst); honoraria from Chugai, Daiichi Sankyo, Eisai, Lilly, Kyowa Kirin, and Taiho; has received support for attending meetings and/or travel from Chugai, Daiichi Sankyo, and Eisai; a leadership role with West Japan Oncology Group; and receipt of equipment, materials, drugs, medical writing, or other services from Daiichi Sankyo. JS reports research funding from AstraZeneca (inst), Boehringer Ingelheim (inst), Lilly (inst), GSK (inst), MSD (inst), Novartis (inst), Pfizer (inst), Roche (inst), and Sanofi (inst) and stock for Daiichi Sankyo. EM, YL, JC, and JS report employment and stock and other ownership interest with Daiichi Sankyo. TY reports research funding from Chugai (inst), Kyowa Kirin (inst), Nippon Kayaku (inst), and Taiho (inst) and honoraria from AstraZeneca, Chugai, Daiichi Sankyo, MSD, Eisai, Lilly, Nippon Kayaku, Kyowa Kirin, Novartis, Pfizer Japan, and Taiho. KT has declared no conflicts of interest. Data sharing Anonymized individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org. In cases where clinical study data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo, Inc, will continue to protect the privacy of our company and our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aim: To investigate the association between the thyroid dysfunction and thyroid radiation dose in regional nodal irradiation (RNI) using volumetric modulated arc therapy (VMAT) for breast cancer., Patients and Methods: We reviewed medical data of 67 patients with breast cancer who underwent curative surgery followed by adjuvant radiotherapy, including RNI using VMAT, between 2018 and 2021. All patients had normal thyroid functional test results, including thyroid stimulating hormone (TSH), T3, and free-T4. We defined subclinical hypothyroidism as increased TSH with or without decreased levels of free-T4 and T3 after the completion of VMAT. We calculated dose-volume histogram parameters (DVHPs), including the mean dose and relative thyroid volume receiving at least 10, 20, 30, and 40 Gy., Results: The median follow-up time was 23.2 months. The 3-year locoregional failure-free survival, progression-free survival, and overall survival rates were 96.3%, 94.7%, and 96.2%, respectively. The mean thyroid dose was 21.4 Gy (range=11.5-29.4 Gy). Subclinical hypothyroidism was noted in 14 patients (20.9%) and the median time to the event was 4.1 months. Among the DVHPs, the relative volume receiving ≥20 Gy (V 20Gy ) was associated with subclinical hypothyroidism. The 2-year rates of subclinical hypothyroidism were 24.8% and 59.1% in patients with V 20Gy ≤46.3% and >46.3%, respectively., Conclusion: A significant proportion of patients with breast cancer developed subclinical hypothyroidism after undergoing VMAT for RNI. Our findings highlight the importance of considering the thyroid as an organ at risk for VMAT planning, and suggest that V 20Gy could be a useful dose-volume constraint., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies., Competing Interests: Disclosure MLTAT declares consulting fees and honoraria from MSD, Roche, Novartis, Eli Lilly and AstraZeneca. HKA declares consulting fees from Daiichi Sankyo, Amgen, Yuhan and Novartis, and honoraria from Roche, BMS, MSD, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Menarini, Eisai, Pfizer, Boryung Pharmaceutical Company, Celtrion, Pharmobio Korea Inc. and Yuhan. GC has served as consultant or advisor for Roche, Eli Lilly and BMS; served on a speaker’s bureau for Roche, Pfizer and Eli Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca and SeaGen, all outside the submitted work. THF declares honoraria from AstraZeneca Oncology Indonesia, Takeda Indonesia, Eisai Indonesia, Roche Oncology Indonesia, J & J Indonesia and Zueling Pharma Indonesia and role as head of division of Area Development for West Java, Indonesia for the Indonesian Society of Hematology and Medical Oncology. AG declares honoraria for advisory boards from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Pfizer and Roche; honoraria for lectures from Eisai and Eli Lilly and honoraria for expert testimony from Gentili. SG declares honoraria from Lupin, Roche, Novartis, Eli Lilly, Eisai, Cipla, CADILA, Intas and AstraZeneca; honoraria for being on committees of the Indian Council of Medical Research (Government of India), Council of Scientific and Industrial Research (Government of India), Department of Biotechnology (Government of India), India Alliance and institutional; honoraria from Novartis and AstraZeneca for participation in steering committees; leadership roles include President of Indian Society of Medical and Paediatric Oncology and General Secretary of Women’s Cancer Initiative - Tata Memorial Hospital, both roles unpaid. NH reports honoraria for lectures, advisory boards and/or personal fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and SeaGen, and minority ownership interest in the West German Study Group. RAH declares honoraria from Roche, Novartis, MSD, Pfizer and Mylan, and support for attending meetings from Roche, MSD and Kalbe Pharma. SAI declares an institutional grant from AstraZeneca, Boryung Pharm, Daewoong Pharm, Eisai, Roche and Pfizer, and honoraria from AstraZeneca, Novartis, MSD, Roche, Pfizer; advisory role for AstraZeneca, Bertis, Daiichi Sankyo, Eisai, Hanmi, Lilly, MSD, Novartis, Roche and Pfizer. JHK declares an institutional grant from Ono Pharma Ltd., and honoraria from Novartis, MSD, Roche Pharma, Roche diagnostics, Pfizer, AstraZeneca, Eisai, Lilly, and Sanofi; fees for participation in data monitoring or advisory boards from Bixink, Eisai, Yuhan, Novartis, Daiichi Sankyo, Pfizer, Roche Pharma and Everest Medicines; institutional gifts from Eisai and Ono Pharma Ltd. SBK declares institutional funding from Novartis, Sanofi-Aventis and Dongkook Pharm Co.; consulting fees from Novartis, AstraZeneca, Lilly, DaeHwa Pharmaceutical Co Ltd., ISU Abxis, Beigene, OBI Pharma and Daiichi Sankyo; honoraria from Novartis, Pfizer, Lilly, OBI Pharma and Legochem Bioscience; participation on data safety monitoring or advisory boards for Novartis, AstraZeneca, MSD, Lilly and Daiichi Sankyo, and purchased stock in Genopeaks and Neogene TC. KHL declares honoraria from Pfizer, Novartis and Eli Lilly. SCL declares grants from Pfizer, Eisai, Taiho, ACT Genomics, MSD, Adagene and Epizyme; honoraria from Pfizer, Novartis, AstraZeneca, ACT Genomics, Eli Lilly, MSD and Roche and participation in data monitoring or advisory boards for Pfizer, Novartis, Eisai, Sanofi, Daiichi Sankyo, MSD and Roche. MYM declares institutional grants from MSD, Astella, Pfizer, Novartis, AstraZeneca, ARCUS, Amgen and honoraria from MSD, Amgen, Pfizer, Roche, Novartis, Zuelling Pharma, Specialised therapeutics, Eisai, GSK, Mundi Pharma, Eli Lilly and AstraZeneca. YN declares institutional grants from the Ministry of Health, Labour and Welfare, Abbvie, Ono, Daiichi Sankyo, Taiho, Pfizer, Boehringer Ingelheim, Eli Lilly, Eisai, AstraZeneca, Chugai, Bayer and honoraria from AstraZeneca, Eisai, Ono, Gardant, Takeda, Eli Lilly, Novartis, Pfizer, Chugai, Fuji Film Toyama Chemistry, Taiho, Mundi, Bristol, Shionogi. NP declares honoraria from AstraZeneca, Eisai, Roche, Eli Lilly, Novartis, Pfizer and MSD. YHP declares grants from AstraZeneca, Pfizer, Novartis, Roche and Gencurix, consulting fees from AstraZeneca, Pfizer, Novartis, Roche, Eisai, Daiichi Sankyo, MSD and Lilly, honoraria from Pfizer, MSD, Novartis and Roche, and participation on data monitoring boards and advisory boards for Roche, Eisai, Daiichi Sankyo, AstraZeneca, MSD and Novartis. SP declares fees for consultancy/advisory roles from Abbvie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Bio Invent, Biocartis, Blueprint Medicines, Boehringer Ingelheim, BMS, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-star, Foundation Medicine, Genzyme, Gilhead, GSK, Illumina, Incyte, IQIVIA, iTHeos, Janssen, Medscape, MSD, Merck Serono, Mirati, Novartis, Novocure, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, SeaGen, Takeda, Vaccibody, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Fishawack, Illumina, Imedex, Medscape, Mirati MSD, Novartis, OncologyEducation, PER, Pfizer, PRIME, RMEI, Roche/Genentech, RTP, Sanofi, Takeda and steering committee and trial chair roles as follows: AstraZeneca, coordinating PI, institutional, no financial interest, MERMAID-1; AstraZeneca, steering committee member, institutional, no financial interest, MERMAID-2, POSEIDON, MYSTIC; Beigene, steering committee member, institutional, no financial interest, BGB-A317-A1217-301/AdvanTIG-301; BMS, steering committee member, institutional, no financial interest, clinical trial steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451; BMS, steering committee member, institutional, no financial interest, RELATIVITY 095; GSK, trial chair, institutional, no financial interest, clinical trial chair ZEAL-1; iTeos, steering committee member, institutional, no financial interest, Phase 2 Inupadenant with chemo; Mirati, steering committee member, institutional, no financial interest, clinical trial steering committee SAPPHIRE; MSD, steering committee member, institutional, no financial interest, clinical trial steering committee PEARLS, MK-7684A; Pharma Mar, steering committee member, institutional, no financial interest, LAGOON; Phosplatin Therapeutics, steering committee member, institutional, no financial interest, phase 1/2 trials; Roche/Genentech, trial chair, institutional, no financial interest, clinical trial chair Skyscraper-01; chair ALEX; steering committee BFAST; steering committee BEAT-Meso; steering committee ImPower-030, IMforte. Also role as ESMO president, ETOP/EORTC/SAKK PI, involved in academic trials, ETOP/IBCSG partners officer. Council member and scientific chair, SAKK, vice-President Lung Group, SAMO, Vice President. BKS declares honoraria from Novartis and Eli Lilly. MS declares honoraria from AstraZeneca, MSD, Accord Health and Novartis, support for attending meetings from the Malaysia Urology Association and roles as an ex-committee member of the Malaysian Oncological Society and chairman of the Annual Scientific congress of the Malaysian Oncological Society. KT declares grants from Pfizer, Daiichi Sankyo, Eli Lilly, AstraZeneca, Eisai; honoraria from Daiichi Sankyo, Eli Lilly, Chugai, MSD; and data monitoring or advisory board fees from Daiichi Sankyo. SSW declares a grant from Pfizer and honoraria from Pfizer, Roche, AstraZeneca, Novartis, Daiichi Sankyo, Eli Lilly, MSD and Henrui. TY declares institutional grants from Amgen, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Genomedia, MSD, Ono, Pfizer, Sanofi, Sysmex and Taiho, and honoraria Bayer, Chugai, Merck biopharma, MSD and Ono. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population., Methods: This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m 2 ; orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m 2 ) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585., Findings: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5-63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0-63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8-26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3-20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5-8·4) in the treatment of physician's choice group (HR 0·36 [0·28-0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%)., Interpretation: DESTINY-Breast02 shows the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one., Funding: Daiichi Sankyo and AstraZeneca., Competing Interests: Declaration of interests FA reports grants or speaker compensation or advisory board participation for Sanofi, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, and Roche. YHP reports grants from MSD, Pfizer, AstraZeneca, and Roche; consulting fees from AstraZeneca, MSD, Pfizer, Eisai, Lilly, Roche, Bixink, Daiichi Sankyo, Menarini, Everest, and Novartis; honoraria from AstraZeneca, Pfizer, Lilly, MSD, Roche, Daiichi-Sankyo, and Novartis; and advisory board participation for AstraZeneca, Pfizer, Roche, Novartis, and Menarini. S-BK reports grants from Novartis, Sanofi-Aventis, Dongkook Pharmaceutical; payment for expert testimony from Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceuticals, ISU Abxis, and Daiichi Sankyo; meeting or travel support (or both) from Novartis, AstraZeneca, and Lilly; advisory board participation for Novartis, AstraZeneca, Lilly, and Daiichi Sankyo; and stock in Genopeaks and Neogene Therapeutics. TT reports honoraria for lectures from Daiichi Sankyo, Chugai, Eisai, Eli Lilly, and Celltrion Healthcare. S-AI reports grants from AstraZeneca, Eisai, Daewoong Pharmaceutical, Daiichi Sankyo, Pfizer, Roche, and Boryung Pharmaceutical; and consulting fees from AstraZeneca, Hanmi, Eisai, Lilly, MSD, Idience, Novartis, Pfizer, Roche, GSK, Daiichi Sankyo, and Bertis. JPL reports grants from MSD, Bristol Myers Squibb, Taiho, Janssen, Mink, Agenus, Daiichi Sankyo, AstraZeneca, Roche, and Seagen; payment or honoraria from Bristol Myers Squibb, AstraZeneca, and Daiichi Sankyo; meeting or travel support (or both) from MSD, Bristol Myers Squibb, and AstraZeneca; and stock in Janssen. SA reports honoraria and consulting compensation from AstraZeneca, Bristol Myers Squibb, Lilly, Merck, Novartis, and Pfizer. JGG reports payment or honoraria, meeting or travel support (or both), and advisory board participation for AstraZeneca, Daiichi Sankyo, Novartis, Roche, Lilly, Seagen, and Pfizer. MDL reports payment or honoraria, meeting or travel support (or both), and advisory board participation for AstraZeneca, Eli Lilly, Novartis, Roche, Pfizer, Seagen, Daiichi Sankyo, MSD, GSK, and Sanofi; and payment or honoraria from Celltrion and Organon. FPD reports grants from Fondation Belge Contre le Cancer; consulting fees from Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead Sciences, and Seagen; and meeting or travel support (or both) from Amgen, Roche, Teva, Pfizer, Daiichi Sankyo, and AstraZeneca. GBi reports consulting fees from Roche, AstraZeneca, MSD, Daiichi Sankyo, Gilead, Sanofi, and Seagen; payment or honoraria from Roche, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Chugai, Eisai, Gilead, and Seagen; meeting or travel support (or both) from Roche, Pfizer, MSD, Chugai, Novartis, and AstraZeneca; and advisory board participation for Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, MSD, Chugai, Daiichi Sankyo, Eisai, Gilead, Seagen, Exact Science, and Agendia. RR reports grants from National Institute for Health and Care Research; consulting fees from IQVIA, Eli Lilly, G1 Therapeutics, Daiichi Sankyo, and AstraZeneca; payment or honoraria from Daiichi Sankyo and AstraZeneca; meeting or travel support (or both) from G1 Therapeutics, Roche, Daiichi Sankyo, and Bristol Myers Squibb; and advisory board participation for Pfizer. YM reports grants from Daiichi Sankyo, Eisai, Chugai, MSD, Kyowa-Kirin, Eli Lilly, and Taiho; consulting fees from Daiichi Sankyo; and payment or honoraria from Daiichi Sankyo, Chugai, Eisai, Eli Lilly, AstraZeneca, Pfizer, Taiho, and Kyowa-Kirin. AA reports grants or contracts from AstraZeneca; meeting or travel support (or both) from MSD and Novartis; advisory board participation for MSD; a leadership role for the Royal College of Obstetricians and Gynaecologists Pregnancy and Breast Cancer Guidelines; and stock or stock options with AstraZeneca. EL reports consulting fees from Ellipses; speaker compensation from AstraZeneca, Lilly, Pfizer, Roche, Novartis, and Gilead; meeting or travel support (or both) from AstraZeneca, Novartis, and Gilead; advisory board participation for AstraZeneca, Lilly, Pfizer, Roche, Novartis, Gilead, and Eisai; leadership or fiduciary roles in the Breast Cancer Trials Scientific Advisory Board and University of New South Wales Medicine Faculty Advisory Board; and research support from Novartis and Pfizer. JE reports consulting fees, honoraria, meeting or travel support (or both), and advisory board participation for Daiichi Sankyo, Lilly, Roche, Pfizer, Novartis, Gilead, Seagen, and AstraZeneca. RY reports a research grant from Roche; and consulting fees and honoraria from Roche, Pfizer, Eli Lilly, Novartis, Gilead, Medison, MSD, and AstraZeneca. FZ reports grants, consulting fees, payment or honoraria, advisory board participation for, research support, leadership or fiduciary roles, and stock or stock options in AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, Genesis Pharmaceuticals, and Roche. TF reports advisory board participation for Daiichi Sankyo, Novartis, Roche, Pfizer, MSD, and Teva Pharmaceuticals. CW was an employee of Daiichi Sankyo during the study. DG, JC, CC, and AE report employment by Daiichi Sankyo. AE reports stock in Daiichi Sankyo. IK reports grants from Pfizer, MacroGenics, Genentech (Roche); consulting fees from AstraZeneca, Daiichi Sankyo, Genentech (Roche), Bristol Myers Squibb, MacroGenics, Taiho Oncology, and Seagen; payment or honoraria from AstraZeneca; advisory board participation for Novartis and Merck; and leadership, fiduciary roles, and stock in Puretech. GBo, RS, and MRB declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Circadian rhythm disruptors (e.g., night-shift work) are risk factors for breast cancer, however studies on their association with prognosis is limited. A small but growing body of research suggests that altered sleep patterns and eating behaviours are potential mechanistic links between circadian rhythm disruptors and breast cancer. We therefore systematically summarised literature examining the influence of circadian rhythm disrupting behaviours on cancer outcomes in women with breast cancer., Methods: A systematic search of five databases from inception to January 2021 was conducted. Original research published in English, assessing the relationship between post-diagnosis sleep patters and eating behaviours, and breast cancer outcomes were considered. Risk of bias was assessed using the Newcastle-Ottawa Assessment Scale for Cohort Studies., Results: Eight studies published original evidence addressing sleep duration and/or quality (k = 7) and, eating time and frequency (k = 1). Longer sleep duration (≥ 9 h versus [referent range] 6-8 h) was consistently associated with increased risk of all outcomes of interest (HR range: 1.37-2.33). There was limited evidence to suggest that measures of better sleep quality are associated with lower risk of all-cause mortality (HR range: 0.29-0.97). Shorter nightly fasting duration (< 13 h versus ≥ 13 h) was associated with higher risk of all breast cancer outcomes (HR range: 1.21-1.36)., Conclusion: Our review suggests that circadian rhythm disrupting behaviours may influence cancer outcomes in women with breast cancer. While causality remains unclear, to further understand these associations future research directions have been identified. Additional well-designed studies, examining other exposures (e.g., light exposure, temporal eating patterns), biomarkers, and patient-reported outcomes, in diverse populations (e.g., breast cancer subtype-specific, socio-demographic diversity) are warranted., (© 2022. The Author(s).)

Background/aims: There have been little research on the cancer risks of patients with Peutz-Jeghers syndrome (PJS) in Korea. We aimed to investigate the clinical features of PJS patients and their cancer incidence rate., Methods: Patients with PJS from nine medical centers were enrolled. In those patients diagnosed with cancer, data obtained included the date of cancer diagnosis, the tumor location, and the cancer stage. The cumulative risks of gastrointestinal cancers and extra-gastrointestinal cancers were calculated using the Kaplan-Meier method., Results: A total of 96 PJS patients were included. The median age at diagnosis of PJS was 23.4 years. Cancer developed in 21 of the 96 patients (21.9%). The age of PJS diagnosis was widely distributed (0.9 to 72.4 years). The most common cancers were gastrointestinal cancer (n = 12) followed by breast cancer (n = 6). The cumulative lifetime cancer risk was calculated to be 62.1% at age 60. The cumulative lifetime gastrointestinal cancer risk was 47.1% at age 70. The cumulative lifetime extra- gastrointestinal cancer risk was 40.3% at age 60., Conclusion: PJS onset may occur at any age and the risks of gastrointestinal and extra-gastrointestinal cancer are high. Thorough surveillance of PJS patients for malignancies is vital.

Background: We evaluated the impact of omitting axillary lymph node dissection (ALND) on oncological outcomes in breast cancer patients with residual nodal disease after neoadjuvant chemotherapy (NAC)., Methods: The medical records of patients who underwent NAC followed by surgical resection and had residual nodal disease were retrospectively reviewed. In total, 1273 patients from 12 institutions were included; all underwent postoperative radiotherapy. Axillary surgery consisted of ALND in 1103 patients (86.6%) and sentinel lymph node biopsy (SLNBx) alone in 170 (13.4%). Univariate and multivariate analyses of disease-free survival (DFS) and overall survival (OS) were performed before and after propensity score matching (PSM)., Results: The median follow-up was 75.3 months (range, 2.5-182.7). Axillary recurrence rates were 4.8% in the ALND group (n = 53) and 4.7% in the SLNBx group (n = 8). Before PSM, univariate analysis indicated that the 5-year OS rate was inferior in the ALND group compared to the SLNBx group (86.6% vs. 93.3%, respectively; P = 0.002); multivariate analysis did not show a difference between groups (P = 0.325). After PSM, 258 and 136 patients were included in the ALND and SLNBx groups, respectively. There were no significant differences between the ALND and SLNBx groups in DFS (5-year rate, 75.8% vs. 76.9%, respectively; P = 0.406) or OS (5-year rate, 88.7% vs. 93.1%, respectively; P = 0.083)., Conclusions: SLNBx alone did not compromise oncological outcomes in patients with residual nodal disease after NAC. The omission of ALND might be a possible option for axillary management in patients treated with NAC and postoperative radiotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

We hypothesized that the intake of fermented soy and dairy products, but not fermented vegetable products, was associated with reduced cancer recurrence and mortality in breast cancer survivors. Women ( n  = 606) who underwent dietary survey using a 24-h recall within 3 years of breast cancer surgery were recruited, and were followed up for a mean of 89 mo,. Cox proportional hazards regression analysis showed that the risk of cancer recurrence was inversely associated with the intake of fermented soy products (Hazard ratios (HRs):0.976, 95% confidence intervals (CI):0.95-0.99) and fermented dairy products (HRs:0.992, 95% CI:0.98-0.99). Furthermore, the risk of cancer recurrence was inversely associated with the intake of fermented soy products in hormone receptor-positive (HRs:0.296, 95% CI:0.11-0.79), estrogen receptor-positive (HRs:0.971, 95% CI:0.94-0.99), and progesterone receptor-positive (HRs:0.972, 95% CI:0.94-0.99) patients. Mortality was inversely associated with the intake of fermented soy products (HRs:0.967, 95% CI:0.93-0.99). Disease-free survival ( P  = 0.001) and overall survival ( P  = 0.004) were positively associated with intake of fermented soy products. Intake of fermented vegetable products had no significant effect on cancer recurrence or mortality. This study suggests that the intake of fermented soy and dairy could be beneficial in preventing cancer recurrence.

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety., Patients and Methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015., Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome., Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Estrogen receptor (ER) expression in breast cancer plays an essential role in carcinogenesis and disease progression. Recently, tumors with low level (1%-10%) of ER expression have been separately defined as ER low positive (ERlow). It is suggested that ERlow tumors might be morphologically and behaviorally different from tumors with high ER expression (ERhigh)., Materials and Methods: Retrospective analysis of a prospective cohort database was performed. Patients who underwent curative surgery for early breast cancer and had available medical records were included for analysis. Difference in clinicopathological characteristics, endocrine responsiveness and five-year recurrence-free survival was evaluated between different ER subgroups (ERhigh, ERlow, and ER-negative [ER-])., Results: A total of 2,162 breast cancer patients were included in the analysis, Tis and T1 stage. Among them, 1,654 (76.5%) were ERhigh, 54 (2.5%) were ERlow, and 454 (21.0%) were ER- patients. ERlow cases were associated with smaller size, higher histologic grade, positive human epidermal growth factor receptor 2, negative progesterone receptor, and higher Ki-67 expression. Recurrence rate was highest in ER- tumors and was inversely proportional to ER expression. Recurrence-free survival was not affected by hormonal therapy in the ERlow group (p=0.418)., Conclusion: ERlow breast cancer showed distinct clinicopathological features. ERlow tumors seemed to have higher recurrence rates compared to ERhigh tumors, and they showed no significant benefit from hormonal therapy. Future large scale prospective studies are necessary to validate the treatment options for ERlow breast cancer.

We herein describe a polychromatic quantum dot array (PQDA) to compose a community signal ensemble enabling accurate and precise quantification of miRNAs in a multiplexed manner. Advanced multicomponent ultrahigh-resolution patterning technique achieved by capsulation-assisted transfer printing following self-assembly-based poly(methyl methacrylate) (PMMA) patterning is utilized to manufacture the PQDA, which is designed to discharge a target miRNAs-specific set of fluorescent quantum dots (QDs) through the activity of duplex-specific nuclease (DSN). On the basis of the community signal ensemble produced by the discharged QD profiles, target miRNAs are very specifically identified down to a femtomolar level (1.27 fM) in a multiplexed manner over a wide dynamic range of up to 6 orders of magnitude. The practical diagnostic capability of this strategy is also demonstrated by reliably identifying breast cancer-specific miRNAs from heterogeneous cancer cell lysates.

Antioxidants decrease the risk of breast cancer by reducing oxidative stress, but the association between dietary total antioxidant capacity (DTAC) and cancer recurrence has not yet been investigated. The present study aimed to test the hypothesis that DTAC is inversely associated with cancer recurrence and mortality in breast cancer patients. Breast cancer patients ( n  = 603) who underwent breast cancer surgery and a dietary survey within 5 years after surgery were recruited. This study observed disease-free survival (DFS) and mortality in breast cancer patients according to DTAC calculated based on 24-hr dietary recall. Total DTAC was significantly lower in patients with cancer recurrence than in those without. DFS was positively associated with the total DTAC ( p  = 0.005) and DTAC of vegetables and legumes ( p  = 0.001 and p  = 0.010), respectively. However, total DTAC was not associated with mortality. Cox proportional hazards regression analysis showed that total DTAC (HR: 0.44, 95% CI 0.26-0.94) and DTAC of vegetables (HR: 0.30, 95% CI 0.14-0.65) and legumes (HR: 0.38, 95% CI 0.18-0.73) were inversely associated with cancer recurrence after adjusting for confounding factors. This study was the first to indicate that total DTAC and DTAC of vegetables and legumes could be beneficial in decreasing breast cancer recurrence.

The survival rates for breast cancer (BC) have improved in recent years, but resistance, metastasis, and recurrence still remain major therapeutic challenges for BC. The acidic tumor microenvironment (TME) has attracted attention because of its association with tumorigenesis, metastasis, drug resistance, and immune surveillance. In this study, we evaluated natural compounds from traditional herbal medicine used to treat cancer that selectively target genes regulated by extracellular acidosis. We integrated four transcriptomic data including BC prognostic data from The Cancer Genome Atlas database, gene expression profiles of MCF-7 cells treated with 102 natural compounds, patterns of gene profiles by acidic condition, and single-cell RNA-sequencing from BC patient samples. Bruceine D (BD) was predicted as having the highest therapeutic potential, having an information gain (IG) score of 0.24, to regulate reprogrammed genes driven by acidosis affecting the survival of BC patients. BD showed the highest IG on EMT (IG score: 0.11) and invasion (IG score: 0.1) compared to the other phenotypes with the CancerSEA database. BD also demonstrated therapeutic potential by interfering with the tumor cell-TME interactions by reducing the amyloid beta precursor protein and CD44 expression. Therefore, BD is a potential candidate to target the acidic TME induced metastatic process in BC.

Background: The aim of this study was to develop a machine learning (ML) based model to accurately predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) using pretreatment clinical and pathological characteristics of electronic medical record (EMR) data in breast cancer (BC)., Methods: The EMR data from patients diagnosed with early and locally advanced BC and who received NAC followed by curative surgery were reviewed. A total of 16 clinical and pathological characteristics was selected to develop ML model. We practiced six ML models using default settings for multivariate analysis with extracted variables., Results: In total, 2065 patients were included in this analysis. Overall, 30.6% (n = 632) of patients achieved pCR. Among six ML models, the LightGBM had the highest area under the curve (AUC) for pCR prediction. After hyper-parameter tuning with Bayesian optimization, AUC was 0.810. Performance of pCR prediction models in different histology-based subtypes was compared. The AUC was highest in HR+HER2- subgroup and lowest in HR-/HER2- subgroup (HR+/HER2- 0.841, HR+/HER2+ 0.716, HR-/HER2 0.753, HR-/HER2- 0.653)., Conclusions: A ML based pCR prediction model using pre-treatment clinical and pathological characteristics provided useful information to predict pCR during NAC. This prediction model would help to determine treatment strategy in patients with BC planned NAC., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting., Methods: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out., Results: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062)., Conclusions: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer., Clinical Trial Registration: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In this study, we evaluated the association between genetic polymorphisms of 23 genes associated with gemcitabine metabolism and the clinical efficacy of gemcitabine in breast cancer patients., Patients and Methods: This prospective, pharmacogenetic study was conducted in cooperation with a phase II clinical trial. A total of 103 genetic polymorphisms of the 23 genes involved in gemcitabine transport and metabolism were selected for genotyping. The associations of genetic polymorphisms with overall survival, progression-free survival (PFS), and 6-month PFS were analyzed., Results: A total of 91 breast cancer patients were enrolled in this study. In terms of 6-month PFS, rs1044457 in CMPK1 was the most significant genetic polymorphism [55.9% for CT and TT and 78.9% for CC, P < 0.001, hazard ratio (HR): 4.444, 95% confidence interval (CI): 1.905-10.363]. For the rs693955 in SLC29A1, the median duration of PFS was 5.4 months for AA and 10.5 months for CA and CC (P = 0.002, HR: 3.704, 95% CI: 1.615-8.497). For the rs2807312 in TLE4, the median duration of PFS was 5.7 months for TT and 10.4 months for CT and CC (P = 0.005, HR: 4.948, 95% CI: 1.612-15.190). In survival analysis with a multi-gene model, the TT genotype of rs2807312 had the worst PFS regardless of other genetic polymorphisms, whereas the CA genotype of rs693955 or the CT genotype of rs2807312 without the AA genotype of rs693955 had the best PFS compared with those of other genetic groups (P < 0.001)., Conclusions: Genetic polymorphisms of rs1044457 in CMPK1, rs693955 in SLC29A1, and rs2807312 in TLE4 were significantly associated with the 6-month PFS rate and/or the duration of PFS. Further studies with a larger sample size and expression study would be helpful to validate the association of genetic polymorphisms and clinical efficacy of gemcitabine., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Shave margins have been shown to decrease positive final margins in partial mastectomy. We investigated prognostic factors associated with residual disease in shave margins., Methods: Patients with invasive breast carcinoma and ductal carcinoma in situ (DCIS) who had circumferential shave margins excised during lumpectomy were abstracted from a retrospective database from 2015 to 2018. We defined residual occult disease (ROD) as either (1) residual disease in a shave margin when the initial lumpectomy specimen had negative margins or (2) residual disease in a shave margin that did not correspond with the positive lumpectomy margin. We identified the frequency of ROD and conducted logistic regression analysis to identify associated prognostic factors., Results: 166 Patients (139 invasive carcinoma, 27 DCIS) were included with median follow-up of 28 months (9-50 months). Residual occult disease existed in 34 (24.5%) with invasive carcinoma and 8 (29.6%) with DCIS. In univariate analyses of the invasive group, invasive lobular carcinoma and a positive initial, non-corresponding lumpectomy margin were predictive of ROD (OR 3.63, p = 0.04, OR 3.48, p = 0.003 respectively). In multivariate analysis, a positive lumpectomy margin remained significant, p = 0.007. No variables were associated with ROD in DCIS., Conclusion: Residual occult disease was shown to be a frequent event in this analysis of lumpectomy with circumferential shave margins. Having a positive initial lumpectomy margin was predictive of ROD in a non-corresponding margin. Surgeons should consider not being selective in their shave margins or margin of re-excision if shave margins were not obtained in their initial surgery., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intake of flavonoids is associated with the incidence of breast cancer, but the association between the intake of flavonoids and cancer recurrence is unclear. This study aimed to investigate the hypothesis that intake of flavonoids and flavonoid-rich foods is negatively associated with cancer recurrence. Among 572 women who underwent breast cancer surgery, 66 patients had a cancer recurrence. Dietary data were collected using a structured 24-h dietary recall, and intake of flavonoids was calculated based on the Korea Rural Development Administration flavonoid database. Among overweight and obese patients, disease-free survival was associated with intake of flavonoids ( p = 0.004) and flavonoid-rich foods ( p = 0.003). Intake of flavonoids (hazard ratio (HR) = 0.249, 95% confidence interval (CI): 0.09-0.64) and flavonoid-rich foods (HR = 0.244, 95% CI: 0.09-0.66) was negatively associated with cancer recurrence after adjusting for confounding factors in overweight and obese patients. Consumption of flavonoids and flavonoid-rich foods was lower in overweight and obese patients with cancer recurrence than those without recurrence and in normal-weight patients. This study suggests that intake of flavonoids and flavonoid-rich foods could have beneficial effects on cancer recurrence in overweight and obese breast cancer survivors.

Background: Type 2 diabetes (T2D) has been associated with increased breast cancer risk, but commonly prescribed antidiabetic medications such as metformin may reduce risk. Few studies have investigated T2D and medications together in relation to breast cancer., Patients and Methods: Data came from 44 541 Sister Study participants aged 35 to 74 years at enrollment (2003-2009) who satisfied eligibility criteria, followed through 15 September 2017. Information on time-varying, self-reported, physician-diagnosed, prevalent and incident T2D, use of antidiabetic medications, and covariates was obtained from baseline and follow-up questionnaires. Incident breast cancers were confirmed with medical records. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated., Results: During follow-up (median, 8.6 years), 2678 breast cancers were diagnosed at least 1 year after enrollment. There were 3227 women (7.2%) with prevalent and 2389 (5.3%) with incident T2D, among whom 61% (n = 3386) were ever treated with metformin. There was no overall association between T2D and breast cancer risk (HR 0.99; 95% CI, 0.87-1.13). However, T2D was associated with increased risk of triple-negative breast cancer (HR 1.40; 95% CI, 0.90-2.16). Compared with not having T2D, T2D with metformin use was not associated with overall breast cancer risk (HR 0.98; 95% CI, 0.83-1.15), but it was associated with decreased risk of estrogen receptor (ER)-positive breast cancer (HR 0.86; 95% CI 0.70-1.05) and increased risk of ER-negative (HR 1.25; 95% CI, 0.84-1.88) and triple-negative breast cancer (HR 1.74; 95% CI, 1.06-2.83). The inverse association with ER-positive cancer was stronger for longer duration (≥10 year) metformin use (HR 0.62; 95% CI, 0.38-1.01; P for trend = 0.09). Results were supported by sensitivity analyses., Conclusion: Our findings suggest that associations between T2D and breast cancer may differ by hormone receptor status and that associations between T2D and ER-positive breast cancer may be reduced by long-term metformin use., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Published by Elsevier Ltd.)

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.

Background: Aromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen., Methods: We analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE., Results: We included 47,569 women for the final analysis. Patients were classified into 'No hormonal treatment (n = 18,807), 'Switch (n = 2097)', 'Tamoxifen (n = 7081)' and 'AI (n = 19,584)'. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74-0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84-1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47-0.84)., Conclusions: Our results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Circadian disruption may play a role in breast carcinogenesis. Previous studies reported relationships between outdoor light at night (LAN) and the breast cancer risk, but their findings are mixed. There is also a need to examine LAN and breast cancer incidence according to different individual and environmental characteristics to identify subpopulations at greater risk associated with LAN exposure. We studied residential outdoor LAN estimated from satellite imagery at baseline (1996) in relation to postmenopausal breast cancer incidence over ~16 years of follow-up in 186 981 postmenopausal women including 12 318 incident postmenopausal breast cancer cases in the NIH-AARP Diet and Health Study. We used Cox proportional hazards models to estimate hazard ratios (HR) and two-sided 95% confidence intervals (CI) of the relationship between quintiles of LAN and postmenopausal breast cancer risk, overall and by hormone receptor status and cancer stage. We found that when compared to women in the lowest quintile of baseline LAN, those in the highest quintile had a 10% increase in postmenopausal breast cancer risk (HR (95% CI), 1.10 (1.02, 1.18), P-trend, .002). The association appeared to be stronger for estrogen receptor (ER) positive breast cancer (1.12 [1.02, 1.24], .007) than for ER-negative cancer (1.07 [0.85, 1.34], .66). Our findings also suggested that the relationship between LAN and breast cancer risk may differ by individual characteristics, such as smoking, alcohol drinking, sleep duration and BMI, and neighborhood environment. In conclusion, our study suggests that higher outdoor LAN exposure may be a risk factor for postmenopausal breast cancer., (© 2020 UICC.)

Background: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients., Patients and Methods: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed., Results: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756)., Conclusions: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: To assess the predictive value of preoperative residual mammographic microcalcifications for residual tumours after neoadjuvant chemotherapy (NAC) for breast cancer., Materials and Methods: This single-centre retrospective study included breast cancer patients who underwent NAC and demonstrated suspicious microcalcifications within or near the tumour bed on mammography from June 2015 to August 2018. The residual microcalcifications and remnant lesion on magnetic resonance imaging (MRI) were correlated with histopathological findings of residual tumours and immunohistochemical markers., Results: A total of 96 patients were included. Ten patients achieved pathological complete response (pCR) and previous suspicious microcalcifications were associated with benign pathology in 10.4% (10/96) of the patients. In the remaining 86 patients who did not achieve pCR, 61.5% (59/96) of the residual microcalcifications were associated with invasive or in situ carcinoma and 28.1% (27/96) with benign pathology. Hormone receptor-positive (HR + ) patients had the highest proportion of residual malignant microcalcifications compared to HR - patients (48.9% versus 13.5%, respectively; p=0.019). MRI correlated better than residual microcalcifications on mammography in predicting residual tumour extent in all subtypes (ICC=0.709 versus 0.365). MRI also showed higher correlation with residual tumour size for the HR - /HER2 + and HR - /HER2 - subtype (ICC=0.925 and 0.876, respectively)., Conclusion: The extent of microcalcifications on mammography after NAC did not correlate with the extent of residual cancer in 38.5% of women. Regardless of the extent of microcalcifications, residual tumour extent on MRI after NAC and molecular subtype could be an accurate tool in evaluating residual cancer after NAC., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated., Methods: Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate., Results: A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025)., Conclusions: The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer., Clinical Trial Registration: Clinical Trial Registration: UMIN-CTR as UMIN000007074.

Background: Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism and are consumed through the diet in high-fat and highly processed foods. They are associated with chronic inflammatory diseases, and evidence suggests that they play a role in carcinogenesis. The authors evaluated the association of dietary AGE intake and the risk of postmenopausal invasive breast cancer., Methods: This was a prospective cohort study of 183,548 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. The main outcome was incident invasive breast cancer. AGE intake was estimated from food-frequency questionnaires. Incident breast cancer cases were identified through state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals for developing breast cancer according to AGE intake quintiles. Multivariable regression models were adjusted for breast cancer risk factors., Results: The mean follow-up was 12.8 years, and 9851 breast cancers (1978 advanced stage) were identified. The median AGE daily intake was 5932 kilo units per 100 kilocalories (KU/1000 kcal). Women with higher intake tended to have lower education levels, higher body mass index, less physical activity, were current smokers, and had higher fat and meat intake. The highest quintile of AGE intake (compared with the lowest) was associated with an increased risk of breast cancer (HR, 1.09; 95% CI, 1.02-1.16; P = .03) after adjusting for breast cancer risk factors and particularly was associated with 37% of advanced-stage tumors (HR, 1.37; 95% CI, 1.09-1.74; P < .02) after adjusting for risk factors and fat and meat intake., Conclusions: Dietary AGEs may play a role in the development of postmenopausal breast cancer., (© 2020 American Cancer Society.)

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries., Competing Interests: Disclosure FC has received fees for consultancy/advisory roles from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medspace, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Seatlle Genetics and Teva. RD has received fees for consultancy/advisory roles from AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, Roche, and for travel and subsistence from Roche, Merck, Pfizer, Eisai. SG has received research funding from Roche, Sanofi, Johnson & Johnson, Oncostem, Amgen, Celltrion, Novartis, Eisai, Intas and Biocon. S-AI has received fees for consultancy/advisory roles from Amgen, AstraZeneca, Hanmi Corp, Medpacto, Pfizer, Eisai, Novartis, Roche and Lilly, and research funding from AstraZeneca, Pfizer and Roche. HI has received fees for consultancy/advisory roles from Chugai, AstraZeneca, Lilly, Daiich-Sankyo, Pfizer, MSD, Eisai, Kyowa Hakko Kirin, Taiho and Novartis, and research funding from Chugai, AstraZeneca, Lilly, Daiich-Sankyo, Pfizer, MSD, Kyowa Hakko Kirin, Bayer, Novartis and GSK. JHK has received research funding from Ono Pharma Korea Co., Ltd. SCL has received fees for consultancy/advisory roles from Roche, Pfizer, Novartis, Eli Lilly, AstraZeneca and research funding from Taiho, ACT Genomics, Eisai and Pfizer. Y-SL has received fees for consultancy/advisory roles from Pfizer, MSD, Novartis, Boehringer-Ingelheim and Roche, and research funding from MSD, Novartis and Roche. SM has received fees for consultancy/advisory roles from MSD and research funding from ASLAN Pharmaceuticals, MSD, Novartis, Astellas and AstraZeneca. MYM has received research funding from MSD, Mundi Pharma, Astellas, Novartis, AstraZeneca, Sanofi, Roche and Pfizer. YHP has received fees for consultancy/advisory roles from AstraZeneca, Pfizer, Eisai, Novartis, Merck, Roche and Lilly, and research funding from AstraZeneca, Eisai, Merck, Pfizer, Novartis and Roche. GP has received fees for consultancy/advisory roles from Roche, Amgen, MSD, Boehringer and Bristol-Myers Squibb, and research funding from Roche, Amgen, Astellas, Pfizer and Novartis. SS has received fees for consultancy/advisory roles from Novartis, Chugai and Kyowa Kirin, research funding from Chugai, Takeda, Eisai, Taiho and Novartis, and fees for non-CME services received directly from commercial interests or their agents (e.g. speakers bureau) from Pfizer, Novartis, AstraZeneca, Eli Lilly, Eisai, Kyowa Kirin and Chugai, and is an executive board member of the Japan Breast Cancer Society (JBCS) and the Japan Breast Cancer Research Group (JBCRG). ES has received honoraria from Amgen, AstraZeneca, Clinigen, EGIS Pharmaceuticals, Eli Lilly, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and TLC Biopharmaceuticals, travel support from Amgen, AstraZeneca, EGIS Pharmaceuticals, Novartis, Pfizer and Roche, and clinical research funding from Amgen, AstraZeneca, Boehringer, Eli Lilly, Merck, Novartis, Pfizer, Roche and Samsung. BKS has received fees for consultancy/advisory roles from Eli Lilly, Dr Reddy's Lab, Cipla and AstraZeneca. TT has received fees for consultancy/advisory roles from AstraZeneca and research funding from Eisai, Chugai, and Novartis Pharma. TY has received research funding from Novartis Pharma K.K., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Sanofi K.K., Daiichi Sankyo Co., Ltd., Parexel International Inc., ONO Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Boehringer Ingleheim Japan, Inc. J-YD, T-YK, KJS, L-MT and YY have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present in silico investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski's rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds - Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18-30, particularly those with RS 26-30, are not known., Methods: Using the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18-30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox's proportional hazards model., Results: Among the breast cancer patients with the RS 18-30, 21% of them had RS 26-30. Compared to breast cancer patients with RS 18-25, patients with RS 26-30 had more aggressive tumor characteristics and chemotherapy use and increased risk of breast cancer-specific mortality and overall mortality. In breast cancer patients who were aged ≤ 70 years and had RS of 26-30, chemotherapy administration was associated with a 32% lower risk of breast cancer-specific mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47-0.99) and a 42% lower risk of overall mortality (HR, 0.58; 95% CI, 0.44-0.76). Survival benefits were most pronounced in breast cancer patients who were younger or had grade III tumor., Conclusions: The 21-gene RS of 18-30 showed heterogeneous outcomes, and the RS 26-30 was a significant prognostic factor for an increased risk of mortality. Adjuvant chemotherapy could improve the survival of node-negative, hormone receptor-positive, and HER2-negative breast cancer patients with the 21-gene RS 26-30 and should be considered for patients, especially younger patients or patients with high-grade tumors.

Cryoablation is a safe and effective nonsurgical treatment for breast fibroadenomas (FAs). The treatment response is inversely related to the tumor size, with lesions less than 2 cm showing an optimal response. Ultrasound (US) imaging follow-up of the ablated tumor is recommended at 6-month intervals for 2 years at our institution. Although a decrease in the size of the FA clinically and on US imaging is the expected treatment response, variations can be seen. Knowledge of typical US changes over time is imperative to prevent unnecessary rebiopsy or excision in patients who have undergone cryoablation. We will review the initial patient selection criteria, cryoablation technique, and US findings at regular follow-up intervals after cryoablation of FAs through a series of cases treated at our institution., (© 2019 by the American Institute of Ultrasound in Medicine.)

Breast cancer (BC) is the leading cause of death among women worldwide devoid of effective treatment. It is therefore important to develop agents that can reverse, reduce, or slow the growth of BC. The use of natural products as chemopreventive agents provides enormous advantages. The aim of the current investigation is to determine the efficacy of the phytochemicals against BC along with the approved drugs to screen the most desirable and effective phytocompound. In the current study, 36 phytochemicals have been evaluated against aromatase to identify the potential candidate drug along with the approved drugs employing the Cdocker module accessible on the Discovery Studio (DS) v4.5 and thereafter analysing the stability of the protein ligand complex using GROningen MAchine for Chemical Simulations v5.0.6 (GROMACS). Additionally, these compounds were assessed for the inhibitory features employing the structure-based pharmacophore (SBP). The Cdocker protocol available with the DS has computed higher dock scores for the phytochemicals complemented by lower binding energies. The top-ranked compounds that have anchored with key residues located at the binding pocket of the protein were subjected to molecular dynamics (MD) simulations employing GROMACS. The resultant findings reveal the stability of the protein backbone and further guide to comprehend on the involvement of key residues Phe134, Val370, and Met374 that mechanistically inhibit BC. Among 36 compounds, curcumin, capsaicin, rosmarinic acid, and 6-shogaol have emerged as promising phytochemicals conferred with the highest Cdocker interaction energy, key residue interactions, stable MD results than reference drugs, and imbibing the key inhibitory features. Taken together, the current study illuminates the use of natural compounds as potential drugs against BC. Additionally, these compounds could also serve as scaffolds in designing and development of new drugs.

The role of tumor-proximal factors in tumor plasticity during chemoresistance and metastasis following chemotherapy is well studied. However, the role of endothelial cell (EC) derived paracrine factors in tumor plasticity, their effect on chemotherapeutic outcome, and the mechanism by which these paracrine factors modulate the tumor microenvironment are not well understood. In this study, we report a novel mechanism by which endothelial miR-125a and let-7e-mediated regulation of interleukin-6 (IL-6) signaling can manipulate vasculogenic mimicry (VM) formation of MDA-MB-231 breast cancer cells. We found that endothelial IL-6 levels were significantly higher in response to cisplatin treatment, whereas levels of IL-6 upon cisplatin exposure remained unchanged in MDA-MB-231 breast cancer cells. We additionally found an inverse correlation between IL-6 and miR-125a/let-7e expression levels in cisplatin treated ECs. Interestingly, IL-6, IL-6 receptor (IL-6R), and signal transducer and activator of transcription 3 (STAT3) genes in the IL-6 pathway are closely regulated by miR-125a and let-7e, which directly target its 3' untranslated region. Functional analyses revealed that endothelial miR-125a and let-7e inhibit IL-6-induced adhesion of monocytes to ECs. Furthermore, conditioned medium from cisplatin treated ECs induced a significantly higher formation of VM in MDA-MB-231 breast cancer cells as compared to that from intact ECs; this effect of cisplatin treatment was abrogated by concurrent overexpression of miR-125a and let-7e. Overall, this study reveals a novel EC-tumor cell crosstalk mediated by the endothelial miR-125a/let-7e-IL-6 signaling axis, which might improve chemosensitivity and provide potential therapeutic targets for the treatment of cancer. [BMB Reports 2019; 52(3): 214-219].

The dietary inflammatory index (DII) has been associated with breast cancer incidence and survival. However, the association between DII and cancer recurrence and mortality among patients with breast cancer has not been investigated. Therefore, the present study aimed to investigate whether DII was positively associated with risk for cancer recurrence and overall mortality among patients with breast cancer. Among 511 women (51.9 ± 10.7 years; stage 0⁻3) who underwent breast cancer surgery, 88 had cancer recurrence, and 44 died during follow⁻up until 213 months (average disease free survival of 84.3 ± 42.4 months and overall survival of 69.3 ± 38.9 months). The DII assessed after surgery (5.4 ± 5.2 months after diagnosis) was significantly higher in patients with recurrence than those without recurrence, and Cox proportional hazards regression analysis showed that it was positively associated with the risk for cancer recurrence (hazard ratio (HR) 2.347, confidence interval (CI) 1.17⁻4.71) and overall mortality (HR 3.049, CI 1.08⁻8.83) after adjusting for confounding factors. Disease-free survival and overall survival rates were significantly lower in patients with higher DII scores. In addition, the DII was positively associated with the risk for cancer recurrence according to prognostic factors, such as age (<50 years), premenopausal status, body mass index (≥25 kg/m²), HR+, tumor size (>2 cm), and presence of lymph node metastasis. The present study showed that anti-inflammatory diets may decrease the risk of cancer recurrence and overall mortality in patients with breast cancer, particularly those with prognostic factors, such as younger age, premenopausal status, obesity, HR+ breast cancer, tumor size >2 cm, and presence of lymph node metastasis.

HER2 overexpression accounts for approximately 15-20% of all breast cancers. We have shown that HER2 overexpression leads to elevated expression of the aryl hydrocarbon receptor (AhR) in breast cancer cells. In this study, firstly, we showed that AhR expression was up-regulated by treatment with the HER3 ligand heregulin (HRG) in HER2-overexpressing breast cancer cell lines. Induction of AhR was mediated by transcriptional activation of the region of AhR promoter corresponding to - 190 to - 100 bp. In addition, HRG treatment elicited nuclear translocation of AhR. To investigate the role of AhR in HRG-HER2/HER3 signaling in HER2-overexpressing cells, we established AhR knockout (KO) HER2-overexpressing cells to perform wound-healing assays. HRG-induced cell migration was markedly attenuated by AhR KO. HRG-induced cell migration was associated with increased expression of the inflammatory cytokines interleukin (IL)-6 and IL-8 in wild type cells, but not in AhR KO cells. These results elucidate that AhR is an important factor for the malignancy in HER2 overexpressing breast cancers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Attitudes toward menopause vary across cultures and influence women's experiences of menopausal symptoms, possibly leading to reduced posttreatment quality of life in breast cancer survivors., Objective: The aim of this study is to examine the effects of menopausal symptoms and attitudes on health-related quality of life in breast cancer survivors who were premenopausal at the time of diagnosis., Methods: A total of 139 women receiving chemotherapy with/without endocrine therapy were assessed with self-report questionnaires of established reliability and validity. Hierarchical regression was conducted to assess the impact of menopausal symptoms and attitudes on quality of life, while controlling for demographic characteristics., Results: Overall, participants endorsed more than half of 46 symptoms, most at the level of mild symptoms, and most reported a less positive attitude toward menopause. Lower quality of life was significantly predicted by more menopausal symptoms endorsed and more negative attitudes when controlling for demographic factors associated with quality of life (R = 26.1%). Most participants experienced change from premenopause to postmenopause after the completion of adjuvant chemotherapy with or without tamoxifen., Conclusions: The results suggest that more menopausal symptoms and negative attitudes toward menopause may affect health-related quality of life considerably in chemotherapy-treated Asian breast cancer survivors., Implications for Practice: Healthcare professionals should develop a better understanding of the effects of menopausal symptoms and attitudes on quality of life by using a culturally relevant perspective based on patients' sociocultural backgrounds. Furthermore, these findings help healthcare professionals communicate with their Asian clients in a more informed way and provide culturally appropriate and individualized care.

Pathway based analysis of high throughput transcriptome data is a widely used approach to investigate biological mechanisms. Since a pathway consists of multiple functions, the recent approach is to determine condition specific sub-pathways or subpaths. However, there are several challenges. First, few existing methods utilize explicit gene expression information from RNA-seq. More importantly, subpath activity is usually an average of statistical scores, e.g., correlations, of edges in a candidate subpath, which fails to reflect gene expression quantity information. In addition, none of existing methods can handle multiple phenotypes. To address these technical problems, we designed and implemented an algorithm, MIDAS, that determines condition specific subpaths, each of which has different activities across multiple phenotypes. MIDAS utilizes gene expression quantity information fully and the network centrality information to determine condition specific subpaths. To test performance of our tool, we used TCGA breast cancer RNA-seq gene expression profiles with five molecular subtypes. 36 differentially activate subpaths were determined. The utility of our method, MIDAS, was demonstrated in four ways. All 36 subpaths are well supported by the literature information. Subsequently, we showed that these subpaths had a good discriminant power for five cancer subtype classification and also had a prognostic power in terms of survival analysis. Finally, in a performance comparison of MIDAS to a recent subpath prediction method, PATHOME, our method identified more subpaths and much more genes that are well supported by the literature information., Availability: http://biohealth.snu.ac.kr/software/MIDAS/., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the role of ultrasound (US) following magnetic resonance imaging (MRI) and mammography in patients with newly diagnosed breast cancers by assessing the additional cancer detection rate of US., Material and Methods: Two hundred and twenty-five women who had undergone 225 MRI examinations followed by US were included. An US-detected additional cancer was defined as a lesion detected using breast US that had not been detected by MRI, and which was shown to be malignant at histopathology. The rate of additional cancer detection, incidence of additional malignancies, positive predictive value (PPV), and false-positive (FP) rate were analysed. Factors associated with an increase in the additional cancer detection rate were analysed., Results: The additional cancer detection rate was 0% (0/225) for the ipsilateral breast and 0.9% (2/225) for the contralateral breast, and the PPVs were 0% (0/5) and 100% (2/2), respectively. The overall TP:FP ratio was 0.4 (2:5). The additional cancer detection rate was higher for cases with moderate and severe background parenchymal enhancement than cases with minimal and mild background parenchymal enhancement (p=0.003). The additional cancer detection rate for cases with moderate and severe background parenchymal enhancement was 5.7% (2/35) for the contralateral breast (p=0.003)., Conclusion: Preoperative breast US following MRI and mammography can help clinicians screen for contralateral cancers with an additional detection rate of 0.9%. Moreover, whole-breast US might be a useful contralateral screening modality in cases with moderate or marked parenchymal enhancement on breast MRI., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Musashi RNA-binding protein 2 (MSI2) has important roles in human cancer. However, the regulatory mechanisms by which MSI2 alters breast cancer pathophysiology have not been clearly identified. Here we demonstrate that MSI2 directly regulates estrogen receptor 1 (ESR1), which is a well-known therapeutic target and has been shown to reflect clinical outcomes in breast cancer. Based on gene expression data analysis, we found that MSI2 expression was highly enriched in estrogen receptor (ER)-positive breast cancer and that MSI2 expression was significantly correlated with ESR1 expression, including expression of ESR1 downstream target genes. In addition, MSI2 levels were associated with clinical outcomes. MSI2 influenced breast cancer cell growth by altering ESR1 function. MSI2 alters ESR1 by binding specific sites in ESR1 RNA and by increasing ESR1 protein stability. Taken together, our findings identified a novel regulatory mechanism of MSI2 as an upstream regulator of ESR1 and revealed the clinical relevance of the RNA-binding protein MSI2 in breast cancer.

Rab coupling protein (RCP)-induced tumor cell migration has been implicated in tumor pathophysiology and patient outcomes. In the present study, we demonstrate that RCP stabilizes β1 integrin leading to increased β1 integrin levels and activation of a signaling cascade culminating in Slug induction, epithelial-to-mesenchymal transition and increased invasion. Ectopic expression of RCP induced Slug expression. Silencing β1 integrin efficiently inhibited RCP-induced Slug expression and subsequent cancer cell invasion. Conversely, ectopic expression of β1 integrin was sufficient to induce Slug expression. Pharmacological inhibition of integrin linked kinase (ILK), EGFR and NF-κB, as well as transfection of a dominant-negative mutant of Ras (RasN17), significantly inhibited RCP-induced Slug expression and cancer cell invasion. Strikingly, ectopic expression of RCP was sufficient to enhance metastasis of ovarian cancer cells to the lung. Collectively, we demonstrate a mechanism by which RCP promotes cancer cell aggressiveness through sequential β1 integrin stabilization, activation of an ILK/EGFR/Ras/NF-κB signaling cascade and subsequent Slug expression.

Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

With the rapid advances in technologies of microarray and massively parallel sequencing, data of multiple omics sources from a large patient cohort are now frequently seen in many consortium studies. Effective multi-level omics data integration has brought new statistical challenges. One important biological objective of such integrative analysis is to cluster patients in order to identify clinically relevant disease subtypes, which will form basis for tailored treatment and personalized medicine. Several methods have been proposed in the literature for this purpose, including the popular iCluster method used in many cancer applications. When clustering high-dimensional omics data, effective feature selection is critical for better clustering accuracy and biological interpretation. It is also common that a portion of "scattered samples" has patterns distinct from all major clusters and should not be assigned into any cluster as they may represent a rare disease subcategory or be in transition between disease subtypes. In this paper, we firstly propose to improve feature selection of the iCluster factor model by an overlapping sparse group lasso penalty on the omics features using prior knowledge of inter-omics regulatory flows. We then perform regularization over samples to allow clustering with scattered samples and generate tight clusters. The proposed group structured tight iCluster method will be evaluated by two real breast cancer examples and simulations to demonstrate its improved clustering accuracy, biological interpretation, and ability to generate coherent tight clusters., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Breast cancer patients undergoing axillary lymph node dissection (ALND) are at risk of lymphedema (LE). Successful management of LE relies on early diagnosis using sensitive modalities. In the current study, we explored the effectiveness of a surveillance program for lymphedema management (SLYM) compared to standard care., Methods: Breast cancer patients who underwent ALND in Seoul National University Bundang Hospital from January 2008 to December 2015 were included in this prospective study. The SLYM commenced in May 2011. The LE outcomes of patients treated prior to initiation of the SLYM were compared with those of patients after SLYM implementation., Results: A total of 707 patients were included, 390 in the SLYM group and 317 in the historical control (HC) group. A total of 203 patients (28.7 %) had episodes of all-stage LE during follow-up. Of these, 126 (19.7 %) were in the surveillance group and 77 (24.3 %) in the HC group. The overall 5-year cumulative incidence of LE (greater than stage 3) was 25 (95 % CI 15.4-34.6) (6.4 %) in the SLYM group and 48 (95 % CI, 15.4-34.6) (15.1 %) in the HC group. In the SLYM group, poor compliance had a significant impact on LE incidence (OR = 2.98, P = 0.002). Low level of self-monitoring and insight scores were significantly related to LE incidence (OR = 1.31, P = 0.025) after adjusting for age, body mass index, the type of surgery chosen, radiation therapy, and chemotherapy. With a cut-off of 29.5 days from operation to the first visit to the LE clinic, the sensitivity was 60 % and the specificity 61 % in terms of predicting a LE event., Conclusions: Surveillance improves LE prevention compared to clinical evaluation. The first visit to the LE clinic should be made within 1 month after surgery. In the first year, visits should be made at intervals of less than 3 months., Competing Interests: All the other authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was not obtained from all individual participants included in the study.

Genome-wide gene expression information has been very useful for understanding cancer at the molecular level. In particular, breast cancer has been widely studied by utilizing a large amount of transcriptome data. Although statistical selection of differentially expressed genes, e.g., PAM50, has been successful to classify breast cancer subtypes, understanding breast cancer in terms of biological functions or pathways is still limited. Thus, it is essential to develop a tailored model that unravels breast cancer mechanisms by identifying disease-specific functional units of biological pathways and apply the model for breast cancer prognosis. In this paper, a systematic characterization of breast cancer functional units or 'subsystems' is presented. We propose a novel concept of decomposing biological pathways into subsystems by utilizing protein interaction network, pathway information, and RNA-seq data. Subsystem activation score (SAS) was developed to measure the degree of activation for each subsystem and each patient. This method revealed distinctive genome-wide activation patterns or landscape of subsystems that are differentially activated among samples and among breast cancer subtypes. Then, we used SAS information for prognostic modeling by performing the classification and regression tree (CART) analysis. Eleven subgroups of patients, defined by 10 most significant subsystems, were identified with the maximal discrepancy in survival outcome. Our model not only defined patient subgroups with similar survival outcomes, but also provided patient-specific decision paths determined by subsystem activation status, suggesting functionally informative gene sets of breast cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)