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We investigated the efficacy and safety of a trastuzumab biosimilar, Herzuma®, in combination with treatment of physician's choice (TPC) in patients with HER2+ metastatic breast cancer (MBC) who had failed at least two HER2 directed chemotherapies.

Background: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS. Patients and methods: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models. Results: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS

Background To investigate outcomes of salvage whole-brain radiotherapy (WBRT) for recurrent brain metastases (BM) from breast cancer (BC), to identify prognostic factors of overall survival (OS), and to propose a novel prognostic classification for OS in these patients. Materials and methods We identified 54 patients who had received salvage WBRT as the second brain-focused treatment for recurrent BM from BC (2000–2014). The median follow-up duration was 4.9 months. A recursive partitioning analysis (RPA) was conducted to develop a model to predict OS at the time of salvage WBRT. Results The median OS was 6.8 months. OS according to BC-specific graded prognostic assessment (breast-GPA), modified breast-GPA, and updated breast-GPA did not represent our cohort. In the multivariate analysis, a long time before salvage WBRT (≥16 months), control of primary BC or extracranial metastases, systemic treatment after salvage WBRT, and administration of a biologically effective dose for an α/β of 10 Gy (BED10) of salvage WBRT >37.5 Gy showed superior OS. We proposed three RPA classes based on the control of both primary BC and extracranial metastasis and BED10 of salvage WBRT: class I, class II, and class III. In this model, patients with class I experienced the best OS (34.6 months; class II, 5.0 months; class III, 2.4 months; P, Highlights • Multicenter retrospective study of salvage WBRT for recurrent brain metastasis. • Subsequent use of systemic treatment after salvage WBRT showing better OS. • Limitations of previous graded prognostic assessments for recurrent brain metastasis. • Novel RPA classification consisting of four simple clinical factors predicts OS.

Summary Background Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. Methods This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov , NCT03056755 . Findings Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5–15·9). 61 (50·4%; 95% CI 41·2–59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. Interpretation BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Funding Novartis Pharmaceuticals.

Heat elicited during the osteotomy for implant placement may have a significant impact on the vitality of surrounding bone and on the healing capacity for osseointegration. This article describes a digital workflow for creating a coolant channel for the direct irrigation of the osteotomy site through an implant surgical guide. This technique can be particularly advantageous when the surgical guide restricts access for direct irrigation of the osteotomy site.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004.FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks.INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.FUNDING: AstraZeneca.

Background: Evidence has shown that frailty is associated with the risk of falls in older people. However, the components of frailty that have the highest association with fall events are largely unknown. Methods: This study analyzed panel data from the Korean Longitudinal Study of Aging. We used the Korean Frailty Instrument, which includes domains for social isolation, exhaustion and weakness estimated by grip strength, to assess frailty. Fall event data were collected during follow-up visits. Results: A total of 3122 community-dwelling adults aged 65 years or older were included at baseline in 2006 and were followed up every 2 years until 2018. The participants with frailty had a higher risk of falls than those without frailty (OR=1.31, 95% CI=1.11-1.54, P=0.001; fully adjusted model). We found that three components of frailty, namely, social isolation, exhaustion, and weakness, were independently and significantly related to fall events in the unadjusted model. In the fully adjusted model, social isolation and exhaustion were significantly associated with fall events (OR=1.38, 95% CI=1.18-1.61, P < 0.001 and OR=1.28, 95% CI=1.10-1.51, P=0.006, respectively), and there was no significant association between weakness and the risk of falls (OR=1.11, 95% CI=0.91-1.34, P=0.307). Conclusions and implications: Frailty was associated with more fall events in Korean older adults. Social isolation and exhaustion but not weakness were significantly associated with fall events. Our study suggests that interventions should be tailored to older adults with social and psychological frailty.

Purpose To investigate the effect of body mass index (BMI) on survival in patients with breast cancer according to tumor subtype, metabolic syndrome, and systemic treatment. Patients and Methods We identified 5668 patients who underwent curative surgery for breast cancer between 1996 and 2013 from the clinical data of a single institution. Disease-free survival (DFS) and overall survival (OS) were calculated and compared between the patients with BMI ≥ 25 kg/m2 and Results In all patients, BMI ≥ 25 kg/m2 was an unfavorable factor for OS (P = .030) but not for DFS. In the HR+/HER2− subgroup, DFS and OS were longer in patients with BMI Conclusion BMI ≥ 25 kg/m2 was an unfavorable survival factor, particularly in patients with HR+/HER2− breast cancer.

The temporal variations (diurnal and seasonal) of the optical properties and direct aerosol radiative forcing (DARF) of different aerosol components (water-soluble, insoluble, black carbon (BC), and sea-salt) were analyzed using the hourly resolution data (PM2.5) measured at an urban site in Seoul, Korea during 2010, based on a modeling approach. In general, the water-soluble component was predominant over all other components (with a higher concentration) in terms of its impact on the optical properties (except for absorbing BC) and DARF. The annual mean aerosol optical depth (AOD, τ) at 500nm for the water-soluble component was 0.38±0.07 (0.06±0.01 for BC). The forcing at the surface (DARFSFC) and top of the atmosphere (DARFTOA), and in the atmosphere (DARFATM) for most aerosol components (except for BC) during the daytime were highest in spring and lowest in late fall or early winter. The maximum DARFSFC occurred in the morning during most seasons (except for the water-soluble components showing peaks in the afternoon or noon in summer, fall, or winter), while the maximum DARFTOA occurred in the morning during spring and/or winter and in the afternoon during summer and/or fall. The estimated DARFSFC and DARFATM of the water-soluble component were in the range of -49 to -84Wm-2 and +10 to +22Wm-2, respectively. The DARFSFC and DARFATM of BC were -26 to -39Wm-2 and +32 to +51Wm-2, respectively, showing highest in summer and lowest in spring, with morning peaks regardless of the season. This positive DARFATM of BC in this study area accounted for approximately 64% of the total atmospheric aerosol forcing due to strong radiative absorption, thus increasing atmospheric heating by 2.9±1.2Kday-1 (heating rate efficiency of 39K day-1τ-1) and then causing further atmospheric warming.

Somatic mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a decisive factor for the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The stability of mutant EGFR is maintained by various regulators, including heat shock protein 90 (Hsp90). The C terminus of Hsc70-interacting protein (CHIP) is a Hsp70/Hsp90 co-chaperone and exhibits E3 ubiquitin ligase activity. The high-affinity Hsp90-CHIP complex recognizes and selectively regulates their client proteins. CHIP also works with its own E3 ligase activity independently of Hsp70/Hsp90. Here, we investigated the role of CHIP in regulating EGFR in lung adenocarcinoma and also evaluated the specificity of CHIP's effects on mutant EGFR. In HEK 293T cells transfected with either WT EGFR or EGFR mutants, the overexpression of CHIP selectively decreased the expression of certain EGFR mutants (G719S, L747_E749del A750P and L858R) but not WT EGFR. In a pull-down assay, CHIP selectively interacted with EGFR mutants and simultaneously induced their ubiquitination and proteasomal degradation. The expressions of mutant EGFR in PC9 and H1975 were diminished by CHIP, while the expression of WT EGFR in A549 was nearly not affected. In addition, CHIP overexpression inhibited cell proliferation and xenograft's tumor growth of EGFR mutant cell lines, but not WT EGFR cell lines. EGFR mutant specific ubiquitination by CHIP may provide a crucial regulating mechanism for EGFR in lung adenocarcinoma. Our results suggest that CHIP can be novel therapeutic target for overcoming the EGFR TKI resistance.

Purpose The present study was conducted to evaluate the patterns of recurrence and factors related to axillary or supraclavicular recurrence (ASR) and to suggest the probable indications of supraclavicular radiotherapy (SCRT) field modification for breast cancer patients with ≥ 10 axillary lymph node (LN) metastases who had received the current standard systemic management and limited-field SCRT. Materials and Methods We performed a retrospective study of patients with breast cancer with ≥ 10 axillary LN metastases who had received standard surgery with postoperative RT, including limited SCRT (level III and supraclavicular area) and taxane-based adjuvant chemotherapy (except for neoadjuvant chemotherapy), from January 2000 to June 2012. ASR was defined as recurrence to levels I to III of the axillary or supraclavicular area. Results The present study included 301 patients with breast cancer with ≥ 10 axillary LN metastases. The median follow-up period was 59.1 months (range, 7.4-167.9 months). Overall, 32 cases (10.6%) of locoregional recurrence were observed, and 27 patients (9.0%) exhibited ASR. Additionally, 16 patients (5.3%) developed recurrence in levels I or II of the axillary area, which are not included in the SCRT field. ASR-free survival was significantly related to the LN ratio (LNR) in both univariate and multivariate analysis. Conclusion ASR was the most prevalent locoregional recurrence pattern in patients with breast cancer with ≥ 10 axillary LN metastases, and LNR was a significant prognostic factor for the development of ASR. Modification of the SCRT field, including the full axilla, should be considered in patients with a greater LNR.

Background: The phase 1b KEYNOTE-173 study assessed the safety and preliminary antitumour activity of neoadjuvant chemotherapy plus pembrolizumab in locally advanced non-metastatic triple-negative breast cancer (TNBC). Methods: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), followed by 8 cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks and then doxorubicin and cyclophosphamide for additional 12 weeks before surgery. Primary endpoints were safety and recommended phase 2 dose (RP2D); secondary endpoints were pathological complete response (pCR) rate, objective response rate (ORR), event-free and overall survival. Exploratory endpoints included the relationship between outcome and potential biomarkers, such as tumour programmed death ligand 1 (PD-L1) expression (combined positive score [CPS]) and stromal tumour-infiltrating lymphocyte levels (sTILs). Study is registered with ClinicalTrials.gov, NCT02622074. Findings: Sixty patients were enrolled between February 18, 2016 and February 28, 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n=9 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold, whereas 2 cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%), which were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range, 30%–80%). 12-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 CPS, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Interpretation: The combination of neoadjuvant chemotherapy with pembrolizumab for locally advanced TNBC showed manageable toxicity and promising antitumour activity. In an exploratory analysis, pCR rate showed positive correlation with tumour PD-L1 expression and sTIL levels. Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: PS has received grants from AstraZeneca, Roche, Genentech, Oncogenex, Novartis, Astellas and consulting fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, and Puma Biotechnology. His spouse has received consulting fees from Genentech and Roche. RS received research support for the scoring of sTILs presented in this manuscript. YHP has received grants, personal fees and non-financial support from Pfizer, Eisai, and Roche, personal fees and nonfinancial support from Merck, grants and personal fees from Novartis, personal fees from Celgene, and non-financial support from Hanmi. SBK has received grants from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and DongKook Pharm Co and has received consulting fees from Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi-Sankyo. JS has received grants from Merck, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GlaxoSmithKline, CONTESSA, and Daiichi Sankyo. TF has received grants and consulting fees (as institutional payments) from Pfizer, grants from Roche, and royalties for authorship from Wolters Kluwer Health (UpToDate). SK has received personal fees from Roche, Genomic Health, Lilly, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, Merck, Pfizer, Puma Biotechnology, and PFM Medical and non-financial support from Roche and Daiichi Sankyo. RD has received personal fees from AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, Roche, and Seattle Genetics. JC has received grants (as institutional payments) from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck, Pfizer, Piqur Therapeutics, Puma Biotechnology, Queen Mary University of London, and Seagen, consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck, GlaxoSmithKline, and Leuko, and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck, and Daiichi Sankyo. SL has received grants (as institutional payments) from Novartis, Bristol-Myers Squibb, Merck, Roche-Genentech, Puma Biotechnologyand Eli Lilly, has acted as a consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and has received consulting fees (to institution) from Aduro Biotech. EMC has nothing to disclose. LY, AW, KT, and VK are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Ethical Approval: The study protocol was approved by the appropriate institutional review board or independent ethics committee at each participating institution. The study was conducted in accordance with the protocol, good clinical practice guidelines, provisions of the Declaration of Helsinki and all local regulations. All patients provided written informed consent to participate.

Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines The purpose of this phase II study was to compare the clinical antitumor activity and safety of combined therapy with exemestane plus gonadotropin-releasing hormone (GnRH) agonist plus palbociclib with that of capecitabine in premenopausal women with HR-positive, HER2-negative MBC. Methods: This was a prospective, two-arm, randomized, multicenter open-label phase II study. Participants were premenopausal women with breast cancer that had relapsed or progressed during prior tamoxifen. One line of previous chemotherapy for metastatic setting was allowed. Patients were randomized to chemotherapy (capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks) or combination endocrine therapy (exemestane 25 mg/day for 28 days and palbociclib 125 mg/day for 21 days every 4 weeks plus leuprolide). Primary end point was progression-free survival (PFS). Findings: Of 189 patients enrolled between 2015 and 2018 from 14 centers, 184 were randomly assigned to chemotherapy (n=92) or endocrine therapy with palbociclib (n=92). Median age was 44 years (range 28–58). Approximately half the patients (51%) were treatment naive for MBC. During a median 17 months of followup, median PFS was superior for endocrine therapy plus palbociclib than for capecitabine [20·1 vs. 14·4 months, p=0·0469 by log-rank test; hazard ratio 0·659 (95 CI 0·437–0·994)]. Hematological toxicities of ≥ grade 3 were significantly more common with palbociclib than with capecitabine (75·0% vs. 16·3%). Diarrhea (12·0% vs. 38·4%) and hand–foot syndrome (1% vs. 77%) were more common with capecitabine. Interpretation: Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in premenopausal patients with HR-positive, HER2-negative MBC. Trial Registration: The ClinicalTrials.gov identifier number was NCT02592746. Funding Statement: This study was supported by Pfizer (exemestane, palbociclib), Shinpoong (capecitabine), Daewoong Korea and Takeda (leuprolide) for study drugs. This work was partly funded by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) and by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). Declaration of Interests: Dr. PARK reports grants and non-financial support from Pfizer, grants and non-financial support from AstraZeneca, grants and non-financial support from Novartis, grants and non-financial support from Merck, grants from Eisai, grants and non-financial support from Roche, outside the submitted work. Dr. Im reports grants from Pfizer, drug supply from Pfizer, Shinpoong, Daewoong, and Dakeda, during the conduct of the study; grants from AstraZeneca and Pfizer, travel expenses for advisory board participation and advisory role for Novartis, advisory role for Hanmi, Pfizer, Eisai, Amgen, Lilly, MediPacto, Roche, outside the submitted work. Dr. Jung reports personal fees from AstraZeneca Korea, personal fees from Roche Korea, outside the submitted work. Dr. Kim reports grants from Ono Pharma Korea Co., Ltd., outside the submitted work. Dr. Ahn reports personal fees and non-financial support from Astrazeneca, Roche, Beringer Ingelheim, Menarini, Pfizer, BMS, ONO, Boryung, grants from Samyang, outside the submitted work. Dr. Lee reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Eisai, personal fees from Novartis, personal fees from Ono, personal fees from Roche, personal fees from Samsung Bioepis, outside the submitted work. Dr. Kim reports grants from Novarts, grants from Sanofi Genzyme, non-financial support from Dongkook Pharma Co Ltd., outside the submitted work. Dr. Ahn reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer-Ingelheim, personal fees from BMS-Ono, personal fees from MSD, personal fees from Janssen, personal fees from Samsung Bioepis, personal fees from Takeda, outside the submitted work. All other authors declare they have no conflicts of interest. Ethics Approval Statement: The study was conducted in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki, and was approved by the institutional ethics committees of each hospital and the KCSG institutional review board. Written informed consent was obtained from each participant.

Ethnopharmacological relevance The mulberry (Morus alba L.) is a plant that mainly grows in East Asian countries such as Korea and China and has been used as a folk remedy for improving inflammation, cancer, and diabetes. Ramulus mori, the twig of Morus alba L., is known as “sangzhi” or “ppongnamugazhi” in Korea and used as a traditional medicine. Moreover, its effective compounds show some health benefits such as cholesterol reduction and attenuation of acute colitis. Aim of the study As the number of obese people is increasing worldwide, the demand for diet drugs or products to treat obesity is also increasing. In this study, we investigated the antiobesity effect of the ethanolic extract of Ramulus mori (ERM) using differentiated 3T3-L1 adipocytes and a high-fat diet (HFD)-induced obese mouse model. Methods The expression levels of genes and proteins related to adipogenesis, lipogenesis, and lipolysis were analyzed by quantitative real-time PCR (qPCR) and western blot, respectively. Oil red O staining was carried out to determine the amount of neutral lipids deposited in the liver. Results Compared with the ERM-untreated group, the ERM-treated groups exhibited reduced expression levels of genes involved in adipogenesis and lipogenesis in differentiated adipocytes and in HFD-induced obese mice, while the expression levels of genes involved in lipolysis increased. The administration of ERM to HFD-induced obese mice reduced the body weight, liver weight, and epididymal adipose tissue weight. Compared with the untreated HFD-induced obese mice, the ERM-treated mice exhibited decreased serum lipid levels. ERM treatment also reduced lipid accumulation in the liver, which was confirmed by oil red O staining. Conclusion ERM has the potential to be an effective natural material for reducing obesity.

Background The aim of the present study was to investigate clinical outcomes and identify prognostic factors in pathologic N3 (pN3) breast cancer patients who received the current standard management. Patients and Methods We performed a retrospective study with 333 pN3 breast cancer patients who received curative surgery with postoperative radiation therapy and taxane-based adjuvant chemotherapy from January 2000 to June 2012. The median follow-up period was 58.3 months (range, 7.4-167.9 months). All of the 243 patients who were hormone receptor-positive received endocrine therapy, and trastuzumab therapy was used in 63 of 88 (71.6%) HER2-positive patients. Results Overall, 112 disease recurrences (33.6%) were documented during the follow-up. The first site of recurrence was locoregional in 21 patients (6.3%), distant metastases in 72 patients (21.6%), and both in 19 patients (5.7%). The disease-free survival (DFS) and overall survival were 63.3% and 86.9% at 5 years, respectively. DFS was significantly related to age (> 40 years; P = .008; hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.40-0.87), nuclear grade (I or II; P = .02; HR, 0.64; 95% CI, 0.44-0.93), and positive lymph node ratio (≤ 60%; P = .004; HR, 0.56; 95% CI, 0.38-0.83) in multivariate analysis. HER2-positive patients who were treated with trastuzumab showed more favorable DFS than HER2-negative patients. Conclusion More than 60% of the pN3 breast cancer patients treated with the current standard management lived without disease longer than 5 years. Age, nuclear grade, and lymph node ratio were significant prognostic factors in pN3 breast cancer patients.

Background The purpose of this study was to evaluate predictive factors and the clinical characteristics of durable responders to capecitabine monotherapy in heavily-treated patients with metastatic breast cancer (MBC). Patients and Methods Between December 2000 and May 2012, a total of 236 evaluable patients with MBC who had been treated with second- or greater-line palliative capecitabine monotherapy after a previous treatment regimen with anthracycline and taxane were included. Capecitabine (1250 mg/m 2 twice daily) was administered for 2 weeks followed by a 1-week rest period. Results The response rate was 23.3% and median progression-free survival (PFS) was 4.7 months (95% confidence interval, 4.0-5.5). Among 236 patients, 33 patients (14.0%) showed durable response (>12 months) to capecitabine monotherapy. Patients with durable response showed significantly greater incidence of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P = .012), single-organ metastasis (51.5% vs. 32.0%; P = .047), and absence of lymph node metastasis (75.8% vs. 54.2%; P = .023), compared with patients without durable response. In multivariate analysis, ER positivity and single-organ metastasis retained a significant association with better PFS to capecitabine monotherapy (hazard ratio [HR], 0.51; P P = .004). Conclusion Our data suggest that ER positivity and single-organ metastasis can be useful predictive markers for better PFS to second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.

The purpose of our study was to investigate and identify comprehensively the clinicopathological features and long-term outcome of young breast cancer (YBC) according to intrinsic subtype. We analyzed clinical and pathological characteristics of 2844 women who were diagnosed with invasive breast cancer from 2000 to 2007 and the treatment outcomes by age at diagnosis. The median age of the patients was 46 years (range, 21–83 years), and we divided them into three age group: ≤35 years (Group 1), 36–50 years (Group 2), and >50 years (Group 3). During a median follow-up of 100 months, the 5-year recurrence-free survival rate (RFSR) and overall survival rate (OSR) were 90.8% and 94.6%, respectively. The 10-year estimated RFSR and OSR were 81.9% and 86.9%, respectively. The prognosis of TN subtype appeared not to be worse than that of other subtypes in Group 1. In Group 1 alone (≤35 years), subtype was not identified as an independent risk factor for distant recurrence-free survival (DRFS) in a Cox-regression multivariate model (hazard ratio, 0.85; 95% CI, 0.68–1.06; p = 0.148). This analysis revealed a very high prevalence of YBC in this cohort. The poor outcomes of YBC patients might result from an increased frequency of triple negative (TN)/HER2 subtypes and the more aggressive clinical behavior of ER-positive tumors compared with older patients. Further research to elucidate the biologic difference of the ER+ tumors of YBC patients is warranted.

Background Skeletal-related events (SREs) cause significant pain and morbidity to many non-small cell lung cancer (NSCLC) patients. We try to evaluate the predictive factor of SREs in NSCLC patients with bone metastases. Patients and methods We retrospectively examined the medical charts of 273 patients diagnosed with bone metastases secondary to NSCLC. The predictive factor of SREs was analyzed using the first-event analyses and a survival-adjusted multiple-event analysis. Results Out of 273 patients with bone metastases, 171 (62.6%) had at least one SRE and 46 of these experienced multiple SREs. In the first-event analyses, a larger proportion of ever-smokers have experienced the SRE compared with never-smokers (odds ratio, 2.80; 95% CI, 1.32–6.00). In addition, ever-smokers (hazard ratio [HR], 1.75; 95% CI, 1.05–2.92), patients without history of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) therapy (HR, 2.12; 95% CI, 1.49–3.00) and patients with histology of nonadenocarcinoma (HR, 1.59; 95% CI, 1.14–2.22) had a shorter median time from bone metastasis to first SRE. In a survival-adjusted multiple-event analysis, clinical characteristics such as ever-smoking, nonadenocarcinoma, poor performance status (ECOG ≥ 2), and no history of EGFR TKI therapy were independent risk factor of development of SRE throughout the course of disease. Conclusion Our data indicate that patients with characteristics such as ever-smoking, nonadenocarcinoma, poor performance status, and no history of treatment with EGFR TKI are more likely to have SRE, so more vigilant surveillance and prevention should be considered to these patients.

Background Pemetrexed is one of the standard second-line therapies in advanced non-small cell lung cancer (NSCLC). Currently, there are no standard cytotoxic treatments beyond second-line therapy. We evaluated the efficacy and safety of pemetrexed as a salvage regimen in heavily pretreated NSCLC patients. We also analyzed thymidylate synthase (TS) expression in tumor tissues to determine whether TS expression is correlated with the clinical efficacy of pemetrexed. Methods One hundred and ten NSCLC patients who received pemetrexed as third- or fourth-line therapy at the Samsung Medical Center between June 2006 and June 2008 were retrospectively reviewed. TS expression was analyzed by immunohistochemical staining in 55 NSCLC tissue specimens. The relationships between TS expression and clinicopathological factors were evaluated. Univariate and multivariate analyses were performed to define the predictive factors and prognostic significances. Results The median age of patients in this study was 59 years (range: 24–84), 50.9% were men, and 27 (24.6%) were smokers or previous smokers. Sixty-five patients (59.1%) received pemetrexed as third-line treatment, and 95 (86.4%) had non-squamous cell carcinoma. Platinum-based chemotherapy (84.6%) was the most common first-line therapy, and EGFR TKIs [erlotinib (17.3%) or gefitinib (43.6%)] were a common second-line therapy. The median time from date of diagnosis to the date of the first pemetrexed treatment was 12.8 months (range: 1.8–62.2 months) and the median number of pemetrexed treatments was 4 (range 1–22). Eighteen patients achieved PR (16.3%), 41 patients SD (37.3%), and 43 patients PD (39.1%), with a disease control rate of 53.6%. The median follow-up duration was 16.1 months, the median progression-free survival (PFS) was 3.2 months (95% CI: 1.9–4.5 months), and the median overall survival (OS) was 11.6 months (95% CI: 9.0–14.1 months). Male gender was the only independent variable for poor PFS (HR = 1.673, 95% CI: 1.103–2.535), with poor performance status (HR = 2.454, 95% CI: 1.405–4.287) and history of smoking (HR = 1.856, 95% CI: 1.087–3.168) being independent adverse factors for OS. Thirteen of 55 tumor tissues (23.6%) showed TS expression; however, there were no significant correlations between TS expression and the clinicopathological factors. Conclusion Pemetrexed was suggested as a third- or fourth-line therapy due to its favorable efficacy and tolerable toxicity. Further studies are warranted to define the adequate sequence of salvage treatments, especially in patients with adenocarcinoma lung cancer.

Background Many pulmonary emboli (PE) are detected unsuspectedly in lung cancer patients. The purpose of our study was to retrospectively evaluate the role of anticoagulation therapy for unsuspected PE in lung cancer patients. We also aimed to evaluate risk factors associated with the development of PE as well as the prognostic power of PE in lung cancer patients. Patients and methods The Samsung Medical Information System was used to evaluate predictors and prognosis of PE in lung cancer patients. We found patients with PE using the Radiation Interpretation Registry and reviewed their medical records. Results Among 8014 lung cancer patients, PE developed in 180 patients (cumulative incidence rates = 2.2%). Metastasis and prior history of chemotherapy were significant predictors of the development of PE. Pulmonary embolism detected within 3 months after diagnosis of lung cancer was a significant poor prognostic factor (hazard ratio [HR], 1.5; 95% CI, 1.1–2.0) in the complete lung cancer cohort. One hundred thirteen (63%) out of total 180 PE patients were incidentally found to have PE. Among the 113 patients with unsuspected PE, 62 patients (55%) did not receive anticoagulation therapy, and died sooner than those who received anticoagulation therapy for unsuspected PE (HR, 4.1; 95% CI, 2.3–7.6). Conclusion Anticoagulation therapy for unsuspected PE is associated with increased overall survival in lung cancer patients.

Background The Response Evaluation Criteria in Solid Tumors (RECIST) has been revised (RECIST 1.1) since initial publication of RECIST 1.0 in 2000. Major changes in RECIST 1.1 involve lymph node measurement, the maximum number of target lesions, and the definition of disease progression (PD). The purpose of this study was to evaluate the accuracy of RECIST 1.1 for non-small cell lung cancer (NSCLC) patients being treated with epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). Patients and methods We compared responses of 104 NSCLC patients treated with TKIs from eight prospective studies using RECIST 1.0 and 1.1. Results The short axis measurement for lymph nodes was the most influential change in RECIST 1.1 for the evaluation of response. Overall response rates (ORRs) using RECIST 1.0 and 1.1 were 35.6% and 38.5%, respectively. Under RECIST 1.1, six best responses were reclassified: two partial responses (PR) were re-categorized as complete responses, three cases of stable disease (SD) were reclassified as PR, and one case of SD was reclassified as PD. The progression-free survivals of three patients were extended. RECIST 1.1 showed a slightly increased ORR compared with RECIST 1.0. Conclusion RECIST 1.1 may reflect tumor burden more accurately than RECIST 1.0 in NSCLC patients treated with TKIs.

Objective This prospective multicenter study conducted by the Korean Cancer Study Group evaluated the efficacy and safety of pemetrexed in Korean patients with advanced non-small cell lung cancer (NSCLC) who had prior chemotherapy. Patients and methods: Patients with stage IIIB or IV NSCLC in whom prior chemotherapy failed received pemetrexed 500mg/m 2 every 3 weeks with folic acid and vitamin B12 supplementation until disease progression or the development of intolerable toxicity. Eighty-one patients were enrolled. Results The overall response rate for 78 evaluable patients was 5.1% [95% confidence interval (CI) 1.4–12.6; partial response 4/78, no complete response]. The disease control rate including complete, partial response and stable disease was 46.2% (36/78, 95% CI 34.8–57.8). With a median 8.7 months follow-up, the median time to progression was 3.1 months (95% CI 1.17–5.03) and the median overall survival (OS) was 7.8 months (95% CI 5.19–10.35). The median OS for patients with adenocarcinoma histology was 18.7 months compared to 6.1 months for non-adenocarcinoma. In a multivariate analysis, Eastern Cooperative Oncology Group performance status 0–1 [hazards ratio (HR)=0.331, 95% CI 0.135–0.814] and adenocarcinoma (HR=0.504, 95% CI 0.283–0.899) were independent factors for prolongation of overall survival.Conclusions Pemetrexed monotherapy has promising efficacy in patients with advanced NSCLC as a second-line therapy with less hematologic and non-hematologic toxicity, especially in those with adenocarcinoma histology.

Purpose: The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell Lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL. Patients and method: From 1990 to 2005, 205 patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression free survival (PFS) and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI. Results: According to our multivariate analysis of PFS and OS of MZL, nodal MZL, ECOG performance ≥ 2 and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low risk group, score 1 as an intermediate risk group, and score ≥2 as a high risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI (P=0.0007) evidenced a more discriminated pattern than IPI (P=NS) or FLIPI (P=0.0044). Conclusion: MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI.

Purpose The aim of this study is to define distinctive clinicopathologic features of malignant lymphoma in pediatric and young adult patients, particularly in Korea. Patients and Methods From May 1993 to November 2005, 294 pediatric and young adult patients (age range, 0-31 years) with malignant lymphoma were analyzed in this study at Samsung Medical Center. We also compared this group with the Korean all-ages group and Western younger age group using previously reported data. Results Hodgkin disease appears more common in the younger age group than in the all-ages group (15% vs. 5.3%; P = .001). Among patients with non-Hodgkin lymphoma (NHL), T/natural killer cell immunophenotype is more common in the present younger age group than the all-ages group (45.5% vs. 25%; P = .001) and Western younger age group (45.5% vs. 13.3%; P = .001). Lymphoblastic lymphoma and T-anaplastic large-cell lymphoma included relatively higher proportions in the younger age group. Overall survival for patients in the group aged 21-31 years was significantly inferior to that of the other younger age group ( P = .014). Conclusion The incidence of Hodgkin disease and T-cell NHL is relatively higher in pediatric and young-adult population group than the all-ages group. However, treatment outcome of the younger age group, excluding lymphoblastic lymphoma, seems to be similar to those in any age group.

We conducted a retrospective analysis to evaluate the Musshoff staging system for high-grade primary gastric lymphoma (HG-PGL), particularly in those patients with stages IE and IIE localized diseases. One hundred twenty-six patients presented with stage IE or IIE diseases were retrospectively reclassified on the basis of a pretreatment CT examination as to whether there was lymph node involvement. A positive M1 node (by AJCC staging system) on pretreatment CT scanning was associated with poor clinical outcome for localized stage I or II patients.

The purpose of this study was to define distinctive clinical features of “nasal” and “nasal-type” NK/T cell lymphomas by assessing prognostic factors. The anatomic definition of extranasal NK/T cell lymphoma has been vague resulting in variable definitions of extranasal sites by different groups. We analysed the clinical behavior of 90 NK/T cell lymphoma patients and attempted to elucidate the prognostic factors for risk-based stratification of therapy. We observed no significant difference between “nasal” and “nasal-type” NK/T cell lymphomas in regards to clinical features and survival using the conventional anatomic classification. We suggest the categorisation of the two subtypes of NK/T cell lymphoma as follows: UNKTL (upper aerodigestive tract NK/T cell lymphoma) including all lymphomas confined to nasal cavity, nasopharynx, and the upper aerodigestive tract and EUNKTL (extra-upper aerodigestive tract NK/T cell lymphoma) group to include all sites other than the UNKTL group. The EUNKTL group in this study had advanced stage at diagnosis, higher LDH, higher IPI score, poorer performance and inferior response to the anthracycline-based chemotherapy with statistical significance. There was a significant difference in survival rate between EUNKTL and UNKTL group (20.0%, 54.0%, respectively, P = 0.0068). More aggressive treatment should be sought for this particular group of patients for EUNKTL patients.

Low incidence of cancer in schizophrenia is one of the interesting puzzles in psychiatric field over decades. Analysis of genetic difference between schizophrenia and lung cancer might provide us with possible clues to understand molecular mechanisms of pathophysiology of schizophrenia. Epidermal growth factor (EGF), one of the potent growth promoting factors, has been studied for its roles in cancer development. EGF is also known to be involved in cognitive function. In order to analyze the genetic difference between schizophrenia and lung cancer, polymorphism of EGF gene was studied from 174 schizophrenia patients, 122 lung cancer patients and 132 controls in Korean population. Genotype frequency analysis of EGF gene (AluI restriction site, 5'-UTR, rs4444903) in the EGF gene was studied. The genotype and allele frequencies of the AluI polymorphism showed significant differences between schizophrenia and lung cancer patients [p0.0001; p0.0001, odds ratio (95% CI), 0.3690 (0.2600-0.5236)]. When compared with controls, schizophrenia patients showed no significant differences from controls in genotype and allele frequencies [p=0.5151; p=0.3516, odds ratio (95% CI), 0.8589 (0.6235-1.1830)]. However, lung cancer patients showed significant differences from controls in genotype and allele frequencies [p0.0001; p0.0001, odds ratio (95% CI), 2.3275 (1.6082-3.3687)]. These results indicate that schizophrenia is not associated with AluI polymorphism of EGF gene and EGF gene polymorphism is different between schizophrenia and lung cancer patients.

The therapeutic goals are palliative for metastatic breast cancer (MBC) and include prolongation of survival with good quality of life (QoL) and symptom control. The purpose of this study was to examine QoL among women with MBC treated on KCSG-BR07-02 with maintenance of paclitaxel plus gemcitabine (PG) chemotherapy after achieving disease control to initial six cycles of PG chemotherapy or observation. Patients were randomized to either maintenance chemotherapy or observation until progression. QoL was assessed using EORTC QLQ-C30 and BR-23. QoL at each cycle was compared between the two treatment arms using the 2-sample t test. Generalized estimating equation method was used to examine the overall difference between the two treatments in QoL. All reported p-values are 2 sided. There were no statistically significant differences between two arms in most of the component of the EORTC QLQ-C30 and BR-23 (p > 0.05). There was no significant difference between two treatments (p = 0.6094 for QLQ-C30, p = 0.5516 for BR23) at baseline, and there did not exist significant change over the cycle (p = 0.0914 for QLQ-C30, p = 0.7981 for BR23). There was no significant interaction effect between treatment and cycle (p = 0.5543 for QLQ-C30. p = 0.5817 for BR23). Maintenance PG chemotherapy in patients with MBC achieving disease control with an initial six cycles of PG chemotherapy resulted in better PFS and OS compared to observation without impeding QoL.

Goals: Our goal was to compare the compression thickness, compression force, mean glandular dose and discomfort between 2D mammograms and DBT. The last goal was to compare the number of indeterminate mammographic results. Methods: All our initial symptomatic patients and follow-up patients having previously undergone breast surgery underwent DBT after its implementation in August 2010. An equal number of patients were selected from the DBT and 2D group. The factors looked at included compression thickness, compression force in newtons and mean glandular dose (MGD). These were calculated by the machine. A questionnaire was made for all the patients concerning the pain comparison between the two modalities from a 1 to 10 level. All mammographic reporting was performed by one radiologist and recorded. Results: 265 patients underwent DBT in our breast unit. 266 patients previously undergoing 2D mammograms were part of the comparison group. In the 2D group, 25 were less than 40 years of age; 69 were between 40 and 50; and 172 were more than 50 years. As for DBT, 36 were less than 40 years; 76 were between 40 and 50; and 153 were more than 50 years. The compression thickness was 60.7±0.8 in the DBT group. It was 55.3±0.8 in the 2D one. The compression force was 91.2±2.7 in the DBT and 111.0±2.8 in the 2D. The mean glandular dose (MGD) per image was 2.65±0.06 in DBT and 1.93±0.03 in 2D. Concerning the MGD per exam, it was 5.20±0.21 for DBT and 3.86±0.12 in 2D. Patients had significantly less discomfort with the DBT. There were only 3 patients with indeterminate (M3) results in the DBT group versus 21 in the 2D group. Conclusion: The mean glandular dose (MGD) was similar for small breasts, but the DBT mode had significantly higher doses for medium and large breasts. This was by a factor of 1.7. The indeterminate mammographic results were significantly lesser in number compared to the 2D group. The overall increased radiation dose has been found to be safe for the patients. With the added benefit of improvement in the image quality, our initial experience with DBT has been good. Disclosure of Interest: None Declared