Associations between missing teeth and the risk of cancer in Korea: a nationwide cohort study.

BACKGROUND: Poor dental health is correlated with an increased risk of cancer. Using a nationwide population cohort database, we investigated which cancer is highly associated with poor dental health and which dental indicator mostly influences cancer risk. METHODS: This study was conducted using the National Health Checkups (NHC) and National Health Insurance System (NHIS) database in Korea. NHC in Korea includes dental examinations. We retrieved subjects who underwent NHC between 2002 and 2003 and their medical information in NHIS database was followed until December 31,2015. RESULTS: Data for 200,170 who participated in the NHC between 2002 and 2003 were analysed. During the maximum follow-up period of 13 years, 15,506 (7.75%) subjects were diagnosed with cancer. The median time to cancer diagnosis after the dental examination was 87 months (range, 51-119 months). The proportion of people with missing teeth was higher in the cancer-diagnosed group than in the non-diagnosed group (26.27% vs. 22.59%, p < 0.001). Among several dental health factors, missing teeth were significantly associated with higher cancer risk. Subjects with missing teeth showed a 12% increased cancer risk compared to those without missing teeth (odds ratio [OR] 1.12, 95% confidence interval [CI], 1.08-1.16). The risk was significantly higher, especially in lung, head and neck, pancreatic, liver, biliary, and esophageal cancers (OR 1.27 [95% CI, 1.14-1.41], 1.32 [95% CI, 1.13-1.55], 1.27 [95% CI, 1.02-1.58], 1.24 [95% CI, 1.1-1.4], 1.28 [95% CI, 1.03-1.6], 1.4 [95% CI, 1.04-1.88], respectively). CONCLUSIONS: Missing teeth were the most important dental indicator associated with cancer risk. Korean adults with missing teeth should be cautious about the risk of several cancers, particularly head and neck, lung, gastrointestinal, hepatobiliary, and pancreatic cancer.

Final results of the randomized phase 2 LEO trial and bone protective effects of everolimus for premenopausal hormone receptor-positive, HER2-negative metastatic breast cancer.

The phase 2 LEO study showed that everolimus (EVE) plus letrozole (LET) with ovarian suppression increased progression-free survival (PFS) in tamoxifen-exposed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer with visceral metastases. Here we report final survival outcomes from the LEO study, and the results of exploratory analyses of bone turnover marker changes and bone-specific progressive disease. Patients who were exposed to or progressed on tamoxifen as adjuvant/palliative treatments were randomly assigned (2:1) to the EVE (leuprorelin + LET + EVE, n = 92) or LET (leuprorelin + LET, n = 45) arm. In a median 51-months of follow-up, the median PFS was 17.5 and 13.8 months in the EVE and LET arms, respectively (P = .245). Patients in the EVE arm with baseline visceral (median PFS 16.4 vs 9.5 months, P = .040) and bone (median PFS 17.1 vs 10.9, P = .003) metastases had greater PFS compared to the LET arm. No differences in overall survival (OS) were observed (median OS, 48.3 vs 50.8 months, P = .948). The 1-year cumulative incidences of bone-specific disease progression were 6.0% and 23.4% in the EVE and LET arms, respectively (hazard ratio 0.26, P < .001). Bone turnover markers at 6 and 12 weeks after treatment decreased in the EVE arm but were increased or stationary in the LET arm. Skeletal-related events occurred in 6.5% and 11.1% of patients in the EVE and LET arms, respectively. EVE + LET with ovarian suppression prolonged PFS in patients with baseline visceral or bone metastases and offered bone-protective effects in the overall study population. However, these clinical benefits did not translate into an OS benefit.

Prognostic effects of cytokine levels on patients treated with taxane and zoledronic acid for metastatic breast cancer in bone (BEAT-ZO) (KCSG BR 10-13).

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-ß1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-ß1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-ß1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-ß1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

Genome-wide association study of genetic variants related to anthracycline-induced cardiotoxicity in early breast cancer.

We performed a genome-wide association study to investigate the association between single nucleotide polymorphisms and anthracycline-induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m2 -300 mg/m2 ) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty-seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23-4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11-5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E-06), rs11894115 (MPP4, P = 4.71E-06), rs58328254 (RPL7, P = 6.09E-06), and rs117299725 (PRUNE2, P = 8.53E-06), although none of these variants reached the Bonferroni-corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E-07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.

Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer.

BACKGROUND: MONARCH 3, a phase III trial (NCT02246621) of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), previously demonstrated significantly improved progression-free survival in patients receiving abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI). This study evaluated patient-reported outcomes, including global health-related quality of life (HRQoL), functioning, and symptoms. METHODS: Patients were randomly assigned 2:1 to receive abemaciclib (150 mg twice daily; n = 328) or placebo (n = 165), plus 1 mg anastrozole or 2.5 mg letrozole daily. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Breast Cancer-Specific Quality of Life Questionnaire HRQoL instruments were administered at baseline, every two cycles during cycles 2 through 19 (each cycle being 28 days), every three cycles thereafter, and once at a short-term posttherapy follow-up visit (approximately 30 days after discontinuation). Longitudinal mixed regression and Cox proportional hazards models evaluated postbaseline change and time to sustained deterioration (TTSD), respectively. RESULTS: Baseline scores were similar between treatment arms. Although select scores statistically favored the placebo arm, global HRQoL, most symptoms, and functioning scales did not meet the threshold for clinically meaningful differences between treatment arms. Only diarrhea favored the placebo arm with statistically and clinically meaningful differences. There were no TTSD differences between treatment arms for global HRQoL, most symptoms (except diarrhea), or functioning. CONCLUSION: Over a 2-year period, there were no clinically meaningful differences in global HRQoL, functioning, and most symptoms for patients receiving abemaciclib plus NSAI compared with NSAI alone. Only diarrhea favored the placebo arm, consistent with prior safety data, which has been shown to be manageable and reversible. Combined with clinical efficacy, results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2- ABC. IMPLICATIONS FOR PRACTICE: The addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) was not associated with a clinically meaningful detriment in patient-reported global health-related quality of life, functioning, and most symptoms in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Prior studies have also demonstrated clinical efficacy of abemaciclib plus NSAI compared with NSAI alone, including improved progression-free survival and objective response rate. These results also complement previously reported toxicity data, as measured by investigator-assessed adverse events. Taken together, these results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2- ABC.

Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients.

PURPOSE: Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. METHODS: We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. RESULTS: Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [adjusted hazard ratio (aHR) = 1.02, 95% confidence interval (CI) 1.00-1.04; p = 0.05], metastasis (aHR = 2.66; 95% CI 1.36-5.20; p < 0.01), and concomitant trastuzumab (aHR = 4.08; 95% CI 2.31-7.21; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. CONCLUSIONS: Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.

Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. METHODS: This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival. FINDINGS: Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9-22), median progression-free survival was 20·1 months (95% CI 14·2-21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1-17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen. FUNDING: Pfizer, Shinpoong, and Daewoong Korea and Takeda.

Integrative molecular profiling identifies a novel cluster of estrogen receptor-positive breast cancer in very young women.

Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER)-positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. TP53, PIK3CA and GATA3 were highly recurrent somatic mutation genes. APOBEC-associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A-like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin-mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial-mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.

Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2 + metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16).

BACKGROUND: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. METHODS: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. RESULTS: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable. CONCLUSIONS: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01730677.

The Sentinel Lymph Node Biopsy Using Indocyanine Green Fluorescence Plus Radioisotope Method Compared With the Radioisotope-Only Method for Breast Cancer Patients After Neoadjuvant Chemotherapy: A Prospective, Randomized, Open-Label, Single-Center Phase 2 Trial.

BACKGROUND: This study aimed to compare the sentinel lymph node (SLN) identification rates for breast cancer patients after neoadjuvant chemotherapy (NAC) between the dual method (DM) of indocyanine green fluorescence (ICG-F) plus a radioisotope (RI) and RI alone. METHODS: This randomized study enrolled 130 patients who received NAC for breast cancer and 122 patients who received SLN biopsy (SLNB) using either DM (n = 58) or RI only (n = 64). The study compared the identification rate, number of SLNs, and detection time of SLNB. RESULTS: Among the 122 patients, 113 (92.6%) were clinically node-positive before NAC. The SLN identification rate was 98.3% in the DM group and 93.8% in the RI group (p = 0.14). The DM group and the RI group were similar in the average number of SLNs (2.2 ± 1.13 vs. 1.9 ± 1.33; p = 0.26) and the time to detection of the first SLN (8.7 ± 4.98 vs. 8.3 ± 4.31 min; p = 0.30). In the DM group, transcutaneous lymphatic drainage was visualized by fluorescence imaging for 65.5% (38 of 58) of the patients. The SLN identification rate was 94.7% using ICG-F and 93% using RI (p = 0.79). During and after the operation, no complications, including allergic reactions or skin necrosis, occurred. CONCLUSIONS: This study is the first randomized trial to use ICG-F for SLNB in breast cancer patients after NAC. The DM including ICG-F could be a feasible and safe method for SLNB in initially node-positive breast cancer patients with NAC.

A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial.

Although the introduction of human epidermal growth factor receptor (HER)2-directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2-positive mBC will eventually progress. Poziotinib is an oral pan-HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who had progressed from more than two HER2-directed therapies. Patients received 12 mg poziotinib once daily on a 14-day on/7-day off schedule. Progression-free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30-76) and had received a median of four prior therapies including two HER2-directed therapies for advanced or metastatic cancers. The median follow-up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94-4.40 months), and median overall survival has not been reached. The most common treatment-related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2-positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.

Prognostic impact of skeletal muscle volume derived from cross-sectional computed tomography images in breast cancer.

PURPOSE: This study aimed to determine whether the prognosis of breast cancer is affected by muscle or fat volume as measured from computed tomography (CT) images. METHODS: We identified 1460 patients with chest CT who were diagnosed as having breast cancer at the National Cancer Center, Korea, between January 2001 and December 2009. Using CT images of 10-mm slices, we measured the cross-sectional areas of skeletal muscle and adipose tissue at the 3rd lumbar vertebrae, and derived their volumes. The skeletal muscle volume, fat volume, and muscle-to-fat ratio were evaluated for association with overall survival (OS) and recurrence-free survival (RFS). RESULTS: The median skeletal muscle and fat volumes among the patients were 93.3 cc (range 39.6-236.9) and 420.1 cc (range 19.5-1392.3), respectively. Patients with higher muscle volume had better prognosis than those with lower muscle volume [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.34-0.92, P = 0.022 for OS; HR 0.72, 95% CI 0.52-0.99, P = 0.046 for RFS]. However, body mass index (BMI) and fat volume were not associated with prognosis. In addition, muscle volume was a significant prognosticator for OS, regardless of BMI (HR 0.55, 95% CI 0.32-0.93, P = 0.034 in BMI < 25.0; HR 0.44, 95% CI 0.21-0.91, P = 0.026 in BMI ≥ 25.0). Among older patients (≥ 50), those with higher muscle volume showed better OS and RFS (HR 0.44, 95% CI 0.23-0.85, P = 0.015; HR 0.55, 95% CI 0.34-0.90, P = 0.017, respectively). CONCLUSION: This study demonstrated that breast cancer patients with higher skeletal muscle volume showed more favorable prognosis.

Use of adjuvant chemotherapy in hormone receptor-positive breast cancer patients with or without the 21-gene expression assay.

PURPOSE: We assessed the use of chemotherapy in breast cancer patients to investigate the factors that changed trends in chemotherapy following the adoption of the 21-gene expression assay in tumor genomic profiling. METHODS: Our study used 2033 patients from the National Cancer Center in Korea diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (tumor size of 0.5 cm or larger and 0-3 node metastases) from 2010 to 2015. We analyzed use of the 21-gene expression assay, changes in frequency of adjuvant chemotherapy use, and clinicopathological factors related to adjuvant chemotherapy to assess the impact of the 21-gene expression assay. RESULTS: Adjuvant chemotherapy use declined from 33.33% (2011) to 13.59% (2015) [relative risk (RR), 0.71; 95% CI 0.56-0.89; ptrend = 0.004] in patients with 21-gene expression assay data. Among patients without assay data, adjuvant chemotherapy use decreased from 76.79 to 40.17% between 2010 and 2015 (RR 0.87; 95% CI 0.84-0.91; ptrend < 0.001), especially for patients with node-negative/micrometastasis (RR 0.85; 95% CI 0.81-0.89; ptrend < 0.001). The frequency of adjuvant chemotherapy was significantly decreased after introduction of the 21-gene expression assay (p < 0.001). Tumor size (p < 0.001), progesterone receptor (PgR) status (p = 0.001), and proliferation index (Ki-67) levels (p < 0.001) were important factors for chemotherapy decision-making in node-negative/micrometastasis patients who did not undergo the assay. CONCLUSIONS: For HR-positive, HER2-negative breast cancer patients with 0-1 node metastases, chemotherapy use declined significantly after the adoption of the 21-gene assay. PgR status and Ki-67 were useful for chemotherapy decision-making in cases without the 21-gene assay.

Incidence and Predictors of Febrile Neutropenia among Early-Stage Breast Cancer Patients Receiving Anthracycline-Based Chemotherapy in Korea.

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

A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy-induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09.

PURPOSE: Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G-CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim. METHODS: In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1. RESULTS: The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 ± 1.79 days vs. 1.54 ± 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non-inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 ± 1.18 days vs. 1.80 ± 1.05 days; difference, -0.15 ± 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (≥2000/µL) was significantly shorter than that of pegfilgrastim (8.85 ± 1.45 days vs. 9.83 ± 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly. CONCLUSIONS: Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression.

Quality of life (QoL) in metastatic breast cancer patients with maintenance paclitaxel plus gemcitabine (PG) chemotherapy: results from phase III, multicenter, randomized trial of maintenance chemotherapy versus observation (KCSG-BR07-02).

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.

Treatment factors affecting breast cancer-related lymphedema after systemic chemotherapy and radiotherapy in stage II/III breast cancer patients.

We evaluated whether the sequence or regimen of systemic chemotherapy could be a risk factor for breast cancer-related lymphedema (LE). We retrospectively analyzed 848 patients with stage II/III breast cancer who underwent curative surgery with adequate systemic therapy from 2004 to 2009. Adjuvant chemotherapy (ACT) was performed in 552 patients (65.1 %) and neoadjuvant chemotherapy (NAC) in 296 (34.9 %). We evaluated the incidence of LE based on clinicopathological factors and treatments. At a median follow-up of 5.1 years, 358 patients (42.2 %) had experienced LE and 243 (28.7 %) had retained (persistent LE) [120/552 (21.7 %) with ACT vs. 123/296 (41.6 %) with NAC; P < 0.001]. The incidence of LE in patients with taxane was greater than in those without taxane [233/704 (33.1 %) vs. 10/144 (6.9 %); P < 0.001]. Multivariate analysis showed that NAC [hazard ratio (HR), 1.63 in LE event; P < 0.001; HR, 1.39 in persistent LE; P = 0.02] and RT including supraclavicular area (SCRT) (HR 1.55; P = 0.02; HR 1.93; P = 0.006), number of dissected axillary lymph nodes (N-ALNs) >10 (HR, 1.37; P = 0.01; HR, 1.71; P = 0.001), advanced stage (HR, 1.31; P = 0.03; HR, 1.60; P = 0.002), and taxane (HR, 1.69; P = 0.03; HR, 2.07; P = 0.04) were independent risk factors for the LE occurrence. In addition to advanced stage, N-ALNs and SCRT, NAC, and taxane were shown to increase the risk of LE, which could help clinicians identify patients at risk for LE.

High volumetric breast density predicts risk for breast cancer in postmenopausal, but not premenopausal, Korean Women.

PURPOSE: We investigated the association between mammographic breast density and breast cancer risk in Korean women according to menopausal status and breast cancer subtypes. METHODS: We enrolled 677 patients diagnosed with breast cancer and 1,307 healthy controls who participated in screening mammography at the National Cancer Center. Breast density was estimated using volumetric breast composition measurement. RESULTS: Of the total population, 1,156 (58.3 %) women were postmenopausal. The risk of breast cancer increased progressively with the increment of volumetric density grade (VDG) in postmenopausal women (p < 0.001). High breast density (VDG 4) was significantly associated with breast cancer compared with low breast density (VDG 1/2) regardless of body mass index. However, the association with parity and history of hormone replacement therapy (HRT) was only found in those with ≥2 children and those not receiving HRT. Breast density was positively associated with breast cancer risk regardless of histologic grade, tumor size, lymph node involvement, Ki67 index, and hormone receptor status. The association was more prominent in human epidermal growth factor receptor 2 (HER2)-positive tumors (VDG 1/2 vs. VDG 4 for HER2 normal, odds ratio [OR] 2.21, 95 % confidence interval [CI] 1.28-3.83, p < 0.001; for HER2 positive, OR 8.63, 95 % CI 3.26-22.83, p = 0.001; P heterogeneity = 0.030). However, no significant association was found between breast density and breast cancer risk in premenopausal women except for those with large-sized tumors (>2 cm) and a Ki67 index >15 %. CONCLUSION: High volumetric breast density is significantly associated with the risk of breast cancer in postmenopausal women; however, these relationships were not found in premenopausal women.

Comparison of sentinel lymph node biopsy guided by the multimodal method of indocyanine green fluorescence, radioisotope, and blue dye versus the radioisotope method in breast cancer: a randomized controlled trial.

PURPOSE: This study aimed to evaluate the identification rate and surgery time of sentinel lymph node biopsy (SLNB) by a multimodal method (MMM) using a mixture of indocyanine green (ICG), radioisotope (RI), and blue dye (BD) compared with the RI alone. METHODS: In this phase II randomized study, 86 patients with clinically node-negative breast cancer were enrolled and received SLNB with either MMM or RI. We compared the identification rate, number of sentinel lymph nodes (SLNs), and detection time of SLNB and evaluated the safety. RESULTS: The mean age of the MMM group and RI group was 48.2 and 51.0 years (p = 0.12), respectively. There were no differences in histopathologic factors, including tumor size, node positivity, and hormone receptor positivity between groups. SLNs were identified in all patients of both groups (100 % in the MMM group and 100 % in the RI group). The average number of SLNs in the MMM group was more than that in the RI group (3.4 ± 1.37 vs. 2.3 ± 1.04, respectively; p < 0.001). The time to detect the first sentinel lymph node was similar in each group (6.5 ± 5.16 vs. 8.0 ± 4.35 min; p = 0.13). In the MMM group, percutaneous lymphatic drainage was visualized by fluorescent imaging in 90.7 % (39 of 43 patients). During and after the operation, there were no complications, including allergic reactions, skin staining, or necrosis. CONCLUSIONS: This study is the first randomized trial that compared MMM using ICG, RI, and BD and the conventional RI method for SLNB. MMM is a feasible and safe method for SLNB.

Identification and clinical implications of circulating microRNAs for estrogen receptor-positive breast cancer.

Cancer-associated microRNAs have been stably detected in blood. The objective of this study was to identify a panel of circulating microRNAs with the potential to serve as biomarkers for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2)- breast cancer. We used microarray-based expression profiling to compare the levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients plus 5 age-matched controls. MicroRNA levels were validated by reverse transcription quantitative polymerase chain reaction in 40 control subjects, 187 early breast cancer patients, and 45 metastatic breast cancer patients. Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2- metastatic breast cancer. Initially, we found that miR-1280, miR-1260, and miR-720 were up-regulated in blood from breast cancer patients (P < 0.05). In validation, miR-1280 levels significantly increased in breast cancer patients and reflected tumor status (control<