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The aim of this study was to investigate candidate genes that might function as biomarkers to differentiate triple negative breast cancers (TNBCs) among patients, who received adjuvant chemotherapy after curative surgery. We tested whether the results of a NanoString expression assay that targeted 250 prospectively selected genes and used mRNA extracted from formalin-fixed, paraffin-embedded would predict distant recurrence in patients with TNBC. The levels of expression of seven genes were used in a prospectively defined algorithm to allocate each patient to a risk group (low or high). NanoString expression profiles were obtained for 203 tumor tissue blocks. Increased expressions of the five genes (SMAD2, HRAS, KRT6A, TP63 and ETV6) and decreased expression of the two genes (NFKB1 and MDM4) were associated favorable prognosis and were validated with cross-validation. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low- and high-risk groups according to gene expression signature were 62% [95% confidence interval (CI), 48.6-78.9%] and 85% (95% CI, 79.2-90.7%), respectively. When adjusting for TNM stage, the distant recurrence-free survival (DRFS)s in the low-risk group was significantly longer than that in the high-risk group (p

Background Paclitaxel plus gemcitabine (PG) combination chemotherapy is a preferred chemotherapeutic regimen for patients with metastatic breast cancer (MBC). Eribulin mesylate is a halichondrin non-taxane inhibitor of microtubule dynamics. A recent pooled analysis with eribulin showed improved overall survival (OS) in various MBC patient subgroups pretreated with anthracycline and taxane. Furthermore, eribulin may have less neurotoxicity than paclitaxel. Patients and methods This study was a prospective randomised phase II, open-label, two-arm, multicentre study comparing eribulin plus gemcitabine (EG) with PG chemotherapy as a first-line treatment for patients with human epidermal growth factor receptor 2-negative MBC. We hypothesised that EG chemotherapy would not be inferior to PG chemotherapy. The primary end-point was progression-free survival (PFS), which was estimated to be 70% at 6 months for each arm. The secondary end-points were as follows: OS, neuropathic scale, toxicity and clinical benefit rate. Results A total of 118 patients (median age: 50, 24–66) were enrolled between March 2015 and March 2016 and were randomly assigned to PG (n = 59) or EG (n = 59) chemotherapy. The mean number of metastatic sites was 3 (range 1–8). The 6-month PFS rates for both arms were 72% for EG and 73% for PG (P = 0.457). There was no significant difference in OS between the two groups (not reached versus 21.2 months, P = 0.2234). The median number of chemotherapy cycles for both groups was 10 for EG and 8 for PG (range 2–32). Clinical benefit rates were 44% for EG and 49% for PG. Major toxicities were neutropenia and neurotoxicity. Grade II or above neurotoxicity was more common with PG than with EG (13.6% for EG versus 45.8% for PG, P Conclusion EG chemotherapy had similar clinical benefits to PG chemotherapy in terms of PFS but less neurotoxicity. Trial registration KCSG BR13-11; ClinicalTrials.gov , NCT02263495.

Purpose Accurate testing for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is essential for breast cancer treatment. At present, immunohistochemistry (IHC)/florescence in situ hybridization (FISH) are widely accepted as the standard testing methods. To investigate the value of NanoString nCounter®, we performed its comparative analysis with IHC/FISH and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) for the assessment of ER, PR, and HER2. Methods Data on IHC/FISH results for ER, PR, and HER2 in 240 patients from a single tertiary hospital in Korea were collected and compared with NanoString nCounter® and qRT-PCR results at a single institution. Results Expression levels for each gene using NanoString nCounter® showed good correlation with the corresponding data for protein expression by IHC (p

Onycholysis and other nail toxicities occur in approximately 20–30% of breast cancer (BC) patients receiving docetaxel chemotherapy. Onycholysis is often associated with painful paronychia, decreasing patients’ quality of life. In this study, we aimed to evaluate the efficacy of hydrating nail solution (HNS) (EVONAIL® solution, Evaux Laboratories, France) for the prevention and treatment of docetaxel-induced onycholysis and nail toxicities. This study was a prospective, randomized, controlled study of HNS for the prevention or treatment of onycholysis in patients with docetaxel after doxorubicin plus cyclophosphamide. In the experimental arm, patients painted HNS on nails and periungual areas once a day till developing onycholysis grade 2. After grade 2 onycholysis development, patients applied HNS twice a day regardless of treatment arm. The primary endpoints were the incidence of onycholysis grade 2 and recovery rate from grade 2 onycholysis. From August 2015 to May 2016, 103 patients were enrolled and completed this study. Of these, 25 cases of grade 1 and 22 of grade 2 onycholysis were observed. Prophylactic application of HNS resulted in a statistically significant reduction of grade 2 onycholysis compared to controls (P = 0.001) and all grade onycholysis was also significantly lower in the experimental arm (P = 0.034). Multivariate analysis showed that HNS decreased grade 2 onycholysis (Hazard ratio (HR) 0.366, 95% confidence interval (CI) 0.148, 0.902; P = 0.029) and all grade onycholysis (HR 0.372, 95% CI 0.201–0.687, P = 0.002). Hydrating nail solution significantly reduced the incidence of docetaxel-induced onycholysis in BC patients (NCT02670603).

Objective:Our objective was to evaluate long-term altered appearance, distress, and body image in posttreatment breast cancer patients and compare them with those of patients undergoing active treatment and with general population controls.Method:We conducted a cross-sectional survey between May and December of 2010. We studied 138 breast cancer patients undergoing active treatment and 128 posttreatment patients from 23 Korean hospitals and 315 age- and area-matched subjects drawn from the general population. Breast, hair, and skin changes, distress, and body image were assessed using visual analogue scales and the EORTC BR–23. Average levels of distress were compared across groups, and linear regression was utilized to identify the factors associated with body image.Results:Compared to active-treatment patients, posttreatment patients reported similar breast changes (6.6 vs. 6.2), hair loss (7.7 vs. 6.7), and skin changes (5.8 vs. 5.4), and both groups had significantly more severe changes than those of the general population controls (p < 0.01). For a similar level of altered appearance, however, breast cancer patients experienced significantly higher levels of distress than the general population. In multivariate analysis, patients with high altered appearance distress reported significantly poorer body image (–20.7, CI95% = –28.3 to –13.1) than patients with low distress.Significance of results:Posttreatment breast cancer patients experienced similar levels of altered appearance, distress, and body-image disturbance relative to patients undergoing active treatment but significantly higher distress and poorer body image than members of the general population. Healthcare professionals should acknowledge the possible long-term effects of altered appearance among breast cancer survivors and help them to manage the associated distress and psychological consequences.

Figure S1. Relationship between biomarkers and pCR by treatment group and estrogen receptor status. CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase, catalytic subunit; PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, TGF transforming growth factor; WT wild-type. (PDF 836Â kb)

Biomarker analyses on the intent-to-treat population: sample sizes and technical success rates. *As a percentage of the ITT population (N = 417). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, SNP single nucleotide polymorphism, TGF transforming growth factor. Table S2. Baseline levels of all biomarkers in all four treatment groups (biomarker population, based on the intent-to-treat population). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, SNP single nucleotide polymorphism, TGF transforming growth factor. Table S3. Relationship between biomarkers and pCR, adjusted for hormone receptor status and breast cancer type (biomarker population, based on the intent-to-treat population). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Mut mutant , Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, SNP single nucleotide polymorphism, TGF transforming growth factor, WT wild-type. Cochran–Mantel–Haenszel Chi-square test based on biomarker subgroup x pCR status (2 × 2) stratified by hormone receptor status and breast cancer type. Table S4. Treatment and biomarker interaction tests comparing groups A (trastuzumab plus docetaxel) and B (pertuzumab, trastuzumab, and docetaxel) (median cut-point; biomarker population, based on the intent-to-treat population). *Subgroup defined by using a cutoff for target:centromere ratio of 2. †Subgroup defined using mutation versus no mutation. CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, SNP single nucleotide polymorphism, TGF transforming growth factor. Table S5. Relationship between biomarkers and pCR by hormone receptor status (biomarker population, based on the intent-to-treat population). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, TGF transforming growth factor. Table S6. Detailed analyses of biomarker levels by ER status. CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase, catalytic subunit; PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, TGF transforming growth factor; WT wild-type. Cochran–Mantel–Haenszel Chi-square test based on biomarker subgroup × pCR status (2 × 2) stratified by breast cancer type. (DOCX 59 kb)

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Background: Breast cancer patients experience a variety of altered appearance - such as loss or disfigurement of breasts, discolored skin, and hair loss - which result in psychological distress that affect their quality of life. This study aims to evaluate the impact of socioeconomic status on the altered appearance distress, body image, and quality of life among Korean breast cancer patients. Materials and Methods: A cross-sectional survey was conducted at advocacy events held at 16 different hospitals in Korea. Subjects were eligible to participate if they were 18 years of age or older, had a histologically confirmed diagnosis of breast cancer, had no evidence of recurrence or metastasis, and had no psychological problems at the time of the survey. Employment status, marital status, education, and income were assessed for patient socioeconomic status. Altered appearance distress was measured using the NCI's cancer treatment side effects scale; body image and quality of life were measured by the EORTC QLC-C30 and BR23. Means and standard deviations of each outcome were compared by socioeconomic status and multivariate linear regression models for evaluating the association between socioeconomic status and altered appearance distress, body image, and quality of life. Results: A total of 126 breast cancer patients participated in the study; the mean age of participants was 47.7 (SD=8.4). Of the total, 83.2% were married, 85.6% received more than high school education, 35.2% were employed, and 41% had more than $3000 in monthly household income. About 46% had mastectomy, and over 30% were receiving either chemotherapy or radiation therapy at the time of the survey. With fully adjusted models, the employed patients had significantly higher altered appearance distress (1.80 vs 1.48; p

Neoadjuvant chemotherapy (NAC) has been used widely in patients with locally advanced breast cancer (LABC). NAC has the added advantage of increasing breast conservation rates with similar disease-free and overall survival compared with adjuvant chemotherapy. A subset of patients receiving NAC experience early failure during the course of therapy or within a short period after breast surgery. There are no established predictors of early therapy failure in LABC patients who received NAC. This study was performed to identify patient groups that may not benefit from NAC. This study was a retrospective single-centre study. Patients with LABC (cT2-4N0-3) were recruited into this analysis from January 2005 to December 2011 at the Samsung Medical Center. The cohort included 397 patients. The clinicopathological characteristics and disease courses of the patients whose disease progressed within 1 year of receiving neoadjuvant chemotherapy were analysed. Thirty-eight of the 397 patients (9.6 %) exhibited progression within 1 year after receiving neoadjuvant chemotherapy. Seven of the 37 patients (18.9 %) with a known disease subtype, as assessed by IHC, were hormone receptor (HR)+ and HER2−. The number of HER2+ irrespective of HR status and triple-negative breast cancer (TNBC) patients was 13 (35.1 %) and 17 (45.9 %), respectively. Pathological complete remission was found in two patients (5.3 %, 2/38). The median overall survival period was 20.4 months (95 % CI 17.3–23.5) in patients with early failure and 69.1 months (95 % CI 52.7–85.4) in the late failure group (p

Introduction. We report detailed safety analyses by geographic region from the phase III study CLEOPATRA with pertuzumab, trastuzumab, and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer. Patients and Methods. Patients received pertuzumab/placebo at 840 mg in cycle 1 and 420 mg in subsequent cycles, and trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles; docetaxel was initiated at 75 mg/m2. All study drugs were given intravenously, 3 times weekly. Results. Docetaxel dose reductions below 75 mg/m2 were more common in patients from Asia (47.0%) than other regions (13.4%); docetaxel dose escalations to 100 mg/m2 were less frequent in Asia (2.4%) than other regions (18.7%). Rates of edema (26.1% and 5.4% for Asia and other regions, respectively), myalgia (42.3%, 14.7%), nail disorder (39.9%, 15.1%), febrile neutropenia (18.6%, 7.1%), upper respiratory tract infection (25.7%, 10.2%), decreased appetite (47.0%, 19.1%), and rash (44.3%, 22.0%) were at least twice as high in Asia as in other regions. Adverse events did not result in a reduction in the median number of study treatment cycles administered in patients from Asia. Efficacy analyses per region showed hazard ratios similar to those of the whole intention-to-treat (ITT) population for progression-free survival (ITT: 0.63; Asia: 0.68; other regions: 0.61) and overall survival (ITT: 0.66; Asia: 0.64; other regions: 0.66). Conclusion. Despite a higher proportion of docetaxel dose reductions in patients from Asia, survival benefits were comparable between regions. The benefit-risk profile of pertuzumab, trastuzumab, and docetaxel supports this regimen as the first-line therapy for patients with HER2-positive metastatic breast cancer from all geographic regions.

Cases of phenotypic heterogeneity of cells within tumors have recently been reported. Here, we report on a patient with characteristic intra-tumor double primary metastases in the lung. This patient was a 40-year-old Korean woman who had been diagnosed with breast cancer (T1N0M0, estrogen receptor/progesterone receptor/HER2 +/+/+) and papillary thyroid cancer three years prior and underwent a complete surgical resection followed by appropriate adjuvant treatment with radiation, hormone, and radioactive iodine. She was recently admitted for newly developed pulmonary nodules. Metastasectomy through video-assisted thoracoscopic surgery revealed recurrent double primary cancer with two different components (metastatic ductal carcinomas from the breast and metastatic papillary carcinomas from the thyroid gland) in each pulmonary nodule in the right upper lobe and right middle lobe. To the best of our knowledge, this is the first report of simultaneous recurrent double metastasis in one organ from different primary origins.

The aim of this study was to both develop and validate a nomogram based on the Ki-67 index to predict recurrence. We constructed a nomogram using the Cox proportional hazards model with 953 N0 and N1 postoperative hormone receptor (HR)-positive breast cancer patients and validated it in an external cohort of 895 patients. A prognostic model that used classical variables, Adjuvant! Online, St. Gallen risk stratification, and the four immunohistochemistry (IHC) markers (IHC4 score) was created and assessed by the likelihood ratio χ2 (LR-χ2) test using the bootstrapping method. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.75 (95% CI 0.72-0.77) in the training set. The validation set showed good discrimination with an AUC of 0.63 (95% CI 0.60-0.66). In the LR-χ2 test, the nomogram score was found to be more informative than the IHC4 with clinical score (CS) [LR-χ2 13.365 (1 d.f.); 95% CI 2.50-24.23 for CS-IHC4 + nomogram score vs. CS-IHC4] on distant recurrence-free survival. This study implies that the amount of prognostic information contained in the nomogram is superior to that in the CS-IHC4 score in HR-positive N0 and N1 breast cancer patients (NCT1273415).

Purpose: Although both gBRCA1/2 mutations are known to increases incidences of breast and ovarian cancer by abruption in homologous recombination pathway, gBRCA1 mutant mainly present with a molecular subtype of triple negative breast cancer (TNBC) and gBRCA2 with hormone receptor (HR) positive which we have little understanding regarding the underlying pathophysiology. In this study, we have comprehensively analyzed clinical characteristics and somatic mutation in gBRCA1/2 mutant patients. Methods: Patients with gBRCA mutation tested (n=2720) in Samsung Medical Center between Jan 2007 to Oct 2018 were retrospectively reviewed. 386 patients were identified as gBRCA mutant and follow-up period less than 2 years (n=105), insufficient clinical data (n=22) and no surgical treatment (n=6) were excluded. Total of 259 patients, gBRCA1 (n=128), gBRCA2 (n=126) and both gBRCA1/2 mutation (n=5), were analyzed. Among the study population, 46 patients had deep target sequencing data with 40 patients also available for matched transcriptome outcome. Results: Median age was 40 years old (range 23-68). Patients were mostly under pre-menopausal status (81.2%) with invasive ductal carcinoma pathology (86.2%). Initial stage at diagnosis were stage 0 (4.7%), 1 (30.3%), 2 (40.6%) and 3 (24.4%). A novel mutation was observed in 16.9% of the study population and frameshift (44.9%) and nonsense (31.5%) mutations were predominant. Molecular subtypes were as follows: HR-positive (n=125, 49.2%), HR/HER2 positive (n=10, 3.9%), HER2 positive (n=3, 1.2%) and TNBC (n=116, 46.7%). TNBC was observed mostly in gBRCA1 mutant patients (71.9% vs. 19.1%) and HR-positive in gBRCA2 mutant patients (76.2% vs. 22.7%). Sixty-seven patients (26.4%) experienced disease recurrence and median time to recurrence were 145.0 months (95% confidential interval 107.3-170.2). Looking into co-altered somatic mutation using target sequencing (n=45), notably, alteration in other DNA-damage response pathway-related genes, such as TP53 (60%), ATR (27%), CHEK2 (20%), MSH6 (20%), were identified. Evaluated for mutual exclusivity, only gBRCA2 was significantly (P Conclusions: From our dataset, we have witnessed similar clinical characteristics but the difference in molecular subtype between gBRCA1/2 mutant. Despite the fact that both gBRCA1/2 mutations disrupt the homologous recombination pathways, this study provides early evidence regarding the hypothesis that difference in co-occurred somatic alteration between gBRCA1/2 lead to different carcinogenesis mechanism which consequences different molecular subtype. Detail analyses using paired transcriptome result will be presented in the poster. Citation Format: Sehhoon Park, Eunjin Lee, Seri Park, Sohee Lee, Joon Young Hur, Sang Eun Yoon, Kangkook Lee, Jang Ho Cho, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Woong-Yang Park, Yeon Hee Park. Clinical characteristics and combined somatic mutation using target sequencing among breast cancer patients with germline BRCA mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3502.

Background: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1–associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. Methods: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan–Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. Results: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1–containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). Conclusions: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing., The Correction to this article has been published in BMC Cancer 2019 19:620

1020 Background: Progression-free and overall survival (PFS and OS) were significantly improved with 1L P + H + D v Pla + H + D in 808 pts with HER2-positive MBC in CLEOPATRA (NCT00567190). OS was increased by an unprecedented 15.7 mo (median 56.5 mo with P + H + D v 40.8 mo with Pla + H + D; HR 0.68; 95% CI 0.56, 0.84; p < .001) with a median follow-up of 50 mo [Swain et al. NEJM 2015]). Here we report the end-of-study analysis with a median follow-up of 99 mo (max 120 mo). Methods: In this descriptive analysis, OS was compared between arms using the log-rank test, stratified by prior treatment status and geographic region. The Kaplan–Meier approach was used to estimate median OS, and a stratified Cox proportional hazards model was used to estimate the HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other baseline characteristics. Results: Clinical cutoff was Nov 23, 2018. Since Jul 2012, 50 pts crossed from the Pla to the P arm. These pts are counted in the Pla arm for efficacy analyses and up to the first dose of P for safety analyses. The OS HR was 0.69 (95% CI 0.58, 0.82), favoring P + H + D. Median OS was 57.1 mo in the P arm (402 pts) and 40.8 mo in the Pla arm (406 pts; Δ 16.3 mo). The 8-year landmark OS rates were 37% and 23%, respectively. The OS benefit in predefined subgroups, including in pts previously treated with H in the (neo)adjuvant setting (88 pts, HR 0.86; 95% CI 0.51, 1.43), remained consistent with the overall result and previous reports. The overall safety profile of P + H + D was consistent with the known P safety profile. There was only one new serious adverse event suggestive of congestive heart failure (onset ~77 mo on treatment in the P arm, resolution in 34 days, pt continued on study medication) and one new symptomatic left ventricular systolic dysfunction (onset ~46 mo after crossing to the P arm, resolution in 34 days) since the previous analysis. Conclusions: The OS improvement with 1L P + H + D v Pla + H + D for pts with HER2-positive MBC was maintained after an additional 4 years of long-term follow-up, as were the safety and cardiac safety profiles. Clinical trial information: NCT00567190.

Purpose The degree of benefit from palliative chemotherapy differs widely among patients with metastatic esophageal squamous cell carcinoma (MESCC). The purpose of this study was to develop and validate a prognostic nomogram to predict survival and aid physicians and patients in the decision-making process regarding treatment options. Materials and Methods Clinicopathologic variables and treatment outcomes of 239 patients who were diagnosed with MESCC and received either fluorouracil/cisplatin (FP) or capecitabine/cisplatin (XP) as first-line chemotherapy were reviewed. A nomogram was developed as a prognostic scoring system incorporating significant clinical and laboratory variables based on a multivariate Cox proportional hazards regression model. An independent series of 61 MESCC patients treated with FP served as an independent data set for nomogram validation. Results No difference in response rate was observed between the FP group (44.8%) and the XP group (54.2%). Similarly, no significant differences in median progression-free survival and median overall survival were observed between regimen groups. Multivariate analysis showed that poor performance status (Eastern Cooperative Oncology Group [ECOG] status≥2), weight loss (10% of the weight loss for 3 months), low albumin level (≤3.5 g/dL), and absence of previous esophagectomy at the time of chemotherapy were significantly associated with low OS in both groups (p135) prognostic groups. The median survival for those with a favorable ECOG was 13.8 months (95% confidence interval [CI], 10.8 to 18.6 months), for intermediate 11.2 months (95% CI, 8.7 to 11.9 months), and for poor, 7.0 months (95% CI, 3.6 to 10.0 months). External validation of the nomogram in a different patient cohort yielded significantly similar findings. Conclusion The nomogram described here predicts survival in MESCC patients and could serve as a guide for the use of FP/XP chemotherapy in MESCC patients.

Background: The ratio of involved to retrieved lymph nodes (LNR) is suggested as a prognostic factor in operable breast cancer. However, there are conflicting results regarding its clinical significance after neoadjuvant chemotherapy. We investigated the prognostic value of LNR with a thorough evaluation of potential prognostic factors in a large cohort constructed from Health Insurance Review and Assessment Service database of Korea. Patients and method: This retrospective analysis is based on the data of 814 patients with clinical stage II/III breast cancer treated with four cycles of adriamycin/cyclophosphamide (AC) followed by four cycles of docetaxel (DOC) before surgery. We evaluated the clinical significance of the LNR (3 categories: Low, 0-0.20 vs. Intermediate, 0.21-0.65 vs. High, 0.66 -1.00) using Kaplan-Meier method, log-rank test, and Cox proportional hazard regression model. Result: A total of 799 patients underwent breast surgery (Median age 45, range 16-74; Mastectomy 369, Lumpectomy 380, and Others 50). Axillary lymph node dissection was performed in 704 (88.1%) patients. Pathologic complete response (pCR, pT0/isN0) was achieved in 129 (16.1%) of 799 patients (HR+/HER2-, 34/373 [9.1%]; HER2+, 45/210 [21.4%]; TNBC 50/216 [23.1%]). The mean numbers of involved LN and retrieved LN were 2.70 (range 0-42) and 13.98 (range 1-64), respectively. The mean LNR was 0.17 (Low, 574 [71.8%]; Intermediate, 170 [21.3%]; High, 55 [6.9%]). In univariate analysis, LNR was significantly associated with worse relapse-free survival (3-yr RFS rate 84.8% in low vs. 66.2% in intermediate vs. 54.3% in high; P Multivariate analysis for relapse-free survival P-valueHR95%CIAGE ( Conclusion: LNR is not superior to ypN-stage in predicting clinical outcome of breast cancer after neoadjuvant chemotherapy. Citation Format: Se Hyun Kim, Jee Hyun Kim, Tae-Yong Kim, In Sil Choi, Yee Soo Chae, Sun Kyung Baek, Seok Yun Kang, In Hae Park, Yoon Ji Choi, Soohyeon Lee, Joo Hyuk Sohn, Yeon-Hee Park, Young-Hyuck Im, Jin-Hee Ahn, Sung-Bae Kim, Kyung Hae Jung. Prognostic value of axillary nodal ratio after neoadjuvant chemotherapy of AC followed by docetaxel: A multicenter retrospective cohort study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-33.

Objective The authors conducted a retrospective cohort study to determine prognostic factors and treatment outcomes of brain metastases (BM) from breast cancer (BC) after Gamma Knife radiosurgery (GKS). Methods Pathologic and clinical features, and outcomes were analyzed in a cohort of 62 patients with BM from BC treated by GKS. The Kaplan-Meier method, the log-rank test, and Cox's proportional hazards model were used to assess prognostic factors. Results Median survival after GKS was 73.0 weeks (95% confidence interval, 46.0-100.1). HER2+ [hazard ratio (HR) 0.441; p=0.045], Karnofsky performance scale (KPS) ≥70 (RR 0.416; p=0.050) and systemic chemotherapy after GKS (RR 0.282; p=0.001) were found to be a favorable prognostic factor of overall survival. Actuarial local control (LC) rate were 89.5±4.5% and 70.5±6.9% at 6 and 12 months after GKS, respectively. No prognostic factors were found to affect LC rate. Uni- and multivariate analysis revealed that the distant control (DC) rate was higher in patients with; a small number (≤3) of metastasis (HR 0.300; p=0.045), no known extracranial metastasis (p=0.013, log-rank test), or the HER2+ subtype (HR 0.267; p=0.027). Additional whole brain radiation therapy and metastasis volume were not found to be significantly associated with LC, DC, or overall survival. Conclusion The treatment outcomes of patients with newly diagnosed BM from BC treated with GKS could be affected primarily by intrinsic subtype, KPS, and systemic chemotherapy. Therapeutic strategy and prognosis scoring system should be individualized based on considerations of intrinsic subtype in addition to traditionally known parameters related to stereotactic radiosurgery.

The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.

Background: This phase II neoadjuvant trial evaluated bevacizumab–docetaxel and carboplatin in triple-negative breast cancer. Patients and methods: Women with hormone receptor- and human epidermal growth factor receptor 2 (HER2)negative, stage II/III breast cancer received six cycles of 75 mg/m 2 docetaxel, carboplatin (AUC = 5) and 15 mg/kg bevacizumab every 21 days. The primary end point was pathological complete response (pCR) in breasts and axillary lymph nodes (ALN). Results: Forty-five patients were recruited from the Korean Cancer Study Group. The median age was 45 (range 30–72) years. ALNs were positive in 80% of patients (n = 36) at diagnosis. Overall, 98% of patients (n= 44) completed therapy and underwent surgery. The pCR rate was 42% (n= 19); clinical response rate 96% (n = 43); complete 13% (n= 6); partial 82% (n = 37); stable disease 2% (n= 1). Breast-conserving surgery was undertaken in 78% of patients (n= 35). Most frequent grade 3/4 adverse events were neutropenia (84%, n= 38) and febrile neutropenia (9%, n= 4). One patient experienced delayed wound healing after surgery. Conclusions: Neoadjuvant bevacizumab, docetaxel and carboplatin resulted in an encouraging pCR rate and negligible wound healing problems after surgery.

We evaluated the tumor response and clinical outcomes according to molecular subtypes in stage II-III breast cancer patients who received neo-adjuvant chemotherapy (NAC) followed by surgery and radiotherapy.We retrospectively analyzed 329 patients with clinical stage II-III breast cancer who received NAC followed by surgery and radiotherapy. Luminal A and B, HER2-enriched and triple-negative subgroups were identified.The overall pathologic complete response (pCR) rate after NAC was 20.1% and the HER2-enriched subgroup had the highest pCR rate (43.6%), whereas luminal A showed the lowest rate of pCR (4.6%). The median follow-up duration was 55 months (range, 5-98 months). The 5-year overall survival (OS) and disease-free survival (DFS) rates were 88.9% and 72.9%, respectively. In subgroup analysis, according to the pathologic response (pCR vs non-pCR), the triple-negative subtype exhibited a significant difference in 5-year OS rate (100.0% vs 71.6%, P = 0.005) and 5-year DFS rate (93.1% vs 55.1%, P0.001). A distinct survival difference according to molecular subtype was found, particularly in the non-pCR group (5-year OS and DFS, P0.001, respectively).The non-pCR group showed significantly decreased 5-year OS and DFS rates compared to the pCR group, especially in triple negative and HER2-enriched breast cancer patients. A significant difference in survival rates and molecular subtypes was found in patients who failed to attain pCR.

In breast cancer (BC), up to 10-20% patients were known to have clinical benefit with immune checkpoint inhibitors, and biomarkers are needed for optimal use of this multi-potential therapeutic strategy. Accordingly, we conducted an experiment to identify expression of genes associated with immune checkpoints that represent potential targets of cancer immunotherapy. We performed whole-transcriptome sequencing and whole-exome sequencing using 37 refractory BC specimens. In the immune pathway gene set expression analysis, we found that HER2 expression and previous taxane treatment were positively correlated with high expression of immune gene set expression (p = 0.070 and 0.008, respectively). The nine genes associated with immune checkpoints - PDCD1(PD-1), CD274(PD-L1), CD276(B7-H3), CTLA-4, IDO1, LAG3, VTCN1, HAVCR2, and TNFRSF4(OX40) - interacted with each other. In addition, HER2 expression also affected the expression levels of these genes (p = 0.044). Lastly, expression of immune checkpoint genes and tissue-infiltrating lymphocytes were positively correlated in metastatic BCs (p < 0.001). In conclusion, we suggest that HER2 expression and previous taxane treatment are potential surrogate markers for high expression of immune checkpoint genes and immune pathway gene sets. Further study of the BC immune signature with large-scale, translational data sets is warranted.

We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = DUSP4 mRNA was downregulated (P = P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4.

We investigated gene expression profiles of the NF-κB pathway in patients with triple-negative breast cancer (TNBC) receiving adjuvant chemotherapy to determine the prognostic value of NF-κB pathway genes according to chemotherapeutic regimen. We used the nCounter expression assay to measure expression of 11 genes (NFKB1, NFKB2, RELA, RELB, REL, TP53, FOXC1, TBP, SP1, STAT3 and IRF1 genes) belonging to the NF-κB pathway using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC. Of the 203 patients, 116 were treated with a chemotherapeutic regimen containing doxorubicin. As revealed by the expression profiles of the 11 genes, increased expression of SP1 was associated with poor prognosis in TNBC patients treated with adjuvant doxorubicin chemotherapy (5-year distant recurrence-free survival [5Y DRFS], low vs. high expression [cut-off: median]: 92.3% vs. 71.6%, P = 0.001). In a multivariate Cox regression model, SP1 expression was a useful marker for predicting long-term prognosis in TNBC patients receiving doxorubicin treatment, and we thus suggest that SP1 expression could serve as a prognostic marker in these patients.

Several pathologic classification systems have been developed to evaluate tumor response after neoadjuvant chemotherapy (NAC) for breast cancer. We aimed to compare pathologic classification systems and to investigate prognostic factors and risk stratification according to molecular subtype in relation to survival. We retrospectively evaluated pathologic response after NAC in 485 breast cancer patients by applying the National Surgical Adjuvant Breast and Bowel Project B18 trial (NSABP-B18), Miller and Payne system, Chevallier’s classification, Sataloff’s classification, residual cancer burden (RCB), residual disease in breast and nodes (RDBN), and clinical–pathologic stage + estrogen receptor status and grade staging system (CPS + EG). All seven classification systems were significantly associated with overall survival (OS) and distant disease-free survival (DDFS). Regarding intrinsic subtypes, all systems were significantly associated with OS and DDFS for triple-negative tumors. Only RCB had prognostic significance for all four subtypes in relation to both OS and DDFS, and RDBN in DDFS only for all subtypes. In risk factor analyses, lymphovascular invasion (LVI), as well as other classic pathologic prognostic factors such as tumor size, lymph node status, and hormonal receptor status, was significantly associated with both OS and DDFS for the entire study group. Regarding subtypes, LVI was associated with DDFS for each subtype except Luminal B-like tumors. Our results suggest that pathologic classification systems that evaluate residual tumors in both breast and lymph nodes after NAC show better association with clinical outcome. Furthermore, combining LVI with other classic prognostic factors might have prognostic value for the assessment of treatment response after NAC.

The biology of breast cancer brain metastasis (BCBM) is poorly understood. We aimed to explore genes that are implicated in the process of brain metastasis of primary breast cancer (BC). NanoString nCounter Analysis covering 252 target genes was used for comparison of gene expression levels between 20 primary BCs that relapsed to brain and 41 BCBM samples. PAM50-based intrinsic subtypes such as HER2-enriched and basal-like were clearly over-represented in BCBM. A panel of 22 genes was found to be significantly differentially expressed between primary BC and BCBM. Five of these genes, CXCL12, MMP2, MMP11, VCAM1, and MME, which have previously been associated with tumor progression, angiogenesis, and metastasis, clearly discriminated between primary BC and BCBM. Notably, the five genes were significantly upregulated in primary BC compared to BCBM. Conversely, SOX2 and OLIG2 genes were upregulated in BCBM. These genes may participate in metastatic colonization but not in primary tumor development. Among patient-matched paired samples (n = 17), a PAM50 molecular subtype conversion was observed in eight cases (47.1%), with a trend toward unfavorable subtypes in patients with the distinct gene expression. Our findings, although not conclusive, reveal differentially expressed genes that might mediate the brain metastasis process.

Background Triple-negative breast cancer (TNBC) is known for aggressive biologic features and poor prognosis. Epidermal growth factor receptor (EGFR) overexpression in TNBC indicates poor prognosis. However, there is no previous study of the relationship between expression of the entire human epidermal growth factor receptor (HER) family genes and patient prognosis in TNBC. Accordingly, we investigated the expression profiles of HER family genes in patients with TNBC to determine the prognostic value and clinical implications of HER family expression. Methods We used the nCounter expression assay (NanoString®) to measure the expression of EGFR, erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, and estrogen receptor 1 (ESR1) genes using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC. Our data were validated using a separate cohort of 84 TNBC patients. Results A total of 203 TNBC patients who received adjuvant chemotherapy after curative surgery from 2000 to 2004 formed the training set. The 84 TNBC patients in the validation consort were selected from breast cancer patients who received curative surgery since 2005 to 2010. Analysis of the expression profiles of the HER family genes in TNBC tissue specimens revealed that increased expression of ERBB4 was associated with poor prognosis according to survival analysis (5-year distant relapse free survival [5Y DRFS], low vs. high expression [cut-off: median]: 90.1 % vs. 80.2 %; p = 0.022). This trend was also observed in the validation set of TNBC patients (5Y DRFS, low vs. high: 69.4 % vs. 44.7 %; p = 0.053). In a multivariate Cox regression model, ERBB4 expression was identified as a indicator of long-term prognosis in patients with TNBC. Conclusions The expression profile of ERBB4, a member of the HER family, might serve as a prognostic marker in patients with TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2195-3) contains supplementary material, which is available to authorized users.

Purpose The purpose of this study was to investigate the clinicopathologic features and prognostic factors affecting outcome in patients with isolated locoregional recurrence of breast cancer (ILRR). Methods We retrospectively analyzed the medical records of 104 patients who were diagnosed with ILRR and underwent curative surgery from January 2000 to December 2010 at Samsung Medical Center. Results Among 104 patients, 43 (41%) underwent total mastectomy and 61 (59%) underwent breast-conserving surgery for primary breast cancer. The median time from initial operation to ILRR was 35.7 months (4.5–132.3 months). After diagnosis of ILRR, 45 (43%) patients were treated with mastectomy, 41 (39%) with excision of recurred lesion, and 18 (17%) with node dissection. During a median follow-up of 8.9 years, the 5-year overall survival was 77% and 5-year distant metastasis-free survival (DMFS) was 54%. On multivariate analysis, younger age (< 35 years), higher stage, early onset of elapse (≤ 24 months), lymph node recurrences, and subtype of triple negative breast cancer (TNBC) were found to be independently associated with DMFS. Patients in the no chemotherapy group showed a longer DMFS after surgery for ILRR than those treated with chemotherapy (median 101.5 vs. 48.0 months, p = 0.072) but without statistical significance. Conclusion Our analysis showed that younger age (< 35 years), higher stage, early onset of relapse (≤ 24 months), lymph node recurrence, and subtype of TNBC are the worst prognostic factors for ILRR.

Baseline characteristics of patientsâ cohort. Table S2. The relationship among expression levels of ERBB family RTKs in TNBC. Table S3. elationships between stage of disease and chemotherapeutic agent. Table S4. Univariate analysis of baseline characteristics affecting ERBB4 expression (N=203). (DOCX 29 kb)

Box plots for the expression level of HER family genes and ESR1 gene. (A) Training set (N = 203). (B) Validation set (N = 84). (C) Group consisting of non-triple negative breast cancer (N = 52). Figure S2. Relationship among expression of the ERBB family genes and ESR1 gene in TNBC. Figure S3. Survival analysis according to the expression level of ESR1 and ERBB4 expression in the training set. (A) Kaplan-Meier survival curve for stage I/IIA (N = 149). (B) Kaplan-Meier survival curve for stage IIB/IIIA/IIIC (N = 54). (PPTX 266 kb)

Forkhead Box Protein 3 (FOXP3) is a marker for immunosuppressive CD4+CD25+ regulatory T cells (Tregs). We investigated whether there were significant numbers of FOXP3-positive Tregs in triple-negative breast cancer (TNBC) using immunohistochemistry, and whether the presence of FOXP3-positive Tregs was associated with other prognostic factors, such as stage or histologic grade. We investigated the number of tumor-infiltrating FOXP3-positive Tregs in formalin-fixed TNBC specimens obtained from patients who received palliative treatment between 1999 and 2007.Immunohistochemistry was used to assess the number of CD4+, CD25+, and FOXP3+ Tregs in tumor tissue and normal breast tissue from 86 TNBC patients. Univariate and multivariate analyses evaluated outcomes according to the number of FOXP3-positive Tregs.Of the 86 tumor specimens, 22 (25.6%) expressed more than 15 FOXP3-positive Tregs per 10 high power fields in the peritumoral area. On multivariate analysis, staining showing ≥ 15 FOXP3-positive Tregs was an independent prognostic factor for overall survival and progression free survival with hazard ratios of 2.4 (95% CI 1.0-5.6; p = 0.049) and 2.0 (95% CI 1.1-3.6; p = 0.032), respectively. In TNBC, FOXP3-positive Tregs had stronger prognostic significance than did FOXP3-negative Tregs. The finding of improved survival associated with highly infiltrating FOXP3-positive Tregs in TNBC contrasted with several other types of solid cancer.TNBC may be differently driven by FOXP3 via an immune mechanism. The inclusion of FOXP3+ Tregs may help to improve prognostication for TNBC.

The purpose of this study is to validate the recently published Breast–Graded Prognostic Assessment (GPA) and propose a new prognostic model and nomogram for patients with brain parenchymal metastases (BM) from breast cancer (BC). We retrospectively investigated 171 consecutive patients who received a diagnosis of BM from BC during 2000–2008. We appraised the recently proposed Sperduto's BC-specific GPA in training cohort through Kaplan-Meier survival curve using log-rank test and area under the curve for the BC-GPA predicting overall survival at 1 year and developed a new nomogram to predict outcomes using multivariate Cox-regression analysis. By putting the Sperduto's Breast-GPA together with our nomogram, we developed a new prognostic model. We validated our new prognostic model with an independent external patient cohort from 2 institutes for the same period. On the basis of our Cox-regression analysis, therapeutic effect of trastuzumab and status of extracranial systemic disease control were incorporated into our new prognostic model in addition to Karnofsky performance status, age, and hormonal status. Our new prognostic model showed significant discrimination in median survival time, with 3.7 months for class I (n = 15), 7.8 months for class II (n = 82), 10.7 months for class III (n = 42), and 19.2 months for class IV (n = 32; P < .0001). The new prognostic model accurately predicted survival among patients with BC from BM in an external validation cohort (P < .0001). We propose a new prognostic model and a nomogram reflecting the different biological features of BC, including treatment effect and status of extracranial disease control, which was excellently validated in an independent external cohort.

Summary Background Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. Methods In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m 2 , escalating, if tolerated, to 100 mg/m 2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Findings Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1–55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6–38·5]; p=0·0141). 23 of 96 (24·0% [15·8–33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3–25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15–20 serious adverse events per group in 10–17% of patients) but lower in group C (four serious adverse events in 4% of patients). Interpretation Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. Funding F Hoffmann-La Roche.

Background: CA 15-3 is derived from proteolytic shedding of the extracellular domain of mucin 1 (MUC1) glycoprotein. Luminal subtype breast cancer shows a higher expression in MUC1 genes, and a positive relationship between MUC1 expression and estrogen receptor (ER) expression has been reported. In this study, we attempted to determine the difference of CA 15-3 level according to the subtype of breast cancer. Methods: From January 2000 to December 2009, a total of 707 patients who were diagnosed with metastatic or recurrent breast cancer at Samsung Medical Center were included in this study. Among these, 536 patients with available clinical data including pretreatment CA 15-3 and immunohistochemistry for ER, progesterone receptor (PgR) and hormone receptor 2 (HER2) were analyzed in this study. Patients were classified into 3 groups according to their receptor status: ER-positive (ER+) and/or PgR+ irrespective of HER2 (HR+), ER–/PgR–/HER2+ (HER2-enriched) and ER–/PgR–/HER2– (triple negative, TN). Results: The supranormal values of CA 15-3 were frequently observed in HR+ breast cancer compared to other types (45.6% for HR+, 24.4% for HER2-enriched and 28.8% for TN; p < 0.001). The increase of marker levels differed significantly among the 3 groups (24 U/ml for HR+, 13 U/ml for HER2-enriched and 18 U/ml for TN; p < 0.001). Conclusions: The increase of both marker levels and the frequency of supranormal values of CA 15-3 were more frequently observed in HR+ breast cancer, which is positively associated with MUC1 expression. These results could potentially serve as a basis for expanding the clinical implications of CA 15-3 in the field of clinical trials for novel targeted therapies in breast cancer.

Purpose: To study clinical features and patterns of recurrence after breast-conserving treatment (BCT) for three molecular subtypes of early stage breast cancer. Methods: The sample studied included 596 patients with T1-2N0-1 breast cancer who received BCT. Three groups were defined by receptor status. Luminal: es trogen receptor (ER) or progesterone receptor (PR) positive; triple negative (TN): ER, PR, and epidermal growth factor receptor-2 (HER2) receptor negative; and HER2 overexpressing: ER and PR negative but HER2 receptor positive. Results: The number of patients in each group was 408 (68.5%), 105 (17.6%), and 83 (13.9%), respectively. The median follow-up period was 79 months. The TN and HER2 subtypes occurred in younger patients (p= 0.0007) and had higher nuclear grade and poorer histologic grade (p< 0.0001 and 0.0071, respectively). During the follow-up period, locoregional recurrence was detected as the first site of recurrence in 26 (6.4%), 11 (10.5%), and 9 (10.8%) patients in the luminal, TN, and HER2 subtypes, respectively (p= 0.1924). Thirty-one (7.6%), 7 (6.7%), and 7 (8.4%) patients in each group had distant metastases as the first sign of recurrence ( p= 0.8996). Median time to locoregional and distant recurrence was shorter in the HER2 subtype (p= 0.0889 and 0.0780, respectively), and the HER2 subtype was significantly associated with poor overall survival (p=0.0009). Conclusion: After BCT in Korean women with early stage breast cancer, the patterns of recurrence were not different among the molecular subtypes, although the TN and HER2 subtypes were associated with younger age, higher nuclear grade, and poorer histologic grade.

Objectives: We evaluated whether skin changes and soft tissue infiltration patterns reflect breast cancer subtypes based on the breast hormonal receptor (HR) and human epidermal growth factor receptor 2 (HER2) status at the time of skin metastasis. Methods: We retrospectively reviewed the patients’ medical records with radiologic imaging studies. Results: The numbers of patients of each subtype were as follows: HR positive (HR+ve) 53 (42.4%), HER2 enriched 43 (34.4%), and triple negative (TN) 29 (23.2%). The presence of skin ulceration was found more commonly in the HR+ve group than in the others (57.1% for HR+ve vs. 25% for HER2 enriched vs. 15.4% for TN, p = 0.019). Erythematous infiltrations were shown predominantly in the TN group (19.0 vs. 54.2 vs. 84.6%, respectively, p < 0.000). On CT scans, soft tissue infiltration appeared to be more common in the HER2-enriched and TN groups than in the HR+ve group (24.5 vs. 41.9 vs. 48.3%, respectively, p = 0.013). Erythematous infiltrative lesions were more common in patients with epidermal growth factor receptor overexpression (p = 0.036). Conclusion: The patterns of skin involvement including surrounding soft tissue infiltration may reflect breast cancer subtype. Prospective evaluation is necessary to confirm their influential effect on breast cancer subtypes.

Triple-negative breast cancer (TNBC) exhibits a distinct pattern of recurrence characterized by a rapidly rising rate in the first 2 years with a peak at 2-3 years, followed by a decline over the next 5 years. However, some TNBC patients exhibit indolent clinical behavior. The aim of this study was to investigate clinical characteristics and outcomes of metastatic TNBCs. In addition, we were to find out the marker which could divide TNBCs into a few subgroups according to different clinical features.We retrospectively analyzed the clinicopathologic characteristics and outcomes of patients with metastatic TNBC who received palliative treatment between 1999 and 2007.The median relapse-free survival (RFS) and overall survival (OS) of 152 patients were 24 and 20 months, respectively. Divided TNBCs based on a RFS of 36 months, the patients with a RFS of ≥36 months had a better disease control rate (DCR), progression-free survival (PFS), and OS than those with a RFS of3 years. Cox-regression multivariate analysis for RFS and OS revealed EGFR positivity and a low BRCA1 score as an independent risk factor for OS.The patients with a RFS ≥ 3 years had a significantly better DCR, PFS, and OS than patients who had a RFS 3 years. BRCA1 and EGFR expression may be candidate determinants to distinguish RFS. A prospective clinical trial for different therapeutic strategies is needed for each subgroup.

The primary purpose of this study was to evaluate the role of thymidylate synthase (TS) and thymidine phosphorylase (TP) as biomarkers to predict clinical outcomes of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC).Of the patients who were previously treated with anthracycline and taxane regimens, 90 patients who had available tissue block for immunohistochemistry with measurable lesions were included. All patients received capecitabine (2,500 mg/m(2)/day) for 14 days every 3 weeks.High TS expression was more common among patients with triple-negative (TN) subtype than among patients with other subtypes (33% for hormone receptor+, 8% for HER2+, and 58% for TN, P = 0.023). The median PFS was significantly lower in patients with high TS (6.6 vs. 3.0 months; P = 0.017) and low TP expressions (6.0 vs. 3.3 months; P = 0.013). A high TS and a low TP expressions were identified as unfavorable independent risk factors for PFS to capecitabine monotherapy in multivariate analysis (hazard ratio [HR], 1.7, P = 0.037 for high TS score; HR, 1.8, P = 0.014 for low TP score).Our data suggest that high TS and low TP scores correlate with a shorter PFS for capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC.

Background and Purpose Studies have suggested that the antigenicity of tumor cell is highly correlated with response to immune checkpoint inhibitors. Checkpoint blockade has been found to be particularly effective in tumors with high tumor mutational burden (TMB) in certain indications such as melanoma and NSCLC, while cancers with lower TMB have been shown to be less responsive to checkpoint inhibitors. In HER2-positive metastatic breast cancer (MBC), TMB has potential to be a candidate prognostic or predictive marker for conventional treatments including HER2 targeting agents. This research was conducted to explore the clinical implication of somatic TMB in a well-defined HER2-positive MBC population who were previously treated but progressed. Methods Forty-six patients with HER2-positive MBC who have progressed from more than two HER2-directed therapies were enrolled from 2007 to 2016. Whole exome sequencing was performed on FFPE tumor samples and matched normal tissue. Sequencing reads were aligned to reference human genome using BWA-MEM followed by standard pre-processing steps and GATK to generate analysis ready BAM files. MuTect suite was used to generate somatic single nucleotide variants (SNV) calls using default parameters by comparing BAM files from tumor and matched normal samples. TMB for a subject was defined as the sum of somatic non-synonymous SNVs that passed all the filters described. Results Among 46 patients, 13 (28.3%) patients were determined to estrogen receptor (ER)-positive and 9 (19.6%) patients were determined to progesterone receptor (PR)-positive in immunohistochemistry (IHC) analysis. The median age 48 years (range: 29-68) and all (100%) patients were female. 20 patients (43.5%) were recurrent MBC compared to de novo (n = 26, 56.5%). 16 (34.6%) patients demonstrated more than 100 mutations (and defined as high TMB in this population). The median follow up of duration was 57.5 months (95% CI: 55.4 - 60.6). The median overall survival (OS) according to low or high TMB status (44.9 months vs. 85.8 months) was significantly different (p = 0.016). In a multivariate Cox regression analysis, TMB was the only independent prognostic factor for good OS when adjusted for age and recurrence (Hazard ratio = 0.32, 95% CI, 0.103 - 0.998, p = 0.049). Conclusions Data implicated that high TMB can be a prognostic marker that predicts good OS outcomes with conventional HER2-directed treatments and chemotherapy. Furthermore, future trials using TMB as a stratification marker could identify the right population with potential to respond to immune checkpoint inhibitor after recurrence following HER2-directed treatments. To our knowledge this is the first report that tumor mutation burden (TMB) associate with response to standard of care therapy in HER2+ breast tumors. Citation Format: Yeon Hee Park, Kyunghee Park, Song Ee Park, Eunjin Lee, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Hun Jung, Chooghoon Lee, Woong-Yang Park, Razvan Cristescu. Clinical implication of mutation load in patients with HER2-positive refractory metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2602.

In our previous work, Ets-1 upregulates human epidermal growth factor receptor 2 (HER2) induced matrix metalloproteinase 1 (MMP-1) expression. Based on the above knowledge and result, we hypothesized that estrogen receptor (ER) and its signaling pathway may affect MMP-1 expression under the influence of HER2. In addition, we investigated how the HER2 pathway cross-talk with the ER signaling pathway in genomic and nongenomic action of ER using reverse transcription-PCR, Western blot analysis, and ELISA assay. The results showed that ER-α expression increased MMP-1 expression under the presence of HER2. These upregulatory effects were mediated mainly by mitogen-activated protein kinase pathway and were reversed by downregulation of HER2 and/or ER. Activator protein DNA binding activity was involved in the MMP-1 expression. In summary, our results showed that ER can upregulate MMP-1 expression under the influence of HER2 in MCF-7 cells. In addition, this upregulatory effect was found to be mediated by mitogen-activated protein kinase pathway. MMP-1 might be an assigned target in interaction between ER and HER2. Mol Cancer Res; 8(7); 1037–47. ©2010 AACR.

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]

1069Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. Methods: EMBRACA (NCT01945775) is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA (1 mg/day) with standard single-agent PCT (capecitabine, eribulin, gemcitabine, or vinorelbine) in pts with advanced breast cancer (aBC) and a germline BRCA1/2 mutation (gBRCAmut). PFS by blinded independent central review (BICR) and ORR by investigator were investigated in clinically important subgroups. Results: Of 431 pts randomized, 287 were assigned to receive TALA and 144 to PCT. PFS and ORR are shown (Table). Conclusions: In pts with advanced gBRCAmut breast cancer, TALA demonstrated a statistically significant improvement in both ORR and PFS in clinically relevant subgroups compared with PCT, including pts with CNS metastases, poor performance status, younger age, and visceral disease. Clinical trial information: NCT0194...

1070Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA in BRCA1/2-mutated cells, preventing DNA damage repair and causing cell death. Methods: EMBRACA (NCT01945775) is a ran...

10117Background: A phase II, multicenter, randomized clinical trial of EG and PG as first-line chemotherapy for patients with HER2-negative MBC showed that EG was less neurotoxic, but conferred a s...

As the use of screening mammography expands, the proportion of invasive breast canceror = 1 cm is increasing. The aims of this study were: (1) to identify risk factors for systemic metastases in patients withor = 1 cm invasive breast cancer and (2) to investigate the patient groups at the greatest risk for metastases with such small tumors. Data were collected retrospectively from the breast cancer registry of our institution for patients with invasive breast cancer from October 1994 to December 2004. Of 4,036 patients who received curative breast cancer surgery, we identified 427 patients who had T1a or T1b breast cancer excluding 39 patients who received neoadjuvant chemotherapy. Ipsilateral axillary lymph node involvement was found in 13% (57/427) of patients at the time of surgery. A multivariate analysis was conducted in 370 (T1aN0, T1bN0) patients without lymph node involvement. In a Cox-regression model, HER-2 positive and triple negative (TN) groups were identified as independent risk factors to predict distant relapse-free survival (DRFS) [Hazard ratio (HR) 8.8, P = 0.003 for HER-2 positive group; HR 5.1, P = 0.026 for TN group] in T1bN0 tumors. Statistical significance was not maintained when the analysis was limited to T1aN0 tumors. Even though T1aN0 and T1bN0 tumors have a relatively low risk of systemic failure, antiHER-2-directed therapy for HER-2 group and new innovative adjuvant systemic treatment for TNBC patients with T1bN0 tumors should be considered. Prospective adjuvant trials are warranted in these subgroups of patients.

The increased survival of patients with breast cancer has given rise to other problems associated with the complications of chemotherapy. One major complication is premature ovarian failure, an especially harmful outcome for women of reproductive age. This study was performed to evaluate the efficacy of GnRH agonist (GnRHa) treatment on protecting ovarian function in young breast cancer patients (30.59+/-5.1 yr) receiving chemotherapy after surgery. Twenty-two women were enrolled and given subcutaneous injections of leuprolide acetate (3.75 mg) every 4 weeks during chemotherapy. Follow-up laboratory tests (luteinizing hormone [LH], follicle stimulating hormone [FSH], and estradiol) were performed 1, 3, and 6 months after chemotherapy. Menstruation patterns and clinical symptoms were followed up for a mean duration of 35.6+/-1.7 months. FSH and LH levels were normal in all patients 6 months after completing chemotherapy (8.0+/-5.3, 4.4+/-2.7 mIU/mL, respectively). During follow-up, none of the patients complained of menopausal symptoms and 81.8% experienced recovery of menstruation. This report is the first trial of GnRHa as a treatment modality to protect ovarian function during adjuvant chemotherapy in young Korean breast cancer patients.

In this retrospective study, we investigated the incidence of esophagorespiratory fistula (ERF) in esophageal squamous cell carcinomas, clinical characteristics and outcomes of esophageal cancer patient with ERF, and effective therapeutic options. From 1998 to 2007, 1,095 patients with squamous cell carcinomas of the esophagus were treated at Samsung Medical Center. A comprehensive retrospective review of all these patients with clinical data of ERF was performed. The incidence of ERF in patients with esophageal cancer was 4.7% (52/1095). Comparing with the patients without ERF, the patients with ERF presented with a more advanced stage of disease, more frequent involvement of upper-mid thoracic esophagus, a longer segment of the tumor, and more initial airway involvement. The median time from the diagnosis of esophageal cancer to the development of a fistula was 7.9 months. ERF could be divided into three different categories according to the causes; (1) ERF associated with complication of the cancer progression (65.4%), (2) ERF related with treatments (28.8%), (3) ERF with mixed causes (5.8%). Four patients (8%) received radiation therapy, and nine patients (17%) underwent surgery to treat the ERF. Many of the patients with ERF were palliated with esophageal stent (40%) and/or gastrostomy (38%). The median survival time after diagnosis of the ERF was 8.0 weeks. An ERF resulting from esophageal cancer entails a poor prognosis in spite of supportive and/or definitive treatment. More comprehensive approach to improve the course of ERF and active supportive care, which can prevent complication from leakage, should be developed.

Background Recently PET is emerged as a method to estimate the response of neoadjuvant chemotherapy (NAC) in advanced breast cancer. This study is aimed to estimate the predictive role of PET CT and other imaging modalities (ultrasound, MRI) through NAC. Methods PET CT was acquired before and after NAC from 41 patients. Pathologic results were classified as pathological complete response (pCR) and non-pCR. The results of clinical responses were assessed with imaging indexes (postTx, postchemotherapy size or peak standardized uptake values (pSUV); delta, the size difference between treatment; RR, reduction rate of tumor size or pSUV), and they were compared with pathologic results. Results Seven patients (17.1%) showed pCR. As a result of comparison of the image index, all image indexes of MRI were predictive for pCR (P

One hundred and twenty-two patients in whom the CA 15-3 level showed either a decline (92 patients) or an acute surge followed by a decline (30 patients) after chemotherapy were included. The clinical characteristics between the two groups and the CA 15-3 kinetics using receiver operating characteristic curves were analyzed. Patients with a surge had a significantly higher risk of disease progression than patients without a surge (P = 0.004; odds ratio 2.62; 95% CI 1.45–4.72). The clinicopathologic characteristics were significantly different between the two groups with respect to the distribution of ER, PR, and HER2 status, relapse-free survival, and the severity and extent of the involved organs. For patients with a surge, a CA 15-3 slope threshold > −0.0038 was chosen with a sensitivity of 80.0% and a specificity of 80.4%. The area under the curve was 0.847 (95% CI 0.771–0.906; P = 0.0001). A significant correlation between PFS and CA 15-3 slope was shown with Cox-regression modeling (P = 0.036; hazard ratio [HR], 2.1; 95% CI 1.01–4.14).These kinetics may serve as a good predictive marker of treatment response and response duration.