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Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies. Gastric cancer is commonly treated by chemotherapy using 5-fluorouracil derivatives and platinum combination, but predictive biomarker remains lacking. Here, the authors develop a 30-gene prediction model to determine the responsiveness to 5-fluorouracil and oxaliplatin-based chemotherapy through the integrative profiling of patient-derived xenografts [ABSTRACT FROM AUTHOR]

Although metabolic intratumoral heterogeneity (ITH) gives important value on treatment responses and prognoses, its association with treatment outcomes have not been reported in gastric cancer (GC). We aimed to evaluate temporal changes in metabolic ITH and the associations with treatment responses, progression-free survival (PFS), and overall survival (OS) in advanced GC patients. Eighty-five patients with unresectable, locally advanced, or metastatic GC were prospectively enrolled before the first-line palliative chemotherapy and underwent [18F]FDG PET at baseline (TP1) and the first response follow-up evaluation (TP2). Standardized uptake values (SUVs), volumetric parameters, and textural features were evaluated in primary gastric tumor at TP1 and TP2. Of 85 patients, 44 had partial response, 33 had stable disease, and 8 progressed. From TP1 to TP2, metabolic ITH was significantly reduced (P < 0.01), and the degree of the decrease was greater in responders than in non-responders (P < 0.01). Using multiple Cox regression analyses, a low SUVmax at TP2, a high kurtosis at TP2 and larger decreases in the coefficient of variance were associated with better PFS. A low SUVmax at TP2, larger decreases in the metabolic tumor volume and larger decreased in the energy were associated with better OS. Age older than 60 years and responders also showed better OS. An early reduction in metabolic ITH is useful to predict treatment outcomes in advanced GC patients. [ABSTRACT FROM AUTHOR]

Background: Polypharmacy is an important issue in the care of older patients with cancer, as it increases the risk of unfavorable outcomes. We estimated the prevalence of polypharmacy, potentially inappropriate medication (PIM) use, and drug–drug interactions (DDIs) in older patients with cancer in Korea and their associations with clinical outcomes. Subjects, Materials, and Methods: This was a secondary analysis of a prospective observational study of geriatric patients with cancer undergoing first‐line palliative chemotherapy. Eligible patients were older adults (≥70 years) with histologically diagnosed solid cancer who were candidates for first‐line palliative chemotherapy. All patients enrolled in this study received a geriatric assessment (GA) at baseline. We reviewed the daily medications taken by patients at the time of GA before starting chemotherapy. PIMs were assessed according to the 2015 Beers criteria, and DDIs were assessed by a clinical pharmacist using Lexi‐comp Drug Interactions. We evaluated the association between polypharmacy and clinical outcomes including treatment‐related toxicity, and hospitalization using logistic regression and Cox regression analyses. Results: In total, 301 patients (median age 75 years; range, 70–93) were enrolled; the most common cancer types were colorectal cancer (28.9%) and lung cancer (24.6%). Mean number of daily medications was 4.7 (±3.1; range, 0–14). The prevalence of polypharmacy (≥5 medications) was 45.2% and that of excessive polypharmacy (≥10 medications) was 8.6%. PIM use was detected in 137 (45.5%) patients. Clinically significant DDIs were detected in 92 (30.6%) patients. Polypharmacy was significantly associated with hospitalization or emergency room (ER) visits (odds ratio: 1.73 [1.18–2.55], p <.01). Neither polypharmacy nor PIM use showed association with treatment‐related toxicity. Conclusion: Polypharmacy, PIM use, and potential major DDIs were prevalent in Korean geriatric patients with cancer. Polypharmacy was associated with a higher risk of hospitalization or ER visits during the chemotherapy period. Implications for Practice: This study, which included 301 older Korean patients with cancer, highlights the increased prevalence of polypharmacy in this population planning to receive palliative chemotherapy. The prevalence of polypharmacy and excessive polypharmacy was 45.2% and 8.6%, respectively. The prescription of potentially inappropriate medications (PIMs) was detected in 45.5% and clinically significant drug–drug interaction in 30.6% of patients. Given the association of polypharmacy with increased hospitalization or emergency room visits, this study points to the need for increased awareness and intervention to minimize polypharmacy in the geriatric cancer population undergoing chemotherapy. Moreover, specific criteria for establishing PIMs should be adopted for the treatment of older adults with cancer. There is limited information on polypharmacy in Asian older adults with metastatic cancer, especially for those undergoing palliative chemotherapy. This article reports on the prevalence of polypharmacy, potentially inappropriate medication use, and potential drug‐drug interactions in older patients with cancer in Korea. [ABSTRACT FROM AUTHOR]

Purpose: Adjuvant chemotherapy in patients with breast cancer often causes hot flashes, impairing quality of life. However, the chronobiological or psychiatric factors associated with the development of chemotherapy-induced hot flashes (CIHFs) remain undetermined. The purpose of this study was to investigate whether chronotype was associated with the incidence of CIHFs. Methods: A total of 119 premenopausal women with non-metastatic breast cancer awaiting adjuvant chemotherapy after surgery without hot flashes were included. The presence of CIHF was defined as having moderate to severe hot flashes, as measured by the subscale of hot flashes in the Menopause Rating Scale, at 4 weeks after the completion of chemotherapy. Chronotype (Morning/Intermediate/Evening) was assessed with the Composite Scale of Morningness before adjuvant chemotherapy. To examine the association between chronotype and CIHF, we built logistic regression models, adjusting for age, body mass index, sleep quality, and radiation therapy. Results: CIHF occurred in 50.4% of participants. Morning type was inversely associated with CIHF (reference: Intermediate type, odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16–0.94; p = 0.040) in the univariate model, and the association remained significant (OR, 0.37; CI, 0.13–0.96; p = 0.045) after adjusting for age, body mass index, sleep quality, and radiation therapy. Conclusions: Morning chronotype is a protective factor against the development of CIHF in patients with breast cancer. Chronotypes should be assessed and considered in the prediction and management of CIHF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To explore whether integrated F-FDG PET/MRI can be used to predict pathological response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Methods: Between November 2014 and April 2016, 26 patients with breast cancer who had received NAC and subsequent surgery were prospectively enrolled. Each patient underwent F-FDG PET/MRI examination before and after the first cycle of NAC. Qualitative MRI parameters, including morphological descriptors and the presence of peritumoral oedema were assessed. Quantitatively, PET parameters, including maximum standardized uptake value, metabolic tumour volume and total lesion glycolysis (TLG), and MRI parameters, including washout proportion and signal enhancement ratio (SER), were measured. The performance of the imaging parameters singly and in combination in predicting a pathological incomplete response (non-pCR) was assessed. Results: Of the 26 patients, 7 (26.9%) exhibited a pathological complete response (pCR), and 19 (73.1%) exhibited a non-pCR. No significant differences were found between the pCR and non-pCR groups in the qualitative MRI parameters. The mean percentage reductions in TLG on PET and SER on MRI were significantly greater in the pCR group than in the non-pCR group (TLG −64.8 ± 15.5% vs. −25.4 ± 48.7%, P = 0.005; SER −34.6 ± 19.7% vs. −8.7 ± 29.0%, P = 0.040). The area under the receiver operating characteristic curve for the percentage change in TLG (0.789, 95% CI 0.614 to 0.965) was similar to that for the percentage change in SER (0.789, 95% CI 0.552 to 1.000; P = 1.000).The specificity of TLG in predicting pCR) was 100% (7/7) and that of SER was 71.4% (5/7). The sensitivity of TLG in predicting non-pCR was 63.2% (12/19) and that of SER was 84.2% (16/19). When the combined TLG and SER criterion was applied, sensitivity was 100% (19/19), and specificity was 71.4% (5/7). Conclusion: F-FDG PET/MRI can be used to predict non-pCR after the first cycle of NAC in patients with breast cancer and has the potential to improve sensitivity by the addition of MRI parameters to the PET parameters. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy, that is, the administration of chemotherapy before surgery, has been commonly used for locally advanced breast cancer to improve the surgical outcomes and increase the opportunity for breast-conserving therapy. Women with breast cancer often receive an anthracycline-based regimen as the neoadjuvant chemotherapy, which is associated with a high risk of emesis. Despite the development of novel antiemetics, chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as a major adverse effect, affecting the quality of life of the patients. However, the factors predicting CINV in women with breast cancer undergoing neoadjuvant chemotherapy remain unclear. In this single-institution, prospective, observational study conducted at an outpatient cancer centre in the Republic of Korea from November 2013 to March 2016, we analysed women with breast cancer who planned to be treated with neoadjuvant chemotherapy before surgery. Candidate factors associated with CINV were assessed before neoadjuvant chemotherapy using the Munich Chronotype Questionnaire, Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale. CINV was assessed after chemotherapy by using the Multinational Association of Supportive Care in Cancer Antiemesis Tool. Of a total of 143 participants, 7 patients were lost to follow-up and 2 patients were excluded due to changes in their treatment plan; thus, 134 patients were finally included in the analyses. Overall, 48.5% of the participants experienced CINV, with delayed CINV prevalence (42.5%) being more common than acute (39.6%). In the univariate analyses, overall CINV was significantly associated with late chronotypes (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.37–8.87;p= 0.009), a history of nausea/vomiting (OR, 2.19; 95% CI, 1.10–4.37;p= 0.026) and anxiety (OR, 2.25; 95% CI, 1.05–4.81;p= 0.036). In the multivariate analyses, late chronotypes (OR, 3.53; 95% CI, 1.27–9.79;p= 0.015) and a history of nausea/vomiting (OR, 2.83; 95% CI, 1.31–6.13;p= 0.008) remained significantly associated with CINV. In conclusion, in women with breast cancer undergoing neoadjuvant chemotherapy before surgery, late chronotypes were found to have an increased risk of CINV; these data suggest that clinicians need to assess and consider the chronotype in the management of CINV. [ABSTRACT FROM PUBLISHER]

Background: Cytopenia occurs frequently during cytotoxic chemotherapy. Little is known about the optimal timing of influenza vaccination for patients receiving chemotherapy. This study compared the immunogenicity of an influenza vaccine administered concurrently with chemotherapy (day 1) and within the cytopenic period (day 11) during 3-week cytotoxic chemotherapy cycles.Methods: Adult patients with solid cancer undergoing scheduled 3-week cytotoxic chemotherapy were randomly assigned to receive the 2014-2015 seasonal influenza vaccine on day 1 or 11 during the chemotherapy cycle. Patients were stratified by their age (<60 and ≥60 years) and previous influenza vaccination status. Antibody responses to influenza vaccine strains H1N1, H3N2, and B were measured before and 21 to 28 days after vaccination with a hemagglutination inhibition antibody assay.Results: Ninety-seven patients were randomized into a day 1 group (n = 43) or a day 11 group (n = 54). Eighty-three patients were included in the final analysis. The mean age was 54 (± 11) years. Cancer types included breast (61%) and lung cancer (30%). Baseline characteristics were not significantly different between the groups. Seroprotection rates after vaccination were also not significantly different for the day 1 and 11 groups (strain H1N1, 67% vs 75% [P = .403]; strain H3N2, 77% vs 80% [P = .772]; strain B, 21% vs 27% [P = .472]). Seroconversion rates and postvaccination geometric mean titers were also similar for the groups. Vaccine-related adverse events were more common in the day 11 group (13% vs. 32%; P = .040).Conclusions: The antibody responses to influenza vaccination on days 1 and 11 during a 3-week cytotoxic chemotherapy cycle were comparable. Influenza vaccination can be performed concurrently with cytotoxic chemotherapy or during the cytopenic period. Cancer 2017;123:841-48. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Little is known about cytokine and angiogenic factors (CAFs) in gastric cancer (GC) in terms of tumor classification and prognostic value. Here, we aimed to correlate CAF signature with overall survival (OS) in GC. Methods: We measured pretreatment serum levels of 52 kinds of CAFs in 68 GC patients who were treated with fluoropyrimidine and platinum combination chemotherapy using multiplex bead immunoassays and enzyme-linked immunosorbent assay. We evaluated correlations between CAF levels and pathological features and OS. Results: Three distinct patient groups were identified: one with high levels of proangiogenic factors, another with high levels of proinflammatory factors, and the other with high levels of both factors. Eleven CAFs [interleukin (IL)-2 receptor-alpha, growth-regulated alpha protein, hepatocyte growth factor, macrophage colony-stimulating factor, stromal cell-derived factor, IL-6, IL-8, IL-10, interferon-gamma, vascular endothelial growth factor, and osteopontin] were independently correlated with poor OS. Clustering analysis of these 11 CAFs revealed distinct high and low 11-CAF signature groups. High 11-CAF signature was associated with shorter OS (10.1 vs. 17.9 months, p = 0.026) along with poor performance status, and the presence of signet ring cell components in multivariate analysis of OS (HR 1.76, p = 0.029). The patients' traditional clinicopathological characteristics were not significantly different between the high and low 11-CAF signature groups. Conclusion: Serum CAF profiling differentiated GC patient groups. A high 11-CAF signature could identify GC patients with a poor prognosis when treated with standard chemotherapy who need urgent new treatment strategies. [ABSTRACT FROM AUTHOR]

Objectives: To investigate usefulness of multiparametric fully integrated 18-FDG PET/MRI in predicting treatment response after chemotherapy for unresectable advanced gastric cancers (AGCs).Methods: Eleven patients with unresectable AGCs underwent multiparametric 18-FDG PET/MRI examinations prior to chemotherapy. Perfusion parameters obtained via dynamic contrast-enhanced MRI, apparent diffusion coefficient values from diffusion-weighted images, and maximum standardized uptake values (SUVmax) from 18-FDG PET were measured. For parameters obtained from 18-FDG PET/MRI data, interobserver agreement was obtained using intraclass correlation coefficients (ICC) and chemotherapy response relationship was evaluated using the Mann-Whitney test and receiver operating characteristic analysis.Results: After chemotherapy, six patients were classified into the responder group and five patients into the non-responder group. For all parameters, moderate to nearly perfect agreement was achieved (ICC = 0.452-0.911). K (trans) values (P = 0.018) and initial area under the curves (iAUCs) (P = 0.045) of gastric cancers were significantly higher in responder group than in non-responder group. The area under the curve was 0.917 for K (trans) and 0.867 for iAUC. However, SUVmax values were not significantly different between the two groups.Conclusion: Multiparametric approach using fully integrated 18-FDG PET/MRI was shown to be feasible for patients with unresectable gastric cancers. In addition, K (trans) and iAUC values can be used as early predictive markers for chemotherapy response.Key Points: • Multiparametric 18-FDG PET/MRI is feasible for patients with unresectable advanced gastric cancer • K (trans) and iAUC were significantly higher in the responder group of patients • K (trans) , iAUC can be utilized as early predictive markers for chemotherapeutic response. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NAC) is a standard treatment for stage II/III breast cancer patients, and response to NAC is a useful prognostic marker. Since its introduction, 6-8 cycles of NAC has become the standard regimen to improve the outcome of these patients. The purpose of this study is to evaluate the prognostic impact of the American Joint Committee on Cancer (AJCC) response criteria and this tool's usefulness in four different breast cancer subtypes.Methods: We conducted a retrospective cohort study of clinical stage II/III breast cancer patients who received NAC of more than 6 cycles. Response after NAC and the clinicopathological factors were reviewed. AJCC response criteria for NAC were adopted from the AJCC Manual, 7th edition: complete response (CR), partial response (PR), and no response (NR).Results: A total of 183 patients were enrolled; 22 (12.0 %), 123 (67.2 %), and 38 (20.8 %) patients showed CR, PR, and NR, respectively. The AJCC response was significantly associated with relapse-free survival (RFS) (P < 0.001), whereas pathologic CR (pCR), the current gold standard for response evaluation for NAC, was not (P = 0.140). AJCC response was a significant prognostic factor for RFS in all four breast cancer subtypes, namely luminal A (P = 0.006), luminal B (P = 0.001), HER-2 enriched (P = 0.039), and triple-negative breast cancer (P = 0.035).Conclusions: The AJCC response criteria represent a simple and easily reproducible tool for response evaluation of NAC patients and a useful clinical prognostic marker for RFS. These criteria also have a prognostic impact in all four breast cancer subtypes, including luminal A in which pCR has a limited role. [ABSTRACT FROM AUTHOR]

Objectives: To prospectively compare performances of single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting pathologic response to neoadjuvant chemotherapy (NAC) in breast cancer patients.Methods: Thirty-five breast cancer patients who received NAC and subsequent surgery were prospectively enrolled. MRS and FDG-PET were performed before and after the 1st NAC cycle. Percentage changes of total choline-containing compounds (tCho) via MRS, and maximum and peak standardized uptake values (SUVmax, SUVpeak) and total lesion glycolysis (TLG) via FDG-PET were measured, and their performances in predicting pathologic complete response (pCR) were compared.Results: Of the 35 patients, 6 showed pCR and 29 showed non-pCR. Mean % reductions of tCho, SUVmax, SUVpeak, and TLG of the pCR group were larger than those of the non-pCR group (-80.3 ± 13.9 % vs. -32.1 ± 49.4 %, P = 0.025; -54.7 ± 22.1 % vs. -26.3 ± 33.7 %, P = 0.058; -60.7 ± 18.3 % vs. -32.3 ± 23.3 %, P = 0.009; -89.5 ± 8.5 % vs. -52.6 ± 36.2 %, P = 0.020). Diagnostic accuracy (area under ROC curve; Az, 0.911) of the % reduction of tCho was comparable to those of %SUVmax (0.822), SUVpeak (0.862), and TLG (0.879) in distinguishing pCR from non-pCR (all P > 0.05).Conclusion: MRS showed comparable performance to FDG-PET in early prediction of pCR in breast cancer patients.Key Points: • MRS can predict response to NAC in breast cancer post-1 (st) cycle. • Changes in tCho and SUV after NAC reflect tumour cellularity changes. • MRS can be an alternative to FDG-PET in predicting response to NAC. [ABSTRACT FROM AUTHOR]

As small bowel adenocarcinoma (SBA) is a rare cancer worldwide, prognostic factors have not been clearly defined. The purpose of this study is to assess the prognostic role of clinicopathologic features, including body mass index (BMI), in patients with advanced SBA. A total of 28 consecutive patients with advanced SBA treated with palliative chemotherapy were retrospectively enrolled and analyzed. Clinicopathologic features, progression-free survival (PFS), and overall survival (OS) were compared according to BMI level. Eighteen patients had BMI < 25 kg/m2(overweight/normal/underweight in Asian) and ten patients had BMI ≥ 25 kg/m2(obese in Asian). Baseline characteristics were similar regardless of patient's BMI. Compared to patients with BMI < 25 kg/m2, patients with BMI ≥ 25 kg/m2had higher response rate to chemotherapy (40.0% vs. 0%,P= 0.010), longer OS (11.2 vs. 7.0 months,P= 0.018) and a tendency toward prolonged PFS (2.1 vs. 1.9 months,P= 0.085). Multivariate analysis revealed that BMI ≥ 25 kg/m2is an independent positive prognostic factor of OS (adjusted hazard ratio 0.35,P= 0.024). In conclusion, baseline BMI ≥ 25 kg/m2has a positive prognostic role in patients with advanced SBA. [ABSTRACT FROM PUBLISHER]

Background: In advanced gastric cancer (AGC), HER2 is a validated therapeutic target. However, the metabolic landscape of AGC based on HER2 status has not been reported. Furthermore, the prognostic value of HER2 in AGC is under debate. The purpose of this study was to determine the metabolic landscape and prognosis on the basis of HER2 status in AGC. Methods: We analyzed 866 AGC patients treated with palliative chemotherapy and whose HER2 status was evaluated. HER2 positivity was defined as HER2 IHC 3+ or HER2/CEP17 ratio ≥2. Among them, 363 patients were evaluated with F FDG-PET before chemotherapy. We analyzed mSUV (maximal standardized uptake value) according to HER2 status and clinical outcomes. Results: Among 866 patients, 225 (26.0 %) had HER2+ GC. The mSUV of HER2+ GC was significantly higher than that of HER2− GC (12.6 vs. 8.7, p < 0.001). Increased HER2 IHC positivity was correlated with increased mSUV (IHC−: 8.1, IHC 1+: 8.2, 2+: 11.4, 3+: 13.2, p < 0.001). Excluding HER2+ patients who received HER2-targeting agents, OS of patients was not different by HER2 status (12.5 vs. 11.9 months, p = 0.688). However, according to tumor metabolism, patients with higher mSUV showed worse OS regardless of HER2 positivity (mSUV < 12.8:14.8, ≥12.8:8.6 months, p < 0.001). Conclusion: Tumor metabolism of AGC adversely influenced OS under treatment with cytotoxic chemotherapy. Tumor metabolism was higher in HER2+ AGC than HER2−. However, HER2 was not a prognostic factor in patients who received chemotherapy without HER2-targeting agents. [ABSTRACT FROM AUTHOR]

Background: Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients with advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC. Methods: We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated the initial body mass index (BMIi), percent weight loss after 1 month of chemotherapy (Δ Wm), percent weight loss after last administration of chemotherapy (Δ W), and average weight loss per month during chemotherapy (Δ W/m). We correlated these data with overall survival (OS) by receiver-operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression. Results: The probabilities of longer OS had stronger correlations with Δ W/m and Δ Wm than with Δ W or BMIi. A significant positive correlation between Δ Wm and Δ W/m ( r = 0.591, p < 0.001) was observed. Median OS of patients with Δ Wm more than 3 % was significantly shorter than in patients with less weight loss (OS: 9.7 vs. 16.3 months, p < 0.001). Subgroup analysis revealed that Δ Wm accompanied poor survival irrespective of other clinical characteristics. Conclusion: Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC. [ABSTRACT FROM AUTHOR]

Purpose: In stage II/III breast cancer, neoadjuvant chemotherapy (NAC) is a standard treatment. Although several biomarkers are used to predict prognosis in breast cancer, there is no reliable predictive biomarker for NAC success. Recently, the hepatocyte growth factor (HGF) and cMet signaling pathway demonstrated to be involved in breast cancer tumor progression, and its potential as a biomarker is under active investigation. In this study, we assessed the potential of serum HGF as a prognostic biomarker for NAC efficacy. Methods: Venous blood samples were drawn from patients diagnosed with stage II/III breast cancer and treated with NAC in Seoul National University Hospital from August 2004 to November 2009. Serum HGF level was determined using an ELISA system. We reviewed the medical records of the patients and investigated the association of HGF level with patients' clinicopathologic characteristics. Results: A total of 121 female patients (median age = 45 years old) were included. Median level of HGF was 934 pg/ml (lower quartile: 772, upper quartile: 1145 pg/ml). Patients with higher HGF level than median value were significantly more likely to have clinically detectable regional node metastasis ( p = 0.017, Fisher's exact test). Patients with complete and partial response according to the American Joint Committee on Cancer 7th Edition criteria tended to have higher HGF level ( p = 0.105 by t test). Patients with an HGF level higher than the upper quartile value had longer relapse-free survival than the other patients (106 vs. 85 months, p = 0.008). Conclusions: High serum HGF levels in breast cancer patients are associated with clinically detectable regional node metastasis and, paradoxically, with longer relapse-free survival in stage II/III breast cancer. [ABSTRACT FROM AUTHOR]

Capecitabine is an orally administered prodrug of 5-fluorouracil (5-FU) and was designed to specifically affect tumor cells more than normal tissues. Capecitabine is as effective and well tolerated as infusional 5-FU in the treatment of advanced gastric cancer (AGC). Following the REAL-2 and ML17032 studies, capecitabine has replaced infusional 5-FU for treating GC. Capecitabine plus platinum is one of the most widely used regimens for the first-line treatment of AGC, regardless of HER2 status. The adjuvant capecitabine/oxaliplatin regimen is one therapeutic option for resectable gastric cancer, especially after D2 resection. Compared with S-1, capecitabine has been shown to have a similar efficacy, but is associated with fewer ethnic differences than S-1, which accounts for the more widespread usage of capecitabine worldwide. [ABSTRACT FROM PUBLISHER]

Background: This is a phase I/II study of second-line chemotherapy with paclitaxel and irinotecan in fluoropyrimidine- and platinum-pretreated patients with metastatic or recurrent gastric cancer. Methods: Phase I part with a standard 3 + 3 dose-escalation design was conducted to define the recommended phase II dose (RP2D) using four predefined dose levels of paclitaxel and irinotecan. The efficacy of RP2D was evaluated in a phase II part. Results: In phase I part, 12 patients were enrolled. Dose-limiting toxicity was not observed. The RP2D was established as level 4 (paclitaxel-135 mg/m and irinotecan-160 mg/m, every 3 weeks). In phase II part, 27 patients were enrolled. Thirty patients, including three patients at dose level 4 in the phase I part, were analyzed for efficacy. There was no complete response. Partial response and stable disease were reported in four and 16 patients, respectively (response rate 13.3 %, 95 % CI 0.0-25.5 %; disease control rate 66.6 %, 95 % CI 49.0-83.0 %). The median time to progression and overall survival was 3.0 months (95 % CI 1.8-4.2) and 10.1 months (95 % CI 6.6-13.6), respectively. Grade 3/4 toxicities included neutropenia (2 patients, 7.4 %), thrombocytopenia (1, 3.7 %), neutropenic fever (1, 3.7 %), and diarrhea (1, 3.7 %). There were no treatment-related deaths. Conclusion: The RP2D of the paclitaxel and irinotecan combination is paclitaxel (135 mg/m) and irinotecan (160 mg/m), every 3 weeks. This combination as a second-line treatment for advanced gastric cancer shows tolerable toxicity and modest efficacy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficacy of gemcitabine plus uracil-tegafur (UFT) combination chemotherapy as a salvage treatment in patients with metastatic colorectal cancer (MCRC). Methods: This single-arm phase II study was conducted at three institutions in Korea. Patients with MCRC refractory to fluoropyrimidine, oxaliplatin and irinotecan were enrolled. Gemcitabine 800 mg/m was administered intravenously on days 1, 8 and 15. UFT 200 mg/m/day was taken orally in three divided doses on days 1-21. Cycles were repeated every 4 weeks, and tumor evaluation was carried out every 8 weeks. The primary endpoint of this study was 8-week progression-free survival (PFS) rate. Results: Forty-one patients were enrolled. Fourteen patients received gemcitabine/UFT as a third-line treatment and 37 patients as a fourth-line or later-line therapy. Toxicities were easily manageable, and non-hematologic toxicities of ≥grade 3 were rare. The most common toxicity of ≥grade 3 was neutropenia (20.0 %). One patient showed partial response (response rate, 2.4 %) and 14 (34.1 %) showed stable disease. The 8-week PFS rate was 42.3 %. The median PFS was 1.7 months [95 % confidence interval (CI) 1.6-1.8 months], and the median overall survival was 9.2 months (95 % CI 5.8-12.6 months). Conclusions: Overall efficacy of gemcitabine/UFT in refractory MCRC was unsatisfactory. However, we could find a minor proportion of patients who showed prolonged tumor stabilization to gemcitabine/UFT. Further studies are warranted to identify a patient subgroup that might have benefits from gemcitabine/UFT therapy. [ABSTRACT FROM AUTHOR]

Purpose: Epidermal growth factor (EGF) is a ligand for the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor 2 (HER2) shares common signal pathways and forms a heterodimer with EGFR. In this study, we investigated the clinical and pathologic implications of serum EGF levels in patients with HER2-positive metastatic breast cancer (MBC). Methods: We analyzed serum EGF levels from baseline serum samples of consecutive patients with HER2-positive MBC who received first-line trastuzumab plus taxane chemotherapy and correlated them with treatment outcomes and pathologic features. Results: A total of 50 women were analyzed. The median age was 47 years (range 27-72 years). Patients with high serum EGF levels (≥10.0 pg/mL) had significantly longer overall survival (47.0 months (95 % confidence interval (CI) 28.3-65.7 months) vs. 23.3 months (95 % CI 13.5-33.1 months); p = 0.009) with a tendency toward longer progression-free survival ( p = 0.123). Serum EGF levels were not associated with hematologic or cardiac adverse events. Progesterone receptor-positive patients had significantly higher serum EGF levels than progesterone receptor-negative patients (24.3 pg/mL (range 9.5-69.0 pg/mL) vs. 12.3 pg/mL (range 0.0-59.5 pg/mL); p = 0.006). Conclusions: Our data suggest that high serum EGF levels may be associated with good prognosis in patients with HER2-positive MBC receiving trastuzumab plus taxane chemotherapy. In addition, serum EGF levels were associated with progesterone receptor positivity. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes. Methods: Eligibility included age 18-75 years, at least one measurable lesion, no prior chemotherapy except adjuvant chemotherapy, and Eastern Cooperative Oncology Group Performance Status (PS) 0-2. S-1 40 mg/m b.i.d. on days 1-7 with 85 mg/m of oxaliplatin on day 1 was repeated every 2 weeks. Genomic DNA from whole blood was analyzed for 15 single-nucleotide polymorphisms (SNPs) among 8 genes. Results: Fifty-two patients (median age 63 years, range 37-74) were enrolled: 37 men and 15 women; 44 with a PS of 0 and 8 with a PS of 1; and 41 with initially metastatic cancer and 11 with relapsed disease. Among 51 evaluable patients, objective response rate was 47.1% [95% confidence interval (CI) 32.9-61.2]. Median follow-up duration was 17.1 months (range 3.9-28.2 months). Median progression-free survival (PFS) was 6.4 months (95% CI 4.8-8.1), and median overall survival had not been reached yet. Reported grade 3 toxicities were neutropenia (7.7%), thrombocytopenia (5.8%), sensory neuropathy (7.7%) and diarrhea (1.9%). There was no grade 4 toxicity or neutropenic fever. Patients with A/G or G/G genotype in GSTP1 Ile105Val SNP had longer PFS than patients with A/A (median 8.3 vs. 6.1 months, P = 0.04). Conclusions: Biweekly S-1 with oxaliplatin is effective and has improved tolerability and convenience compared to other fluoropyrimidine with oxaliplatin combinations. GSTP1 Ile105Val SNP is associated with treatment outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Arbitrary upfront dose reduction (UDR) of palliative chemotherapy has often been performed according to the judgement of the physician of older adults with metastatic solid cancer in current practice. UDR might decrease treatment efficacy in older adults but may be helpful for palliation, so selecting older adults who benefit from UDR and the identification of predictors of UDR are required. The authors investigated the prevalence and predictors of UDR through variables of geriatric assessment (GA). Chemotherapy compliance between the UDR and standard dose patient groups was also compared. The results of this study demonstrated that approximately 60% of older adults with metastatic solid cancer received UDR. Poor performance status (PS) and living without a spouse were predictive factors of UDR of first-line palliative chemotherapy, and patients with UDR better-tolerated chemotherapy compared with patients with standard doses. Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (≥70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4–47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3–5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose. [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib. [ABSTRACT FROM AUTHOR]

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 < 0.0001 ). 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. [ABSTRACT FROM AUTHOR]