Exploratory analysis of biomarkers associated with clinical outcomes from the study of palbociclib plus endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer

Background: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS. Patients and methods: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models. Results: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS <6 month. Conclusion: Of palbociclib plus ET, luminal type showed better prognosis and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy and resistance.ope

Implications of Tamoxifen Resistance in Palbociclib Efficacy for Patients with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Subgroup Analyses of KCSG-BR15-10 (YoungPEARL)

Purpose: YoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study. Materials and methods: Patients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC. Results: In total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients. Conclusion: This post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2- MBC patients irrespective of tamoxifen sensitivity.ope

Ramosetron versus Palonosetron in Combination with Aprepitant and Dexamethasone for the Control of Highly-Emetogenic Chemotherapy-Induced Nausea and Vomiting

Purpose: The purpose of this study was to compare ramosetron (RAM), aprepitant (APR), and dexamethasone (DEX) [RAD] with palonosetron (PAL), APR, and DEX [PAD] in controlling highly-emetogenic chemotherapy (HEC)-induced nausea and vomiting. Materials and methods: Patients were randomly assigned (1:1) to receive RAD or PAD:RAM (0.3 mg intravenously) or PAL (0.25 mg intravenously) D1, combined with APR (125 mg orally, D1 and 80 mg orally, D2-3) and DEX (12 mg orally or intravenously, D1 and 8 mg orally, D2-4). Patients were stratified by sex, cisplatin-based chemotherapy, and administration schedule. The primary endpoint was overall complete response (CR), defined as no emesis and no rescue regimen during 5 days of HEC. Secondary endpoints were overall complete protection (CP; CR+nausea score < 25 mm) and total control (TC; CR+nausea score < 5 mm). Quality of life was assessed by Functional Living Index Emesis (FLIE) questionnaire on D0 and D6. Results: A total of 279 patients receiving RAD (n=137) or PAD (n=142) were evaluated. Overall CR rates in RAD and PAD recipients were 81.8% and 79.6% (risk difference [RD], 2.2%; 95% confidence interval [CI], -7.1 to 11.4), respectively. Overall CP and TC rates for RAD and PAD were 56.2% and 58.5% (RD, -2.3%; 95% CI, -13.9 to 9.4) and 47.5% vs. 43.7% (RD, 3.8%; 95% CI, -7.9 to 15.5), respectively. FLIE total score ≥ 108 (no impact on daily life) was comparable between RAD and PAD (73.9% vs. 73.4%, respectively). Adverse events were similar between the two groups. Conclusion: In all aspects of efficacy, safety and QOL, RAD is non-inferior to PAD for the control of CINV in cancer patients receiving HEC.ope

CD44/CD24 and aldehyde dehydrogenase 1 in estrogen receptor-positive early breast cancer treated with tamoxifen: CD24 positivity is a poor prognosticator

CD44(+)/CD24(-) or aldehyde dehydrogenase 1 (ALDH1) has been suggested as a potential marker for breast cancer stem cells. In the cohort of 819 patients with resected ER-positive breast cancer, the '5-year relapse group' within 5 years postsurgery during adjuvant tamoxifen treatment and the 'non-relapse group' longer than 9 years postsurgery were defined. Paraffin-embedded tumor tissues were available in 31 patients from 5-year relapse group and 68 from the non-relapse group. CD44/ CD24 and ALDH1 expression was evaluated by immunohistochemical staining. Phenotypes of CD44/CD24 were CD44(+)/CD24(-) in one patient (1%), CD44(+)/CD24(+)in one patient (1%), CD44(-)/CD24(+) in 12 patients (12%), and CD44(-)/CD24(-) in 67 patients (68%). Four patients (4%) showed ALDH1-positivity. Due to the rarity of CD44-positivity or ALDH1-positivity, we dichotomized the patients into CD24-positive status (13%, 13/99 patients) and CD24-negative status (87%, 86/99 patients) only based on CD24 status, and only the status of CD24 was further analyzed. CD24-positivity was higher in the 5-year relapse group (32%) than in the non-relapse group (4%). CD24-positivity was associated with negative PR (P=0.026), higher N stage (P=0.029), and higher histologic grade (P=0.034). However, in the multivariate logistic regression adjusted for the known prognostic factors, CD24-positivity was still a significant predictive factor for 5-year relapse (hazard ratio=8.5; P=0.006). Our results indicated that the expression of CD24 was a significant poor prognostic factor in ER-positive early breast cancer treated with adjuvant tamoxifen. CD24 is worth further investigation as a novel biomarker for tamoxifen resistance beyond general aggressiveness of cancer cells.ope

Detection of Circulating Tumor Cells in Breast Cancer Patients Using Cytokeratin-19 Real-Time RT-PCR

PURPOSE: The roles of circulating tumor cells (CTCs) as predictive and prognostic factors, as well as key mediators in the metastatic cascade, have been investigated. This study aimed to validate a method to quantify CTCs in peripheral blood using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay for cytokeratin (CK)-19 and to evaluate the utility of this assay in detecting CTCs in breast cancer patients. MATERIALS AND METHODS: Real-time monitoring PCR of fluorescently labeled specific hybridization probes for CK-19 mRNA was established. Peripheral blood samples from 30 healthy donors, 69 patients with early breast cancer, 47 patients with locally advanced breast cancer, and 126 patients with metastatic breast cancer were prospectively obtained and analyzed for CTC detection. RESULTS: CK-19 mRNA was not detectable in healthy subjects using the real-time RT-PCR method. The detection rates of CK-19 mRNA in breast cancer patients were 47.8% for early breast cancer (33/69), 46.8% for locally advanced breast cancer (22/47), and 61.1% for metastatic breast cancer (77/129). The detection rate of CK-19-positive CTCs in metastatic disease was slightly higher than early or locally advanced breast cancer; however, the detection rate according to disease burden was not statistically different (p=0.097). The detection rate was higher in patients with pleural metastasis (p=0.045). CTC detection was associated with poor survival (p=0.014). CONCLUSION: A highly specific and sensitive CK-19 mRNA-based method to detect CTCs in peripheral blood in breast cancer patients can be used in further prospective studies to evaluate the predictive and prognostic importance of CTCs.ope

A case of combined hepatocellular-cholangiocarcinoma with favorable response to systemic chemotherapy

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare form of primary liver cancer composed of cells with histopathologic features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of its low incidence, the information on clinical outcomes of cHCC-CC is very limited and there are no published reports describing non-surgical treatment options for cHCC-CC. We report a case of cHCC-CC exhibiting a favorable response to systemic chemotherapy with doxorubicin and cisplatin. A 62-year-old man who recurred after a right lobectomy for cHCC-CC received sorafenib for palliative systemic therapy, but follow up imaging studies showed disease progression. He received 2nd line chemotherapy with doxorubicin at 60 mg/m(2) together with cisplatin at 70 mg/m(2). After 2 cycles of chemotherapy, a computed tomography scan of the chest showed markedly decreased size and number of the multiple lung metastases. After completing 8 cycles of 2nd line therapy, we changed the regimen to a fluorouracil (5-FU) mono therapy because of the toxicities associated with doxorubicin and cisplatin. To date, the patient has completed his 15th cycle of 5-FU mono therapy with the disease status remaining stable during 18 months of follow-up.ope

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OBJECTIVES: In our institutional experience, involved-field radiation therapy (IFRT) yields favorable outcomes in patients with recurrent epithelial ovarian cancer (EOC). This retrospective study aimed to investigate the clinical benefits of IFRT in this patient population. METHODS: Among patients treated with IFRT for recurrent EOC between 2010 and 2017, 61 patients with 90 treatments were included. IFRT encompassed all treatable lesions identified via imaging studies with 10-15-mm margins. Prescribed doses were ≥45 Gy (equivalent dose in 2 Gy/fraction). RESULTS: Patients were followed up for a median of 19.0 (Interquartile range, 8.6-34.9) months after IFRT. The 2-year in-field control, progression-free survival, and overall survival (OS) rates were 42.7%, 24.2%, and 78.9%, respectively. Fifty-three IFRT sessions (58.9%) were followed by systemic chemotherapy, and the median chemotherapy-free interval (CFI) was 10.5 (95% confidence interval=7.3-13.7) months. A higher carbohydrate antigen-125 (CA-125) level correlated with a worse 2-year OS (69.2% vs. 91.0%; p=0.001) and shorter median CFI (4.7 vs. 11.9 months; p12 months. For patients with a normal CA-125 level and/or platinum-sensitive tumor, IFRT prolonged CFI regardless of pre-existing carcinomatosis, gross tumor volume, and number of treatment sites. CONCLUSION: Our early experience demonstrates the safety and feasibility of IFRT as an effective salvage therapy and enables a "chemotherapy holiday" in selected recurrent EOC settings. The CA-125 value before IFRT (within normal range) and/or platinum sensitivity could be used as selection criteria for IFRT.ope

Cardiotoxicity evaluation using magnetic resonance imaging in breast Cancer patients (CareBest): study protocol for a prospective trial

Background: Cardiovascular disease is second only to cancer recurrence as a determinant of lifespan in cancer survivors, and cancer therapy-related cardiac dysfunction is a clinically important risk factor. We aim to investigate the use of cardiac magnetic resonance imaging (MRI) to evaluate early tissue changes and perform functional assessment of chemo- and radiation-induced cardiotoxicity and to identify MRI prognostic indicators of cardiotoxicity in breast cancer patients. Methods: A 3-min cardiac imaging protocol will be added to the breast MRI examination to diagnose cardiotoxicity in breast cancer patients. Standardized MRI-based evaluation of breast cancer and the left ventricular myocardium will be performed at baseline and at 3, 6, and 12 months and 2 years or more after cancer treatment. We will analyze both ventricular volume and ejection fraction (EF), strain of left ventricle (LV), native T1, extracellular volume fraction (ECV), and T2 values acquired in the mid LV. Discussion: The primary result of this study will be the comparison of the prognostic value of MRI parameters (native T1, ECV, both ventricular systolic function and LV strain) for cardiotoxicity. The endpoint is defined as the occurrence of a major adverse cardiac event (MACE). The secondary outcome will be an assessment of the temporal relationships between contractile dysfunction and microstructural injury over 4 years using MRI. This study will assess the usefulness of quantitative MRI to diagnose cardiotoxicity and will clarify the temporal relationships between contractile dysfunction and microstructural injury of the LV myocardium using MRI during breast cancer treatment. Trial registration: The protocol was registered at clinicaltrials.gov (Clinical trial no. NCT03301389) on October 4, 2017.ope

A Case of Meropenem-Resistant Ochrobactrum anthropi Bacteremia

Ochrobactrum anthropi is an oxidase-producing, non-lactose-fermenting, gram-negative bacillus that is frequently isolated from the environment including sinks, baths, soil, and hospital water sources. Recently O. anthropi have been reported as an emerging opportunistic pathogen in immunocompromised patients, particularly in those with indwelling venous catheters. Most O. anthropi were highly resistant to beta-lactam antibiotics except carbapenem. We report a case of O. anthropi bacteremia with an unusual pattern of antibiotic resistance compared to previous reports. A 47-year-old woman undergoing camptobell/cisplatin chemotherapy via indwelling venous catheter (chemoport) for stage IV ovarian cancer, had septicemia due to O. anthropi of unknown origin. The isolates were resistant to all beta-lactams and meropenem and susceptible to aminoglycoside, ciprofloxacin, and trimethoprim-sulfamethoxazole. She recovered from sepsis with combination treatment with imipenem and ciprofloxacin for 3 weeks.ope

Prevalence and prognostic implications of psychological distress in patients with gastric cancer

BACKGROUND: The aim of this study was to investigate the prevalence and prognostic significance of psychological distress in gastric cancer patients. METHODS: The study population included 229 gastric cancer patients visiting Yonsei Cancer Center between November 2009 and March 2011. The distress was measured by available tools including the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies-Depression Scale (CES-D). Patients with psychological distress were defined as those who scored above the cut-off values in both the MDT and either one of the HADS or CES-D. RESULTS: The median age of patients was 56 (range, 20 to 86) and 97 (42.4%) patients were with stage IV disease status at enrollment. The overall prevalence of psychological distress was 33.6% (95% CI: 27.5-39.8%) in 229 gastric cancer patients. In multiple logistic regression analysis, lower education level (odds ratio [OR] 2.39; 95% confidence interval [CI] 1.11-5.17, P = 0.026) and higher disease stage (OR 2.72; 95% CI 1.47-5.03, P = 0.001) were associated with psychological distress. In stage I-III disease, patients with psychological distress had worse disease-free survival (DFS) (5-year DFS rate: 60% vs 76%, P = 0.49) compared with those without psychological distress. In stage IV disease (n = 97), patients with psychological distress showed poorer overall survival than those without psychological distress (median OS (Overall Survival): 12.2 vs. 13.8 months, P = 0.019). CONCLUSION: Psychological distress is common in patients with all stages of gastric cancer and is associated with worse outcomes.ope