ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

CREB-Regulated Transcriptional Coactivator 2 Proteome Landscape is Modulated by SREBF1.

cAMP response element-binding protein (CREB) regulated transcriptional coactivator 2 (CRTC2) is a critical transcription factor that maintains glucose homeostasis by activating CREB. Energy homeostasis is maintained through multiple pathways; therefore, CRTC2 may interact with other transcription factors, particularly under metabolic stress. CRTC2 liver-specific KO mice were created, and the global proteome, phosphoproteome, and acetylome from liver tissue under high-fat diet conditions were analyzed using liquid chromatography-tandem mass spectrometry and bioinformatics analysis. Differentially regulated proteins (DRPs) were enriched in metabolic pathways, which were subsequently corroborated through animal experiments. The consensus DRPs from these datasets were used as seed proteins to generate a protein-protein interaction network using STRING, and GeneMANIA identified fatty acid synthase as a mutually relevant protein. In an additional local-protein-protein interaction analysis of CRTC2 and fatty acid synthase with DRPs, sterol regulatory element binding transcription factor 1 (SREBF1) was the common mediator. CRTC2-CREB and SREBF1 are transcription factors, and DNA-binding motif analysis showed that multiple CRTC2-CREB-regulated genes possess SREBF1-binding motifs. This indicates the possible induction by the CRTC2-SREBF1 complex, which is validated through luciferase assay. Therefore, the CRTC2-SREBF1 complex potentially modulates the transcription of multiple proteins that fine-tune cellular metabolism under metabolic stress.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06).

BACKGROUND: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC. METHODS: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan). RESULTS: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy. CONCLUSIONS: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732).

MicroRNA 29a therapy for CEACAM6-expressing lung adenocarcinoma.

BACKGROUND: Non-coding microRNAs (miRNAs) play critical roles in tumor progression and hold great promise as therapeutic agents for multiple cancers. MicroRNA 29a (miR-29a) is a tumor suppressor miRNA that inhibits cancer cell growth and tumor progression in non-small cell lung cancer. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which plays an important role in lung cancer progression, has been identified as a target of miR-29a. Here, we evaluated the therapeutic efficacy of a peptide vector capable of delivering miR-29a intracellularly using the acidic tumor microenvironment in a lung adenocarcinoma xenograft mouse model. METHODS: A miRNA delivery vector was constructed by tethering the peptide nucleic acid form of miR-29a to a peptide with a low pH-induced transmembrane structure (pHLIP) to enable transport of the miRNAs across the plasma membrane. Tumor suppressive effects of pHLIP-miR29a on lung adenocarcinoma development in vivo were assessed using a BALB/c xenograft model injected with A549 cells. RESULTS: Incubation of A549 cells with pHLIP-miR-29a at an acidic pH downregulated endogenous CEACAM6 expression and reduced cell viability. Intravenous injection of the mice with pHLIP-miR-29a inhibited tumor growth by up to 18.1%. Intraperitoneal injection of cisplatin reduced tumor volume by 29.9%. Combined pHLIP-miR-29a + cisplatin treatment had an additive effect, reducing tumor volume up to 39.7%. CONCLUSIONS: Delivery of miR-29a to lung adenocarcinoma cells using a pHLIP-mediated method has therapeutic potential as a unique cancer treatment approach.

The new diagnostic criteria for myelodysplasia-related acute myeloid leukemia is useful for predicting clinical outcome: comparison of the 4th and 5th World Health Organization classifications.

Mutations in myelodysplasia-related (MR) genes, rather than morphological features, have been included in the diagnostic criteria of the new 5th World Health Organization (WHO) classification for myelodysplastic syndrome (MDS)-associated acute myeloid leukemia (AML). This study compares the clinical relevance of the new criteria with those of the previous version. In a cohort of 135 patients with newly diagnosed AML, the MDS-related AML patients were classified according to the 5th and 4th edition of the WHO classification (AML, myelodysplasia-related [AML-MR5th] and AML with myelodysplasia-related changes [AML-MRC4th], respectively). The median age of the patients was 70.4 years. MR gene mutations were found in 48 patients (35.6%). Sixty-one patients (46.6%) were diagnosed with AML-MRC4th, while 71 patients (53.0%) were diagnosed with AML-MR5th. Patients with AML-MR5th were significantly older with significantly lower treatment response rate, higher recurrence rate, and shorter relapse-free survival after chemotherapy, whereas AML-MRC4th patients did not show any association with the treatment outcome. Overall, the following prognostic factors for survival were identified: age over 75 years, antecedent MDS or MDS/myeloproliferative neoplasm, chromosome 5 or 7 abnormalities, and KRAS and ZSZR2 mutations. The 5th WHO classification is more useful for predicting the treatment response of patients with AML-MR than the previous version. Among the MR genes, ZSZR2 mutations were found to be independent prognostic factors affecting survival.

Ramucirumab plus paclitaxel as a second-line treatment in HER2-positive gastric cancer: subgroup analysis of a nationwide, real-world study in Korea (KCSG-ST19-16).

BACKGROUND: A subgroup analysis of data from a nationwide study (KCSG-ST19-16) was performed to evaluate the efficacy and safety of second-line ramucirumab plus paclitaxel treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma. METHODS: The KCSG-ST19-16 study enrolled a total of 1063 patients from 56 hospitals in South Korea with advanced gastric or GEJ adenocarcinoma, who had received second-line treatment with ramucirumab plus paclitaxel. HER2 status was known for 994 (93.5%) of these patients, who were thus included in the subgroup analysis. RESULTS: In total, 163 of 994 patients (16.4%), had HER2-positive gastric or GEJ adenocarcinoma. The objective response rate to ramucirumab plus paclitaxel treatment was significantly higher in patients with HER2-positive disease compared to those with HER2-negative disease (23.0% [95% confidence interval (CI), 15.9-30.1] vs. 15.1% [95% CI, 12.3-17.9], p = 0.025). The median progression-free survival was longer in patients with HER2-positive versus HER2-negative disease, but the difference was not statistically significant (4.3 months [95% CI, 3.7-5.3] vs 3.7 months [95% CI, 3.4-4.0], p = 0.054). There was no statistically significant difference in median overall survival (OS) between the groups (9.8 months [95% CI, 8.9-12.3] vs 10.1 months [95% CI, 9.2-10.9], p = 0.564). CONCLUSIONS: In patients with HER2-positive gastric or GEJ adenocarcinoma, the objective response rate to second-line treatment with ramucirumab plus paclitaxel was significantly higher compared to patients with HER2-negative disease. However, an increased response to treatment was not associated with an improvement in OS.

Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial).

BACKGROUND: In East Asia, S-1 plus cisplatin (SP) is one of the standard first-line chemotherapy regimens for metastatic or recurrent gastric cancer (MRGC). Oxaliplatin is generally less toxic and more convenient to administer than cisplatin. PATIENTS AND METHODS: This was a multicenter, phase III study assessing whether S-1/oxaliplatin (SOX) was non-inferior/superior to SP in terms of progression-free survival (PFS). Patients with MRGC were randomized 1:1 to receive either SOX (S-1 80 mg/m2/day on days 1-14; oxaliplatin 130 mg/m2 on day 1; every 3 weeks) or SP (S-1 80 mg/m2/day on days 1-14; cisplatin 60 mg/m2 on day 1; every 3 weeks [SP3]). RESULTS: Between October 2012 and October 2014, 338 patients were randomized. The median age was 56 years, and 51% of patients had measurable lesions. SOX was significantly non-inferior but not superior to SP3 in terms of PFS [median 5.6 versus 5.7 months; hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.67-1.07]. In patients with measurable disease, objective response rates were similar between SOX and SP3 (58% versus 60%). Overall, the survival in both groups did not differ (median 12.9 versus 11.4 months; HR 0.86; 95% CI 0.66-1.11). Treatment was well tolerated in both arms. Anemia, leucopenia, neutropenia, febrile neutropenia, and oral mucositis were more common with SP3. In contrast, thrombocytopenia, nausea, vomiting, and peripheral neuropathy were more common with SOX. CONCLUSIONS: SOX was non-inferior to SP3. The two regimens were well tolerated with different toxicity profiles. The SOX regimen can be recommended as a first-line treatment for MRGC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01671449.

The Prognostic Ability of RAS Pathway-Related Gene Mutations in Patients with Myeloid Neoplasms Treated with Hypomethylating Agents.

INTRODUCTION: This study aimed to identify genetic predictors of treatment response and survival in patients with myeloid neoplasms treated with hypomethylating agents (HMAs). METHODS: We performed next-generation sequencing on bone marrow aspiration samples of 59 patients diagnosed with acute myeloid leukemia (AML), myelodysplastic syndrome with excess blasts-2, or chronic myelomonocytic leukemia and treated with decitabine or azacitidine as a frontline therapy. RESULTS: A single gene with the most common mutations was TP53 (14 of 59 patients), and mutations in RAS pathway-related genes including KRAS, NRAS, FLT3, PTPN11, CBL, and KIT were found in 28.8% of patients. The overall response rate to HMAs was 33.9%. Predictive factors for a poor response were an age >75 years (p = 0.007), 3 or more gene mutations (p = 0.004), mutations in RAS pathway-related genes (p = 0.033), and a mutated NRAS gene (p = 0.042). An age >75 years (hazard ratio 2.946), diagnosis of AML (hazard ratio 2.915), and mutations in NRAS (hazard ratio 4.440) were identified as poor prognostic factors for survival. CONCLUSION: In conclusion, mutations in RAS pathway-related genes were predictors of a poor response to HMAs. Particularly, mutated NRAS was associated with inferior survival rates.

Analysis of EGFR mutation status in malignant pleural effusion and plasma from patients with advanced lung adenocarcinoma.

Background: Cell-free DNA (cfDNA) is emerging as a surrogate sample type for mutation analyses. We investigated the suitability of malignant pleural effusion (MPE) and plasma as a biomaterial for analyzing epidermal growth factor receptor (EGFR) mutation by peptide nucleic acid (PNA) clamping-assisted fluorescence melting curve (PANAMutyper™) analysis. Methods: Matched tissue, MPE cell block (MPE-CB), MPE supernatant, and plasma samples were collected from patients with advanced lung adenocarcinoma who had a MPE at the time of diagnosis. EGFR mutation was assessed by PANAMutyper™. Results: Mutation analyses in matched tumor tissues, MPE-CB, MPE supernatant, and/or plasma samples were available for 67 patients. In comparison with tumor tissue and MPE-CB, MPE supernatant exhibited 84.4% sensitivity, 97.1% specificity, 96.4% positive predictive value (PPV), and 87.2% negative predictive value (NPV). In the same comparison, plasma exhibited 70.6% sensitivity, 100.0% specificity, 100.0% PPV, and 73.7% NPV. When sorted by mutation type, MPE supernatant had better sensitivity than plasma for the detection of two major EGFR mutations: 93.8% vs. 75.0% for exon 19 deletion and 73.3% vs. 60.0% for L858R. Conclusions: In this cohort of patients with MPEs, MPE supernatant demonstrated superior diagnostic performance compared with plasma using a PNA-based real-time PCR method.

Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p as potential biomarkers for cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is from cholangiocytes, and therefore bile is a potentially rich source of biomarkers for CCA. The aim of the study was to identify and validate microRNAs (miRNAs) in bile samples that are differentially expressed between benign biliary disease (BBD) and CCA. METHODS: Bile samples from 106 patients with obstructive biliary disease were allocated consecutively to a discovery set (10 patients with BBD and 11 with CCA) and then a validation set (48 patients with BBD and 37 with CCA). An miRNA microarray platform was used to screen 1209 miRNAs in the discovery set. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the profiling results in the discovery and validation sets. In addition, the levels of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were determined from patient serum samples. RESULTS: Microarray profiling showed that miR-30d-5p and miR-92a-3p were significantly upregulated in bile from the CCA group compared with those from the BBD group. qRT-PCR results indicated that the expression levels of miR-30d-5p and of miR-92a-3p were significantly upregulated in the CCA group compared to the BBD group, validating the miRNA microarray results. Pathway analysis suggested that putative target genes of miR-30d-5p and of miR-92a-3p were involved in CCA-associated signalling pathways, such as Hippo, Wnt, p53, MAPK, and EGFR. Receiver operating curve analysis revealed that the areas under the curve for bile miR-30d-5p, miR-92a-3p, serum CA19-9, and CEA were 0.730, 0.652, 0.675, and 0.603, respectively, and bile miR-30d-5p showed the best diagnostic performance with a sensitivity of 81.1% and a specificity of 60.5%. CONCLUSIONS: The levels of extracellular miR-30d-5p and miR-92a-3p in bile were significantly higher in patients with CCA than those in patients with BBD. Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p are potential biomarkers for discriminating CCA from BBD.

The SMILE transcriptional corepressor inhibits cAMP response element-binding protein (CREB)-mediated transactivation of gluconeogenic genes.

Under fasting conditions, activation of several hepatic genes sets the stage for gluconeogenesis in the liver. cAMP response element-binding protein (CREB), CREB-regulated transcription coactivator 2 (CRTC2), and peroxisome proliferator-activated receptor γ coactivator 1-alpha (PGC-1α) are essential for this transcriptional induction of gluconeogenic genes. PGC-1α induction is mediated by activation of a CREB/CRTC2 signaling complex, and recent findings have revealed that small heterodimer partner-interacting leucine zipper protein (SMILE), a member of the CREB/ATF family of basic region-leucine zipper (bZIP) transcription factors, is an insulin-inducible corepressor that decreases PGC-1α expression and abrogates its stimulatory effect on hepatic gluconeogenesis. However, the molecular mechanism whereby SMILE suppresses PGC-1α expression is unknown. Here, we investigated SMILE's effects on the CREB/CRTC2 signaling pathway and glucose metabolism. We found that SMILE significantly inhibits CREB/CRTC2-induced PGC-1α expression by interacting with and disrupting the CREB/CRTC2 complex. Consequently, SMILE decreased PGC-1α-induced hepatic gluconeogenic gene expression. Furthermore, SMILE inhibited CREB/CRTC2-induced phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression by directly repressing the expression of these genes and by indirectly inhibiting the expression of PGC-1α via CREB/CRTC2 repression. Indeed, enhanced gluconeogenesis and circulating blood glucose levels in mice injected with an adenovirus construct containing a constitutively active CRTC2 variant (CRTC2-S171A) were significantly reduced by WT SMILE, but not by leucine zipper-mutated SMILE. These results reveal that SMILE represses CREB/CRTC2-induced PGC-1α expression, an insight that may help inform potential therapeutic approaches targeting PGC-1α-mediated regulation of hepatic glucose metabolism.

Discordance in HER2 status between primary gastric adenocarcinoma tumors and cells from the corresponding malignant effusions.

BACKGROUND: Metastasis of gastric cancer commonly manifests as a malignant effusion, which presents an alternative cell source for human epidermal growth factor receptor 2 (HER2) status identification. This study aimed to compare HER2 status in primary gastric adenocarcinoma tumors and corresponding cell blocks prepared from malignant effusions (CB-MEs). METHODS: HER2 status was retrospectively evaluated by immunohistochemistry (IHC) in primary gastric adenocarcinomas and paired pathologically confirmed CB-MEs of 45 patients. Silver in situ hybridization (SISH) was also performed in cases with IHC 2+ for primary gastric adenocarcinomas and above IHC 1+ for CB-MEs. RESULTS: HER2 positivity was observed in 4.4% (2/45) of primary gastric adenocarcinomas and 6.7% (3/45) of CB-MEs. The HER2 concordance rate between primary gastric adenocarcinomas and CB-MEs was 88.9% (40/45) (κ = - 0.056). All five patients with HER2 positivity in the primary tumor or a CB-ME had a negative result in the corresponding paired sample. Of the 15 patients with two or more serially sampled CB-MEs, HER2 expression determined by IHC differed between each CB-ME in six (40%) patients, and all three patients with HER2 positivity in CB-MEs exhibited HER2 positivity in one of the serially sampled CB-MEs. CONCLUSIONS: The HER2 positivity rate was very low in gastric cancer patients with malignant effusions. Our results suggest that HER2 positivity was discordant between the primary gastric adenocarcinoma and corresponding CB-MEs and among serially sampled CB-MEs. The possibility of detecting HER2 positivity can be improved if the primary gastric adenocarcinoma tumor as well as all the available CB-MEs from each patient are analyzed.

A phase I/II study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer.

BACKGROUND: Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC). METHODS: Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m2 infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks. RESULTS: In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8-21.9) and 29.5 weeks (95% CI 17.9-59.2), respectively. CONCLUSIONS: The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.

A Case of Acquired Amegakaryocytic Thrombocytopenia with Anti-c-mpl Autoantibody: Comparison with Idiopathic Thrombocytopenic Purpura.

Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare disease that causes severe bleeding. The pathogenesis and treatment of AAMT have not yet been defined. We report the case of a 60-year-old woman diagnosed with AAMT, who presented with severe thrombocytopenia, gastroin-testinal bleeding, and significantly reduced bone marrow megakaryocytes. The patient was treated with methylprednisolone, cyclosporin, and intravenous immunoglobulin. After 2 weeks of treatment, her platelet count started to increase, and her bone marrow megakaryocyte count had normalized 3 months after diagnosis. At the time of diagnosis, the patient was seropositive for anti-c-mpl antibody but was seen to be seronegative once the platelet count recovered. In contrast, anti-c-mpl antibodies were not detected in the serum of 3 patients with idiopathic thrombocytopenic purpura. This case study suggests that anti-c-mpl antibody plays an important role in the development of AAMT, and that intensive immunosuppressive treatment is required for autoantibody clearance and recovery of megakaryocyte count.

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

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

Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG).

BACKGROUND: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.

Cancer cost communication: experiences and preferences of patients, caregivers, and oncologists-a nationwide triad study.

PURPOSE: We assessed cost communication between cancer patients, caregivers, and oncologists and identified factors associated with communication concordance. METHODS: A national, multicenter, cross-sectional survey of patient-caregiver-oncologist triads was performed, and 725 patient-caregiver pairs, recruited by 134 oncologists in 13 cancer centers, were studied. Discordance in preferences and experiences regarding cost communication between patients, caregivers, and oncologists were assessed. Hierarchical generalized linear models were used to identify predictors of concordance and to identity the possible association of concordance with patient satisfaction and degree of trust in the physician. RESULTS: Although the oncologists thought that patients would be affected by the cost of care, only half of them were aware of the subjective burden experienced by their patients, and the degree of concordance for this parameter was very low (weighted kappa coefficient = 0.06). Caregivers consistently showed similar preferences to those of the patients. After controlling for covariates, the education level of patients [adjusted odds ratio (aOR) for > 12 vs. < 9 years, 2.92; 95% confidence interval (CI), 1.87-4.56], actual out-of-pocket costs [aOR for ≥ 8 million vs. < 2 million Korean Won, 0.56; 95% CI, 0.34-0.89], and physician age (aOR for ≥ 55 vs. < 45 years, 1.83; 95% CI, 1.04-3.21) were significant. CONCLUSIONS: The results show underestimation by oncologists regarding the subjective financial burden on a patient, and poor patient-physician concordance in cost communication. Oncologists should be more cognizant of patient OOP costs that are not indexed by objective criteria, but instead involve individual patient perceptions.

Feasibility and accessibility of electronic patient-reported outcome measures using a smartphone during routine chemotherapy: a pilot study.

PURPOSE: There is growing interest in integrating electronic patient-reported outcome (PRO) measures into routine oncology practice for symptom monitoring. Here, we evaluated the feasibility and accessibility of electronic PRO measures using a smartphone (PRO-SMART) for cancer patients receiving routine chemotherapy. METHODS: The proposed PRO-SMART application obtains daily personal health record (PHR) data from cancer patients via a smartphone. An analysis report of cumulative PHR data is provided to the clinician in a format suitable for upload to electronic medical records (EMRs). Cancer outpatients who had received at least two cycles of chemotherapy and who were scheduled for two more cycles were enrolled. RESULTS: Between February 2015 and December 2016, 111 patients were screened and 101 of these were included. One-hundred patients used PRO-SMART at least once and were included in the final analysis (90.1% overall accessibility among all screened patients). The number of symptomatic adverse events (AEs) related to chemotherapy recorded in EMRs (mean ± standard deviation [SD]) increased from 0.92 ± 0.80 to 2.26 ± 1.80 (P < 0.001), and grading of AEs increased from 0.81 ± 0.69 to 1.00 ± 0.62 (P = 0.029). After using PRO-SMART, the numeric rating scale for pain (mean ± SD) increased from 0.20 ± 0.72 to 0.99 ± 1.55 (P < 0.001). A patient-reported questionnaire revealed that 64.2% of patients found it useful and 83% found it easy to use. CONCLUSIONS: This study suggests that the proposed PRO-SMART is feasible and accessible for assessment of symptomatic AEs in cancer patients receiving chemotherapy for a prospective randomized trial.

Efficacy and Safety of FOLFIRI Regimen in Elderly Versus Nonelderly Patients with Metastatic Colorectal or Gastric Cancer.

BACKGROUND: Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients. PATIENTS AND METHODS: Using the patient cohort (n = 1,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC (n = 934) or GC (n = 611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy. RESULTS: Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345; p = .244, and HR, 0.989; 95% CI, 0.774-1.264; p = .931, respectively) and the GC cohort (HR, 1.093; 95% CI, 0.854-1.400; p = .479, and HR, 1.188; 95% CI, 0.891-1.585; p = .241, respectively). In both cohorts, febrile neutropenia (22.1% vs. 14.6% in CRC cohort and 35.2% vs. 22.5% in GC cohort) and asthenia (grade 3: 8.4% vs. 1.7% in CRC cohort and 5.5% vs. 2.9% in GC cohort) were more frequent in elderly patients. In the CRC cohort, mucositis and anorexia were more frequent in elderly patients. In the GC cohort, nausea and vomiting were less frequent in elderly patients. CONCLUSION: The efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia. The Oncologist 2017;22:293-303 IMPLICATIONS FOR PRACTICE: The efficacy of FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy in elderly patients with metastatic colorectal cancer or gastric cancer was similar to that in nonelderly patients. However, special attention should be paid to elderly patients because of the increased risk for febrile neutropenia and asthenia. These data suggest that the FOLFIRI regimen could be considered as a standard backbone of therapy in elderly patients with metastatic colorectal cancer or gastric cancer and that the clinical decision between doublet and singlet chemotherapy may not be based solely on age. However, the data require further assessment of frailty and performance status.

A Case of Pulmonary Langerhans Cell Sarcoma Simultaneously Diagnosed with Cutaneous Langerhans Cell Histiocytosis Studied by Whole-Exome Sequencing.

Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) are clonal proliferations of Langerhans-type cells. Unlike in LCH, the pathophysiology and clinical course of LCS are unclear due to its rarity. Here, we report the case of a 73-year-old male patient who was diagnosed with cutaneous LCH and pulmonary LCS at the same time. Pathological review of these 2 tumors revealed similar immunohistochemical findings. However, the tumor cells in LCS had more aggressive cytological features than those in LCH. Results of BRAF mutation analysis using real-time PCR were negative for both tumors. In whole-exome sequencing (WES), stop-gain mutations in TP53 gene were discovered only in LCS cells. The mechanism of development of LCS from various progenitor cells is currently unclear. According to the results of the WES study, changes in TP53 gene might have contributed to the malignant features of LCS.