Epstein-Barr virus-associated gastric cancer: disease that requires special approach.

Epstein-Barr virus-associated gastric cancer [EBV-associated GC, EBV( +) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV( +) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV( +) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease.

Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study.

BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer. METHODS: We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m(2) intravenously on day 1, cisplatin 60 mg/m(2) intravenously on day 1, capecitabine 625 mg/m(2) twice a day orally on days 1-21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550. FINDINGS: Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9-7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5-7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5-7·0) in both rilotumumab groups combined, and 4·2 months (2·9-4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49-0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38-0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45-0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3-4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none). INTERPRETATION: Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress. FUNDING: Amgen Inc.

Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes.

Background: Mutations in homologous recombination (HR) and Fanconi anemia (FA) genes may predispose to pancreatic cancer (PC) and enable the prediction of sensitivity to platinum-based chemotherapy. FOLFIRINOX is a standard treatment option for non-selected PC patients and could be effective due to undiagnosed DNA repair deficiency. Here, we aimed to determine the frequency of mutations in genes involved in the HR and FA pathways, evaluate their clinical implications, and determine the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of PC patients treated with platinum. Methods: We performed targeted DNA sequencing of 30 genes (ABRAXAS1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK1, CHEK2, FANCC, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, RAD52, RAD54B, RBBP8, RINT1, SLX4, and XRCC2) for 543 PC patients. Results: In BRCA/PALB2-mutated patients with advanced PC (33 patients, 6.1%), the PFS and OS were higher for first-line platinum therapy than for non-platinum therapy [PFS: HR = 0.28, 95% confidence interval (CI) = 0.10-0.81, p = 0.02; OS: HR = 0.31, 95% CI = 0.08-1.16, p = 0.08]. Among 93 patients (17.1%) with mutations in other HR/FA genes, no statistically significant difference in PFS and OS was observed between first-line platinum therapy and non-platinum therapy (PFS: HR = 0.83, 95% CI = 0.43-1.62, p = 0.59; OS: HR = 0.58, 95% CI = 0.28-1.22, p = 0.15). For patients with early PC, no prognostic value was observed for BRCA1/2, PALB2, or other HR/FA genes mutations. Moreover, a personal history of breast, ovarian, pancreatic, or prostate cancer was identified as the only independent predictor of the risk of BRCA/PALB2 mutations (HR = 5.83, 95% CI = 2.16-15.73, p < 0.01). Conclusion: Mutations in the BRCA1/2 and PALB2 genes increase the sensitivity of PC to platinum agents. Thus, alterations in these genes in PC patients must be determined prior to anticancer therapy.

Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort.

BACKGROUND: The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab. METHODS: We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495. FINDINGS: Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61-78; n=36 events] with trastuzumab, vs 56% [46-65; n=51 events] without; hazard ratio 0.59 [95% CI 0.38-0.90]; p=0.013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs. INTERPRETATION: The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses. FUNDING: F Hoffmann-La Roche.

Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice.

BACKGROUND: Prolgolimab is an IgG1 anti-PD-1 (programmed cell death protein 1) monoclonal antibody containing the Fc-silencing 'LALA' mutation. We assessed the efficacy and safety of two dosing regimens of prolgolimab in patients with advanced melanoma in a multicenter open-label parallel-arm phase II trial (MIRACULUM). We present the final analysis after 1 year of follow-up and additional efficacy results from 2 years of follow-up. METHODS: Patients with advanced cutaneous or non-cutaneous melanoma, including stable brain metastasis, without autoimmune disease and who underwent no prior targeted therapy, anti-PD-(L)1 or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) therapy were randomly assigned (1:1) to receive prolgolimab in 2 dosing regimens, 1 mg/kg every 2 weeks (arm 1) or 3 mg/kg every 3 weeks (arm 2), until disease progression or intolerable toxicity. Randomisation was stratified based on performance status (Eastern Cooperative Oncology Group 0 or 1), lactate dehydrogenase levels (elevated or normal) and prior systemic therapy (naive or previously treated). The primary outcome was the objective response rate, assessed as per immune-related Response Evaluation Criteria in Solid Tumours by independent central review. The hypothesis that each dosing regimen of prolgolimab has an overall response rate >28% was tested independently for each study arm comprising all patients who received at least one dose of prolgolimab. Exploratory assessment of efficacy, including subgroup analysis, at 2 years of follow-up was not specified in the protocol. This study is registered withClinicalTrials.gov(NCT03269565). RESULTS: Between August 2017 and March 2018, 126 patients with advanced melanoma were enrolled. At main 1-year data cut-off, the median follow-up was 13.8 and 14.5 months in arm 1 and 2, respectively. An objective response was observed in 38.1% of patients (arm 1) and in 28.6% (arm 2). Grade III-IV treatment-related adverse events occurred in 12.7% and 3.2% of patients in arm 1 and 2, respectively. For exploratory efficacy analysis, the median follow-up was 25.4 and 25.7 months in arm 1 and 2, respectively. The 2-year progression-free survival was 33.3% in arm 1 and 30.2% in arm 2, and the 2-year overall survival was 57.1% and 46.0%, respectively. CONCLUSIONS: The MIRACULUM study met its primary end-point in both the study arms. Prolgolimab showed significant antitumour activity and a manageable safety profile in patients with advanced melanoma.

Intratumoral Heterogeneity of SMAD4 Immunohistochemical Expression and Its Role in Prediction of Recurrence Pattern in Patients with Resectable Pancreatic Cancer.

BACKGROUND: The aim of our study was to evaluate consistency of SMAD4 expression in different tumor areas and its correlation with recurrence pattern in patients after resection for pancreatic cancer (PC). METHODS: Records of patients who underwent resection for nonmetastatic PC between 2001 and 2015 were analyzed. Formalin-fixed, paraffin-embedded tissue sections from different areas of primary tumor and lymph node metastases were analyzed immunohistochemically (IHC) for SMAD4 expression using TMA technology. RESULTS: SMAD4 expression was assessed in 356 tissue sections obtained from 91 patients. SMAD4 expression was positive in all assessed tumor slides only in 7 of 26 patients (26.9%). There were 54 recurrences (9 locoregional, 41 distant, and 4 both local and distant) with median follow-up of 21.7 months. There was no correlation between SMAD4 expression and locoregional recurrence pattern (p = 0.30). SMAD4 status influenced neither distant recurrence-free survival (p = 0.99) nor overall survival (p = 0.13). CONCLUSIONS: Different areas inside primary tumor and lymph node metastases express SMAD4 heterogeneously. SMAD4 IHC expression is not a biomarker of the recurrence pattern after surgical resection for PC.

A phase II study of pemetrexed and carboplatin in patients with locally advanced or metastatic breast cancer.

BACKGROUND: Pemetrexed and carboplatin have demonstrated activity in breast cancer. Their potential synergism in experimental models and the proven efficacy of pemetrexed/platinum in other indications make pemetrexed/carboplatin an attractive combination in breast cancer. Thus, this two-stage, sequential, open-label, multicenter, phase II study assessed the efficacy and safety of pemetrexed plus carboplatin as first-line therapy in patients with locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients >or= 18 years with a histologic/cytologic diagnosis and no prior chemotherapy for LABC or MBC received pemetrexed 600 mg/m(2) and carboplatin AUC 5.0 on day 1 every 21 days with folic acid and vitamin B(12) supplementation. RESULTS: From June 2003 to April 2005, 50 patients with stage IIIB (30.0%) and stage IV (70.0%) disease were enrolled at 3 study centers. Twenty-eight percent of patients previously received adjuvant chemotherapy, 46.0% had visceral metastases, and 36.0% had >or=3 organs involved. Partial responses (RECIST criteria) were achieved in 27 (54.0%) patients (ORR = 54.0%; 95% CI, 39.3-68.2%). The median response duration was 11.1 months (95% CI, 6.5-14.0 months) and the median time to disease progression was 10.3 months (95% CI, 8.3-14.6 months). CTC hematologic toxicities were grade 3/4 neutropenia (58.0%/28.0%) and grade 3 thrombocytopenia (10.0%) and anemia (18.0%). Two (4.0%) patients had febrile neutropenia, 1 of whom died. No grade 4 non-hematologic toxicities occurred. Grade 3 non-hematologic toxicities were ALT (4.0%) and AST elevation, and edema, fatigue, pruritus, rash/desquamation, and renal toxicity (2.0% each). CONCLUSIONS: Results of this study suggest that the combination of pemetrexed and carboplatin has promising efficacy and an acceptable safety profile. Further assessment of this combination in a randomized trial of various breast cancer patient populations is warranted.

Detection of ALK rearrangements in 4002 Russian patients: The utility of different diagnostic approaches.

BACKGROUND: Clinical guidelines highly recommended the detection of potentially targetable genetic aberrations such as anaplastic lymphoma kinase (ALK) rearrangements in patients with non-small cell lung cancer (NSCLC). Few methods, such as the ALK break apart FISH assay and IHC for ALK protein, are approved for routine diagnostics. However, some challenges exist in selecting the most reliable, robust and cost-effective algorithm, especially for large-scale screening of NSCLC patients. MATERIALS AND METHODS: A total of 4002 FFPE samples from Russian patients with NSCLC were tested for ALK rearrangement using two algorithms: FISH testing only (2334 samples) and IHC screening supported by FISH in positive or equivocal cases (1546 samples). Cross validation of the methods was performed blindly in 122 specimens. All discrepant IHC/FISH cases were examined for unbalanced 5'/3'-end ALK expression and variant-specific RT PCR. RESULTS: The sensitivity and specificity of IHC compared to FISH was 100% and 99%, respectively, therefore initial IHC screening was strongly supported. The prevalence of ALK rearrangements was estimated to be 7.8% and 6.6% for the FISH and IHC/FISH groups, respectively, with significant correlations for female gender, non-smoking status and age below 60. The use of FISH after IHC screening revealed 10 additional positive cases among equivocal samples (13.4%). Seven IHC/FISH cases (0.5% of the total group) characterized as discordant were reevaluated, and four were reclassified as truly discrepant. The PCR-based investigation revealed chimeric transcripts in IHC-/FISH+ and IHC+/FISH borderline samples, while no transcript was found in two IHC+/FISH- cases. CONCLUSION: These results reveal the utility of the two-step testing algorithm for the evaluation of potentially complicated cases with preanalytic defects, providing additional information for IHC equivocal cases without a significant increase in cost. The evaluation of discrepant cases appears to be necessary to better understand ALK biology and should be included in the routine testing algorithm.

Nuclear Protein of the Testis Midline Carcinoma Masquerading as a Primary Mediastinal Seminoma.

Nuclear protein of the testis (NUT) midline carcinomas are rare aggressive carcinomas characterized by chromosomal rearrangements that involve the gene encoding the NUT. This article reviews the clinicopathologic features and the differential diagnosis of these malignancies.

Distribution of EGFR Mutations in 10,607 Russian Patients with Lung Cancer.

INTRODUCTION: This study was aimed to evaluate distribution of epidermal growth factor receptor (EGFR) mutations in a large series of Russian lung cancer (LC) patients. METHODS: 10,607 LC samples were considered for EGFR analysis; EGFR status was successfully determined in 10,426 cases (98.3 %), indicating relatively low failure rate. RESULTS: EGFR mutations (ex19del and L858R) were detected in 1759/8716 (20.2 %) adenocarcinomas, 28/669 (4.2 %) squamous cell carcinomas (SCC) and 8/119 (6.7 %) large cell carcinomas. The occurrence of EGFR mutations in adenocarcinomas gradually increased with age, being attributed mainly to the increment of the L858R frequency in non-smokers (patients aged 18-30 years: 1/27 (3.7 %); 31-40 years: 5/98 (5.1 %); 41-50 years: 18/276 (6.5 %); 51-60 years: 102/944 (10.8 %); 61-70 years: 138/1011 (13.7 %); 71-80 years: 85/496 (17.1 %); 81-100 years: 5/27 (18.5 %); p < 0.0001). The EGFR mutation was detected in 804/2107 (38.2 %) non-smoking women versus 125/806 (15.5 %) non-smoking men (p < 0.0001), while the corresponding figures for smokers were 60/273 (22.0 %) versus 147/2214 (6.6 %) (p < 0.0001). The obtained gender-related data differ from the estimates obtained in Asian studies; they indicate that increased prevalence of EGFR mutations in white females may not be entirely attributed to the low prevalence of smoking, but is likely to be related to gender factors per se. CONCLUSION: Biological causes of distinct age- and gender-related distribution of EGFR mutations in LC deserve further investigation.

Prognostic factors and efficacy of different chemotherapeutic regimens in patients with mediastinal nonseminomatous germ cell tumors.

PURPOSE: Patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT) are belonged to poor prognostic group by IGCCCG. We retrospectively studied the prognostic factors and efficacy of different chemotherapeutic regimen in pts with MNGCT. METHODS: We analyzed data on 61 pts with MNGCT. Conditional induction chemotherapy BEP was performed in 38 %, TBEP-in 28 %, CBOP-in 28 %, accelerated (two weekly) version of BEP-in 6 % pts. Based on similar efficacy of CBOP and TBEP regimens, we combines pts with CPOB and TBEP regimen in one group-55.8 % and different variants of BEP regimen in the second group-44.2 %. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival. RESULTS: We revealed the following independent negative prognostic factors: age ≥ 24 years (p = 0.07), size of the primary mediastinal tumor ≥19 cm (p = 0.03). Median overall survival (OS) has not been reached, and 2-year OS was 66 % in pts with good prognosis (age < 24 years and/or size of mediastinal tumor < 19 cm) versus 15 months and 40 % in pts with poor prognosis (p = 0.03). Objective marker negative response was revealed more often in pts with CPOB/TBEP group: 26/34 (76.5 %) versus 14/27 (52 %), p = 0.08. Median OS was also higher in pts with CPOB/TBEP group: nonreached versus 15 months (p = 0.01). CONCLUSION: CPOB and TBEP regimen were significantly associated with better outcome in pts with MNGCT. Age ≥ 24 years and size of the primary mediastinal tumor ≥ 19 cm were found as independent negative prognostic factors.