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.

Preoperative chemotherapy in patients with resectable esophageal carcinoma: a single center Phase II study.

OBJECTIVE: The role of preoperative chemotherapy in squamous cell esophageal carcinoma remains controversial. A prospective trial was initiated to investigate whether preoperative chemotherapy followed by surgery results in increased progression-free survival in patients with resectable thoracic esophageal carcinoma. METHODS: Patients with Stage IIb-IIIa/b resectable esophageal carcinoma were eligible for the study. They received two cycles of FLEP regimen chemotherapy (cisplatin, etoposide, leucovorine, 5-fluorouracil) followed by transthoracic extended 2- or 3-field esophagectomy. Two-year progression-free survival was the primary endpoint. To evaluate the potential benefit of the dual-modality approach we compared these results with the outcome of patients who were treated in our center in the same period of time and were non-randomly allocated to surgery alone. RESULTS: From 2001 to 2008, 63 patients were included in the study (bimodality group) and 58 patients into the surgery-alone group. Median follow-up was 68 (range, 4-123) months. Squamous cell carcinoma had 93% patients. Two-year progression-free survival for all patients was 45.3 and 30.7% (hazard ratio 0.71, 95% confidence interval 0.46-1.08) and median overall survival was 26.5 months and 18.0 months (hazard ratio 0.67, 95% confidence interval 0.41-1.01) in bimodality- and surgery-alone groups, respectively. Patients who underwent R0-resection after bimodality treatment had significantly better overall survival (40.9 months) than after surgery alone (19.0 months, hazard ratio 0.51, 95% confidence interval 0.30-0.81). CONCLUSIONS: Two cycles of preoperative chemotherapy did not improve progression-free survival of patients with resectable thoracic esophageal carcinoma in intent-to-treat population. However, significantly better results of bimodality approach was seen in R0-resected patients which warrants further trials with more effective chemotherapy combinations.

Mutations in Mismatch Repair Genes and Microsatellite Instability Status in Pancreatic Cancer.

Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy.

Utility of public knowledge bases for the interpretation of comprehensive tumor molecular profiling results.

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I-II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I-II treatment options for 34 of them (97%), OncoKB/CGI-for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC-12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I-II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II-IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation.

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.

TYMS 3'-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that has the worst 5-year survival rate of all of the common malignant tumors. Surgery, chemotherapy, and/or chemoradiation remain the main tactics for PDAC treatment. The efficacy of chemotherapy is often compromised because of the substantial risk of severe toxicities. In our study, we focused on identification of polymorphisms in the genes involved in drug metabolism, DNA repair and replication that are associated with inter-individual differences in drug-induced toxicities. Using the microarray, we genotyped 12 polymorphisms in the DPYD, XPC, GSTP1, MTHFR, ERCC1, UGT1A1, and TYMS genes in 78 PDAC patients treated with FOLFIRINOX. It was found that the TYMS rs11280056 polymorphism (6 bp-deletion in TYMS 3'-UTR) predicted grade 1-2 neurotoxicity (p = 0.0072 and p = 0.0019, according to co-dominant (CDM) and recessive model (RM), respectively). It is the first report on the association between TYMS rs11280056 and peripheral neuropathy. We also found that PDAC patients carrying the GSTP1 rs1695 GG genotype had a decreased risk for grade 3-4 hematological toxicity as compared to those with the AA or AG genotypes (p = 0.032 and p = 0.014, CDM and RM, respectively). Due to relatively high p-values, we consider that the impact of GSTP1 rs1695 requires further investigation in a larger sample size.

Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies.

The aim of our study was to determine the effect of homologous recombination deficiency (HRD) on prognosis and efficacy of platinum-based chemotherapy in patients with pancreatic cancer (PC). We performed PubMed and Embase database queries. We included 4 studies into the meta-analysis and 16 studies in the systematic review. Our systematic analysis showed that the average weighted median overall survival (OS) in patients with HRD with advanced PC was 19.8 and 15.6 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 23.8 and 17.1 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 8.3 and 12.0 months in patients without HRD. For resected PC, our meta-analysis demonstrated that HRD status did not affect the prognosis (HR 1.03, 95% CI 0.46 to 2.33), but results were rather heterogeneous (I2=83%, p=0.003). Our systematic analysis showed that the average weighted median OS in patients with HRD was 34.6 and 27.0 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 46.1 and 36.3 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 24.2 and 42.9 months in patients without HRD. Results of our meta-analysis and systematic review support the idea of platinum use in patients with HRD both in resected and metastatic PCs, although a randomised trial is warranted to make a more reliable conclusion. PROSPERO REGISTRATION NUMBER: CRD42019121914.

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.

Maintenance therapy following first-line chemotherapy in metastatic colorectal cancer: toxicity and efficacy-single-institution experience.

A role of maintenance chemotherapy (mCT) in patients (pts) with metastatic colorectal cancer (mCRC) is still controversial. The purpose of this retrospective study was to investigate the toxicity and efficacy of mCT in pts with mCRC. There were 97/291 (33 %) pts with mCRC completed 18-20 weeks of first-line CT from 2007 to 2013 in our center. Then, pts who had no disease progression were non-randomly allocated to mCT with capecitabine ± bevacizumab (n = 35) or surveillance (n = 62). PFS was used as a primary endpoint and was calculated from the date of completion of first-line CT. Multivariate Cox stepwise regression analysis was performed to determine independent prognostic factors. Median follow-up time was 15 (range 5-60) months. Median PFS and OS were higher in pts with mCT: 7 versus 3 months (HR 0.5, 95 %CI 0.28-0.82, p = 0.007) and 29 vs 16 months (HR 0.6, 95 %CI 0.3-1.1, 0.04-Gehan-Breslow-Wilcoxon test). Following independent negative prognostic factors was significant on multivariate analysis: CEA level >2.5 ng/ml before start of first-line CT (p = 0.02), liver metastases (p = 0.03) and number of metastatic zones >2 (p = 0.008). MCT had an independent positive impact on PFS (HR 0.5, p = 0.003). MCT prolonged PFS in pts with at least one negative prognostic factors (7 vs. 3 months, p = 0.001, HR 0.38, 95 % CI 0.22-0.68). The mCT was most beneficial in pts with negative prognostic factors: CEA level >2.5 ng/ml before start of first-line CT and/or liver metastases and/or number of metastatic zones >2.

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.