Single nucleotide polymorphisms as the new predictors of therapy decisions in gastroesophageal junction and gastric adenocarcinoma?
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ABSTRACT:
SUBMITTER: Perkhofer L
PROVIDER: S-EPMC8798244 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
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Project description:Pembrolizumab is a monoclonal antibody directed against PD-1 that is US FDA approved for treatment of advanced PD-L1 positive gastric and gastroesophageal junction adenocarcinoma in patients who have progressed on at least two prior lines of chemotherapy. This article summarizes the clinical evidence regarding safety, tolerability and efficacy of pembrolizumab in this setting. In addition, this article describes the investigational use of pembrolizumab as first- and second-line therapy and in combination with other treatments. Finally, this review compares other checkpoint inhibitors to pembrolizumab for the treatment of this disease, and explores predictive biomarkers of response to PD-1 blockade.
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Project description:ImportanceCombining immune checkpoint blockade (ICB) with chemotherapy improves outcomes in patients with metastatic gastric and gastroesophageal junction (G/GEJ) adenocarcinoma; however, whether this combination has activity in the perioperative setting remains unknown.ObjectiveTo evaluate the safety and preliminary activity of perioperative chemotherapy and ICB followed by maintenance ICB in resectable G/GEJ adenocarcinoma.Design, setting, and participantsThis investigator-initiated, multicenter, open-label, single-stage, phase 2 nonrandomized controlled trial screened 49 patients and enrolled 36 patients with resectable G/GEJ adenocarcinoma from February 10, 2017, to June 17, 2021, with a median (range) follow-up of 35.2 (17.4-73.0) months. Thirty-four patients were deemed evaluable for efficacy analysis, with 28 (82.4%) undergoing curative resection. This study was performed at 4 referral institutions in the US.InterventionsPatients received 3 cycles of capecitabine, 625 mg/m2, orally twice daily for 21 days; oxaliplatin, 130 mg/m2, intravenously and pembrolizumab, 200 mg, intravenously with optional epirubicin, 50 mg/m2, every 3 weeks before and after surgery with an additional cycle of pembrolizumab before surgery. Patients received 14 additional doses of maintenance pembrolizumab.Main outcomes and measuresThe primary end point was pathologic complete response (pCR) rate. Secondary end points included overall response rate, disease-free survival (DFS), overall survival (OS), and safety.ResultsA total of 34 patients (median [range] age, 65.5 [25-90] years; 23 [67.6%] male) were evaluable for efficacy. Of these patients, 28 (82.4%) underwent curative resection, 7 (20.6%; 95% CI, 10.1%-100%) achieved pCR, and 6 (17.6%) achieved a pathologic near-complete response. Of the 28 patients who underwent resection, 4 (14.3%) experienced disease recurrence. The median DFS and OS were not reached. The 2-year DFS was 67.8% (95% CI, 0.53%-0.87%) and the OS was 80.6% (95% CI, 0.68%-0.96%). Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 20 patients (57.1%), and 12 (34.3%) experienced immune-related grade 3 or higher adverse events.Conclusion and relevanceIn this trial of unselected patients with resectable G/GEJ adenocarcinoma, capecitabine, oxaliplatin, and pembrolizumab resulted in a pCR rate of 20.6% and was well tolerated. This trial met its primary end point and supports the development of checkpoint inhibition in combination with perioperative chemotherapy in locally advanced G/GEJ adenocarcinoma.Trial registrationClinicalTrials.gov Identifier: NCT02918162.
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Project description:ObjectiveEsophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues.MethodsWe analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC.ResultsWe identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG.ConclusionOur study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC.
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Project description:The comprehensive molecular characterization of gastric and gastroesophageal junction adenocarcinomas has led to the improvement of targeted and more effective treatments. As a result, several biomarkers have been introduced into clinical practice and the implementation of innovative diagnostic tools is under study. Such assessments are mainly based on the evaluation of limited biopsy material in clinical practice. In this setting, the pathologist represents a key player in the selection of patients facilitating precision medicine approaches.
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Project description:Tumors of the upper gastrointestinal tract are increasing in incidence; yet, approaches to the treatment of advanced gastric and/or gastroesophageal junction cancer vary widely, with no internationally agreed first-line regimens. Recent clinical trials have shown that second-line treatment is now possible for selected patients with advanced disease, and current data suggest that the combination of ramucirumab plus paclitaxel may become a standard of care in the second-line setting for metastatic gastric cancer. Several prognostic factors have been identified for overall survival in the second-line setting; this emphasizes the need for careful sequencing of all treatments to ensure that individual patients receive optimum care. This article reviews published data on the treatment of advanced gastric cancer, with a particular emphasis on second-line chemotherapy, and suggests treatment sequences based on current understanding.
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Project description:Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein-Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.
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Project description:To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.
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Project description:The poor survival of adenocarcinomas of the gastroesophageal junction (GEJ) makes them clinically important. Discovery of host genetic factors that affect outcome may guide more individualized treatment. This study tests whether constitutional genetic variants in matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) genes are associated with outcome of GEJ adenocarcinoma. Single nucleotide polymorphisms (SNPs) at four TIMP (TIMP1-4) and three MMP genes (MMP2, MMP7 and MMP9) were genotyped in DNA samples from a prospective cohort of patients with primary adenocarcinoma of the GEJ admitted to the British Columbia Cancer Agency. Cox proportional hazards regression, with adjustment for patient, disease and treatment variables, was used to estimate the association of SNPs with survival. Genotypes for 85 samples and 48 SNPs were analyzed. Four SNPs across TIMP3, (rs130274, rs715572, rs1962223 and rs5754312) were associated with survival. Interaction analyses revealed that the survival associations with rs715572 and rs5754312 are specific and significant for 5FU+cisplatin treated patients. Sanger sequencing of the TIMP3 coding and promoter regions revealed an additional SNP, rs9862, also associated with survival. TIMP3 genetic variants are associated with survival and may be potentially useful in optimizing treatment strategies for individual patients.
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Project description: Not available
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Project description:In gastroesophageal junction (GEJ) adenocarcinoma cases, a prognosis based on ypTNM staging could be affected by preoperative therapy. Patients with esophageal adenocarcinoma and gastric adenocarcinoma who underwent preoperative therapy followed by surgical resection from 2006 through 2017 were identified in the National Cancer Database. To enable stage-by-stage OS comparisons, tumors were classified into four gross ypTNM groups: ypT1/2, N-negative; ypT1/2, N-positive; ypT3/4, N-negative; and ypT3/4, N-positive. Prognostic factors were examined, and an OS prediction nomogram was developed for patients with abdominal/lower esophageal and gastric cardia adenocarcinoma, representing GEJ cancers. We examined 25,463 patient records. When compared by gross ypTNM group, the abdominal/lower esophageal and gastric cardia adenocarcinoma groups had similar OS rates, differing from those of other esophageal or gastric cancers. Cox regression analysis of patients with GEJ cancers showed that preoperative chemoradiotherapy was associated with shorter OS than preoperative chemotherapy after adjustment for the ypTNM group (hazard ratio 1.31, 95% CI 1.24-1.39, p < 0.001), likely owing to downstaging effects. The nomogram had a concordance index of 0.833 and a time-dependent area under the curve of 0.669. OS prediction in GEJ adenocarcinoma cases should include preoperative therapy regimens. Our OS prediction nomogram provided reasonable OS prediction for patients with GEJ adenocarcinoma, and future validation is needed.
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