Molecular profiling in gastric cancer: Examining potential targets for chemotherapy

Miura, John T.; Johnston, Fabian M.; Thomas, James P.; George, Ben; Eastwood, Dan; Tsai, Susan; Christians, Kathleen K.; Turaga, Kiran K.; Gamblin, T. Clark

doi:10.1002/jso.23639

Cited by 7 publications

(3 citation statements)

References 25 publications

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“…The implementation of the biomarker-driven therapy as reflected in our study is consistent with the increasing use of molecular analysis of tumors in oncology. The biomarker analysis results in the current cohort are overall consistent with those in a recent study involving 230 gastric cancer specimens, in which positive TOPO1 was reported for 68% of patients, negative TS for 63% of patients, high TOP2A for 60% of patients, and negative ERCC1 for 55% of patients [ 23 ]. Also, overall, our results are aligned with findings from recent studies describing the potential benefit of biomarker-driven therapy including studies in numerous tumor types such as pancreatic, breast, salivary gland, and others [ 7 – 12 ].…”

Section: Discussionsupporting

confidence: 89%

Biomarker-Driven Therapy in Metastatic Gastric and Esophageal Cancer: Real-Life Clinical Experience

et al. 2018

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BackgroundPrecision treatment of cancer uses biomarker-driven therapy to individualize and optimize patient care.ObjectiveTo evaluate real-life clinical experience with biomarker-driven therapy in metastatic gastric and esophageal cancer in Israel.Patients and MethodsThis multicenter retrospective cohort study included patients with metastatic gastric or esophageal cancer who were treated in the participating institutions and underwent biomarker-driven therapy. Treatment was considered to have a benefit if the ratio between the longest progression-free survival (PFS) post biomarker-driven therapy and the last PFS before the biomarker-driven therapy was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit.ResultsThe analysis included 46 patients (61% men; median age, 58 years; 57% with poorly-differentiated tumors). At least one actionable (i.e., predictive of response to a specific therapy) biomarker was identified for each patient. Immunohistochemistry was performed on all samples and identified 1–8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A). Twenty-eight patients received therapy after the biomarker analysis (1–4 lines). In the 1st line after biomarker analysis, five patients (18%) achieved a partial response and five (18%) stable disease; the median (range) PFS was 129 (12–1155) days. Twenty-four patients were evaluable for PFS ratio analysis; in seven (29.2%), the ratio was ≥1.3. In a one-sided exact binomial test vs. the null hypothesis, p = 0.019; therefore, the null hypothesis was rejected.ConclusionsOur findings demonstrated that implementing biomarker-driven analysis is feasible and could provide clinical benefit for a considerable proportion (~30%) of patients with metastatic gastric or esophageal cancer.

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Section: Discussionsupporting

confidence: 89%

Biomarker-Driven Therapy in Metastatic Gastric and Esophageal Cancer: Real-Life Clinical Experience

et al. 2018

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“…7,8 In the present study, a multiplatform approach was utilized that confirmed a high frequency of biomarker expression profiles that would suggest potential sensitivity to first line chemotherapeutic drugs. Interestingly, biomarkers such as RRM1, MGMT, PTEN, and SPARC were identified by IHC with increasing frequency, along with mutations including KRAS, PIK3CA, PTEN, ERBB2, BRAF, and EGFR, highlighting additional areas for targeted therapies.…”

Section: Discussionmentioning

confidence: 74%

Tumor profiling of gastric and esophageal carcinoma reveal different treatment options

Miura

Xiu

Thomas

et al. 2015

Cancer Biology & Therapy

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Background: NCCN states that chemotherapies for advanced esophageal and gastric cancers may be used interchangeably. Biomarkers from gastroesophageal cancer patients were interrogated to identify actionable alterations with therapeutic implications. Methods: 666 gastric and 640 esophageal cancer cases referred to Caris Life Sciences between 2009 thru 2013 were evaluated. Specific testing was performed, which included a combination of sequencing (Sanger, NGS) and protein expression (IHC). Results: In the complete cohort (n D 1306), 30 of 45 genes tested harbored mutations; highest rates were seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%), and PIK3CA (5.1%). IHC of TOP2A was high in 76% of cases, TOPO1 in 51% and SPARC in 25%; low IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating potential benefit from epirubicin, irinotecan, nab-paclitaxel, platinum-based agents, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2C cohort (n D 88), 50% of patients demonstrated possible benefit from a combination of trastuzumab with 5FU/capecitabine based on concurrent low TS, 53% with irinotecan (high TOPO1), 63% with cisplatin (low ERCC1) and 55% with gemcitabine (low RRM1). Subgroup analysis by tumor origin demonstrated significant differences in actionable biomarker profiles with HER2 (13% vs. 4.6%), SPARC (34% vs. 15%), TOP2A (86% vs. 67%), and TOPO1 (55% vs. 46%) in esophageal and gastric adenocarcinoma cases respectively (P < 0.05). Conclusion: A comprehensive multiplatform biomarker analysis suggested significant biomarker differences between gastric and esophageal cancers. These results can assist in the development of future clinical trials.

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“…Similar to genetic biomarkers, the analysis of common biomarkers of proteinaceous nature is highly informative in personalized cancer therapy. Examples of such biomarkers include the elevated expression of Topoisomerase I and 4E-Binding protein (p4E-BP1), which relate to a beneficial response to Topoisomerase 1 inhibitors and PI3K/mTOR inhibitors, respectively (14,15). On the contrary, multiple studies suggest that increased expression of the excision repair complementation group 1 (ERCC1) protein induces resistance to platinum-based chemotherapy (16)(17)(18).…”

Section: Molecular Analysis Of Protein Pharmacogenomic Biomarkersmentioning

confidence: 99%

Pharmacogenomic Testing to Guide Personalized Cancer Medicine Decisions in Private Oncology Practice: A Case Study

et al. 2020

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Innovative tumor profiling methodologies are utilized to elucidate the pharmacogenomic landscape of tumor cells in order to support the molecularly guided delivery of therapeutics. Indeed, improved clinical outcomes are achieved in oncology practice by providing the physicians with expert-guided, standardized, and easily interpretable knowledge, translated from molecular profiling analysis to support clinical decisionmaking. However, there is still limited utilization of the technology especially in small private oncology practices. In this work, we analyzed how molecularly guided interventions in 17 consented cancer patients led to an overall improvement of disease response rates in a private oncology center. The precision medicine strategy was based on the OncoDEEP TM profiling solutions and focused on finding clinically actionable relationships between tumor biomarkers and drug responses. The obtained data support the notion that (a) following the pharmacogenomic-derived recommendations favorably impacted cancer therapy progression, and (b) the earlier profiling followed by the delivery of molecularly targeted therapy led to more durable and improved pharmacological response rates. Moreover, we report the example of a patient with metastatic gastric adenocarcinoma who, based on the molecular profiling data, received an off-label therapy that resulted in a complete response and a current cancer-free maintenance status. Overall, our data provide a paradigm on how molecular tumor profiling can improve decision-making in the routine private oncology practice.

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Molecular profiling in gastric cancer: Examining potential targets for chemotherapy

Abstract: MP of GC has the potential to define patients who would derive the greatest benefit from current therapies. Prospective controlled studies are required to validate the role of biomarkers in the management of GC patients.

Cited by 7 publications

References 25 publications

Biomarker-Driven Therapy in Metastatic Gastric and Esophageal Cancer: Real-Life Clinical Experience

Biomarker-Driven Therapy in Metastatic Gastric and Esophageal Cancer: Real-Life Clinical Experience

Tumor profiling of gastric and esophageal carcinoma reveal different treatment options

Pharmacogenomic Testing to Guide Personalized Cancer Medicine Decisions in Private Oncology Practice: A Case Study

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