The application of genomic profiling assays using plasma circulating tumor DNA (ctDNA) is rapidly evolving in the management of patients with advanced solid tumors. Diverse plasma ctDNA technologies ...in both commercial and academic laboratories are in routine or emerging use. The increasing integration of such testing to inform treatment decision making by oncology clinicians has complexities and challenges but holds significant potential to substantially improve patient outcomes. In this review, the authors discuss the current role of plasma ctDNA assays in oncology care and provide an overview of ongoing research that may inform real‐world clinical applications in the near future.
Abstract Purpose Gastric and esophageal adenocarcinomas are common and aggressive malignancies. Systemic therapy for these tumors is based primarily on cytotoxic chemotherapy, but outcomes remain ...poor. Precision medicine, where treatments are tailored to specific molecular abnormalities of tumors, holds great promise for improving outcomes in this disease. Methods A search was performed in PubMed to identify studies that have characterized the molecular basis of gastric and esophageal adenocarcinoma, as well as clinical trials exploring targeted therapies in this disease. Findings Recent genomic studies have identified potentially targetable genomic alterations in gastroesophageal adenocarcinoma. Specifically, The Cancer Genome Atlas study defined 4 subgroups of gastric cancer, each harboring distinct genomic features. However, development of targeted therapies for gastroesophageal cancer has been challenging. The only biomarker-driven therapy in clinical practice, trastuzumab for the ~15% of patients with human epidermal growth factor receptor 2−positive disease, is modestly effective, extending median overall survival by 2.7 months. Clinical trials of other targeted therapies, including epidermal growth factor receptor, fibroblast growth factor receptor 2, and MET inhibitors, have had disappointing results so far. Implications The availability of genomic tools provides an unprecedented opportunity to develop new rational therapeutic strategies. New trial designs of targeted therapies in biomarker-selected patient populations have the potential to improve outcomes in this lethal disease. As these clinical trials are being developed, it is increasingly important to incorporate correlative studies that will allow us to identify biomarkers of response or resistance to targeted therapies.
Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such ...therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.
We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated.
.
Fallopian Tube Carcinoma: A Review Pectasides, Dimitrios; Pectasides, Eirini; Economopoulos, Theofanis
The oncologist (Dayton, Ohio),
September 2006, Letnik:
11, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Purpose. Primary fallopian tube carcinoma (PFTC) is a rare tumor that histologically and clinically resembles epithelial ovarian cancer (EOC). The purpose of this study is to review the current ...available literature data on PFTC.
Patients and Results. Early clinical manifestation and prompt investigation often lead to diagnosis at an early stage of disease. However, the diagnosis of PFTC is rarely considered preoperatively and is usually first appreciated by the pathologist. Surgical staging/management and the use of chemotherapy follow the concepts used in epithelial ovarian cancer (EOC). In contrast to EOC is the importance of early lymphatic spread in this disease. The earlier diagnosis of PFTC leads to an apparent better survival compared with EOC. However, as with EOC, stage and residual tumor are the most important prognostic variables.
Conclusion. Until more extensive clinical research has been performed, ovarian carcinoma management principles should be used in clinical practice.
Gastric and esophageal adenocarcinomas are aggressive malignancies. Systemic therapy for these tumors relies primarily on cytotoxic chemotherapy but outcomes remain poor. In recent years, ...immunotherapy has emerged as a new, promising therapeutic approach for a variety of solid tumors. Characterization of gastroesophageal cancers has revealed genomic and immune features of these tumors that may predict response to immunotherapy. Indeed, preliminary results from the initial trials of immune checkpoint inhibitors have been encouraging, with objective response rates of 20% in heavily pretreated patient populations. Based on these results, additional trials of single-agent checkpoint inhibitors as well as combinations with chemotherapy and targeted therapies are currently ongoing. Further work to identify predictive biomarkers will be crucial for the successful implementation of immunotherapy.
Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, ...the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/
genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell-intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell-intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis. SIGNIFICANCE: This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.
Patients with gastric and esophageal (GE) adenocarcinoma tumors in which the oncogene ERBB2 has been amplified are routinely treated with a combination of cytotoxic chemotherapy and the ...ERBB2-directed antibody trastuzumab; however, the addition of trastuzumab, even when tested in a selected biomarker-positive patient population, provides only modest survival gains. To investigate the potential reasons for the modest impact of ERBB2-directed therapies, we explored the hypothesis that secondary molecular features of ERBB2-amplified GE adenocarcinomas attenuate the impact of ERBB2 blockade. We analyzed genomic profiles of ERBB2-amplified GE adenocarcinomas and determined that the majority of ERBB2-amplified tumors harbor secondary oncogenic alterations that have the potential to be therapeutically targeted. These secondary events spanned genes involved in cell-cycle regulation as well as phosphatidylinositol-3 kinase and receptor tyrosine kinase signaling. Using ERBB2-amplified cell lines, we demonstrated that secondary oncogenic events could confer resistance to ERBB2-directed therapies. Moreover, this resistance could be overcome by targeting the secondary oncogene in conjunction with ERBB2-directed therapy. EGFR is commonly coamplified with ERBB2, and in the setting of ERBB2 amplification, higher EGFR expression appears to mark tumors with greater sensitivity to dual EGFR/ERBB2 kinase inhibitors. These data suggest that combination inhibitor strategies, guided by secondary events in ERBB2-amplified GE adenocarcinomas, should be evaluated in clinical trials.
Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic ...targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR). Here, we demonstrate that EGFR-targeting small-molecule inhibitors have efficacy in EGFR-amplified oesophageal squamous cell carcinoma (ESCC), but may become quickly ineffective. Resistance can occur following the emergence of epithelial-mesenchymal transition and by reactivation of the mitogen-activated protein kinase (MAPK) pathway following EGFR blockade. We demonstrate that blockade of this rebound activation with MEK (mitogen-activated protein kinase kinase) inhibition enhances EGFR inhibitor-induced apoptosis and cell cycle arrest, and delays resistance to EGFR monotherapy. Furthermore, genomic profiling shows that cell cycle regulators are altered in the majority of EGFR-amplified tumours and a combination of cyclin-dependent kinase 4/6 (CDK4/6) and EGFR inhibitors prevents the emergence of resistance in vitro and in vivo. These data suggest that upfront combination strategies targeting EGFR amplification, guided by adaptive pathway reactivation or by co-occurring genomic alterations, should be tested clinically.
Learning Objectives
After completing this course, the reader will be able to:
Discuss the clinical features of OCCC.
Discuss the current data regarding treatment strategies and outcome of patients ...with OCCC.
Explain the rationale for using alternative treatment approaches (i.e., clinical trials) in patients with OCCC.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Background. Ovarian clear cell carcinoma (OCCC) is a distinct histopathologic subtype of epithelial ovarian cancer (EOC) with an incidence of <5% of all ovarian malignancies. Our goal was to review the clinical features and management of patients with OCCC.
Methods and Results. We performed a PubMed search using the phrase “clear cell ovarian cancer.” We reviewed 54 articles referring to OCCC. OCCC patients have a high incidence of stage I disease and frequently present with a large pelvic mass. Recurrences are more frequent with this entity than with other types of EOC. The clinical management of advanced EOC includes maximal cytoreduction and platinum plus paclitaxel–based chemotherapy. The survival rates of patients with advanced OCCC are lower than those of patients with advanced serous EOC (serous subtype). The poor response rate to platinum‐based regimens may be related to the intrinsic chemoresistance of these tumors. Despite their aggressive clinical course, OCCCs are still treated similarly to the other EOCs at the present time, because the rarity of these tumors prevents the conduction of randomized studies.
Conclusion. Novel treatment approaches should be adopted in OCCC. Molecular‐targeted therapies and effective new agents without cross‐resistance to platinum compounds should be evaluated in a prospective clinical trial in OCCC.
BackgroundThe clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR ...deficiency in patients with stage I-III colorectal and endometrial cancer.MethodsPatients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)’s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS).ResultsFrom May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ2, p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021).ConclusionsDMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy.
PDF
