Emergence of RTK/RAS/PI3K pathway alterations in trastuzumab-refractory HER2-positive esophagogastric (EG) tumors.

Janjigian, Yelena Y.; Sánchez-Vega, Francisco; Tuvy, Yaelle; Bouvier, Nancy; Riches, Jamie C.; Margolis, Matthew; Millang, Brittanie M; Scott, Sasinya N.; Kundra, Ritika; Castel, Pau; Ku, Geoffrey Yuyat; Hechtman, Jaclyn F.; Kelsen, David P.; Ilson, David H.; Vakiani, Efsevia; Scaltriti, Maurizio; Solit, David B.; Taylor, Barry S.; Berger, Michael F.; Schultz, Nikolaus

doi:10.1200/jco.2016.34.15_suppl.11608

Cited by 5 publications

(4 citation statements)

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“…Additionally, molecular alterations emerging upon tumor progression after trastuzumab treatment have been observed in several candidate genes such as TP53 (92%), EGFR (13%), cell-cycle mediators, i.e. cyclin-dependent kinases (42%) and in the PI3K/AKT/mTOR axis (21%) [ 103 ]. Similarly, a recently reported biomarker analysis from a phase II study evaluating the efficacy of lapatinib in combination with chemotherapy as first-line treatment in HER-2-positive GC showed the emergence of genomic aberrations such as MYC , EGFR , FGFR2 and MET amplifications at disease progression [ 104 ].…”

Section: Biomarkers In Gastro-esophageal Cancer: Where Are We Goingmentioning

confidence: 99%

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

et al. 2018

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Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue.

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Section: Biomarkers In Gastro-esophageal Cancer: Where Are We Goingmentioning

confidence: 99%

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

et al. 2018

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“…Given the multifocal origin of gastroesophageal cancers 43 , the emergence of resistant clones following suppression of HER2 with inhibitors should not be surprising. Genetic surveillance in such cases indeed revealed that the resistant clones were relying on other upregulated oncogenic receptor tyrosine kinases such as MET, EGFR 44 .…”

Section: Mechanistic Considerations Of Her2 Targetingmentioning

confidence: 99%

“…Similar results were seen in the second-line trial of MM-111 plus trastuzumab-based chemotherapy, where a lower rate of HER2 amplification was seen in pre-treatment biopsies than in archived tumor specimens 86 . Additionally, the development of resistance to trastuzumab-based therapy was associated with additional genomic alterations that most commonly affected cell cycling or PI3 kinase signaling 44 . Further work on the mechanisms of resistance to front-line HER2-targeted therapies is needed to elucidate the optimal population in which to test future therapies, and it is likely that confirmation of persistent HER2-positivity will be necessary before initiating HER2-targed therapy in refractory patients.…”

Section: Outstanding Questions: Resistance Treatment Opportunitiementioning

confidence: 99%

Perspectives of HER2-targeting in gastric and esophageal cancer

Gerson

Skariah

Denlinger

et al. 2017

Expert Opinion on Investigational Drugs

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Introduction The blockade of HER2 signaling has significantly improved the outlook for esophagogastric cancer patients. However, targeting HER2 still remains challenging due to complex biology of this receptor in gastric and esophageal cancers. Areas covered Here, we review complex HER2 biology, current methods of HER2 testing and tumor heterogeneity of gastroesophageal cancer. Ongoing and completed clinical research data are discussed. Expert Opinion HER2 overexpression is a validated target in gastroesophageal cancer, with therapeutic implications resulting in prolonged survival when inhibited in the front-line setting. With standardized HER2 testing in gastro-esophageal cancer, the ongoing trials are testing newer agents and combinations including combination of anti-HER2 antibodies with immunotherapy. Clonal heterogeneity and emergence of resistance will challenge our approach to treating these patients beyond the frontline settings.

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“…Loss of HER2 was identified as a mechanism of resistance in 32% of samples and the probability of loss of HER2 positivity was significantly higher in patients with baseline IHC score 2+ vs 3+. Similarly, loss of HER2 and frequent secondary alterations in the RTK/RAS/PI3K pathway in HER2 positive adenocarcinoma have been observed in patients treated with trastuzumab[40].…”

Section: Her2: Primary and Acquired Resistancementioning

confidence: 99%

Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives

Pellino

Riello

Nappo

et al. 2019

WJG

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Gastric cancer (GC) represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year. In the last decade, the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients. At the same time, global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling. Nonetheless, several randomized studies aimed at exploring new innovative agents, such as immune checkpoint inhibitors, failed to demonstrate clinically meaningful survival advantages. Therefore, it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients’ selection and stratification in future clinical development programs and subsequent trials. The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.

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Emergence of RTK/RAS/PI3K pathway alterations in trastuzumab-refractory HER2-positive esophagogastric (EG) tumors.

Cited by 5 publications

References 0 publications

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

Perspectives of HER2-targeting in gastric and esophageal cancer

Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives

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