Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

Park, Sook Ryun; Park, Young Soo; Ryu, Min‐Hee; Ryoo, Baek‐Yeol; Woo, Chang Gok; Jung, Hwoon Yong; Lee, Jeong Hoon; Lee, Gin Hyug; Kang, Yoon‐Koo

doi:10.1016/j.ejca.2015.09.018

Cited by 78 publications

(55 citation statements)

References 22 publications

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“…Prior reports using FISH and IHC to assess select targets across different samples have yielded discrepant results (24,25,(27)(28)(29). But some recent reports are consistent with our data.…”

Section: Discussionsupporting

confidence: 82%

“…Studies using FISH, IHC, or multiplex PCR to query amplification of specific oncogenes identified discrepant profiles of targets, including ERBB2 within the PT or between the PT and lymph node (LN) metastases in approximately 30% to 50% of cases (24)(25)(26). In contrast, other studies that queried discordance of ERBB2 within distinct regions of the PT found discrepancies in only 12% of cases (27,28), or that patients with metastatic GEA with negative ERBB2 testing from a biopsy of the PT showed ERBB2 positivity in the metastatic disease in only 5.7% of cases (29). In addition, other studies have shown 87.5% to 98.5% concordance of ERBB2 between PT and paired metastatic sites (30,31).…”

Section: Introductionmentioning

confidence: 85%

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Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

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Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited effi cacy. A potential reason for the failure of such therapies is that genomic profi ling 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, fi nding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed signifi cant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplifi cation profi les commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifi cations not detected in PT sampling. Lastly, we profi led 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 profi ling 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 profi ling to enhance selection of therapy. SIGNIFICANCE: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 profi ling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1);[37][38][39][40][41][42][43][44][45][46][47][48]

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 85%

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

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“…Thus, we reaffirm the importance of retrieving a second tumor block should a negative HER2 status be detected in a first tumor block. Of note, the results of our study closely mirror those originating from the GAS-THER1 study, where it has been elegantly shown that 8.7 % of HER2-negative primary tumors turn out to be HER2 positive upon repeat endoscopic biopsy [37]. These observations are relevant especially in light of the eligibility criteria for trastuzumab-based therapies [20].…”

Section: Discussionsupporting

confidence: 74%

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications

et al. 2016

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Background HER2 and topoisomerase 2 alpha (TOP2A) genomic status was previously reported to predict benefit from anthracyclines in breast cancer. We sought to define the prognostic impact and possible pitfalls related to these biomarkers in resectable gastroesophageal adenocarcinoma. Methods HER2 and TOP2A gene amplification by fluorescent in situ hybridization and HER2 protein expression by immunohistochemistry (IHC) were assessed on whole tissue sections from 101 patients receiving peri-or postoperative epirubicin-based chemotherapy. In a subgroup of patients, at least two matched tumor blocks, originating either from surgical procedures (n = 88) or diagnostic biopsies (n = 32), were available for HER2 analyses by IHC. Results Eighteen of 101 patients (17.8 %) were HER2 positive, whereas TOP2A was amplified in 4 of 84 patients (4.7 %). HER2 positivity was significantly associated with improved disease-free survival [HR = 0.47 (95 % CI 0.22-0.99), P = 0.046] and overall survival [HR = 0.33 (95 % CI 0.13-0.83), P \ 0.018], independent of clinicalpathologic features. HER2 expression in matched tumor blocks from the same resection specimen was discordant in up to 11.8 % of pairs, while this rate increased up to 27.2 % when diagnostic biopsies and paired surgical samples were compared. Conclusions HER2 status is an independent prognostic biomarker in gastroesophageal adenocarcinomas receiving epirubicin-based chemotherapy. Compared to diagnostic biopsies, HER2 assessment in multiple resection specimens might lower the risk of sampling errors. These findings have several implications with respect to the optimal choice of the sample to be submitted to IHC testing of HER2.

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“…Tumors originally classified as IHC 1+ or 2+ were more than three times more likely to show HER2 positivity on repeat biopsy than IHC 0 tumors, and liver as a site of metastasis was almost six times more likely to show HER2 positivity than reassessment of other metastatic sites. Patients found to have HER2 positivity on repeat tumor sampling appeared to show similar treatment benefits with trastuzumab to those identified as HER2 positive at initial evaluation 65. In contrast to breast cancer, re-biopsy of newly relapsed metastatic sites is not recommended in GE cancer.…”

Section: Challenges In Her2 Assessment and Patient Selectionmentioning

confidence: 98%

“…The GASTHER1 study evaluated the utility of repeat endoscopic biopsy in patients whose tumors were initially found to be HER2 negative (IHC 0–2+ and ISH negative) 65. Repeat biopsy identified a “rescue” HER2 positivity rate of 8.7%, with 16 HER2-positive tumors identified out of the 183 retested.…”

Section: Challenges In Her2 Assessment and Patient Selectionmentioning

confidence: 99%

Trastuzumab in the management of gastroesophageal cancer: patient selection and perspectives

Davidson¹,

Starling²

2016

OTT

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The addition of trastuzumab to the treatment of a subset of patients with advanced gastric and gastroesophageal junction cancers showing HER2 positivity has been shown to confer clinical benefit; however, questions remain over the optimal methods for defining and selecting such patients. This review provides an overview of current standards for assessing HER2 positivity, the evolving treatment landscape for HER2-positive gastric and esophageal cancers and the challenges and potential future directions in optimal patient selection for HER2-targeted therapy.

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Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

Cited by 78 publications

References 22 publications

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications

Trastuzumab in the management of gastroesophageal cancer: patient selection and perspectives

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