Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites

El‐Deiry, Wafik S.; Vijayvergia, Namrata; Xiu, Joanne; Scicchitano, Angelique; Lim, Bora; Yee, Nelson S.; Harvey, Harold A.; Gatalica, Zoran; Reddy, Sandeep K.

doi:10.1080/15384047.2015.1113356

Cited by 77 publications

(79 citation statements)

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“…In the context of brain metastases from GI primary malignancies being a rare event, the current study represents the largest cohort, to our knowledge, of patients with GI cancer with paired tissue from a brain metastasis and prior site of disease examined for HER2 status by FISH and IHC. Several prior studies have examined HER2 status in primary GI tumors or metastatic sites of disease and have variably suggested that HER2+ GI cancers may have a predisposition for spread to the brain, but very few patients included in these studies have had paired prior tissue and brain metastasis tissue available, which has limited the ability to see the dynamics of HER2 status over the course of disease evolution .…”

Section: Discussionmentioning

confidence: 99%

“…As in breast cancer, prior studies in GI cancer have suggested HER2+ primary malignancies have a propensity for central nervous system (CNS) metastases. However, most of these studies have focused on GEJ AC, with pathologic evaluation typically performed on primary tumor lesions with infrequent availability of paired intracranial metastatic tissue . The current study examines the HER2 status of patients with a variety of GI primary malignancies, all of whom have brain metastases with tissue available and the majority of whom also have tissue from a prior site of disease.…”

Section: Introductionmentioning

confidence: 99%

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Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies

et al. 2018

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Background In nongastric gastrointestinal (GI) cancers, HER2‐positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2‐targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially. Materials and Methods We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty‐four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH. Results A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017). Conclusion In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue. Implications for Practice HER2 amplification is a well‐known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2‐directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies

et al. 2018

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“…Recent studies of ERBB2 amplification and sequence mutations in colorectal cancer (CRC) suggest that HER2 is a therapy target in this disease, in addition to being a mechanism of resistance to epidermal growth factor receptor (EGFR)‐targeted therapies such as cetuximab and panitumumab . Similarly, reports of high‐level ERBB3 amplification being a negative prognostic factor within the context of CRC suggest that HER3 may also be a target in this tumor type .…”

Section: Introductionmentioning

confidence: 99%

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

Ross¹,

Fakih

Ali³

et al. 2018

Cancer

176

116

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BACKGROUNDIn contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2‐targeted therapies.METHODSIn this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer‐related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas.RESULTSA total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB‐mutated samples, and ERBB3‐mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2‐amplified samples compared with wild‐type CRC samples (51.8%), and ERBB2‐ or ERBB3‐mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways.CONCLUSIONSAlthough observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti‐HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2‐positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti‐HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358‐73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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“…Mutation profiles of primary tumor versus the metastatic lesion locoregional lymphatic metastasis versus distant metastasis need to be carefully assessed, as often the profiles are not identical. [57][58][59] Similarly, you cannot assume that multiple tumors in the same patient and of the same tumor type will possess the same mutation profile. Second, what criteria are appropriate for defining a positive test result that will then impact clinical management?…”

Section: Technical Issues To Consider For Implementing Somatic Mutatimentioning

confidence: 99%

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

Tsongalis

Coleman

2017

The Journal of Clinical Pharma

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Somatic mutation analysis of human cancers has become the standard of practice. Whether screening for single gene variants or sequencing hundreds of cancer-related genes, this genomic information is the basis for precision medicine initiatives in oncology. Genomic profiling results in information that allows oncologists to make a more educated selection of appropriate therapeutic strategies that more often combine traditional cytotoxic chemotherapy and radiation with novel targeted therapies. Here we discuss the nuances of implementing somatic mutation testing in a clinical setting. Keywordsclinical genomics, oncology, precision medicine, pharmacogenomics, somatic mutation Novel therapies, including the use of directed monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies, have come to fruition as our understanding of the etiology of human cancer expands. From the identification of the first oncogenes and tumor-suppressor genes to current full gene sequencing for the identification of somatic mutations, knowledge of tumor-cell genetic variant profiles has become critical to the management of the cancer patient.1-3 One projection of the Human Genome Project was to gain a more fundamental understanding of human disease at the genomic level such that novel therapeutics could be designed to provide a more personalized approach to disease management. The identification of numerous driver mutations in various human cancers, which are causally implicated in establishing growth advantages to a cell, have also become the target of novel therapies that confer more efficacious outcomes. 4,5 The rapid development of targeted therapies is also resulting in more advanced and focused clinical trial designs whereby testing protocols aim to match patients whose tumors harbor specific somatic mutations with those specific therapies targeting the gene or pathway affected. 6,7 Precision Medicine in OncologyWith respect to the cancer patient, the concept of targeted or individualized therapy can include 2 aspects of what is often termed pharmacogenomics. The first is the more traditional concept that encompasses how an individual may metabolize, absorb, transport, and excrete therapeutic drugs differently based on polymorphisms in the genes that code for these functions. This type of individual variation in metabolism was first described in 510 BC when Pythagoras recognized hemolytic anemia developing in some individuals who consumed fava beans.8 This phenotype was later attributed to a glucose-6-phosphate dehydrogenase deficiency. 9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics.10,11 The conversion of a parent compound to an inactive metabolite or to one that is more easily excreted and the conversion of a prodrug to its active metabolite are examples of PGX m .PGX t is the second aspect of pharmacogenomics that involves the selection of a therapeutic drug based on the...

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Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites

Cited by 77 publications

References 61 publications

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

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