Comparison of <scp>HER</scp>2 expression between primary colorectal cancer and their corresponding metastases

Lee, Won Suk; Park, Yeon Ho; Lee, Jung Nam; Baek, Jeong‐Heum; Lee, Tae‐Hoon; Ha, Seung Yeon

doi:10.1002/cam4.228

Cited by 49 publications

(50 citation statements)

References 24 publications

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“…The rate of HER2/ neu amplification was lower in our study compared to published literature but differential amplification was observed in primary colon tumors and lung metastases (1.8% vs 4%). Previous studies have quoted a 5-9% incidence of HER2/neu amplification in CRC 26,27 and HER2/neu amplification was shown to be concordant in only 5% of the primary and metastatic lesions. 27 In a study by Ramanathan et al, HER2/neu-positive patients with advanced colorectal cancer were treated with trastuzumab (Herceptin Ò and irinotecan).…”

Section: Discussionmentioning

confidence: 86%

“…Previous studies have quoted a 5-9% incidence of HER2/neu amplification in CRC 26,27 and HER2/neu amplification was shown to be concordant in only 5% of the primary and metastatic lesions. 27 In a study by Ramanathan et al, HER2/neu-positive patients with advanced colorectal cancer were treated with trastuzumab (Herceptin Ò and irinotecan). Of the 138 screened patients, Her2 protein overexpression was only detected in 11 (8%; 2+ in 5 and 3+ in 6 patients), and this resulted in premature termination of the study.…”

Section: Discussionmentioning

confidence: 86%

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

El‐Deiry

Vijayvergia

Xiu

et al. 2015

Cancer Biology & Therapy

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Metastatic colorectal cancer (mCRC) carries a poor prognosis with an overall 5-year survival of 13.1%. Therapies guided by tumor profiling have suggested benefit in advanced cancer. We used a multiplatform molecular profiling (MP) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC. We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), immunohistochemistry (IHC) and in-situ hybridization (ISH). mCRC metastases to liver, brain, ovary or lung (n D 1507) showed differential expression of markers including high protein expression of TOPO1 (52%) and/or low RRM1 (57%), TS (71%) and MGMT (39%), suggesting possible benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide, respectively. Lung metastases harbored a higher Her2 protein expression than the primary colon tumors (4% vs. 1.8%, p D 0.028). Brain and lung metastases had higher KRAS mutations than other sites (65% vs 59% vs 47%, respectively, p D 0.07, <0.01), suggesting poor response to anti-EGFR therapies. BRAF-mutated CRC (n D 455) showed coincident high protein expression of RRM1 (56%), TS (53%) and low PDGFR (22%) as compared with BRAF wild-type tumors. KRAS-mutated mCRC had higher protein expression of c-MET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting consideration of c-MET inhibitors and temozolomide. KRAS-mutated CRC had high TUBB3 (42% vs. 33%) and low Her2 by IHC (0.5%) and HER2 by FISH (3%, p <0.05). CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer (10% and 3.3%, respectively). MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types. Our findings are hypothesis generating and need to be examined in prospective studies. Specific therapies may be considered for different actionable targets in mCRC as revealed by MP.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 86%

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

El‐Deiry

Vijayvergia

Xiu

et al. 2015

Cancer Biology & Therapy

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“…Previous studies have reported ERBB2 and EGFR amplifications to occur in 0% to 25% and 1% to 8% of colorectal carcinoma patients (9–11); with a degree of heterogeneity (15% of cases) between amplification status in different lesions (10). Our results are concordant with both general incidence in colorectal carcinoma patients and heterogeneity; however, our heterogeneity was intratumoral and demonstrated by percent of tumor cells staining with IHC.…”

Section: Discussionmentioning

confidence: 99%

Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF

Hechtman

Zehir

Yaeger

et al. 2016

Molecular Cancer Research

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Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, and ETV6-NTRK3. Only 1 of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.

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“…4 Methodologies for HER2 testing and defining positivity in mCRC are not yet standardized, and efforts to standardize testing in order to identify patients who may be eligible for HER2-directed treatment are underway. 6–8 …”

Section: Discussionmentioning

confidence: 99%

“…12–14 Notably, approximately 15% discordance between HER2 expression in colon primaries and metastases has been reported, and HER2 expression may change over time, highlighting the need to further prospectively study the role of HER2 in mCRC. 6 The prognostic effect of HER2 overexpression in mCRC remains unclear, with conflicting evidence from retrospective analyses. 8,14 Another factor yet to be explored in CRC is the interplay of MYC alterations with HER2 overexpression.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer

Parikh¹,

Atreya²,

Korn³

et al. 2016

J Natl Compr Canc Netw

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HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti–epidermal growth factor receptor–based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient’s disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient’s functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.

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Comparison of HER2 expression between primary colorectal cancer and their corresponding metastases

Cited by 49 publications

References 24 publications

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

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

Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF

Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer

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