Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

S Siena, A Sartore-Bianchi, S Marsoni, H I Hurwitz, S J McCall, F Penault-Llorca, S Srock, A Bardelli, L Trusolino, S Siena, A Sartore-Bianchi, S Marsoni, H I Hurwitz, S J McCall, F Penault-Llorca, S Srock, A Bardelli, L Trusolino

Abstract

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

Figures

Figure 1.
Figure 1.
Scenarios for positioning of clinical trials with HER2-targeted treatments in mCRC.

References

    1. Bertotti A, Papp E, Jones S. et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature 2015; 526(7572): 263–267.
    1. Sartore-Bianchi A, Loupakis F, Argilés G. et al. Challenging chemoresistant metastatic colorectal cancer: therapeutic strategies from the clinic and from the laboratory. Ann Oncol 2016; 27(8): 1456–1466.
    1. Siravegna G, Marsoni S, Siena S. et al. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 2017; 14(9): 531–548.
    1. Bertotti A, Migliardi G, Galimi F. et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 2011; 1(6): 508–523.
    1. The Cancer Genome Atlas Network (TCGAN). Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–337.
    1. Sartore-Bianchi A, Trusolino L, Martino C. et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 17(6): 738–746.
    1. Hurwitz H, Raghav KPS, Burris HA. et al. Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): Interim data from MyPathway. J Clin Oncol 2017; 35: (suppl 4S; abstr 676).
    1. Hainsworth JD, Meric-Bernstam F, Swanton C. et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol 2018; 36(6): 536–542.
    1. Laurent-Puig P, Balogoun R, Cayre A. et al. ERBB2 alterations a new prognostic biomarker in stage III colon cancer from a FOLFOX based adjuvant trial (PETACC8). Ann Oncol 2016; 27: (suppl 6; abstr 459O).
    1. Hynes NE, Lane HA.. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5(5): 341–354.
    1. Tzahar E, Waterman H, Chen X. et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 1996; 16(10): 5276–5287.
    1. Rakha EA, Pinder SE, Bartlett JM. et al. Updated UK recommendations for HER2 assessment in breast cancer. J Clin Pathol 2015; 68(2): 93–99.
    1. Rüschoff J, Hanna W, Bilous M. et al. HER2 testing in gastric cancer: a practical approach. Mod Pathol 2012; 25(5): 637–650.
    1. Kim EK, Kim KA, Lee CY. et al. The frequency and clinical impact of HER2 alterations in lung adenocarcinoma. PLoS One 2017; 12(2): e0171280.
    1. Ni S, Peng J, Huang D. et al. HER2 overexpression and amplification in patients with colorectal cancer: a large-scale retrospective study in Chinese population. J Clin Oncol 2017; 35: (suppl; abstr e15099).
    1. Richman SD, Southward K, Chambers P. et al. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol 2016; 238(4): 562–570.
    1. Valtorta E, Martino C, Sartore-Bianchi A. et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 2015; 28(11): 1481–1491.
    1. Ingold Heppner B, Behrens HM, Balschun K. et al. HER2/neu testing in primary colorectal carcinoma. Br J Cancer 2014; 111(10): 1977–1984.
    1. Song Z, Deng Y, Zhuang K. et al. Immunohistochemical results of HER2/neu protein expression assessed by rabbit monoclonal antibodies SP3 and 4B5 in colorectal carcinomas. Int J Clin Exp Pathol 2014; 7(7): 4454–4460.
    1. Conradi LC, Styczen H, Sprenger T. et al. Frequency of HER-2 positivity in rectal cancer and prognosis. Am J Surg Pathol 2013; 37(4): 522–531.
    1. Kruszewski WJ, Rzepko R, Ciesielski M. et al. Expression of HER2 in colorectal cancer does not correlate with prognosis. Dis Markers 2010; 29(5): 207–212.
    1. Kountourakis P, Pavlakis K, Psyrri A. et al. Clinicopathologic significance of EGFR and Her-2/neu in colorectal adenocarcinomas. Cancer J 2006; 12(3): 229–236.
    1. Schuell B, Gruenberger T, Scheithauer W. et al. HER 2/neu protein expression in colorectal cancer. BMC Cancer 2006; 6: 123..
    1. Essapen S, Thomas H, Green M. et al. The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters. Int J Oncol 2004; 24(2): 241–248.
    1. McKay JA, Loane JF, Ross VG. et al. c-erbB-2 is not a major factor in the development of colorectal cancer. Br J Cancer 2002; 86(4): 568–573.
    1. Rossi HA, Liu Q, Banner B. et al. The prognostic value of invariant chain (Ii) and Her-2/neu expression in curatively resected colorectal cancer. Cancer J 2002; 8(3): 268–275.
    1. Osako T, Miyahara M, Uchino S. et al. Immunohistochemical study of c-erbB-2 protein in colorectal cancer and the correlation with patient survival. Oncology 1998; 55(6): 548–555.
    1. Kapitanović S, Radosević S, Kapitanović M. et al. The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology 1997; 112(4): 1103–1113.
    1. Ross JS, Ali SM, Elvin JA. et al. Targeted therapy for HER2 driven colorectal cancer. J Clin Oncol 2017; 35: (suppl 15; abstr 3583).
    1. Shimada Y, Yagi R, Kameyama H. et al. Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer. Hum Pathol 2017; 66: 1–9.
    1. Gong J, Cho M, Sy M. et al. Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience. Oncotarget 2017; 8(26): 42198–42213.
    1. Schrock AB, Young L, Klempner SJ. et al. Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced cancers of the GI tract and anus. J Clin Oncol 2017; 35: (suppl 4S; abstr 618).
    1. Takegawa N, Yonesaka K, Sakai K. et al. HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer. Oncotarget 2016; 7(3): 3453–3460.
    1. Edenfield WJ, Chung KY, Gatalica Z. et al. Molecular profiling of HER2-positive colorectal cancer for identification of multiple potential drug targets. J Clin Oncol 2014; 32: (suppl 15; abstr e14508).
    1. Weinberg BA, Poorman K, Arguello D. et al. Impact of patient age on molecular alterations in left-sided colorectal tumors. J Clin Oncol 2017; 35: (suppl 15; abstr 3592).
    1. Marshall J, Lenz H-J, Xiu J. et al. Molecular variances between rectal and left-sided colon cancers. J Clin Oncol 2017; 35: (suppl 4S; abstr 522).
    1. Siena S, Sartore-Bianchi A, Trusolino L. et al. Final results of the HERACLES trial in HER2 amplified colorectal cancer. Anti-HER2 treatment in HER2+ mCRC. Oral presentation at the AACR Annual Meeting 2017, Washington, DC. Abstract CT005.
    1. Raghav KPS, Overman MJ, Yu R. et al. HER2 amplification as a negative predictor biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. J Clin Oncol 2016; 34: (suppl 15; abstr 3517).
    1. Wolff AC, Hammond ME, Hicks DG. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J clin Oncol 2013; 31(31): 3997–4013.
    1. Bartley AN, Washington MK, Colasacco C. et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35(4): 446–464.
    1. Seo AN, Kwak Y, Kim DW. et al. HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS One 2014; 9(5): e98528.
    1. Witzel I, Loibl S, von Minckwitz G. et al. Monitoring serum HER2 levels during neoadjuvant trastuzumab treatment within the GeparQuattro trial. Breast Cancer Res Treat 2010; 123(2): 437–445.
    1. Gevensleben H, Garcia-Murillas I, Graeser MK. et al. Noninvasive detection of HER2 amplification with plasma DNA digital PCR. Clin Cancer Res 2013; 19(12): 3276–3284.
    1. Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990; 113(10): 779–788.
    1. Mik M, Berut M, Dziki L. et al. Right- and left-sided colon cancer – clinical and pathological differences of the disease entity in one organ. Arch Med Sci 2017; 13(1): 157–162.
    1. Arnold D, Lueza B, Douillard JY. et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomised trials. Ann Oncol 2017; 28(8): 1713–1729.
    1. Petrelli F, Tomasello G, Borgonovo K. et al. Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol 2016. [Epub ahead of print], doi: 10.1001/jamaoncol.2016.4227.
    1. Holch JW, Ricard I, Stintzing S. et al. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer 2017; 70: 87–98.
    1. Missiaglia E, Jacobs B, D'Ario G. et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 2014; 25(10): 1995–2001.
    1. Nam SK, Yun S, Koh J. et al. BRAF, PIK3CA, and HER2 oncogenic alterations according to KRAS mutation status in advanced colorectal cancers with distant metastasis. PLoS One 2016; 11(3): e0151865.
    1. Sclafani F, Roy A, Cunningham D. et al. HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab. Ann Oncol 2013; 24(12): 3123–3128.
    1. Sun S-J, Lin Q, Sun Q. et al. High HER-2 protein levels correlate with clinicopathological features in colorectal cancer. J Can Res Ther 2016; 12(1): 323–333.
    1. Leto SM, Trusolino L.. Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies. J Mol Med 2014; 92(7): 709–722.
    1. Siena S, Sartore-Bianchi A, Garcia-Carbonero R. et al. Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer. Ann Oncol 2018; 29(1): 119–126.
    1. Sepulveda AR, Hamilton SR, Allegra CJ. et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Clin Oncol 2017; 35(13): 1453–1486.
    1. Van Cutsem E, Cervantes A, Adam R. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27(8): 1386–1422.
    1. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer v2.2017. (5 October 2017, date last accessed).
    1. Yonesaka K, Zejnullahu K, Okamoto I. et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 2011; 3(99): 99ra86.
    1. Martin V, Landi L, Molinari F. et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer 2013; 108(3): 668–675.
    1. Ramanathan RK, Hwang JJ, Zamboni WC. et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest 2004; 22(6): 858–865.
    1. Clark JW, Niedzwiecki D, Hollis D. et al. Phase-II trial of 5-fluororuacil (5-FU), leucovorin (LV), oxaliplatin (Ox), and trastuzumab (T) for patients with metastatic colorectal cancer (CRC) refractory to initial therapy. Onkologie 2003; 26: 13–46.
    1. Mohammed TA, Dennie T, Holen KD.. Activity of oxaliplatin plus capecitabine (CapeOx) with lapatinib for metastatic colorectal cancer: results from two patients treated on a clinical study. Clin Adv Hematol Oncol 2011; 9(6): 492–500.
    1. Kavuri SM, Jain N, Galimi F. et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov 2015; 5(8): 832–841.
    1. Martinelli E, Troiani T, Sforza V. et al. Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case. ESMO Open 2018; 3(1): e000299.
    1. Haslem DS, Ji HP, Ford JM, Nadauld LD.. Precision oncology strategy in trastuzumab-resistant human epidermal growth factor receptor 2-positive colon cancer: case report of durable response to ado-trastuxumab emtansine. JCO Precis Oncol 2017; 10.1200/PO.16.00055.
    1. Parikh A, Atreya C, Korn WM, Venook AP.. Prolonged response to HER2-directed therapy in a patient with HER2-amplified, rapidly progressive metastatic colorectal cancer. J Natl Compr Canc Netw 2017; 15(1): 3–8.
    1. Hyman DM, Piha-Paul SA, Won H. et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 2018; 554(7691): 189–194.
    1. Sartore-Bianchi A, Marsoni S, Siena S.. Human epidermal growth factor receptor 2 as a molecular biomarker for metastatic colorectal cancer. JAMA Oncol 2018; 4(1): 19–20.
    1. André F. Developing anticancer drugs in orphan molecular entities – a paradigm under construction. N Engl J Med 2018; 378(8): 763–765.
    1. Peeters M, Oliner KS, Price TJ. et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res 2015; 21(24): 5469–5479.
    1. Loupakis F, Cremolini C, Masi G. et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014; 371(17): 1609–1618.
    1. Douillard JY, Oliner KS, Siena S. et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369(11): 1023–1034.
    1. Gelsomino F, Barbolini M, Spallanzani A. et al. The evolving role of microsatellite instability in colorectal cancer: a review. Cancer Treat Rev 2016; 51: 19–26.
    1. Corcoran RB, André T, Atreya CE. et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov 2018; 8(4): 428–443.
    1. Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18(9): 1182–1191.

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