HER2 positive rates are enriched amongst colorectal cancer brain metastases: a study amongst 1920 consecutive patients
Authors: R.Y.C. Tan, M.D. Camat, M. Ng, T.H. Lim, A.S.T. Lim, K.H. Lim, I.B.H. Tan
Journal: Annals of Oncology (2018)

Brain metastases from colorectal cancer (CRC) are a rare but increasing event as patients survive longer. While HER2 gene amplification in breast cancer is well described and known to increase risk of brain metastases [1.Aversa C. Rossi V. Geuna E. et al.Metastatic breast cancer subtypes and central nervous system metastases.Breast. 2014; 23: 623-628Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar], information in CRC patients with brain metastases is lacking. A multi-centre phase II trial has shown that HER2-directed therapies are efficacious in HER2 positive (HER2+) stage IV CRC without brain metastases [2.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: 738-746Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar]. If HER2 is enriched in CRC patients with brain metastases, it may provide a possible therapeutic target. We carried out a comprehensive review to identify CRC patients with brain metastases at the National Cancer Centre Singapore. All brain radiology reports between June 2012 and June 2017 from 1920 consecutive CRC patients were retrospectively reviewed. This identified 40 patients with radiological evidence of brain metastases, an incidence of 2% (40 of 1920). We retrieved resected primary tumour specimens or biopsies of metastatic sites from these 40 patients for fluorescence in situ hybridization testing for HER2 gene amplification (Figure 1). HER2 amplification was defined as an HER2/CEP17 ratio ≥2.0 in at least 100 tumour nuclei. HER2 amplification was observed in 20% (8 of 40) of CRC patients who develop brain metastases (Figure 1). HER2 amplification was observed across most primary sites in the HER2+ patients (4 rectum, 3 right colon and 1 left colon) and was also seen in KRAS mutant CRC (2 of 8 patients). This is higher than the previously reported HER2 positive rate of 5% amongst 912 KRAS wild-type metastatic CRC patients without brain metastases in the HERACLES study [2.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: 738-746Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar] and 0% (0/44) amongst KRAS mutant patients reported in literature by Valtorta et al. [3.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: 1481-1491Crossref PubMed Scopus (167) Google Scholar]. Brain metastases was also preceded by metastases in either the lung or the liver in 95% of patients (38 or 40) including all of the HER2+ patients, suggesting it appears later in the disease course (supplementary Table S1, available at Annals of Oncology online). At present, HER2 testing is not routinely carried out in most clinical practices. Our study suggests that physicians can consider HER2 testing in patients who develop brain metastases. Conversely, in patients known to have HER2+ CRC, our study may prompt a lower clinical threshold to evaluate neurological symptoms in view of the enrichment in brain metastases. While further studies are necessary to validate our findings, they highlight intriguing insights into brain organotropism for HER2+ cancers and provide a possible therapeutic target for a population of CRC patients for which there are still no good systemic therapies. RYCT and IBHT received grant funding through the National Cancer Centre Singapore Research Fund during the conduct of this study. No grant numbers apply.