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Research Letter
April 23, 2020

Central Nervous System as Possible Site of Relapse in ERBB2-Positive Metastatic Colorectal Cancer: Long-term Results of Treatment With Trastuzumab and Lapatinib

Author Affiliations
  • 1Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
  • 2Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy
  • 3Oncologia Medica 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy
  • 4Istituto di Candiolo, Fondazione del Piemonte per l’Oncologia, IRCCS, Candiolo, Italy
  • 5Dipartimento di Oncologia, Università degli Studi di Torino, Turin, Italy
  • 6Università della Campania “L. Vanvitelli”, Naples, Italy
  • 7Precision Oncology, IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
JAMA Oncol. Published online April 23, 2020. doi:10.1001/jamaoncol.2020.0571

In colorectal cancer, ERBB2 amplification occurs in 5% of RAS wild-type metastatic tumors.1 In the pivotal HERACLES-A trial, chemorefractory patients with ERBB2 (formerly HER2)-positive metastatic colorectal cancer (mCRC) were treated with the combination of trastuzumab and lapatinib,2 demonstrating the proof of concept that the dual ERBB2 blockade previously found actionable in preclinical models3 could be successfully translated to the clinic with remarkable clinical benefit. We also reported that ERBB2 copy number in plasma was associated with that detected in tumor tissue, identified a cutoff value associated with clinical response,4 and studied acquired resistance on therapeutic ERBB2 blockade by longitudinal monitoring of circulating tumor DNA. Along this line, we documented that the onset of resistance was associated with emerging KRAS variant clones, BRAF amplification, and other molecular alterations already known in breast cancer, such as those of ERBB2, EGFR, PIK3CA, and PTEN.5

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