Potential Resistance Mechanism to Tucatinib in HER2+ Breast Cancer

The HER2-targeting tyrosine kinase inhibitor tucatinib was recently approved for the treatment of HER2+ breast cancer, with proven central nervous system (CNS) activity. To better understand the genomic mechanisms of drug resistance to tucatinib, this retrospective analysis assessed the genomic landscape of heavily pretreated patients with advanced HER2+ breast cancer who received dual HER2-targeted therapy with tucatinib and trastuzumab.

A total of 11 patients treated with tucatinib, capecitabine, and trastuzumab were identified. Clinical data (baseline) as well as tumor and plasma samples (baseline and end of treatment) were collected. Next-generation sequencing (NGS) was performed on plasma samples collected from all 11 patients (n=107 serial samples across multiple timepoints) and in tumor samples from 6 (54%) patients. In the total cohort, median progression-free survival (PFS) of the study cohort was 9.6 months; median overall survival (OS) was 36.2 months. In the CNS cohort (n=7), median PFS was 13.5 months and median OS was 36.2 months.

NGS detected an average of 18.4 mutations per patient in tumor samples, 5.1 mutations in baseline plasma, and 5.8 mutations in end-of-treatment plasma samples. In baseline tumor samples, the most frequent mutations were ERBB2 (92%), KMT2C (67%), and NCOR1 (58%); in baseline plasma samples, the most frequent mutations were KMT2C (64%), NOTCH4 (36%), and PIK3CA (27%). A trend toward improved PFS was noted with a lower number of ctDNA mutations at baseline versus a higher number of mutations (14 months vs 7.5 months), indicating a potential mechanism of resistance to tucatinib.

Hypothesis-generating findings of this retrospective study in a small cohort of tucatinib-treated patients indicate a potential correlation between KMT2C mutations and unfavorable clinical outcomes; validation in larger validation data sets is warranted.


Blackley E, van Geelen C, Ko Y-A, et al. Investigation of the genomic evolution of HER2-positive breast cancer following progression on dual HER2-targetted therapy with trastuzumab and tucatinib. Presented at the 46th San Antonio Breast Cancer Symposium Annual Meeting, December 5-9, 2023; San Antonio, TX: Abstract PO2-04-06.

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