Abstract

HER2 signaling is activated in response to somatic HER2 mutations, which are often found in invasive lobular breast cancer (ILC) and are associated with poor prognosis. Tyrosine kinase inhibitors (TKIs) have demonstrated considerable antitumor activity in patients with HER2-mutated advanced breast cancer (BC). Further, several clinical trials have indicated that HER2-targeted antibody-drug conjugates (ADCs) exhibit promising efficacy in lung cancer with HER2 mutations, and the efficacy of ADCs against HER2-mutated BC is currently being evaluated. Several preclinical studies have demonstrated that the therapeutic efficacy of ADCs in HER2-mutated cancer can be enhanced by the addition of irreversible TKIs, but the potential of such a combined treatment regimen for the treatment of HER2-mutated BC has not been reported. Herein, we describe a case in which a patient with estrogen receptor-positive/HER2-negative metastatic ILC with 2 activating HER2 mutations (D769H and V777L) exhibited a significant and durable response to anti-HER2 treatment with pyrotinib (an irreversible TKI) in combination with ado-trastuzumab emtansine, which was administered after multiple lines of therapy that had resulted in disease progression. Further, based on the evidence from the present case, TKI plus ADC seems to be a promising combination anti-HER2 regimen for patients with HER2-negative/HER2-mutated advanced BC, although further rigorous studies are warranted to confirm these findings.

Key Points

  • Patients with breast cancer (BC) with HER2-activating mutations may benefit from anti-HER2 therapy, especially irreversible TKI and ADC (ongoing trial), while trials have confirmed that the clinical activity of single-target therapy (TKI) in treating HER2-mutated breast cancer is limited by various factors.

  • Preclinical studies showed that irreversible TKI can enhance the antitumor activity of ADC, which indicate that combined treatment with TKIs and ADCs in BC with HER2 mutations is worthy of further exploration.

  • The present report is the first to describe the treatment of MBC carrying HER2 activating mutations with combined treatment involving TKI and ADC.