Effects of Ado-Trastuzumab Emtansine and Fam-Trastuzumab Deruxtecan on Metastatic Breast Cancer Harboring HER2 Amplification and the L755S Mutation

Abstract

Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of resistance to conventional anti-HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2-amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti-HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find co-existent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2-targeted drugs, particularly antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and the recently approved fam-trastuzumab deruxtecan (T-DXd), remains unclear. In this study, we described a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T-DM1 and T-DXd after exhibiting clinical resistance to other HER2-targeted drugs. Our current case findings suggested that anti-HER2 ADCs should be prioritized over conventional trastuzumab-or lapatinib-based therapies for patients with HER2-amplified and co-mutated tumors. The Oncologist 2021;9999:• • KEY POINTS • Although HER2 mutations were implicated in resistance to anti-HER2 monoclonal antibodies or HER2 TKIs in preclinical studies, their clinical impact on sensitivity to anti-HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification. • A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab-or lapatinib-based therapies but good responses to T-DM1 and T-DXd. • Anti-HER2 ADCs such as T-DM1 and T-DXd may be prioritized over conventional trastuzumab-or lapatinibcontaining therapies for patients with HER2-amplified and co-mutated tumors.

Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Botrytis cinerea Pers.

“…The development of new targeted therapies, such as aromatase inhibitors, monoclonal antibodies (trastuzumab, pertuzumab, T-DM1), and lapatinib, has improved remarkably the outcome for endocrine-sensitive or HER2-positive breast cancer subtypes ( Giordano et al, 2004 ). Some interesting developments resulted in further improvement of these agents, such as creation of clinically approved trastuzumab-based antibody-drug conjugates (Ado-Trastuzumab Emtansine and Fam-Trastuzumab Deruxtecan) ( Mukohara et al, 2021 ). Additionally, HER2-positive tumors respond well to several clinically approved tyrosine kinase inhibitors ( Schlam and Swain, 2021 ).…”

Dramatic Response to Pyrotinib and T-DM1 in HER2-Negative Metastatic Breast Cancer With 2 Activating HER2 Mutations

“… 41 Mukohara et al reported a case of BC with HER2 amplification and L755S mutation in which the patients exhibited an excellent response to T-DXd, after initial progression with trastuzumab and lapatinib therapy. 42 Both T-DM1 and T-DXd have been demonstrated to be promising agents for the treatment of lung cancer with HER2 mutations. 22 , 42 At present, the potential of these ADCs for the treatment of HER2 -mutated metastatic BC is unclear, but there is an ongoing clinical trial on the efficacy of T-DXd for the treatment of HER2 -mutated BC (NCT04639219).…”

Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report

“…mPFS was 8.2 months and median overall survival was 17.8 months. Mukohara et al 62 reported a breast cancer case with both HER2 amplification and the L755S mutation showing excellent responses to T-DM1 and then T-DXd after progression on trastuzumab and lapatinib.…”