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William J. Gradishar, MD, FACP, FASCO


ESMO 2022: Biomarker Analyses Focus on Resistance to T-DXd in Metastatic Breast Cancer

By: Julia Fiederlein
Posted: Friday, September 30, 2022

In the multicenter phase II DAISY trial, fam-trastuzumab deruxtecan-nxki (T-DXD) demonstrated efficacy in three cohorts of patients with HER2-overexpressing and HER2-low metastatic breast cancer, according to Maria Fernanda Mosele, MD, of Gustave Roussy, Villejuif, France, and colleagues. The results of the recent biomarker analyses, which were presented during the European Society for Medical Oncology (ESMO) Congress 2022 (Abstract LBA72), further explored the mechanism of action and resistance to this anti-HER2 antibody-drug conjugate.

“Trastuzumab deruxtecan could trigger antitumor immune response in HER2-negative metastatic breast cancer,” the investigators remarked. “ERBB2 hemizygous deletion seems to be associated with trastuzumab deruxtecan upfront resistance. SLX4 could induce secondary resistance; however, it needs to be confirmed.”

After the first cycle of T-DXd, spatial genomic response was assessed in biopsies according to HER2 expression (n = 8). Biopsies with no baseline immunohistochemical detection of HER2 were assessed by reverse transcription polymerase chain reaction (n = 36). Using whole-exome sequencing, the investigators explored primary and secondary resistance in biopsies at baseline (n = 88) and disease progression (n = 20); distribution of T-DXd was assessed by immunohistochemistry up to 6 weeks after the last infusion at disease progression (n = 6).

Serotonin receptor and interferon alpha pathways were found to be activated in HER2-overexpressing and HER2-negative areas, respectively, after the administration of T-DXd. There appeared to be no association between ERBB2 expression and clinical response. No recurrent driver alterations seemed to be associated with resistance. A total of 6% of patients harbored an ERBB2 hemizygous deletion at baseline; of this population, four did not respond to treatment. According to the investigators, SLX4 mutation was acquired in 20% of biopsies at disease progression and was found in 20% of samples unmatched with baseline. In two breast cancer cell lines, SLX4 silencing appeared to mediate resistance. Distribution of T-DXd was reported in four patients at disease progression.

Disclosure: For full disclosures of the study authors, visit

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