Trastuzumab Deruxtecan: a new hope for HER2-mutated triple-negative breast cancers without HER2 expression

12 octobre 2025

By Lila Rouland | Published on October 12, 2025 | 3 min readThe HER2 receptor (ERBB2) is a transmembrane protein with tyrosine kinase activity, involved in cell proliferation, tumor invasion, and angiogenesis. Its overexpression has historically been associated with a poor prognosis in breast cancer. HER2-targeted therapies, such as trastuzumab and its antibody-drug conjugates (ADCs), have profoun

By Lila Rouland | Published on October 12, 2025 | 3 min read

The HER2 receptor (ERBB2) is a transmembrane protein with tyrosine kinase activity, involved in cell proliferation, tumor invasion, and angiogenesis. Its overexpression has historically been associated with a poor prognosis in breast cancer. HER2-targeted therapies, such as trastuzumab and its antibody-drug conjugates (ADCs), have profoundly changed the management of HER2-positive patients.

However, the use of these treatments in patients without HER2 expression (IHC 0+) but harboring a HER2 mutation remains largely unexplored. No clinical trial currently includes this population. This case report highlights a patient with metastatic triple-negative breast cancer harboring an HER2 L755S mutation but no HER2 expression, who was treated with trastuzumab deruxtecan monotherapy, achieving an exceptional long-lasting response of more than 3 years.

An unprecedented case of long-term response to an anti-HER2 ADC

Clinical profile: A 71-year-old woman with pleomorphic lobular carcinoma, grade 2, hormone receptor–negative, and HER2 1+ on initial immunohistochemistry (IHC), which later became HER2 0+ on a brain metastasis. She experienced disease progression with a large cerebellar metastasis, classifying her cancer as stage IV.

After failure or intolerance to multiple standard therapies (chemotherapies, PARP inhibitor, and the tucatinib–capecitabine–trastuzumab combination), she began trastuzumab deruxtecan monotherapy in April 2022 at a reduced dose (374.8 mg every 3 weeks). This decision was based on encouraging data from the DESTINY-Breast04, PanTumor01, and DEBBRAH trials, despite the absence of official recommendations for this particular profile (HER2 0+/HER2 mutation).

Clinical evolution: Brain imaging (MRI) showed regression of metastases as early as July 2022, confirmed by follow-ups through December 2024, with no tumor recurrence. PET scans and lung examinations also remained stable. Cardiac function (MUGA scan) was preserved (ejection fraction 65–69%), and no significant adverse events required treatment discontinuation.

Toward a new era for HER2-mutated, HER2-nonexpressing patients?

This unique case demonstrates for the first time the long-term efficacy of trastuzumab deruxtecan in a triple-negative breast cancer patient with an HER2 mutation but no HER2 expression (IHC 0+). After three years of treatment, the patient remains clinically stable, without tumor progression or major side effects.

Originally developed for HER2-positive cancers and later extended to HER2-low cases, ADCs could now potentially be used in HER2-mutated cancers, regardless of protein expression. This could open a new therapeutic category for patients previously excluded from anti-HER2 targeted therapies.

The main limitation of this observation lies in its single, uncontrolled nature. Nevertheless, it underscores the urgent need for clinical trials exploring the use of ADCs in HER2-mutated but nonexpressing metastatic breast cancers. The emergence of bispecific antibodies or dual-loaded bioconjugates also represents a promising avenue for these complex cases.

Read next: Targeting to treat better?

About the author – Lila Rouland

Doctor of Oncology, specialized in Biotechnology and Management

With dual expertise in science and marketing, Lila brings her knowledge to the service of healthcare innovation. After five years in international academic research, she transitioned into medical and scientific communication within the pharmaceutical industry. Now working as a medical writer and content developer, she is committed to highlighting scientific knowledge and conveying it to healthcare professionals with clarity and relevance.

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Scientific reference

Idamakanti M, et al. Long Durable Response With Trastuzumab Deruxtecan Monotherapy in a Triple-Negative Metastatic Breast Cancer Patient With Human Epidermal Growth Factor Receptor 2 Mutation[…]. J Med Cases. 2025;16(6):212-221.

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