HER2 low-expression breast cancer included in Korean guidelines for 1st time

For the first time, HER2 low-expression breast cancer has been specified in national treatment guidelines, strengthening the recommendation for Enhertu (trastuzumab deruxtecan, T-DXd).

This is expected to further expand the scope of HER2-targeted therapy beyond the traditional HER2-negative/positive dichotomy.

The Korean Breast Cancer Society recently released the 11th Korean Breast Cancer Practice Recommendations 2025, the first revision in two years.

The recommendations have been revised to reflect the latest clinical evidence across all areas of non-invasive breast cancer, early breast cancer, recurrent and metastatic breast cancer, and hereditary breast cancer. Notably, among recurrent and metastatic breast cancer, Enhertu treatment is recommended for various types of breast cancer, including HER2 positive, HER2 low expression, and brain metastases.

Enhertu now recommended for patients with HER2 low-expression metastatic breast cancer

The most notable change is that, for the first time, treatment guidelines for HER2 low-expression metastatic breast cancer have been specified.

In the 10th Korean Breast Cancer Practice Recommendation, published two years ago, the results of the phase 3 DESTINY-Breast04 study in patients with HER2 low-expression breast cancer were introduced at the reference level.

However, following Enhertu’s expansion in Korea in May last year, the revised guideline now states that Enhertu is recommended for patients with HER2 low-expression metastatic breast cancer who have received at least one or two cytotoxic chemotherapy regimens.

That recommendation is based on the phase 3 DESTINY-Breast04 study, which compared the efficacy and safety of Enhertu to a physician-selected chemotherapy arm in 557 patients with unresectable or metastatic HER2 low-expression breast cancer who received one or more lines of chemotherapy in the metastatic stage.

In the study, the median progression-free survival (mPFS) in the hormone receptor-positive (HR+) patient cohort was 10.1 months with Enhertu vs. 5.4 months with the control arm, a nearly twofold difference. The risk of disease progression or death was reduced by about 50 percent compared to the control arm.

New ADC therapy introduced for triple-negative breast cancer

Rapid progress has also been made in the treatment of triple-negative breast cancer, which has a poor prognosis and limited treatment options, and guidelines have been further refined.

In particular, a new category for antibody-drug conjugate (ADC) therapies has been created, suggesting that Enhertu may be considered for treating patients with HER2 low-expression triple-negative metastatic breast cancer in second-line treatment or later.

In the triple-negative breast cancer subgroup (58 patients) of the DESTINY-Breast04 study, mPFS in the Enhertu arm was 6.3 months compared to 2.9 months in the control arm, a significant prolongation (HR 0.29). In addition, median overall survival (mOS) more than doubled to 17.1 months vs. 8.3 months, respectively (HR 0.58).

Based on these results, the experts stated that Enhertu can be used in the second-line treatment of patients with HER2 low-expression metastatic triple-negative breast cancer (LE 1, GR A).

Extensive clinical results described for Enhertu in breast cancer patients with brain metastases

Another noteworthy change is the inclusion of many clinical studies of Enhertu in the treatment of breast cancer patients with brain metastases.

The revision categorizes breast cancer patients with brain metastases as HER2-positive or HER2-negative. The HER2-positive group includes results from the pooled analysis of Enhertu's TUXEDO-01 study and the DESTINY-Breast01, 02, and 03 studies, and the HER2-negative group includes results from the DESTINY-Breast04 and DEBBRAH studies.

In the TUXEDO-1 study in patients with HER2-positive breast cancer with brain metastases, the mPFS in the Enhertu arm was reported to be 21 months (LE 3, GR A). In addition, in a pooled analysis of the DESTINY-Breast01, 02, and 03 studies, the median duration of response (mDOR) was 12.3 months in patients with previously treated or stable brain metastases (treated/stable) and 17.5 months in patients with untreated active brain metastases (untreated/active).

HER2-negative breast cancer with brain metastases requires a more complex and diverse approach.

In a 24-patient subgroup analysis of the DESTINY-Breast04 study, the overall response rate (ORR) in the brain was 0 percent (0/11 patients) in the control arm compared to 25 percent (6/24 patients) in the Enhertu arm, suggesting promising therapeutic potential. The DEBBRAH study, a single-arm phase 2 trial, confirmed these consistent results, with an ORR of 41.7 percent (five of 12) for Enhertu in patients with active brain metastases.

“The demonstrated efficacy of Enhertu in HER2 low-expression breast cancer, which has not been demonstrated with existing HER2-targeted therapies, has enabled HER2-targeted therapy to be used in a broader range of patients,” said Professor Park Yeon-hee of the Department of Hematology-Oncology at Samsung Medical Center, who participated in the revision of the Korean breast cancer guidelines.

“This revision focuses on rapidly incorporating the latest clinical research findings to provide more precise and effective treatment strategies, and we expect that the recommendations for the HER2 low-expressing patient population will become an important evidence base for treatment decisions in real-world clinical practice,” Professor Park added.