Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer

Abstract

Background: The previous second-line treatment for HER2-positive metastatic breast cancer were adotrastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited. Materials and methods: We retrospectively analyzed data for patients with HER2-positive metastatic breast cancer who received T-DXd at our institution from April 2020 to March 2021. We evaluated the associations between clinicopathological and molecular biomarkers and the efficacy of T-DXd. Results: Twenty-two patients were enrolled in this study. The median progression-free survival (PFS) was 9.7 months (95% confidence interval [CI], 7.0enot reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3þ and 2þ/1þ at initial diagnosis (ORR: 50.0% vs. 72.7%, p ¼ 0.39; median PFS, 9.7 months [95%CI, 2.6eNR] vs. 8.3 months [95%CI, 7.1eNR]; hazard ratio, 1.86 [95%CI, 0.53e6.57], p ¼ 0.34). Two patients with heterogenous HER2 expression had a partial response or long stable disease (!6 months). Three of four patients with re-biopsy samples after anti-HER2 targeted therapy and with latest HER2 immunohistochemistry scores of 1þ experienced partial responses (75.0%) to T-DXd, but none had responded to prior T-DM1. Conclusions: T-DXd demonstrated favorable activity in clinical practice. Moreover, T-DXd showed meaningful benefit in patients with heterogeneity, reduction, or loss of HER2 expression.

Resistance to antibody‐drug conjugates in breast cancer: mechanisms and solutions

“…T‐DM1 failed to suppress HER2‐ cells, while DS‐8201a induced cytotoxicity to HER2‐ cells which neighbor HER2+ cells due to its effective bystander effect, which is also confirmed using phosphor‐integrated dots imaging [97]. According to a recent retrospective clinical study, patients with various statuses of HER2 (heterogenous, reduced, and loss) benefited from DS‐8201a [98].…”

Revolutionizing Breast Cancer Treatment: Unveiling the Effectiveness and Safety of Trastuzumab Deruxtecan through a Comprehensive Meta-Analysis

“…Through manual retrieval, a total of 1437 articles were obtained, 523 articles were obtained after removing duplicates, 28 articles were obtained by checking the titles and abstracts of the articles, 12 articles [16][17][18][19][20][21][22][23][24][25][26][27] were finally included in the analysis by reading the full text. See Figure 1.…”

“…A total of 12 studies were included, of which 3 [22,24,25] were RCTs with data, and 9 [16][17][18][19][20][21][22][23]25] were single-arm studies. Controls in RCTs were T-DM1 or chemotherapy.…”

“…There are only 3 studies [16,17,24] did report the median OS，and 3 studies [26,23,19] did not report the median PFS. HER2 status is an important feature of BC treatment, and HER2-positive, especially HER2 3+, was reported in 8 of the included literature [17][18][19][20]23,[25][26][27] .the specific characteristics of the literature are shown in Table 1.…”

Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression

“…16 Therefore, we envision that the administration of TNFα blocking agents in the clinical setting will be able to enhance the effect of trastuzumab-based conjugates, such as T-DM1 and trastuzumab-deruxtecan, antitumor effects. 44 Immune checkpoint inhibitors (ICI) have been recently introduced for triple-negative breast cancer treatment, and several trials are now running for HER2+ breast cancer. The current body of evidence points out that MDSCs, M2-like macrophages and poor TILs within the TME are associated with failure of ICI treatment.…”