Clinical and genomic characteristics of HER2-ultralow breast cancer and implications for T-DXd therapy

Abstract

Background: The clinical benefit of T-DXd in advanced breast cancer with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-ultralow tumors in the DESTINY-Breast06 trial has drawn attention to this subtype.

Methods: We re-evaluated 473 pathological specimens from 302 HER2-negative breast cancer patients in our next generation sequencing database, classifying HER2-negative status into HER2-ultralow, IHC 0 without membrane staining (MS−) and HER2-low. Clinicopathologic characteristics and genomic profiles were analyzed by HER2 status.

Results: Overall, 35.5% of primary and 49.0% of metastatic HER2-IHC 0 tumors were reclassified as ultralow. Subtype analysis based on HR status showed no distinct clinicopathological characteristics in the HER2-ultralow subgroup. Upon metastasis, 40% of HER2-ultralow primary tumors converted to IHC 0 (MS−) and 46.7% to HER2-low. In the metastatic tumors, 60% of HER2-IHC 0 (MS−) and 50% of HER2-ultralow translated to other HER2 statuses in re-obtained samples. HER2-ultralow status was associated with worse disease-free survival than HER2-IHC 0 (MS−) and HER2-low status in HR-negative breast cancer, but no differences of overall survival were observed. The median progression-free survival for first-line chemotherapy was 7.2 months in HR+ HER2-low, 6.8 months in ultralow, and 8.8 months in IHC 0 (MS−) patients (P= 0.06). PIK3CA mutations were more common in the HER2-low subtype than in HER2-ultralow tumors in the HR− subtype.

Conclusion: In conclusion, HER2-ultralow status is not associated with distinct clinicopathologic or genomic characteristics. HER2-IHC 0 (MS−) and ultralow statuses often coexist within the same patient.

Keywords

HER2 ultralow breast cancer / T-DXd / HER2-IHC 0 without membrane staining (MS−) / DESTINY-Breast06 / genetic alterations

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (grant No. 81903084 to J.J., 82303646 to G.D.C., and 82473071 to H.X.C.), the Program for Shanghai Outstanding Academic Leader (grant No. LJRC2102 to H.X.C.), and the Shanghai Anticancer Association SOAR PROJECT (grant No. SACA-AX202106 to H.X.C.). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Juan Jin (Data curation, Funding acquisition, Writing— original draft, Writing—review & editing), Tiantian Liu (Data curation, Writing—review & editing), Mengyuan Cai (Resources, Writing—review & editing), Mingchuan Zhao (Resources, Writing—review & editing), Duanchen Guo (Data curation, Funding acquisition, Writing—review & editing), Hong Lv (Resources, Writing—review & editing), Leiping Wang (Project administration, Writing—review & editing), Biyun Wang (Project administration, Writing—review & editing), Hongxia Wang (Project administration, Writing—review & editing), Zhonghua Tao (Writing—original draft, Writing—review & editing), Wentao Yang (Conceptualization, Writing—review & editing), and Xichun Hu (Conceptualization, Funding acquisition, Writing—review & editing).

Supplementary data

Supplementary data is available at PCMEDI Journal online.

Conflict of interests

None declared.

Ethics statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 1705172-9). The patients/participants provided their written informed consent to participate in this study.

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