Future potential targets of antibody-drug conjugates in breast cancer

 

by Chiara Corti, Luca Boscolo Bielo, Ambra Carnevale Schianca, Beatrice Taurelli Salimbeni, Carmen Criscitiello, Giuseppe Curigliano 

 

The Breast: VOLUME 69, P312-322, JUNE 2023 (Published: March 24, 2023)

 

Abstract

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required.

Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7–H4.

In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided.

Breast Surgery Bulletin - January 2022

 

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

by Hiromichi Nakajima, Kenichi Harano, Tokiko Nakai, Shota Kusuhara, Takehiro Nakao, Chikako Funasaka, Chihiro Kondoh, Nobuaki Matsubara, Yoichi Naito, Ako Hosono, Shuichi Mitsunaga, Genichiro Ishii, Toru Mukohara 

 

The Breast: Published: January 03, 2022

 

Highlights

•T-DXd showed favorable clinical activity against HER2-positive metastatic breast cancer.

•T-DXd showed benefit in patients with heterogeneity, reduction, or loss of HER2 expression.

•Patients with liver metastasis tended to have worse outcomes.

 

Abstract

Background

The previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab 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], 7.0–not reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3+ and 2+/1+ at initial diagnosis (ORR: 50.0% vs. 72.7%, p = 0.39; median PFS, 9.7 months [95%CI, 2.6–NR] vs. 8.3 months [95%CI, 7.1–NR]; hazard ratio, 1.86 [95%CI, 0.53–6.57], p = 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 1+ 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.

Validated biomarkers: The key to precision treatment in patients with breast cancer

Validated biomarkers: The key to precision treatment in patients with breast cancer

The Breast
Duffy MJ et al

Recent DNA sequencing and gene expression studies have shown that at a molecular level, almost every case of breast cancer is unique and different from other breast cancers. For optimum management therefore, every patient should receive treatment that is guided by the molecular composition of their tumor, i.e., precision treatment. While such a scenario is still some distance into the future, biomarkers are beginning to play an important role in preparing the way for precision treatment. In particular, biomarkers are increasingly being used for predicting patient outcome and informing as to the most appropriate type of systemic therapy to be administered. Mandatory biomarkers for every newly diagnosed case of breast cancer are estrogen receptors and progesterone receptors in selecting patients for endocrine treatment and HER2 for identifying patients likely to benefit from anti-HER2 therapy. Amongst the best validated prognostic biomarker tests are uPA/PAI-1, MammaPrint and Oncotype DX. Although currently, there are no biomarkers available for predicting response to specific forms of chemotherapy, uPA/PAI-1 and Oncotype DX can aid the identification of lymph node-negative patients that are most likely to benefit from adjuvant chemotherapy, in general. In order to accelerate progress towards precision treatment for women with breast cancer, we need additional predictive biomarkers, especially for enhancing the positive predictive value for endocrine and anti-HER2 therapies, as well as biomarkers for predicting response to specific forms of chemotherapy. The ultimate biomarker test for achieving the goal of precision treatment for patients with breast cancer will likely require a combination of gene sequencing and transcriptomic analysis of every patient's tumor.