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Updated: May 14, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
ROS1 immunohistochemistry as a potential predictive biomarker for ROS1-targeted therapy in breast cancer: impact of
Anna Sokolova1,2, Vaibhavi Joshi1, Haarika Chittoory1
1Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
Aims:
Invasive lobular carcinoma (ILC) may show targetable vulnerabilities secondary to the characteristic loss of the cell adhesion protein E-cadherin. Specifically, a synthetic lethal interaction was identified between E-cadherin loss and ROS1 inhibition. Several clinical trials are currently under way to assess the efficacy of ROS1 inhibitors in ILC; however, ROS1 expression has not been confirmed in ILC tumours and ROS1 has not been validated as a biomarker in the breast cancer setting. This study aimed to (i) examine ROS1 expression in a large cohort of breast cancer cases and (ii) investigate the biology and clinical significance of ROS1 positivity in breast cancer.
Methods And Results:
ROS1 immunohistochemistry was performed on a large cohort of ILC (n = 274) and invasive carcinoma of no special type (NST; n = 431) cases with extensive clinicopathological data. The staining performance of four ROS1 antibody clones was compared. There was marked variation in ROS1 status according to antibody clone. D4D6 and SP384 were negative in almost all breast cancer cases, whereas EP282 and EPMGHR2 were positive in 37 and 47% of ILC cases, and 49 and 74% of NST cases, respectively. Only data from clones D4D6 and SP384 were highly concordant, while EP282 and EPMGHR2 were positive in distinct breast cancer subtypes.
Conclusions:
Assessment of ROS1 status in breast cancer appears to be highly antibody clone-dependent. ROS1 antibody clone selection will be an important consideration in the design of clinical trials investigating the clinical validity of ROS1 as a predictive biomarker in breast cancer.
Insights
ROS1 expression in breast cancer is highly dependent on the antibody clone used for testing. Accurate ROS1 testing is crucial for developing ROS1 inhibitors as a potential breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunohistochemistry
Background:
- Invasive lobular carcinoma (ILC) exhibits E-cadherin loss, potentially creating vulnerabilities.
- A synthetic lethal interaction between E-cadherin loss and ROS1 inhibition suggests a therapeutic target in ILC.
- Clinical trials are evaluating ROS1 inhibitors for ILC, but ROS1 expression and biomarker validation in breast cancer are lacking.
Purpose of the Study:
- To examine ROS1 expression in a large cohort of breast cancer cases.
- To investigate the biology and clinical significance of ROS1 positivity in breast cancer.
Main Methods:
- ROS1 immunohistochemistry was performed on 274 ILC and 431 invasive carcinoma of no special type (NST) cases.
- The staining performance of four different ROS1 antibody clones was compared.
- Clinicopathological data were extensively analyzed alongside ROS1 expression.
Main Results:
- Significant variation in ROS1 status was observed based on the antibody clone used.
- Two clones (D4D6, SP384) were largely negative, while two others (EP282, EPMGHR2) showed positivity in 37-74% of cases.
- EP282 and EPMGHR2 identified distinct breast cancer subtypes, unlike the concordant D4D6 and SP384 clones.
Conclusions:
- ROS1 assessment in breast cancer is critically dependent on the chosen antibody clone.
- Antibody clone selection is a key factor for clinical trials validating ROS1 as a predictive biomarker in breast cancer.
