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Receptor conversion in distant breast cancer metastases
Laurien D C Hoefnagel1, Marc J van de Vijver, Henk-Jan van Slooten
1Department of Pathology, University Medical Center Utrecht, The Netherlands.
Introduction:
When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor ("receptor conversion"), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections.
Methods:
233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ERα, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result.
Results:
Using a 10% threshold, receptor conversion by IHC for ERα, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from "ER+ or PR+" to ER-/PR- and in 3.4% from ER-/PR- to "ER+ or PR+" was found. Using a 1% threshold, ERα and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from "ER+ or PR+" to ER-/PR-, and 8.2% from ER-/PR- to "ER+ or PR+" occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ERα and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases.
Conclusions:
Receptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ERα and HER2, and more frequent for PR, especially in brain, liver and gastro-intestinal metastases.
Insights
Receptor conversion in breast cancer metastases is uncommon for ERα and HER2 but more frequent for PR, particularly in liver, brain, and gastro-intestinal sites. This finding impacts systemic treatment choices for advanced breast cancer.
Area of Science:
- Oncology
- Pathology
- Genetics
Background:
- Systemic treatment for metastatic breast cancer relies on primary tumor characteristics (ERα, PR, HER2).
- Immunophenotype differences between primary tumors and metastases ('receptor conversion') can lead to suboptimal treatment.
- Previous studies on receptor conversion were limited by small sample sizes and suboptimal methods.
Purpose of the Study:
- To investigate the frequency and patterns of receptor conversion for ERα, PR, and HER2 in a large cohort of distant breast cancer metastases.
- To compare receptor status between primary tumors and their corresponding metastases using standardized IHC and ISH methods.
- To provide data that may inform clinical practice regarding treatment selection for metastatic breast cancer.
Main Methods:
- Analyzed 233 distant breast cancer metastases (skin, liver, lung, brain, GI) and their primary tumors.
- Performed immunohistochemistry (IHC) for ERα, PR, and HER2 on all samples.
- Utilized HER2 in situ hybridization (ISH) for cases with IHC conversion or equivocal results.
Main Results:
- Receptor conversion rates (10% threshold) were 10.3% for ERα and 30.0% for PR.
- HER2 conversion occurred in 5.2% of cases.
- PR conversion was significantly more frequent in liver, brain, and GI metastases compared to other sites.
Conclusions:
- Receptor conversion is a documented phenomenon in distant breast cancer metastases.
- ERα and HER2 conversion are relatively uncommon, while PR conversion is more frequent.
- The observed conversion rates, particularly for PR, highlight the need for careful consideration in selecting systemic therapy for patients with metastatic breast cancer.
