Receptor conversion in distant breast cancer metastases

Abstract

The routine pathological work-up of breast cancer includes the evaluation of the estrogen receptor (ERα), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) which reveals biological information about the tumour as well as provides predictive biomarkers regarding hormonal therapy or trastuzumab treatment. At the occurrence of distant breast cancer metastases, the choice of systemic treatment used to be based on the receptor expression of the primary breast tumor, refraining from routine biopsies of the metastatic lesions as part of the standard workup. In this thesis we showed that the receptor status of breast cancer metastases may differ from the primary tumor, generally denoted “receptor conversion”. We found receptor conversion in 10.3% and 30% of patients for ERα and PR, respectively, when using a 10% threshold for positivity. When using the 1% ERα and PR thresholds according to the ASCO guidelines, conversion rates were even higher at 15.1% and 32.6%. Together with a 2.6% conversion rate for HER2 by SISH (5.2% by immunohistochemistry), receptor conversion would thereby have had direct consequences for the choice of the therapeutic regimen in 16.7-25.8% of women.We additionally showed that receptor conversion for ERα and PR from positive in the primary tumor to negative in the distant metastases has unfavourable prognostic impact. In conclusion, therapy management of metastatic disease is suboptimal when only based on primary tumor characteristics. For this reason, receptor status should therefore be reassessed on available biopsies from distant metastases and the tests results should be critically evaluated in conjunction with ER, PR and HER2 status of the primary tumor. Most contemporary guidelinesindeed now advice to biopsy distant metastases to re-evaluate receptor status to guide treatment in the metastatic setting. Despite the clear rationale for a metastatic breast cancer biopsy, this may not always be feasible because of limited lesion accessibility or potential complications. Therefore we described the development of prediction models for hormone receptor conversion in metastatic breast cancer patients using widely available clinicopathological information. We showed that especially the absence of positive tonegative hormone receptor conversion can be accurately predicted based on percentage ERα and PR positive cells of the primary tumor, which are easy and inexpensive to measure. Depending on ERα/HR and 1/10% threshold subgroups, 22 to 45% of all metastatic breast cancer patients of our study population with primary receptor positive disease had a predicted conversion risk below 5%, potentially obviating the need to biopsy. Previous studies have been done on single distant metastases, while patients often develop multiple metastases. We therefore aimed to study discordance of receptor status between different distant metastases from the same patient. We showed in a substantial proportion of 50 metastatic breast cancer patients discordance in ERα status (7-11%) and PR status (29-31%) across different distant breast cancer metastases within the same patient, with potential consequences for hormonal treatment in 11-15% of cases when only one random metastasis would be biopsied. As a consequence, several metastases may need to be biopsied when possible to fully assess receptor status in case of multiple metastases, while molecular imaging with hormone receptor probes may be an alternative.