Testing for Discordance at Metastatic Relapse of Breast Cancer Matters (2012)

TO THEEDITOR: In an editorial 1 that accompanied two articles on receptor conversion of distant breast cancer metastases, 2,3 Chia stated, “The contribution to this discordance from preanalytic and analytic variables or from true biology based on heterogeneity of clonal populations in breast cancer and treatment is unclear.” 1(p576) We agree that this is an important issue, and indeed, most studies on receptor conversion may have suffered as a result of these variables. However, we have recently published a study 4 on receptor conversion wherein we have at least ruled out the analytic features that Chia mentions. Our series was large, with 233 paired cases. Bone metastases were excluded, given that they may provide problems with antigenicity as a result of decalcification, 2 and only biopsies were used, not fine needle aspirations. We used whole sections, not tissue arrays, to rule out tumor heterogeneity problems. Fresh sections were cut and stained with current, optimal, standardized staining methods to rule out differences in antigen retrieval, antibodies and antibody concentrations, and detection methods. Human epidermal growth factor receptor 2 (HER2) discrepancies between primary tumors and distant metastases were further evaluated by in situ hybridization. All sections were scored by one experienced pathologist to prevent interobserver variation. In addition, normal tissue next to tumor tissue was carefully evaluated as an internal control to also (partly) deal with preanalytical variables. Even with all of these variables excluded, we still found receptor conversion in 10.3% and 30% of patients for estrogen receptor (ER) and progesterone receptor (PR), respectively, when using a decision threshold of 10%. In 10.7% of patients, conversion from ER positive or PR positive to ER negative/PR negative occurred, and in 3.4% of patients, conversion from ER negative/PR negative to ER positive or PR positive occurred, which is obviously relevant with respect to the decision on hormonal therapy. For the 1% decision threshold, ER and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients, conversion from ER positive or PR positive to ER negative/PR negative occurred, and in 8.2% of patients, conversion from ER negative/PR negative to ER positive or PR positive occurred. Together with a 5.2% conversion rate for HER2, this means that a potentially clinically relevant receptor conversion occurred in more than 19% of patients using the 10% threshold (10.7% 3.4% 5.2%) and almost 26% (12.4% 8.2% 5.2%) for the 1% threshold. Conversion for ER and PR was mainly from positive to negative, whereas HER2 conversion was equally both ways. 4 In a follow-up study, we additionally showed that receptor conversion for ER and PR, being positive in the primary tumor and converted to negative in the distant metastases, has unfavorable prognostic impact. 5 All in all, these data show that despite potential preanalytic and analytic variables in different published studies, receptor conversion in distant breast cancer metastases can still be demonstrated in a significant percentage of patients when ruling out most of these error sources. Such receptor conversion could result in not only withholding effective endocrine- or HER2-blocking agents from patients but could also result in unjust administration of these same agents. At the same time, receptor conversion for ER and PR has prognostic value. Like Amir et al 2 and Niikura et al, 3 we therefore believe that distant metastases should be biopsied whenever possible to re-evaluate recep