Until recently, metastatic tumors were presumed to have the same estrogen receptor (ER), progesterone receptor (PR) and HER2 status as the initial primary tumor. However, discordance between the status of original tumors and corresponding metastases occurs in at least 25% of cases. Changes in ER or HER2 status can be a marker of increased breast cancer aggressiveness. Given the opportunity, oncologists will make appropriate changes to their treatment plans in response to tumor marker discordance. Some observers are of the opinion that biopsy of metastases should be part of routine management of recurrences in order to optimize treatment decisions.

Receptor status changes are a natural part of breast cancer progression

When the existence of discordance between the receptor status of original tumors and corresponding metastases was first reported, it was explained away by some observers as the result of differences in how receptor status was determined. In other words, it was thought that the receptor analysis of metastases performed by the study authors was more carefully and accurately done than the receptor analysis of the original tumor.

However, researchers have made a point of addressing this criticism in recent studies by determining the receptor status of both the primary and metastatic tumors using the same methodology. In addition, the rate of discordance varies according to site of metastasis (ER discordance is highest in bone metastases). This also suggests that discordance is a characteristic phenomenon of breast cancer.

It is not clear to what extent discordance is a response to treatment. For example, to what degree anti-estrogen treatment contributes to a change from ER+ to ER- status during disease progression. However, discordance has been found between primary tumors and corresponding positive lymph nodes before any treatment, showing that receptor status changes are a natural part of disease progression for some women.

On the other hand, one 2016 study that used two to four core samples of 1,085 tumors reported discordant biomarker status between cores in 2%, 7%, and 8% of cases for ER, PR, and HER2, respectively. Therefore, it appears that receptor status can vary in different portions of a single breast tumor.

Rates of biomarker discordance

Based on published reports to date, the likelihood of discordance between a primary breast tumor and its distant metastases is estimated as follows:

Change                Likelihood

ER+ → ER-            5 to 25%

ER- → ER+            3 to 14%

PR+ → PR-           19 to 46%

PR- → PR+            5 to 15%

HER2+ → HER2-    4 to 19%

HER2- → HER2+     1 to 6%

As the table shows, PR status changes are more common than ER changes; HER2 changes are the least likely. Loss of receptor expression is more common than gain. However, one study reported that, in 5% of cases, disease changed ER status back and forth throughout tumor progression.

Impact of tumor marker discordance on prognosis

Changes in ER or HER2 status can be a marker of increased disease aggressiveness; the significance of a change in PR status has not been established. One study found that when the primary tumor was ER+, the time to relapse was significantly shorter in the cases that switched to ER- status than those that remained ER+. A change from ER+ to ER- appears to be a sign that the disease is adapting to treatment and other aspects of the tumor environment. The same study reported that discordance was not associated with time to recurrence in originally ER- women.

Women with discordant HER2 status between the primary tumor and recurrence were found to have a significantly increased risk of dying compared to patients with concordant HER2+ status, according to one study. Another study reported that a change from HER2+ to HER2- in particular resulted in worse post-recurrence survival than cancer that remained HER2+ as it progressed. Still another study found that HER2 expression can vary within an initial primary tumor and that this predicts shorter disease-free survival than consistent HER2 gene amplification. However, a 2017 Japanese study found that changes in HER2 status after neoadjuvant chemotherapy did not affect prognosis.

Changes in treatment decisions because of discordant status

Treatment decisions in relapsed breast cancer are usually based on the ER, PR and HER2 status of the primary tumor. This raises the question as to whether oncologists would change their treatment plans if they had more information concerning metastases. In one study, the medical oncologist provided a treatment plan both before and after biopsy of suspected metastases. The biopsy results led to a change in treatment of 14% of the women. Study participants were followed for a median of 12 months with respect to disease progression and death. No trends for an association between receptor discordance and either time to treatment failure or overall survival were observed during follow up, indicating that the adjustments in treatment were effective.

Lymph node metastases can also have different tumor status

Lymph node metastases can also have discordant receptor status compared to the primary tumor. Triple-negative breast cancer was found to have different lymph node receptor status in 23% of the cases in one study. Since lymph node metastases represent disease progression, it might make sense to base treatment decisions on the receptor status of positive lymph nodes, if any. However, more studies are needed to determine the significance of the receptor status of lymph node metastases.

Biopsy of metastases could improve treatment decisions

Biopsy of metastases is technically feasible in most cases, although one study noted that both the use of fine-needle aspiration to obtain tissue samples and bone biopsies were associated with reduced ability to analyze receptors of metastases. Several authors have commented that biopsies of metastases should be performed routinely in order to optimize treatment decisions for breast cancer patients.

Below are links to recent studies on this topic. For a more complete list of studies, please click on discordance.