Until recently, metastatic tumors were presumed to have the same estrogen receptor (ER), progesterone receptor (PR) and HER2 status as the primary tumor. However, discordance between the status of original tumors and corresponding metastases occurs in at least 25% of cases. Such receptor conversion can influence outcomes.
Some observers are of the opinion that biopsy of metastases should be part of routine management of recurrences in order to optimize treatment decisions. Given the opportunity, oncologists can make appropriate changes to their treatment plans in response to tumor receptor discordance.
Receptor changes are a natural part of breast cancer progression
Receptor status changes have validity
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.
Treatment can result in discordance
Discordance can occur as a response to treatment, however very little data is available concerning this possibility. One 2021 study found that 22% of HER2+ tumors became HER2- following neoadjuvant treatment. Another 2023 study reported a 28% rate of HER2 loss after neoadjuvant treatment.
Lymph node discordance can occur
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.
Discordance can occur within a tumor
One 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
- ER+ → ER-
- ER- → ER+
- PR+ → PR-
- PR- → PR+
- HER2+ → HER2-
- HER2- → HER2+
- Likelihood
- 5 to 30%
- 3 to 22%
- 19 to 49%
- 4 to 16%
- 4 to 28%
- 1 to 40%
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 is not well 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.
HER2 discordance
Women with discordant HER2 status between the primary tumor and recurrence have a significantly increased risk of mortality compared to patients with concordant HER2+ status, according several studies. It has been reported that a change from HER2+ to HER2- in particular results in worse post-recurrence survival than cancer that remains HER2+ as it progresses, however not all studies are in agreement. One 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, one study reported that gain in HER2 positivity (HER2- to HER2+) was associated with improved overall survival. A Japanese study found that changes in HER2 status after neoadjuvant chemotherapy did not affect prognosis. A 2021 study reported that loss of HER2 positivity in association with Herceptin treatment was not associated with worse five-year recurrence-free survival.
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. However, one 2020 study reported that breast cancer patients had longer progression-free survival when treatment matched the HER2 status of metastases rather than that of the primary tumor if they were discordant. This raises the question as to whether oncologists would change their treatment plans if they had more information concerning metastases. 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.
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.
Below are links to 20 recent studies concerning this topic. For a more complete list of studies, please click on discordance.