Assessing Biomarkers in Metastatic Breast Cancer

In In The News by Barbara Jacoby

By: Kate M. O’Rourke


Growing evidence demonstrates that changes in biomarker status occur frequently during the metastatic progression of breast cancer and can affect treatment response. “When a woman is first diagnosed with metastatic disease, it is important to reevaluate markers, because these do occasionally change from the time of primary diagnosis.” says Eric Winer, MD, a medical oncologist at Dana-Farber Cancer Institute.

Although many, if not most, clinicians usually reassess biomarkers in metastatic breast cancer (MBC), we don’t really know how important it is to evaluate changes in biomarker status in these patients, according to Lisa Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, chief of the Division of Hematology/Oncology, and deputy director of clinical sciences at University of North Carolina-Chapel Hill.

The Clinical Practice Guideline of the American Society of Clinical Oncology (ASCO) states that reevaluation of MBC lesions, including biomarker status, is important, and some suggest that multiple metastases should be biopsied. Here, experts shed light on the prognostic value of biomarker reassessment and the impact it may have on determining treatment options during the course of MBC.

Changing Biomarker Status

“Existing data suggest about 15% change in clinically important receptors (ER [estrogen receptor], PR [progesterone receptor], HER2 [human epidermal growth factor receptor 2]) between primary disease and metastasis, which in some series had a poorer outcome that might be due to change in appropriate therapy, but that cause-and-effect relationship has not really been studied. That said, most of us believe it is something you would want to know about, and it does influence treatment choices,” Carey commented. She said that loss of ER/PR is probably the most common biomarker change.

“During the course of a woman’s metastatic disease, I often repeat a biopsy and obtain markers again, particularly if there was any question about the HER2 status being borderline and/or in patients with ER-positive disease where ER-positive disease can evolve to ER-negative. That said, I do not think there is a single time point at which a repeat biopsy has to be performed. Instead, it is something to be considered (and not necessarily acted upon) each time there is a need for a change in treatment,” Winer remarked.

Not all biomarkers can change their status. Winer noted that PI3K is an important biomarker because it predicts for benefit with alpelisib, but PI3K typically does not change over time. Winer said that other biomarkers of interest in MBC include ESR1 mutations, which predict for lack of benefit from an aromatase inhibitor. “In addition, germline mutations of BRCA1 and BRCA2 predict for benefit with PARP inhibitors. There are also recent data that somatic BRCA mutations may predict for benefit from PARP inhibitors,” Winer commented.

According to Winer, biomarkers can be obtained from either tumor biopsy or circulating DNA, depending on the situation. “Next-generation sequencing (NGS) has been of little value to date in women with MBC but does occasionally leads to clinical trial enrollment. NGS may become more useful in the future,” Winer remarked.

Evidence for Change

The actual incidence of conversion of biomarkers in MBC is unclear. In a study of 152 patients diagnosed with MBC at the time of initial diagnosis or during postsurgical follow-up, ER, PR, HER2, and Ki-67 status changed in 9 (6.0%), 40 (26.3%), 12 (7.9%), and 29 (19.1%) patients, respectively. ER, PR, and HER2 mainly showed positive to negative conversion, whereas Ki-67 changed mostly from a low to high index. The researchers did not find any differences in the frequencies of biomarker changes according to the metastatic sites. Survival analyses demonstrated that a positive to negative conversion of ER was an independent poor prognostic factor in patients with primary ER-positive breast cancer.

In a study of multiple distant metastases from 55 female patients with MBC, 36.4% of cases showed discordance in ER alpha and PR status. In another study of 56 patients with MBC, conversion from hormone receptor–positive in the primary tumor to hormone receptor–negative in the metastasis occurred in 12 patients (21.4%), and hormone receptor–negative to hormone receptor–positive conversion occurred in two patients (3.6%). HER2 status was discordant between primary and metastatic lesions in seven patients (12.5%).

A recent meta-analysis sheds light on the incidence of conversion. The meta-analysis included 39 studies assessing receptor conversion from primary breast tumors to paired distant breast cancer metastases. Overall, the incidence of receptor conversion varied largely between studies. For ER alpha, PR, and HER2, the researchers discovered that random effects pooled positive to negative conversion percentages of 22.5%, 49.4%, and 21.3%, respectively. Negative to positive conversion percentages were 21.5%, 15.9%, and 9.5%. ER alpha discordance was statistically significantly higher in the central nervous system and bone compared with liver metastases (20.8% and 29.3% vs 14.3%, respectively; P = .008 and P < .001, respectively), and PR discordance was higher in bone (42.7%; P < .001) and liver metastases (47.0%; P < .001) compared with central nervous system metastases (23.3%).

Information about changing biomarker status has important ramifications for choosing targeted therapies for patients. Because receptor status in breast cancer is directly related to the patient’s treatment, many feel it is necessary to identify any receptor changes in patients with MBC. Negative conversion generally means that the current medication is no longer effective, and positive conversion opens the door for the possible use of a new therapy. As evidence grows that changes in biomarker status can occur, it becomes even more clear how important retesting of biomarkers is for the treatment of MBC.

The cause of receptor conversion during metastatic progression is not well understood, but there are several theories. One is intratumoral heterogeneity, or that breast cancer cells within a single tumor mass can exhibit phenotypic and genetic heterogeneity, with only a small number of these cells acquiring metastatic potential and forming a metastatic lesion. If biomarker status is heterogeneous in the primary tumor and is associated with different metastatic potential, then it can also change during metastatic progression. Selection pressure from treatment is another possible reason for receptor conversion. Because patients diagnosed with MBC receive endocrine or HER2-targeted therapy based on their receptor status, only breast cancer cells that have survived the therapy end up forming a metastatic tumor.

Ongoing studies should continue to help clarify the value in assessing biomarker changes in MBC. One trial currently in progress is designed to evaluate whether treatment with dual blockade promotes changes to biomarkers associated with immunomodulation. This multicenter, open-label, phase 2 study is in patients with HER2-positive MBC who received at least two prior lines of anti-HER2 targeted therapies, of which at least one included a trastuzumab-containing regimen.