Ongoing Biomarker Measurements Inform Treatment Decisions in Breast Cancer

Adrian Lee, PhD

Adrian Lee, PhD

Measuring molecular biomarkers after metastasis could inform treatment decisions for women with breast cancer that has spread to the brain, according to results of a small study at the University of Pittsburgh Cancer Institute (UPCI) and Magee-Women’s Research Institute.¹Investigators found that approximately 20% of patients whose primary tumors did not harborERBB2/HER2mutations acquired those alterations with the development of brain metastases.

The retrospective study offers a rare comparison of primary breast cancer tissue with the matching brain metastasis. Adrian Lee, PhD, professor of Pharmacology and Chemical Biology at the University of Pittsburgh Cancer Institute, and colleagues tested tumors in a total of 20 patients: 10 with breast cancer who were estrogen receptor (ER)-negative and 10 with brain metastases who were ER-positive from 2 academic institutions, the University of Pittsburgh and the Royal College of Surgeons in Ireland. Two validation sequencing cohorts were used: a published data set of 17 patient-matched cases of brain metastases and a cohort of 7884 breast cancer tumors enriched for metastatic samples.

For molecular analysis, investigators used NanoString expression counts for target genes from tumor RNA extracts along with clusters, PAM50/Oncotype DX assignments, and expression values from normalized counts. Standard immunohistochemistry was used for ER testing; whole-exome sequencing forERBB2/HER2copy number alterations and site-specific testing with FoundationOne assays also were conducted.

Overall, researchers reported brain metastases expression changes in 127 genes. “The brain is a common and catastrophic site of metastasis for breast cancer patients,” said Lee, who also is director of the Women’s Cancer Research Center in Pittsburgh, in a statement. “Our study showed that, despite the large degree of similarity between the initial breast tumor and the brain metastatic tumor, there were enough alterations to support comprehensive profiling of metastases to potentially alter the course of treatment.”

“We found clinically actionable targets in the samples,” Lee said in an interview withTargeted Oncology. “Our findings add to the concept that there is a clear molecular evolution that goes on in metastasis. There’s clearly a change in targets—simply looking at the targets in the primary cancer is not enough, it’s not sufficient.”

The implications of the findings are significant. Researchers have reported that approximately 10% to 15% of patients diagnosed with breast cancer go on to develop central nervous system metastasis, although 1 study of autopsy findings estimated the rate at up to 30%.²Patients who develop brain metastases face a median overall survival of 8.5 months.¹

The study shows that clinically actionable information may be gleaned from repeating molecular testing for patients with brain metastases. “This now means we can screen for the presence of HER2 so that we can change and target the therapy to improve outcomes for our patients,” said Lee. The researchers found that patient-matched primary breast cancer and brain metastases have similar intrinsic subtypes; however, when examining on a gene level, clinically actionable alterations were identified in all but 3 pairs. The most recurrent gain in brain metastases wasERBB2/HER2, which showed expression increases in 7 of 20 (35%) of brain metastases and changes fromERBB2/HER2-negative toERBB2/HER2-positive levels.

Novel recurrent targetable alterations beyondERBB2/HER2were also discovered, including expression increases inFGFR4(30% of pairs),FLT2(20%), andAURKA(10%),EGFR(10%), and a loss ofESR1expression (45%). Investigators said each one of these targets is being studied in an clinical trials ongoing and results suggest that trial eligibility requiring expression of these markers should assess metastatic tumors if available, especially given greater than 4-fold microRNA expression gains over primary tumors in patient-matched metastases.

Significant loss of gene expression from the primary to metastatic lesions was also observed. The most recurrent expression losses involved cytokeratins, reported the researchers. “Cytokeratins have shown a complex role in oncogenesis and breast cancer metastasis, with loss of cytokeratin expression being a hallmark of epithelial—mesenchymal transition and metastasis,” the authors wrote.

Intermediate steps of metastasis—such as processes taking place within circulating tumor cells—may be masked with the use of paired analyses. The most recurrently lost clinically actionable gene wasESR1. Lee reported that loss of ER expression was an established mediator of therapy resistance.

The findings, presented during the 2016 San Antonio Breast Cancer Symposium, indicate that patients’ treatments should be tailored not only for the original breast cancer, but also the brain tumors, said Lee.

Lee anticipates larger studies will focus on the study of metastatic samples, with the greater use of liquid biopsies, which take advantage of the concept that the blood may be a good source of information. “Blood is a good reservoir of the repertoire of mutations that are in metastases,” he said. Because biopsy sites in metastases can be difficult to access, liquid biopsies could be the only option to obtain samples. “It’s a big research area that’s under development,” Lee said.

References:

1. Priedigkeit N, Hartmaier RJ, Chen Y, et al. Intrinsic subtype switching and acquiredERBB2/HER2amplifications and mutations in breast cancer brain metastases [published online December 7, 2016].JAMA Oncol. doi:10.1001/jamaoncol.2016.5630.
2. Dawood S, Broglio K, Esteva FJ, et al. Defining prognosis for women with breast cancer and CNS metastases by HER2 status.Ann Oncol. 2008;19(7):1242-1248.