In HER2-Negative Breast Cancer, Brain Mets Are HER2-Positive 20% of Time

Nick Mulcahy

December 15, 2016

SAN ANTONIO — The finding that a patient with human epidermal growth factor receptor 2 (HER2)–negative breast cancer can have brain metastases that are HER2-positive warrants "immediate clinical attention," say researchers who found this was the case in one in five patients in a small, unique study.

Immediate steps are needed because such patients could benefit from a HER-targeted therapy but will not receive one because they tested HER2 negative for the primary breast cancer, they point out.

"There are many [Food and Drug Administration]-approved drugs against this [HER2], including trastuzumab, lapatinib, pertuzumab, and TDM1," lead author Adrian V. Lee, PhD, from the University of Pittsburgh Research Institute in Pennsylvania, told Medscape Medical News in an email.

The new study from Dr Lee and colleagues was published online December 7 in JAMA Oncology and presented as a poster the same day at the San Antonio Breast Cancer Symposium (SABCS) 2016.

However, there are limitations to this call for action, observed an expert who was asked for comment.

Most patients (about 80%) with brain metastases, which are diagnosed via MRI, do not have surgery because of its riskiness, and thus there is no way of acquiring and testing brain tissue to learn of any metastasis-acquired molecular alterations, said Cary Anders, MD, from the Lineberger Comprehensive Cancer Center of the University of North Carolina, Chapel Hill.

Only about 20% of patents with brain metastases will undergo resection and thus have brain tumor tissue available. Resection usually occurs only when the diagnosis of metastasis is unclear or a large lesion is causing central nervous system (CNS) problems, she said.

The new paper is potentially "very helpful" for patients who have a resection, Dr Anders pointed out.

She also praised the investigators.

"The authors are tackling one of the greatest challenges we have in the treatment of breast cancer, which is metastasis to the brain and CNS recurrence," she told Medscape Medical News.

The new study is "unique," she further said, because they had 20 patients who provided, via archived tumor tissue, a sample of their primary breast cancer as well as tissue from resected brain metastases.

Such patient-matched samples are a "rarity," said the authors.

The 20 cases consisted of 10 estrogen receptor [ER]–negative and 10 ER-positive primary breast cancers from 2 academic institutions.

Overall, 17 of 20 brain metastases retained the basic gene signature subtype of the primary breast cancer. However, despite this concordance, 17 of 20 of the brain mets harbored gene expression changes in "clinically actionable genes," including gains of FGFR4 (n = 6 [30%]), FLT1 (n = 4 [20%]), AURKA (n = 2 [10%]), and loss of ESR1 expression (n = 9 [45%]).

The most recurrent expression gain was HER2, which showed a greater than 2-fold expression increase in 7 of 20 brain mets (35%).

In total, 3 of 13 HER2-negative cases in the primary breast cancer cohort turned out to have HER2-positive brain mets.

The authors summarized the main finding: Approximately 20% of HER2-negative breast tumors had HER2-positive metastases to the brain.

The team also used 2 validation sequencing cohorts — a published data set of 17 patient-matched cases of brain mets and a cohort of 7884 breast cancer tumors enriched for metastatic samples. Both produced results in keeping with their findings from the discovery cohort.

The new results indicate that clinicians are underinformed when treating brain mets, said Dr Anders: "We don't know what we are necessarily treating in one in five cases."

She likened such a HER2-positive brain cancer, when undetected in patients with primary HER2-negative disease, to "a wolf in sheep's clothing" and called the study data "very provocative."

Will Available Drug Therapy Actually Work?

This is a setting in breast cancer care that needs to evolve, said Dr Anders, because of the riskiness of brain surgery. "We need less an invasive surrogate markers for what's happening in the brain — I think it will be a blood- or CNS-based biomarker."

There is another "big hurdle" in treating brain mets: getting a drug there, she added.

"The CNS is adapted to keep toxins out and what we are doing is trying to get cytotoxins into the brain," she said.

Does trastuzumab work in these patients? "Maybe," said Dr Anders.

"Herceptin's tough because it is a big bulky monoclonal antibody" that may not be able to pass through the blood-brain barrier, she said.

Other the other available candidates, TDM-1 has shown some activity in the brain in case reports, and lapatinib is a small molecule drug. Multiple other small molecule inhibitors that target HER2 are also in clinical trials.

When metastatic disease manifests in the brain, standard therapy includes radiotherapy and the adjuvant chemotherapy and endocrine therapy "to treat what we believe we are treating," says Dr Anders, alluding to the fact that the new results cast doubt on such beliefs.

The study authors point out that other research confirms their main results. For example, two different teams have reported HER2-negative to HER2-positive switching frequencies of 16% and 18%, respectively, in brain metastases (Breast Cancer Res. 2012;14:R119 and Br J Cancer. 2016;114:793-800).

The need for improved evaluation and treatment of these metastases is significant. Brain metastases occur in 10% to 15% of patients with metastatic breast cancer and present a "major clinical challenge," highlighted by a "poor" 8.5-month median overall survival, write the authors. They are a "catastrophic site" for a metastasis, they add.

The patients with metastatic breast cancers that are most likely to have brain mets are HER2-positive and triple-negative patients — with rates as high as 30% to 50%, respectively, said Dr Anders.

The field of metastatic breast cancer research will be further informed about brain mets by the Aurora Project, sponsored by the Breast Cancer Research Foundation, in which multiple institutions are donating paired metastatic biopsy specimens (including from the brain) with primary breast cancer tissue. Dr Anders is in charge of the clinical portion of the study, and Dr Lee the bioinformatics.

"This project will allow us to follow up on these findings in a larger data set," she said, adding that the eventual results could be confirmatory of the current data.

The study was supported by funds from the Breast Cancer Research Foundation, National Cancer Institute, Fashion Footwear Association of New York, the Shear Family Foundation, and Magee-Womens Research Institute and Foundation. Dr Lee has no financial disclosures, but multiple authors have ties to industry. Dr Anders has financial ties with multiple pharmaceutical companies, including those with investigational agents for brain metastases.

San Antonio Breast Cancer Symposium (SABCS) 2016. Abstract PD1-05. Presented December 7.

JAMA Oncol. Published online December 7, 2016. Abstract

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