Although strategies for treating brain metastases in patients with advanced breast cancer are showing signs of efficacy, new approaches are needed to prevent high-risk, HER2-positive early disease from spreading to the central nervous system.
Although strategies for treating brain metastases in patients with advanced breast cancer are showing signs of efficacy, new approaches are needed to prevent high-risk, HER2-positive early disease from spreading to the central nervous system (CNS), according to Michelle E. Melisko, MD.
Introducing agents that can cross the blood-brain barrier into the adjuvant or neoadjuvant treatment paradigms should be the primary priority, Melisko said during a presentation at the 19th Annual International Congress on the Future of Breast Cancer® West, a virtual program hosted by Physicians’ Education Resource®, LLC (PER®).1
The development of screening paradigms designed to increase earlier detection of CNS metastases and an improvement in the understanding of the biology of the disease are additional areas that should be pursued, Melisko said.
“This talk is really a thought experiment, because there is not much to say right now about what we can actually do to prevent brain metastases in these patients, but [efforts to] prevent metastases in HER2-positive [early] breast cancer should take a 3-pronged approach,” said Melisko, an associate clinical professor in the Department of Medicine (Hematology/Oncology) at the University of California, San Francisco.
Although brain metastases are common consequences of metastatic breast cancer, the incidence of CNS involvement is far lower in earlier stages. Only 0.41% of patients newly diagnosed with breast cancer between 2010 to 2013 presented with brain metastases (968 of 238,726 patients), according to a study based on data from the Surveillance, Epidemiology, and End Results Program. The incidence ranged from 0.61% to 1.09% among those with HER2-positive disease.2
Brain metastases pose challenges for drug delivery because antibodies and antibody-drug conjugates are too large to cross an intact blood-brain barrier, Melisko said.
In advanced disease, tucatinib (Tukysa) became the first tyrosine kinase inhibitor to demonstrate prolonged overall survival in patients with HER2-positive metastatic breast cancer with brain metastases in a randomized clinical trial, Melisko said. In April 2020, the FDA approved tucatinib (Tukysa) in combination with trastuzumab (Herceptin) plus capecitabine for patients with advanced or unresectable metastatic HER2-positive disease who have received 1 or more prior HER2-targeting regimens based on findings from the HER2CLIMB trial (NCT02614794).3
However, several recent efforts to introduce brain-penetrant treatments in the neoadjuvant and adjuvant settings have not been successful. Melisko cited 2 studies: the phase 3 ExteNET study (NCT00878709) of adjuvant neratinib (Nerlynx) monotherapy in 2840 women with HER2-positive early breast cancer; and the phase 3 KATHERINE trial (NCT01772472) comparing trastuzumab with ado-trastuzumab emtansine (T-DM1; Kadcyla) in 1486 women with HER2-positive early disease who had residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane, with or without anthracycline, and trastuzumab.
No reductions in CNS metastases were observed in ExteNET. Although the rate of CNS recurrence in the neratinib arm (n = 1420) was lower than that in the placebo arm (n = 1420), the difference was not statistically significant (P = .333). “It should be noted that there was no protocol-defined CNS imaging built into the study, so patients were not getting brain MRIs to detect small, asymptomatic brain metastases,” Melisko said. To date, no data have been presented or published on CNS recurrences in ExteNET’s subpopulations, she said.
Similarly, findings from KATHERINE showed “no reduction in CNS recurrences as the first site of recurrence,” Melisko said. The rate of CNS recurrence was 4.3% in the trastuzumab cohort (n = 743) and 5.9% in the group that received T-DM1 (n = 743).
“We’ve been somewhat disappointed with the performance of neratinib and T-DM1 in the ExteNET and KATHERINE trials. Maybe these trials need to be structured differently,” Melisko suggested, indicating that efforts to move brain-penetrant therapies into the adjuvant and neoadjuvant settings could include inventive revisions of past clinical strategies.
Beyond adding brain-penetrant interventions to adjuvant and neoadjuvant treatment sequences, the field of breast oncology must also work toward a fuller, deeper knowledge of the biology of HER2-positive early breast cancer vulnerable to brain metastases to identify the optimal preventive. “We really need to have increased understanding of the biology of disease prone to spread to the CNS,” Melisko said.
A more comprehensive biological basis would help clinicians understand why achieving a pathological complete response does not protect HER2-positive patients from developing CNS metastases, as observed in the adaptive, phase 2 I-SPY 2 study (NCT01042379) testing a variety of neoadjuvant treatment interventions in patients with histologically confirmed invasive breast cancer, Melisko added.
Developing a screening paradigm to support earlier detection of CNS disease could be both beneficial for and enticing to this high-risk patient population, Melisko hypothesized. “I believe that patients would vote with their feet if there were a trial [to test screening’s efficacy]. They would be very, very interested in some type of screening paradigm, because I do believe that there may be a subset of patients who could still enjoy an extremely long survival if we diagnosed them with CNS disease very early,” Melisko said.
Securing funding for such an initiative, however, could prove difficult. “Since there would not be a pharmaceutical company involved, the question is, ‘Who would pay for this?’” Melisko added.
Despite the complexities that devising a screening process could present, it is possible that preemptive testing for CNS spread could culminate in improved survival for patients. This idea is supported by data from Niwińska et al that demonstrated a reduced risk of death from CNS progression in patients who completed brain MRI screening every 3 months and subsequently underwent whole-brain radiotherapy upon identification of brain metastases.
The study population included 80 patients with metastatic HER2-positive breast cancer who received prior chemotherapy and trastuzumab. As investigators routinely performed MRI evaluations, 2 patient groups formed. Group 1 included 29 patients with occult brain metastases, while group 2 encompassed 52 patients with symptomatic brain metastases.
At a median follow-up of 20 months, routine screening and subsequent radiotherapy did not improve the median overall survival in group 1 or 2 (53 months vs 51 months, respectively; P = .94). However, patients with occult brain metastases uncovered during MRI screening had a lower rate of death from CNS progression compared with group 2 patients (16% vs 48%; P = .009).
“I remember these data being published 10 years ago and thinking that it was interesting and really required repetition or re-analysis in a more modern era,” Melisko said. “Looking at the data and the tools we have in the metastatic setting is the place to start” when conceptualizing future strategies for preventing CNS spread in high-risk, HER2-positive early breast cancer, she concluded.