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Clinical Assistant Professor
Virginia Cancer Specialists
Co-Director, Virginia Cancer Specialists Research Program
Associate Chair, US Oncology Breast Cancer Research Committee
Neelima Denduluri, MD, has disclosed that she has received consulting fees from Seattle Genetics and funds for research support to her institution from Amgen, AstraZeneca, Daiichi Sankyo, Genentech, and Novartis.
Central nervous system (CNS) metastases will affect up to one half of patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Effectively managing brain metastasis in our patients remains an ongoing challenge, especially in light of emerging new HER2-targeted options with CNS activity and open questions as to how to optimally sequence these agents with our standard-of-care regimens. In this commentary, I discuss a case from my own practice to illustrate how I approach treating patients with HER2-positive MBC and CNS metastases.
Case Study: Treatment of a Patient With de novo HER2-Positive MBC
A 67-year-old woman presented with a cough in December 2019. She underwent a CT scan of the chest with contrast, which revealed possible liver metastases, a very large left-sided pleural effusion, and a collapsed lower left lung. She underwent transbronchial biopsy and pleural fluid drainage, which showed ER/PgR-negative and HER2-positive (IHC 3+) metastatic carcinoma.
PET/CT imaging in early January 2020 revealed diffuse osseous metastatic disease in the right scapula, ribs, vertebrae, bony pelvis, and proximal femoral head. A mediastinal mass was also evident with a consolidated left lower lobe plus multifocal hepatic metastases (largest: 3.8 cm). Based on her diagnosis of de novo HER2-positive MBC, she was slated to begin trastuzumab/pertuzumab plus paclitaxel, the standard-of-care regimen in this setting based on the results from the phase III CLEOPATRA trial.
However, the patient then noted increasing difficulty in articulating words, and her speech pattern had changed. A subsequent brain MRI scan showed multiple intracranial masses in the cerebellum, fourth ventricle, and parietal and occipital areas. In addition, she had significant edema in the left cerebral hemisphere with a mass > 4 cm.
How Did the Presence of New Brain Metastases Affect My Choice of Treatment Approach?
The primary challenge in treating any patient with brain metastases is that the blood–brain barrier selectively regulates what enters the brain, and there may be decreased penetration of some chemotherapy agents and monoclonal antibodies. Therefore, surgery and radiation historically have been the cornerstone of treating CNS disease. However, as we will discuss, HER2-targeted TKIs with known activity in the brain are an important option in this setting.
Choice of Local Therapy
Historically, the standard of care for patients with breast cancer–related brain metastases has depended on the size and location of the tumor(s), related symptoms, and the patient’s overall health. Single brain metastases are typically treated with surgery followed by radiation, or stereotactic radiosurgery for unresectable metastases in a patient without symptoms. Patients with 2-4 brain metastases are typically treated with stereotactic radiosurgery or resection for larger lesions if feasible. Whole-brain radiosurgery is used for widely disseminated brain metastases
For this patient, the neurosurgeon felt surgery was important to remove the biggest brain lesion due to the midline shift she was experiencing. In addition to the neurosurgical team removing her biggest lesion, she underwent stereotactic radiosurgery to 2 smaller areas.
Choice of Systemic Therapy
As mentioned above, I originally recommended trastuzumab/pertuzumab plus paclitaxel for this patient with de novo HER2-positive MBC before we knew she had brain metastases. This choice was based on results from the phase III CLEOPATRA trial, which showed that the addition of pertuzumab to a trastuzumab/taxane backbone improved OS in patients with HER2-positive MBC vs placebo plus trastuzumab/taxane (median OS: 51.7 vs 40.8 months, respectively; HR: 0.69).
However, now that we know the cancer has spread to her brain, should we instead consider using one of the newly approved HER2-targeted TKIs, neratinib or tucatinib, that are known to penetrate the CNS and have demonstrated activity against HER2-positive brain metastases?
In March 2020, neratinib, a next-generation TKI that binds to HER4, HER2, and HER1, was approved by the FDA in combination with capecitabine for the treatment of patients with HER2-positive MBC who have received at least 2 previous anti-HER2–based regimens in the metastatic setting. This approval was based on results from the phase III NALA trial that showed a significant PFS benefit, including a prolongation of the time to intervention for CNS metastases, with neratinib/capecitabine vs lapatinib/capecitabine (the first HER2-targeted TKI-based regimen approved for HER2-positive MBC) in patients with HER2-positive MBC who had received at least 2 previous lines of HER2-targeted therapy. Although treatment with neratinib was associated with diarrhea, proper aggressive prophylaxis can make its use more tolerable.
In April 2020, tucatinib, a more selective HER2-targeted TKI, was approved by the FDA in combination with trastuzumab and capecitabine for the treatment of patients with HER2-positive MBC who have received at least 1 previous anti-HER2–based regimen in the metastatic setting. This approval was based on results from the phase II HER2CLIMB trial that showed a significant PFS benefit, including in patients with brain metastases, with tucatinib plus trastuzumab/capecitabine vs placebo plus trastuzumab/capecitabine in patients with HER2-positive MBC who had received previous trastuzumab, pertuzumab, and T-DM1. Of note, HER2CLIMB also showed an OS improvement with tucatinib (median OS: 21.9 vs 17.4 months with placebo; HR: 0.66; P = .0048). Because of its selectivity for HER2, tucatinib is associated with less EGFR-associated toxicity, such as diarrhea.
Although it might be tempting to change course and give our case patient with de novo HER2-positive MBC one of these HER2-targeted TKIs because of her CNS metastases, I would still choose to give her the first-line standard-of-care regimen of trastuzumab/pertuzumab plus paclitaxel and here is why. HER2-positive MBC is truly a chronic disease, with more than one third of patients living 8 years or longer. With the understanding that HER2-positive MBC is a marathon with a range of treatment options, I would choose the regimen shown to have a survival benefit in the first-line setting over the HER2-targeted TKIs, which were evaluated in patients previously treated with HER2-targeted agents for metastatic disease. That said, we will give this patient a HER2-targeted TKI later in her disease course.
So, we started her on the standard regimen of trastuzumab, pertuzumab, and a taxane, and she is currently doing very well.
What About Patients Who Progress With CNS Metastases After Already Having Received HER2-Targeted Agents?
In contrast to our case patient, most patients with HER2-positive MBC who progress with CNS metastases already will have been treated with anti-HER2 therapies. In the metastatic setting, T-DM1 is the current standard of care following first-line trastuzumab/pertuzumab plus paclitaxel. However, per the FDA approval, tucatinib could be given to a patient with CNS progression in the second-line setting instead of T-DM1. Trastuzumab deruxtecan, a HER2-targeted antibody–drug conjugate, was also recently approved by the FDA for treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received at least 2 previous lines of anti-HER2–based regimens for metastatic disease. It is remarkable to have new options for our patients with later-line disease, but now our challenge is how to optimally sequence these agents in the absence of clinical data to guide us.
Furthermore, patients are increasingly receiving multiple HER2-targeted agents including in the neoadjuvant and adjuvant settings for early-stage HER2-positive breast cancer, such that when they require treatment for metastatic disease, they may have already been treated with agents including trastuzumab, pertuzumab, T-DM1, and even neratinib (for high-risk patients). As a result, our new HER2-targeted options may be used earlier in metastatic disease for these patients in actual practice. With regard to using tucatinib in patients who received neratinib as extended adjuvant therapy for early-stage disease, my decision would depend on the disease-free interval from the time they received neratinib and whether there were clinical trials available.
Importance of Multidisciplinary Care in the Treatment of Patients With HER2-Positive MBC and CNS Metastases
A multidisciplinary approach is required for optimal care of patients with HER2-positive MBC and CNS metastases. As mentioned above, medical oncologists, radiation oncologists, and neurosurgeons need to collaborate to determine the best approach to treating a patient with CNS disease. With the advent of new therapies for HER2-positive MBC with clear activity in the CNS, medical oncologists will need to educate our radiation oncology colleagues about the prospect of treating patients with new or progressing brain metastases with a systemic agent, with very close symptomatic and radiographic follow-up, and delaying radiation and its associated toxicities (eg, necrosis, cognition issues). Furthermore, emergency department physicians and nurses need to be educated on how to best monitor for and manage toxicities in patients receiving these new agents (eg, neratinib-associated diarrhea) to avoid drug discontinuation. Lastly, we must be cognizant of the potential for financial toxicity. Thus, the multidisciplinary team should also include patient benefit specialists to help reduce costs by working with insurance carriers, foundations, and pharmaceutical companies.
What are the biggest challenges you face when treating patients with HER2-positive MBC and brain metastases? Please take a moment to share your thoughts in the comment box below.