ASCO Guideline Update Aims to Improve Patient Outcomes for HER2-Positive Breast Cancer With Brain Metastases

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Rapid developments over the past decade in the treatment of patients with advanced HER2-positive breast cancer may lead to better outcomes and improved quality of life for patients with brain metastases, according to findings incorporated into a new ASCO guideline update.1

“The difference this guideline could make to practice patterns—and to patients, more importantly—is what’s most exciting,” said Naren Ramakrishna, MD, PhD, of the Orlando Health Cancer Institute and Chair of the Expert Panel that wrote both the original guideline and the update.1,2

Naren Ramakrishna, MD, PhD

Naren Ramakrishna, MD, PhD

Additionally, in an effort to synthesize findings from multiple guidelines on various management approaches for brain metastases, ASCO, the Society for Neuro-Oncology, and the American Society for Radiation Oncology spearheaded the development of a separate novel publication to inform and update physician decision-making in late 2021.3

“The treatment of brain metastases has advanced by leaps and bounds,” Dr. Ramakrishna said. “Ten years ago, when I was treating patients like this, the number of long-term survivors was so few. But now, with all of the options we have, patients are doing so much better than they used to. This progress has been a real blessing to these patients.”

The most recent breast cancer guideline update reflects data published since the original guideline was released in 2014.2The update could inform more appropriate use of local and systemic therapies that have activity in the central nervous system. For instance, the phase III HER2CLIMB clinical trial helped establish the effectiveness of combination tucatinib, trastuzumab, and capecitabine for improving progression-free and overall survival in patients with HER2-positive breast cancer, representing a new treatment regimen for certain patients with this disease.4 Additionally, enhancements in local therapy techniques are helping to mitigate poor neurocognitive outcomes in patients receiving whole-brain radiotherapy; they must be routinely incorporated into treatment decision-making.

These advances are critical given the difficulty oncologists face in managing HER2-positive breast cancer that has metastasized to the brain while preserving patients’ functional status and neurocognitive ability. There is a strong need to optimize treatments—not just for survival, but also for functioning and quality of life—given that as many as half of all patients who have HER2-positive disease will develop brain metastases.5 This is, in part, why patient advocates were included in the expert panel and recommendation process for this guideline update.

Making More Informed Practice Decisions

The Expert Panel made two key changes in guidance, Dr. Ramakrishna said. First, although most patients will still receive local therapy, the update recommends that systemic treatment may be appropriate for certain individuals. Specifically, patients who are asymptomatic and have a good prognosis with single or multiple brain metastases—particularly with lesions less than 2 cm and without mass effect—can now be considered for upfront systemic therapy after multidisciplinary review. Dr. -Ramakrishna called this a “huge development” and a major departure from the original 2014 guideline, which—at the time—lacked strong evidence to justify recommending upfront systemic therapy as a way to reduce metastatic brain-disease burden. This change came as a result of data from HER2CLIMB.

The second major update to the guideline concerns mitigation of the neurocognitive impact of whole-brain radiotherapy. “There are clinical studies [demonstrating] that we can reduce the effects on neurocognitive function by using…a neuroprotectant and, in select cases, using advanced techniques to reduce the dose of radiotherapy to certain parts of the brain—namely, the hippocampus,” Dr. Ramakrishna said. “So, we want everyone to use these modalities if their patients need whole-brain treatment, rather than traditional approaches to whole-brain radiotherapy.”

As a result of these recommendations, Dr. Ramakrishna anticipates that practice patterns will shift as more oncologists incorporate systemic therapy into their treatment paradigm. Consequently, the use of whole-brain radiotherapy will be reduced; when it is used, it will ideally be implemented with the modifications suggested by the expert panel.

Supporting a More Collaborative Approach

Because the use of systemic treatment will require involvement of a neurosurgeon, radiation oncologist, and medical oncologist, an indirect but critical consequence of the guideline update is that it should lead to more integrated, multidisciplinary approaches to patient care. This, in turn, will lead to better outcomes for patients. Hospital-based oncology practices are already set up for this type of collaboration; multidisciplinary case reviews and tumor boards employ a team approach. However, community oncologists may need to take extra steps to ensure their patients receive collaborative care.

“It’s interesting because the old pattern for patients with brain metastases was to go directly to radiation oncology and neurosurgery. The medical oncologist really wasn’t involved in the therapy selection at that point, but all of that has now changed with this guideline,” Dr. Ramakrishna said. “Patient care has to be very integrated because otherwise, the patient may not receive all of the possible treatment options.” 


1. Ramakrishna N, Anders CK, Lin NU, et al: Management of advanced human epidermal growth factor receptor 2–positive breast cancer and brain metastases: ASCO guideline update. J Clin Oncol. May 31, 2022 (early release online).

2. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:2100-2108, 2014.

3. Vogelbaum, MA, Brown PD, Messersmith H, et al: Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol 40:492-516, 2022.

4. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.

5. Zimmer AS, Van Swearingen AED, Anders CK: HER2-positive breast cancer brain metastasis: A new and exciting landscape. Cancer Rep (Hoboken) 5:e1274, 2022.

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, June 2, 2022. All rights reserved.