Aggressive HER2-Targeted Therapy May Have a Role Following Disease Progression in Patients With Breast Cancer and Brain Metastases


Patients with HER2-positive breast cancer and brain metastases experienced a median progression-free survival of 8 months and a median overall survival of 14 months with HER2-targeted therapy.

Real-world evidence demonstrated that patients with HER2-positive breast cancer that has metastasized to the brain and who experienced disease progression following HER2-directed therapy may still derive benefit from continued aggressive treatment with HER2-directed regimens.

Investigators of the retrospective analysis from a single institution highlighted outcomes from after the development of brain metastases for 102 patients who were treated with any HER2-targeted therapy between January 2013 and December 2017. The findings were published in JCO Global Oncology.

At a median follow-up of 13.5 months (range, 1-55), 91 progression-free survival (PFS) events and 80 deaths occurred. Following treatment with HER2-targeted therapy, the median PFS was 8.0 months (95% CI, 6.2-9.8) and the median overall survival (OS) was 14.0 months (95% CI, 10.8-17.2). The estimated 2-year OS rate was 25% (95% CI, 16.7%-34.4%).

Among patients who received a combination of capecitabine and lapatinib (Tykerb), the median PFS was 9.0 months (95% CI, 7.3-10.7) and among patients who received trastuzumab (Herceptin), both alone and in combination with chemotherapy, the median PFS was 7.0 months (95% CI, 2.7-11.3). For patients who underwent surgery, the median PFS was 22.0 months (95% CI, 0.0-54.1) and the median OS was 25.0 months (95% CI, 22.1-27.9).

In a subset of patients who developed leptomeningeal disease, the median PFS was 8.0 months (95% CI, 1.6-14.4), and the median OS was 19.0 months (95% CI, 8.3-29.7). According to investigators, these findings suggest that intrathecal trastuzumab is efficacious in this population; however, the small number of patients limits definite conclusions.

For 24 patients for whom brain was the only site of metastasis, the median PFS was 10.0 months (95% CI, 5.2-14.8) and the OS was 21.0 months (95% CI, 18.1-23.9) months. Of note, 6 patients (25%) underwent surgery.

“There has been an improvement in the outcomes of patients with HER2-positive metastatic breast cancer because of newer HER2-targeted agents, but the presence of brain metastases continues to be associated with poor prognosis,” wrote Prabhat Bhargava, MD, professor of medical oncology at Tata Memorial Centre, in Mumbai, India, and coinvestigators. “Our analysis of the real-world outcome in these patients suggests a substantial clinical benefit of multimodality treatment in some of them, with a 2-year OS of 25%. Notably, almost 15% of patients could receive 3 or more lines of HER2-targeted therapy after developing brain metastasis.”

According to study authors, there is insufficient data documenting the lived experienced of patients with HER2-positive breast cancer and brain metastases. Further, in areas where access to newer HER2-directed therapies (for instance, fam-trastuzumab deruxtecan-nxki [Enhertu]) may be limited, information is even more scarce. For these reasons, investigators sought to evaluate the real-world evidence surrounding local and systemic therapy in this patient population in an area where access to newer agents is limited.

Patient Characteristics

The median patient age was 52 years (IQR, 47-57). At the time of brain metastasis diagnosis, 96.1 % (n = 98) of patients were experiencing neurological symptoms, 42.1% (n = 43) had at least 5 brain lesions, and 5% (n = 5) had developed leptomeningeal disease.

At baseline, 31.6% had received previous treatment with trastuzumab prior to surgery. Prior to the diagnosis of brain metastases, 61.8% of patients had received 1 line of HER2-targeted therapy, 13.7% had received 2 lines, 4.9% had received 3 lines, and 19.6% had not received any prior treatment with HER2-targetd therapy. In addition, 2% of patients were treatment naïve at the time of diagnosis of brain metastasis. For 17.6% of patients, brain metastases developed during adjuvant treatment or within 6 moths of completing adjuvant treatment.

The median time between diagnosis of breast cancer and the development of brain metastases was 19 months (IQR, 13-39). The median time was also 19 months among patients who had received HER2-targteed treatment and 18 months among those who were HER2-targeted therapy naïve.

Treatment Strategies

Many patients received local treatment for their brain metastases. Specifically, 87 patients (85.3%) received whole brain radiation therapy (WBRT) alone, 3 (2.9%) received repeated stereotactic radiosurgery (SRS) alone, 5 (2.9%) received WBRT and SRS, and 1 (1%) underwent surgery alone. In addition, 7 (6.9%) of patients underwent surgical resection and continued to receive postoperative radiation therapy.

At the time of brain metastases diagnosis, 42.2% (n = 43) had documented disease progression in at least 1 site other than the brain. Following local therapy for brain metastases, all patients received systemic therapy. After detection of brain metastases, 91 patients (89.2%) adopted HER2-targeted therapy or adapted their HER2-targeted therapy. Six patients continued to take HER2-targetd therapy as previously prescribed, resulting in a total of 97 patients (95%) receiving systemic HER2-targeted therapy following brain metastasis diagnosis. The remaining patient eventually adopted HER2-targeted therapy in subsequent line of treatment.

Among these 97 patients, 69.6% (n = 71) received lapatinib, either alone in combination with capecitabine, and 18.6% (n = 19) received trastuzumab, 3.9% (n = 4) received ado-trastuzumab emtansine (Kadcyla), and 2.9% (n = 3) received lapatinib plus trastuzumab.

Study authors noted that the highest PFS was observed among patients who underwent surgery or SRS followed by systemic therapy, suggesting that those with HER2-positive tumors and brain metastasis may have a better prognosis than those with brain metastases and other subtypes of breast cancer and that a more aggressive treatment approach may be optimal in this setting. In addition, the notable difference between PFS and OS (8 vs 14 months) indicates that continuing treatment after disease progression may be therapeutically beneficial in this population.

“There is good clinical efficacy of combined modality treatment, comprising radiotherapy, chemotherapy, and lapatinib or trastuzumab, in patients with breast cancer with brain metastases who have HER2-positive tumors,” the study authors wrote adding that there may be clinical benefit in continuing treatment beyond first disease progression in these patients, and intrathecal trastuzumab is a promising treatment in patients who experience leptomeningeal involvement.


Bhargava P, Rathnasamy N, Shenoy R, et al. Clinical profile and outcome of patients with human epidermal growth factor receptor 2-positive breast cancer with brain metastases: real-world experience. JCO Glob Oncol. 2022;8:e2200126. doi:10.1200/GO.22.00126

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