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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
The brain is the weak point of HER2-positive breast cancer: antibodies control the rest of the body but cross poorly into the brain, so up to half of patients with advanced disease develop brain metastases. Tucatinib with trastuzumab and capecitabine was the first drug proven to help, and trastuzumab deruxtecan shrinks brain lesions in most patients.
Brain metastases became the signature problem of HER2-positive disease once trastuzumab began to control it elsewhere: antibodies are too large to cross an intact blood-brain barrier, so the brain was often the first and only site of progression. Lesions present with headache, seizures or focal deficits, or are found on staging MRI; guidelines do not recommend routine screening MRI, though the landmark trials required it. Local treatment follows the number and size of lesions: stereotactic radiosurgery for a limited number, which the Alliance N0574 trial showed preserves cognition better than adding whole-brain radiotherapy, surgery for a large symptomatic lesion, and whole-brain radiotherapy held back for many lesions or leptomeningeal spread.
HER2CLIMB was the first randomised trial to enrol patients with active, untreated brain metastases and prove a drug helps them. It randomised 612 women who had received trastuzumab, pertuzumab and trastuzumab emtansine, almost half with brain metastases, to tucatinib or placebo with trastuzumab and capecitabine: progression-free survival rose from 5.6 to 7.8 months (hazard ratio 0.54), overall survival from 17.4 to 21.9 months (hazard ratio 0.66), and the risk of intracranial progression fell by about two thirds, leading to approval in April 2020. Earlier, lapatinib with capecitabine had shown intracranial responses in the single-arm LANDSCAPE study, and neratinib reduced the need for brain interventions in NALA; HER2CLIMB-02 later added tucatinib to trastuzumab emtansine with a modest gain concentrated in patients with brain disease, and HER2CLIMB-05 in 2025 showed tucatinib added to first-line antibody maintenance delays progression by more than eight months.
| Setting | Approach | Guideline |
|---|---|---|
| Limited brain metastases at first presentation | Stereotactic radiosurgery to each lesion, or surgery for a large symptomatic lesion, followed by HER2-directed systemic therapy; whole-brain radiotherapy reserved for many lesions. | not mapped |
| Active brain metastases after trastuzumab, pertuzumab and trastuzumab emtansine | Tucatinib with trastuzumab and capecitabine (HER2CLIMB), which improved survival and delayed brain progression. | not mapped |
| Brain metastases, stable or active, second line | Trastuzumab deruxtecan, with intracranial responses in most patients (DESTINY-Breast12), positioned as second-line therapy after DESTINY-Breast03. | not mapped |
| First-line maintenance to delay brain progression | Tucatinib added to trastuzumab and pertuzumab maintenance after induction chemotherapy (HER2CLIMB-05). | not mapped |
| Later lines | Neratinib or lapatinib with capecitabine, trastuzumab emtansine with tucatinib (HER2CLIMB-02), repeat radiosurgery, or a clinical trial. | not mapped |