No abstract

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Taxanes are powerful chemotherapy agents that target the microtubule cytoskeleton, leading to mitotic arrest and cell death; however, their clinical efficacy has been hampered due to the development of drug resistance. Therefore, other proteins involved in spindle assembly are being examined as potential targets for anticancer therapy. The mitotic kinesin, Eg5 is critical for proper spindle assembly; as such, inhibition of Eg5 leads to mitotic arrest making it a potential anticancer target. We wanted to validate Eg5 as a therapeutic target and determine if Eg5 inhibitors retain activity in Taxol-resistant cells. Using affinity chromatography we first show that the compound HR22C16 is an Eg5 inhibitor and does not interact with other microtubule motor proteins tested. Furthermore, HR22C16 along with its analogs, inhibit cell survival in both Taxol-sensitive and -resistant ovarian cancer cells with at least 15-fold greater efficacy than monastrol, the first generation Eg5 inhibitor. Further analysis with HR22C16-A1, the most potent HR22C16 analog, showed that it retains efficacy in PgP-overexpressing cells, suggesting that it is not a PgP substrate. We further show that HR22C16-A1 induces cell death following mitotic arrest via the intrinsic apoptotic pathway. Interestingly, the combination of HR22C16-A1 with Taxol results in an antagonistic antiproliferative and antimitotic effect, possibly due to the abrogation of Taxol-induced mitotic spindles by HR22C16-A1. Taken together, our results show that Eg5 inhibitors have promising anticancer activity and can be potentially used to overcome Taxol resistance in the clinical setting.