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. 2020 Oct 1;147(7):1939-1952.
doi: 10.1002/ijc.32937. Epub 2020 Mar 9.

Landscape of combination therapy trials in breast cancer brain metastasis

Jawad Fares  1   2 , Deepak Kanojia  1 , Aida Rashidi  1 , Ilya Ulasov  3 , Maciej S Lesniak  1
Affiliations

Landscape of combination therapy trials in breast cancer brain metastasis

Jawad Fares et al. Int J Cancer. .

Abstract

Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional and therapeutic clinical trials involving combination therapy for BCBM, without limiting for date or location. Information on trial characteristics was collected. Combination therapies used in trials were analyzed and explored in line with evidence from the medical literature. Sixty-five combination therapy trials were selected (n = 65), constituting less than 0.7% of all breast cancer trials. Most trials (62%) combined ≥2 chemotherapeutic agents. Chemotherapy with radiation was main-stay in 23% of trials. Trastuzumab was mostly used in combination (31%), followed by lapatinib (20%) and capecitabine (15%). Common strategies involved combining tyrosine kinase inhibitors with thymidylate synthase inhibitors (6 trials), dual HER-dimerization inhibitors (3 trials), microtubule inhibitors and tyrosine kinase inhibitors (3 trials), and HER-dimerization inhibitors and tyrosine kinase inhibitors (3 trials). The combination of tucatinib and capecitabine yielded the highest objective response rate (83%) in early phase trials. The triple combination of trastuzumab, tucatinib and capecitabine lowered the risk of disease progression or death by 52% in patients with HER2-positive BCBM. Combining therapeutic agents based on biological mechanisms is necessary to increase the effectiveness of available anti-cancer regimens. Significant survival benefit has yet to be achieved in future combination therapy trials. Enhancing drug delivery through blood-brain barrier permeable agents may potentiate the overall therapeutic outcomes.

Keywords: brain metastasis; breast cancer; clinical trials; combination therapy; meta-analysis; systematic review.

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Conflict of interest statement

Conflict of Interest: None declared

Figures

Figure 1
Figure 1
Mechanism of action of therapeutic agents used in combination trials for breast cancer brain metastasis.
See this image and copyright information in PMC

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