Preclinical Models of Brain Metastasis

Research at the Brain Metastasis Group is supported by MINECO grants MINECO-Retos SAF2017-89643-R (M.V.), Bristol-Myers Squibb- Melanoma Research Alliance Young Investigator Award 2017 (498103) (M.V.), Beug Foundation’s Prize for Metastasis Research 2017 (M.V.), Fundación Ramón Areces (CIVP19S8163) (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972)N

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade ≥3 toxicity (50 vs. 70%). Conclusions: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway (ClinicalTrials.gov NCT02915744)

Abstract P3-12-03: Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases.

Abstract Brain metastases remain a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Unlike HER2-amplified breast tumors growing in extra-cranial locations, brain metastases do not respond well to HER2 inhibitors and are often the reason for treatment failure. One of the major challenges in studying brain metastases is the lack of preclinical models. We developed a HER2-amplified mouse model of brain metastasis using an orthotopic xenograft of BT474 cells in mice. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib failed to contain brain metastatic tumor growth. Based on previous findings from our laboratory suggesting a role of vascular endothelial growth factor (VEGF) in the resistance of HER2-overexpressing breast cancer brain metastases to trastuzumab, we combined HER2 inhibitors with the anti-VEGFR2 antibody DC101. The combination of either trastuzumab and DC101 or lapatinib and DC101 significantly slowed metastatic tumor growth in the brain, and resulted in a striking improvement in overall survival. The benefit is due largely to an anti-angiogenic effect. The combination of anti-HER2 and anti-VEGFR2 therapy reduced both the total and functional microvascular density in the brain metastatic tumors. Moreover, tumor tissues under combination therapy showed a marked increase in necrosis. Preclinical and clinical evidence suggest that the combination of trastuzumab and lapatinib is superior to either agent alone – though this has never been tested in the brain metastatic setting. We consistently observed increased phosphorylation of HER2 in breast tumor cells growing in the brain compared with the mammary fat pad. In addition, while short-term lapatinib treatment significantly reduced HER2 activation in the brain, it could do so only to the level of that observed in the untreated mammary fat pad - and this effect disappeared over time. We hypothesized that more pronounced HER2 inhibition would be beneficial to these brain metastases with increased HER2 activation. We show here a significant growth delay with the combination of the two HER2 inhibitors compared with monotherapy. Moreover, we found a dramatic brain metastatic tumor growth delay in mice treated with both HER2 inhibitors, trastuzumab and lapatinib, and DC101. The triple combination prolonged overall survival 5 times longer than control-treated mice. Brain metastasis from breast cancer is considered the “final frontier” of breast cancer research and treatment. Our findings support the clinical development of a three-drug regimen of trastuzumab, lapatinib and a VEGF pathway inhibitor for the treatment of HER2-amplified breast cancer brain metastases. While the anti-VEGF antibody bevacizumab in combination with trastuzumab and chemotherapy has shown some promise in HER2-positive metastatic breast cancer patient, there are no data on its efficacy in the context of brain metastases. A clinical trial is now recruiting patients to evaluate the efficacy of bevacizumab in breast cancer patients with active brain metastases, including its combination with trastuzumab in patients with HER2-positive disease. This trial may provide clinical evidence for the approach presented here. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-03.</jats:p