HER2-positive Breast Cancer Brain Metastases Research Articles

T-DM1 in HER2-positive breast cancer brain metastases (BM).

650 Background: Local treatment options such as radiotherapy or neurosurgery are the mainstay of BM management. Whole brain radiotherapy (WBRT), however, is associated with severe late-toxicity. Th...

Breast cancer brain metastases responding to primary systemic therapy with T-DM1

Brain metastases are frequent in HER2-positive breast cancer and are associated with poor prognosis. Severe neurological symptoms such as neurocognitive decline, aphasia, paresis, seizures and impaired quality of life are common. The standard therapy options for brain metastases comprise local approaches such as radiotherapy, radiosurgery and neurosurgery. Novel treatments are urgently needed to improve patients’ outcomes. Recently, trastuzumab-emtansine (T-DM1), a novel antibody-cytotoxin conjugate has shown favourable activity and been approved for therapy of metastatic HER2-positive breast cancer. However, so far no data are available on brain penetration and intracerebral activity of T-DM1 [1]. Here, we report on a patient with multiple and locally untreated HER2-positive breast cancer brain metastases responding to systemic monotherapy with T-DM1. This patient was offered T-DM1 (3.6 mg/kg body weight every 3 weeks) as palliative second-line treatment in the setting of recurrent liver and newly diagnosed bone and lung lesions after prior first line therapy with docetaxel (100 mg/m) plus trastuzumab (8 mg/kg body weight loading dose, followed by 6 mg/kg) every 3 weeks. Before the first dose of T-DM1 a brain MRI-scan was performed, which revealed a total number of 20 contrast-enhancing brain metastases throughout the brain (12 supratentorial, 8 infratentorial). Two larger lesions were found in the left post-central region with a maximal diameter of 1.6 cm (index lesion M1; Fig. 1a, contrast-enhanced T1-weighted MRI) and in the right occipital region with a maximal diameter of 8 mm (index lesion M2; Fig. 1e, contrast-enhanced T1-weighted MRI), while all other lesions were only 1–2 millimetres in diameter. Fluid attenuated inversion recovery (FLAIR) imaging showed slight peritumoural brain oedema surrounding the index lesion M1 (Fig. 1c). The patient did not suffer from any neurological symptoms; especially no signs of increased cranial pressure or focal neurological deficits were present. Prognostic assessment was performed according to the diagnosis specific graded prognostic assessment (ds-GPA) based upon Karnofsky Performance Score (KPS), breast cancer subtype, and age, whereupon the patient belonged to the most favourable class [2]. In this situation, potential treatment options were extensively discussed in an interdisciplinary tumour conference of breast cancer and brain tumour specialists. As our patient had no neurological symptoms and presented with KPS 100 %, there was no clear indication for immediate initiation of WBRT. We initiated T-DM1 therapy, as T-DM1 was superior to lapatinib plus capecitabine for the control of systemic disease in the prospective randomized phase III EMILIA study [1]. Intense clinical and radiological followup of brain lesions was planned. T-DM1 was well tolerated. Importantly, neither neurological symptoms nor a deterioration of her general health status was observed. A computed tomography restaging conducted after 4 T-DM1 administrations revealed a complete remission of lung metastases and partial remission of liver lesions. The brainMRI also indicated considerable activity of T-DM1: both index lesions showed a significant decrease in size (M1: from 1.6 cm to 0.8 cm, Fig. 1b; M2: from 8 mm to 5 mm, Fig. 1f) as compared to the baseline scan; perifocal oedema of the index lesion M1 had decreased as well (Fig. 1d). No new lesions were evident and all other minute lesions appeared stable in size, but were too small for formal comparative measurements. R. Bartsch A. S. Berghoff M. Preusser (&) Medical University of Vienna, Vienna, Austria e-mail: matthias.preusser@meduniwien.ac.at

Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis

Metastasis, which remains incompletely characterized at the molecular and biochemical levels, is a highly specific process. Despite the ability of disseminated cancer cells to intravasate into distant tissues, it has been long recognized that only a limited subset of target organs develop clinically overt metastases. Therefore, subsequent adaptation of disseminated cancer cells to foreign tissue microenvironment determines the metastatic latency and tissue tropism of these cells. As a result, studying interactions between the disseminated cancer cells and the adjacent stromal cells will provide a better understanding of what constitutes a favorable or unfavorable microenvironment for disseminated cancer cells in a tissue-specific manner. Previously, we reported a protein signature of brain metastasis showing increased ability of brain metastatic breast cancer cells to counteract oxidative stress. In this study, we showed that another protein from the brain metastatic protein signature, neurotrophin-3 (NT-3), has a dual function of regulating the metastatic growth of metastatic breast cancer cells and reducing the activation of immune response in the brain. More importantly, increased NT-3 secretion in metastatic breast cancer cells results in a reversion of mesenchymal-like (EMT) state to epithelial-like (MET) state and vice versa. Ectopic expression of NT-3 in EMT-like breast cancer cells reduces their migratory ability and increases the expression of HER2 (human epidermal growth factor receptor 2) and E-cadherin at the cell-cell junction. In addition, both endogenous and ectopic expression of NT-3 reduced the number of fully activated cytotoxic microglia. In summary, NT-3 appears to promote growth of metastatic breast cancer cells in the brain by facilitating the re-epithelialization of metastatic breast cancer cells and downmodulating the cytotoxic response of microglia. Most importantly, our results provide new insights into the latency and development of central nervous system macrometastases in patients with HER2-positive breast tumors and provide mechanistic rationale to target HER2 signaling for HER2-positive breast cancer brain metastasis.

LCCC 1025: A phase II study evaluating the mTOR inhibitor everolimus with trastuzumab and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

TPS656 Background: HER2+ breast cancer (BC) is an aggressive subset of BC with high rates of brain metastases (BM) and poor survival. A recent study illustrates activation of the PI3K/mTOR pathway in approximately two-thirds of BCBM across all subtypes. Everolimus, a novel oral derivative of rapamycin that selectively inhibits mTOR, is clinically-active in combination with trastuzumab (with or without chemotherapy) in advanced HER2+ BC. Everolimus penetrates the blood brain barrier. We are evaluating the efficacy and safety of everolimus plus trastuzumab and vinorelbine in patients (pts) with HER2+ BCBM. Methods: Pts with HER2+ BCBM progressing following cranial radiation and measuring > 0.5cm are eligible for enrollment. Treatment with prior vinorelbine or mTOR inhibition is prohibited. Steroid treatment is allowed if stable or decreasing doses ≥7 days prior to study entry. Pts with leptomeningeal disease are excluded. Pts receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine 25mg/m2 (both IV days 1, 8, 15) of a 21 day cycle. Intra- and extracranial disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial response rate (RR) assessed by modified RECIST. Secondary objectives include extracranial RR (assessed by RECIST 1.1), intra- and extracranial time to progression, progression free survival, overall survival, quality of life, and correlative science endpoints. Statistical considerations: In this two stage design, a sample size of 28 evaluable pts (n=11 in Stage 1) has 80% power to detect a difference between the null (≤5% intracranial RR) and alternative hypothesis (>5%) at a 0.05 significance level. If 1 pt has a CR, PR or SD for ≥ 3 months in the 1st stage, 17 additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts will be enrolled. Correlative studies: Archival primary and/or metastatic tissues are required from all pts to evaluate intrinsic BC subtype, protein (p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may be predictive of response or resistance to this novel combination (NCT01305941).

Abstract A1: NT-3 modulates HER2 signaling to promote the metastatic growth of HER2-positive breast cancer brain metastasis

Abstract The purpose of our study is to determine the role of neurotrohpin-3 in promoting the growth of HER2-positive breast cancer brain metastasis in vivo. The establishment of metastatic-permissive microenvironment may require adaptation of metastatic cancer cells and hijacking of cellular immune responses. To understand the complexity of breast cancer metastasis in hopes of identifying targets and developing drugs against brain metastasis, we utilized large-scale mass-spectrometry-based proteomics to identify differentially expressed proteins in metastatic breast cancer cells with propensity to colonize the lung, the bone, and brain. We detected 250 proteins that were specifically up- or downregulated in the brain-colonizing breast cancer cells and found that a growth factor, neurotrophin-3 (NT-3) was specifically upregulated in brain colonizing breast cancer cells. The expression of NT-3 was particularly high in the HER2 positive brain colonizing breast cancer cell line, MDA-MB 361. Since brain metastases often appears in patients long after the resection of primary breast tumors (5–15 years) and NT-3 expression is low in primary breast tumors, we believe that adaptation to the brain microenvironment is the rate limiting factor for the development of breast cancer brain metastasis and examined the hypothesis that NT-3 expression promotes the formation of macrometastasis from metastatic breast cancer cells in the brain. We showed that by implanting metastatic breast cancer intracranially at low cell numbers, brain parenchyma permits the growth of brain colonizing metastatic breast cancer cell lines such as MDA-MB 361 cells and suppresses of unselected metastatic breast cancer cell lines such as MDA-MB 231 cells. The metastatic growth of GFP-expressing breast cancer cells in vivo can be measured quantitatively by the scanning confocal microscope. We discovered a novel NT-3 induced HER2 signaling in the development of HER2-positive breast cancer brain metastasis. Using a brain colonizing breast cancer cell line, MDA-MB 361, with endogenously high level of NT-3 and HER2, we found NT-3 signals through HER2 by inducing HER2 phosphorylation and NT-3/HER2 signaling can be inhibited by small molecule inhibitors targeting HER2 activation. More importantly, NT-3/HER2 signaling promotes the luminal epithelial phenotype and suppresses the epithelialmesenchymal transition (EMT)-like phenotype in metastatic breast cancer cells. By knocking down NT-3 in MDA-MB 361 cells, we found NT-3 expression is necessary to sustain the metastatic growth of brain colonizing breast cancer cells in the brain. Knocking down NT-3 reduced the expression of HER2 and E-cadherin and increased the expression of EMT-inducing transcription factor, Snail, in the nucleus. By overexpressing NT-3 in breast cancer cells with a poor brain-colonizing ability such as MDA-MB 231, we found NT-3 expression is sufficient to promote breast cancer brain metastasis. Ectopic expression of NT-3 increased HER2 and E-cadherin at the cell-cell junction and suppressed the nuclear expression of Snail and migratory ability of MDA-MB 231 breast cancer cells. Furthermore, both endogenous and ectopic expression of NT-3 reduced the number of fully activated cytotoxic microglia. In conclusion, our data suggest that NT-3 promotes EMT to MET conversion of metastatic breast cancer cells and allows brain colonizing cells to evade the cytotoxic immune response from the resident CNS immune cells, microglia. Most importantly, our results provide new insights into the latency and development of CNS macrometastases in patients with HER2-positive breast tumors and provide mechanistic rationale to target HER2 signaling for HER2-positive breast cancer brain metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A1.

HER2-positive Breast Cancer Brain Metastases: Multiple Responses to Systemic Chemotherapy and Trastuzumab—a Case Report

Brain metastases from metastatic breast cancer typically occur in 10-15% of patients and are associated with survival of 3-6 months. Recent series have shown that women with HER2-positive metastatic breast cancer receiving the drug trastuzumab develop brain metastases more frequently than this, but also that continuation of trastuzumab after diagnosis of brain metastases in such patients is associated with extended survival. Authors have speculated that this is due to improved systemic control of disease; however, a possibility is that trastuzumab may have a beneficial effect on cerebral metastases themselves. We report the case of a woman with HER2-positive metastatic breast cancer who developed multiple brain metastases while on trastuzumab, in whom the addition of systemic chemotherapy to continued trastuzumab has produced multiple treatment responses associated with prolonged survival. This is the first report of its kind.