Response Of Brain Metastases Research Articles

P13.02 The ambiguity of brain metastasis response to radiotherapy driven by cellular adhesion molecules

P13.02 The ambiguity of brain metastasis response to radiotherapy driven by cellular adhesion molecules

Repeated diffusion MRI reveals earliest time point for stratification of radiotherapy response in brain metastases

An imaging biomarker for early prediction of treatment response potentially provides a non-invasive tool for better prognostics and individualized management of the disease. Radiotherapy (RT) response is generally related to changes in gross tumor volume manifesting months later. In this prospective study we investigated the apparent diffusion coefficient (ADC), perfusion fraction and pseudo diffusion coefficient derived from diffusion weighted MRI as potential early biomarkers for radiotherapy response of brain metastases. It was a particular aim to assess the optimal time point for acquiring the DW-MRI scan during the course of treatment, since to our knowledge this important question has not been addressed directly in previous studies. Twenty-nine metastases (N = 29) from twenty-one patients, treated with whole-brain fractionated external beam RT were analyzed. Patients were scanned with a 1 T MRI system to acquire DW-, T2*W-, T2W- and T1W scans, before start of RT, at each fraction and at follow up two to three months after RT. The DW-MRI parameters were derived using regions of interest based on high b-value images (b = 800 s mm−2). Both volumetric and RECIST criteria were applied for response evaluation. It was found that in non-responding metastases the mean ADC decreased and in responding metastases it increased. The volume based response proved to be far more consistently predictable by the ADC change found at fraction number 7 and later, compared to the linear response (RECIST). The perfusion fraction and pseudo diffusion coefficient did not show sufficient prognostic value with either response assessment criteria. In conclusion this study shows that the ADC derived using high b-values may be a reliable biomarker for early assessment of radiotherapy response for brain metastases patients. The earliest response stratification can be achieved using two DW-MRI scans, one pre-treatment and one at treatment day 7–9 (equivalent to 21 Gy).

Comparing available criteria for measuring brain metastasis response to immunotherapy

The response assessment in neuro-oncology (RANO) working group recently proposed standardized response criteria for brain metastases (RANO-BM). We sought to compare RANO-BM to other criteria in an ongoing brain metastasis trial.The first 36 patients enrolled on NCT02085070, an ongoing trial of pembrolizumab for patients with untreated brain metastases, were included in this analysis. As RANO-BM had not been proposed when the protocol was written, response on trial was assessed using an institutional modification of RECIST 1.1 (mRECIST), wherein minimum target brain lesion size was 5mm in longest diameter and up to five target brain lesions were followed. We here additionally assessed response using standard RECIST 1.1, RANO high-grade glioma (RANO-HGG), and RANO-BM.Comparison between the four criteria sets using cases eligible across the board revealed excellent concordance (kappa statistic > 0.8), with only one discordant case. However, compared to RECIST 1.1 or RANO-BM, using a 5mm threshold for target brain lesions in mRECIST allowed enrollment of 13 additional patients, five of whom had durable responses. Compared to RANO-HGG, 19 additional patients were enrolled using mRECIST, eight of whom had durable responses. Consequently, this resulted in response rates ranging from 12% with RANO-HGG to 28% with mRECIST. This study supports using a 5mm threshold for target brain lesions when using high resolution MRI with ≤2mm slices to facilitate accrual to similar clinical trials and provide earlier access to novel therapies for brain metastasis patients. Concordance among the four criteria studied was otherwise very high.

JCES01.23 EGFR Mutation Status Analysis in Cerebrospinal Fluid and Plasma of Advanced Lung Adenocarcinoma with Brain Metastases

We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the detection of epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cfDNA) from cerebrospinal fluid (CSF) and plasma of advanced Lung Adenocarcinoma (ADC) with brain metastases (BM). Fourteen advanced ADC patients with BM carrying activating EGFR mutations in tumor tissues were enrolled in this study, and their matched CSF and plasma samples were collected. EGFR mutations were detected by the Amplification Refractory Mutation System (ARMS) in tumor tissues. EGFR mutations, including 19del, L858R, and T790M were examined in cfDNA isolated from 2milliliter CSF or plasma by ddPCR assay. The clinical response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Overall survival (OS) and progression free survival (PFS) after the diagnosis of BM were also evaluated. Out of 14 patients, eleven were females and three males aged from 34 to 74 years old (median age of 55 years old). In all of cases, CSF cytology were negative. In ddPCR assays, EGFR mutations were detected in CSF of three patients (21.4%; one of 19del and two of L858R), and in plasma of six patients (42.9%; one of 19del, one of L858R, one of T790M, two of L858R&T790M, and one of 19del&T790M). All EGFR T790M mutations were found during or after EGFR-TKIs treatments. The three patients with activating EGFR mutations in CSF achieved partial response (PR) of BM after treated with combination of WBRT and EGFR-TKIs. The median OS and PFS after the diagnosis of BM were 18.0 months and 9.0 months, respectively.Tabled 1PatientTissue EGFRCSF EGFRPlasma EGFRSystematic TreatmentBM Treatment119delWTT790MErotinib+ChemotherapyWBRT+Gamma knife219delWT19delErotinib+ChemotherapyWBRT3L858RL858RL858RGefitinib+ChemotherapyWBRT4L858RWTWTGefitinib+ChemotherapyWBRT519delWTWTGefitinib+ChemotherapyWBRT6L858RWTL858R/T790MErotinib+ChemotherapyWBRT7L858RWTWTGefitinibWBRT819del19Del19Del/T790MGefitinibWBRT9L858RWTWTErotinib+ChemotherapyNONE1019delWTWTErotinib+ChemotherapyWBRT1119delWTWTIcotinib+ChemotherapyWBRT12L858RWTL858R/T790MChemotherapyWBRT13L858RL858RWTIcotinibWBRT1419delWTWTGefitinib+ChemotherapyWBRT Open table in a new tab It was feasible to test EGFR mutation in CSF. CSF may serve as liquid biopsy of advanced ADC with BM by enabling measurement of cfDNA within CSF to characterize EGFR mutations.

Rapid response of brain metastasis to crizotinib in a patient with KLC1-ALK fusion and MET gene amplification positive non-small cell lung cancer: a case report.

Non-small cell lung cancer (NSCLC) ranks as the leading cause of cancer-related death in the world. Brain metastasis (BM) is a common complication of NSCLC, with 25%–40% of patients developing BM during the course of the disease. A significant strategy of local disease control in the central nervous system is radiation therapy. With the development of precision medicine, the concept of treating lung cancer BM has gradually changed. In this case, we performed a surgical procedure to obtain enough tumor tissue for the detection of the target gene and other related experiments after the patient was informed. Finally, we found that the patient had both hepatocyte growth factor receptor (MET) gene amplification and kinesin light chain 1-anaplastic lymphoma kinase fusion (KLC1-ALK) through next-generation sequencing and showed sensitivity to the targeted therapy of crizotinib. The patient exhibited good response. Our case was successful and underwent targeted therapy with the guidance of precise diagnosis.

P2.03b-010 EGFR Mutation Status Analysis in Cerebrospinal Fluid and Plasma of Advanced Lung Adenocarcinoma with Brain Metastases: Topic: Brain Meta

We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the detection of epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cfDNA) from cerebrospinal fluid (CSF) and plasma of advanced Lung Adenocarcinoma (ADC) with brain metastases (BM). Fourteen advanced ADC patients with BM carrying activating EGFR mutations in tumor tissues were enrolled in this study, and their matched CSF and plasma samples were collected. EGFR mutations were detected by the Amplification Refractory Mutation System (ARMS) in tumor tissues. EGFR mutations, including 19del, L858R, and T790M were examined in cfDNA isolated from 2 milliliter CSF or plasma by ddPCR assay. The clinical response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Overall survival (OS) and progression free survival (PFS) after the diagnosis of BM were also evaluated. Out of 14 patients, eleven were females and three males aged from 34 to 74 years old (median age of 55 years old). In all of cases, CSF cytology were negative. In ddPCR assays, EGFR mutations were detected in CSF of three patients (21.4%; one of 19del and two of L858R), and in plasma of six patients (42.9%; one of 19del, one of L858R, one of T790M, two of L858R&T790M, and one of 19del&T790M). All EGFR T790M mutations were found during or after EGFR-TKIs treatments. The three patients with activating EGFR mutations in CSF achieved partial response (PR) of BM after treated with combination of WBRT and EGFR-TKIs. The median OS and PFS after the diagnosis of BM were 18.0 months and 9.0 months, respectively.Tabled 1PatientTissue EGFRCSF EGFRPlasma EGFRSystematic TreatmentBM Treatment119delWTT790MErotinib+ChemotherapyWBRT+Gamma knife219delWT19delErotinib+ChemotherapyWBRT3L858RL858RL858RGefitinib+ChemotherapyWBRT4L858RWTWTGefitinib+ChemotherapyWBRT519delWTWTGefitinib+ChemotherapyWBRT6L858RWTL858R/T790MErotinib+ChemotherapyWBRT7L858RWTWTGefitinibWBRT819del19Del19Del/T790MGefitinibWBRT9L858RWTWTErotinib+ChemotherapyNONE1019delWTWTErotinib+ChemotherapyWBRT1119delWTWTIcotinib+ChemotherapyWBRT12L858RWTL858R/T790MChemotherapyWBRT13L858RL858RWTIcotinibWBRT1419delWTWTGefitinib+ChemotherapyWBRT Open table in a new tab It was feasible to test EGFR mutation in CSF. CSF may serve as liquid biopsy of advanced ADC with BM by enabling measurement of cfDNA within CSF to characterize EGFR mutations.

Impact of Blood-Brain Barrier Integrity on Tumor Growth and Therapy Response in Brain Metastases.

The role of blood-brain barrier (BBB) integrity for brain tumor biology and therapy is a matter of debate. We developed a new experimental approach using in vivo two-photon imaging of mouse brain metastases originating from a melanoma cell line to investigate the growth kinetics of individual tumor cells in response to systemic delivery of two PI3K/mTOR inhibitors over time, and to study the impact of microregional vascular permeability. The two drugs are closely related but differ regarding a minor chemical modification that greatly increases brain penetration of one drug. Both inhibitors demonstrated a comparable inhibition of downstream targets and melanoma growth in vitro In vivo, increased BBB permeability to sodium fluorescein was associated with accelerated growth of individual brain metastases. Melanoma metastases with permeable microvessels responded similarly to equivalent doses of both inhibitors. In contrast, metastases with an intact BBB showed an exclusive response to the brain-penetrating inhibitor. The latter was true for macro- and micrometastases, and even single dormant melanoma cells. Nuclear morphology changes and single-cell regression patterns implied that both inhibitors, if extravasated, target not only perivascular melanoma cells but also those distant to blood vessels. Our study provides the first direct evidence that nonpermeable brain micro- and macrometastases can effectively be targeted by a drug designed to cross the BBB. Small-molecule inhibitors with these optimized properties are promising agents in preventing or treating brain metastases in patients. Clin Cancer Res; 22(24); 6078-87. ©2016 AACRSee related commentary by Steeg et al., p. 5953.

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial

Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Merck and the Yale Cancer Center.

Preparation and biodistribution of 2-(5-[18F]fluoro-pentyl)-2-methyl-malonic acid and its clinical application

Objective To synthesize 2-(5-[18F]fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) and to investigate the biodistribution in mice and the primary clinical application. Methods 18F-ML-10 was synthesized by domestic synthesis module MF-2V-IT-1. Quality control of the probe was performed after automated synthesis. The biological characteristics of 18F-ML-10 were assessed by biodistribution assay on male Kunming mice and microPET imaging on a male SD rat. Six patients with brain metastasis (4 males, 2 females, and age 21-68 years) were enrolled in this study. 18F-ML-10 PET images were acquired before and at 48 h after radiotherapy. SUVmean and SUVmax of ROI were calculated. GTV changes were measured by MRI before and 3 months after radiotherapy. Response of brain metastasis to radiotherapy was assessed by PET imaging with 18F-ML-10. Two-sample t test was used. Results The non-corrected radiochemical yield of 18F-ML-10 was (26.5±7.3)% with acceptable quality. The radiochemical purity exceeded 99%. 18F-ML-10 was excreted through the kidneys, and the radiouptake in the blood was declined rapidly. The radiotracer accumulation was low in most of other organs. The testis showed a significant uptake. The SUVmean and SUVmax after radiotherapy (5.54±2.72 and 7.29±3.09) were significantly higher than the baseline values(3.81±1.13 and 4.97±1.05; t=2.670, 2.663, both P<0.05). The GTV after radiotherapy was significantly lower than the baseline value: (13.14±9.39) cm3vs (23.34±18.13) cm3;t=3.002, P<0.05. Conclusions 18F-ML-10 could be synthesized reliably and repeatedly by domestic synthesis module. It has satisfactory properties in vivo and is probably suitable for early assessment of the response to radiotherapy in patients with brain metastasis. Key words: Methylmalonic acid; Isotope labeling; Fluorine radioisotopes; Tomography, emission-computed; Neoplasm metastasis; Brain

Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin

Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil® resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients.

Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin

Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin

Abstract OT1-03-04: A phase 2 study of abemaciclib in patients with brain metastases secondary to hormone receptor positive breast cancer

Abstract Background: Abemaciclib, an oral drug administered twice daily on a continuous schedule, is an inhibitor of both CDK4 and CDK6. In study JPBA, abemaciclib demonstrated evidence of single-agent activity in a cohort of patients with heavily pretreated metastatic breast cancer (MBC, median of 7 prior therapies); all responses were observed in women with hormone receptor positive (HR+) disease. Preclinical results demonstrating that abemaciclib crosses the blood-brain barrier coupled with the clinical responses observed in study JPBA support further investigation of abemaciclib in the current phase 2 trial (JPBO) of patients with brain metastases secondary to HR+ breast cancer. Trial design: Study JPBO (NCT02308020) is an open-label, phase 2 trial that will evaluate the safety and efficacy of abemaciclib 200 mg administered orally every 12 hours in patients with HR+ MBC and brain metastases. The study will consist of 3 parts; 2 of these parts will each accrue from 23 to 56 patients.These 2 parts will include patients with HER2+ breast cancer (Part A) and HER2- breast cancer (Part B). Part C will include approximately 8 MBC patients with either HER2+ or HER2- disease who have 1 to 3 intracranial lesions and for whom surgical resection is clinically indicated, with the goal of assessing drug concentrations in plasma, CSF, and brain tumor tissue. These patients may resume abemaciclib post-operatively. Eligibility criteria: Eligible patients include women with HR+ MBC who have completed local therapy ≥14 days prior to abemaciclib treatment, a life expectancy ≥12 weeks, and a Karnofsky performance status of ≥70. Part A includes MBC with confirmed HER2 overexpression and/or amplification (HER2+) status. Part B includes MBC that does not demonstrate HER2 overexpression and/or amplification (HER2-). For Parts A and B, patients will have ≥1 new or not previously irradiated measurable metastatic brain lesion ≥10 mm in the longest diameter or a progressive previously irradiated metastatic brain lesion identified by gadolinium-enhanced MRI. For Part C (surgical), patients have either HER2+ or HER2- MBC with brain lesion(s) for which surgical resection is clinically indicated and agree to provide post-treatment brain tumor tissue. Specific aims: The primary efficacy measure is objective intracranial response rate (complete response + partial response) as defined by Response Assessment in Neuro-Oncology brain metastases response criteria. Secondary intracranial objectives include best overall response, duration of response, disease control rate, and clinical benefit rate. The following overall objectives (intracranial + extracranial) include: overall survival, objective response rate, and progression-free survival. Change in neurologic symptoms will also be assessed. Statistical methods: Two separate Simon 2-stage designs will be employed for Part A and Part B. Each design assumes a 1-sided type-I error of 0.05 and 80% power. All tests will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated. All confidence intervals will be given at a 2-sided 95% level. Target accrual: Approximately 120 patients. Contact information: For further information, please contact 1-877-CTLILLY (1-877-285-4559). Citation Format: Anders C, Zielinski C, Klise SR, Wang HT, Thornton D, Tolaney SM. A phase 2 study of abemaciclib in patients with brain metastases secondary to hormone receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-04.

The predictive capacity of apparent diffusion coefficient (ADC) in response assessment of brain metastases following radiation.

To investigate the predictive capacity of the apparent diffusion coefficient (ADC) as a biomarker of radiation response in brain metastases. Seventy brain metastases from 42 patients treated with either stereotactic radiosurgery or whole brain radiotherapy were imaged at baseline, 1 week, and 1 month post-treatment using diffusion-weighted MRI. Mean and median relative ADC for metastases was calculated by normalizing ADC measurements to baseline ADC. At 1 year post-treatment, or last available follow-up MRI, volume criteria determined final tumour response status. Uni- and multivariate analysis was used to account for factors associated with tumour response at 1 week and 1 month. A generalized estimating equations model took into consideration multiple tumours per subject. Optimal thresholds that distinguished responders from non-responders, as well as sensitivity and specificity were determined by receiver operator characteristic analysis and Youden's index. Lower relative ADC values distinguished responders from non-responders at 1 week and 1 month (P < 0.05). Optimal cut-off values for response were 1.060 at 1 week with a sensitivity and specificity of 75.0 and 56.3 %, respectively. At 1 month, the cut-off was 0.971 with a sensitivity and specificity of 70.0 and 68.8 %, respectively. A multivariate general estimating equations analysis identified no prior radiation [odds ratio (OR) 0.211 and 0.137, P = 0.033 and 0.0177], and a lower median relative ADC at 1 week and 1 month (OR 0.619 and 0.694, P = 0.0036 and 0.005), as predictors of tumour response. Lower relative ADC values at 1 week and 1 month following radiation distinguished responders from non-responders and may be a promising biomarker of early radiation response.

Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery.

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7%, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

Long-term disease control in advanced renal cell cancer with brain metastases with pazopanib (case report and literature review)

We report the case of advanced clear cell renal cell carcinoma with brain, pulmonary, hepatic and bone metastases treated with pazopanib. We observed the complete response in brain metastases and stable extracranial disease after 4 years of the treatment. According to the literature review this is the first reported case of complete response to pazopanib in brain metastases in renal cell carcinoma.

Functional diffusion map: A biomarker of brain metastases response to treatment based on magnetic resonance image analysis.

Validated biomarkers for treatment response in patients suffering from brain metastases are needed in daily clinical practice as they may improve survival by providing reliable prognostic information and allowing alternative therapies. This work presents a new analysis tool for an early and non-invasive evaluation of treatment response in patients with brain metastases. A set of twenty-five metastases from sixteen patients were examined by T1-weighted and diffusion magnetic resonance imaging before starting radiotherapy and at least once after treatment. Diffusion MRI can show a correlation between water diffusion variation within metastasis area and its clinical evolution. Images were co-registered to pretreatment scans. Diffusion changes, resulting in spatially varying changes in apparent diffusion coefficient values of metastatic lesions, were quantified and presented as a functional diffusion map (fDM). These functional maps were compared to two traditional criteria for assessing oncological response. Of the twenty-five metastases analyzed, seven were classified as partial response (PR), eight as stable disease (SD) and nine as progressive disease (PD). Normalized volume values of the metastases for each response group were obtained, disclosing that apparent diffusion coefficient increase was a good predictor of response. Sensitivity was 88%, specificity 100%, positive predictive value 100% and negative predictive value was 94%. Outcome reveals that the implemented tool, based on functional diffusion mapping as evolution biomarker, provides a reliable prediction of metastases response to treatment.

Abstract P6-16-10: Activity of T-DM1 in HER2-positive breast cancer brain metastases

Abstract Background Different local therapy options such as radiotherapy, radiosurgery and neurosurgery remain the mainstay of brain metastases (BM) management, especially in case of oligometastatic or symptomatic disease. Recently, the LANDSCAPE study established lapatinib plus capecitabine (LapCap) as potential standard option for primary systemic treatment in oligosymptomatic patients (pts) with multiple Her2-positive BM. Limited evidence exists with regards to the potential activity of antibodies in BM. Due to a disruption of the blood-brain-barrier at the metastatic site, it is anticipated that even large molecules such as antibodies may penetrate into the central-nervous system (CNS). On the other hand, the CNS is an immune-privileged organ which may hamper activity of trastuzumab. This problem may be overcome by the use of T-DM1. T-DM1 is an antibody-drug conjugate linking trastuzumab (T) to an anti-microtubule agent providing higher activity and lower toxicity as compared to LapCap. Here, we investigated the activity of T-DM1 in newly diagnosed or progressive BM. Patients and Methods Nine pts (median age 55 years) with Her2-positive BM treated at two Austrian centres were included. All pts had received prior treatment with T, five pts (55.6%) had already received lapatinib, and two pts (22.2%) pertuzumab as well. In two asymptomatic pts, T-DM1 was administered as primary therapy, while seven pts had documented CNS progression upon prior local treatment. T-DM1 was administered every three weeks at a dose of 3.6 mg/kg. Restaging was conducted every twelve weeks with MRI or whenever symptoms of disease progression occurred. Results Median follow-up was 6 months and median brain metastases-free survival 11 months. Seven pts (two with primary treatment and five receiving T-DM1 upon CNS progression) are currently assessable for CNS response. 3/7 pts (42.9%) had partial remission, one patient progressing upon prior local therapy had stable disease lasting for 10 months, and one patient had stable disease for 5 month. One patient progressing of prior WBRT had minor response of BM on MRI but no reduction of brain oedema and increasing cortisol doses and was therefore deemed PD. The other patient with primary PD was also progressing after WBRT. Conclusion This prospectively sampled case series again indicates that systemic therapy offers activity in Her2-positive BM. LapCap remains the standard of care but T-DM1 offers relevant clinical activity and should be investigated within the context of larger clinical studies. Citation Format: Rupert Bartsch, Anna S Berghoff, Ursula Vogl, Margaretha Rudas, Elisabeth Bergen, Michael Gnant, Karin Dieckmann, Katja Pinker, Zsuzsanna Bago-Horvath, Arik Galid, Leopold Oehler, Christoph C Zielinksi, Guenther G Steger, Matthias Preusser. Activity of T-DM1 in HER2-positive breast cancer brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-10.

Comparison of radiographic characteristics of renal cell carcinoma (RCC) brain metastases treated with vascular endothelial growth factor (VEGF)-directed therapies or radiotherapy.

479 Background: With improvements in systemic therapy for metastatic RCC (mRCC), an increased frequency of brain metastases (BM) has been observed, perhaps owing to the central nervous system (CNS) serving as a sanctuary site. The response of BM to VEGF-directed therapies has been poorly characterized. Methods: Patients (pts) with mRCC BM were identified from an institutional database. Selection of pts was further refined to pts who had received either VEGF-directed therapy during their diagnosis with BM or radiotherapy directed to their BM. Only those pts with brain MRI straddling systemic therapy and radiotherapy were selected for analysis. Imaging studies were anonymized and transmitted to an independent radiologist for review. Descriptive statistics were applied to characterize the change in sum of long axis dimensions (SLD) in two separate groups: (1) pts treated with VEGF-directed therapy and (2) pts treated with radiotherapy. Results: Of 276 pts with mRCC in our institutional database, 34 pts with BM were identified. Of these pts, 6 pts had serial MRI assessments at timepoints straddling receipt of VEGF-directed therapy. Pts had received sunitinib (n=2), sorafenib (n=2) or bevacizumab (n=2). A further 13 pts received radiotherapy with MRI imaging straddling delivery of either stereotactic radiation therapy (SRT) and whole brain radiotherapy (WBRT). Of these 19 patients, all patients had clear cell histology, and 13 patients were male. In pts receiving VEGF-directed agents, the average change in SLD of BM was -13.8%. In pts receiving radiotherapy, the average change in SLD was -6.5% (-13.0% in pts receiving SRT and +2.0% in pts receiving WBRT). Qualitatively, greater tumor necrosis and lesser rim enhancement was observed in post-treatment scans amongst pts receiving VEGF-directed agents. Conclusions: This pilot study suggested differences in CNS response with VEGF-directed therapy and radiotherapy. Multicenter collaborations are underway to validate these results in larger series.

Non-small cell lung cancer molecular alterations impact on brain metastases response to gamma knife radiosurgery: Identification of potential radiosensitive tumor phenotypes

Introduction Results from clinical studies regarding the radiosensitivity of non-small cell lung cancer (NSCLC) brain metastases (BMs) are scarce and inconclusive. Indeed, little is known about the actual impact of the primary tumor molecular profile and radiological response to radiosurgery. We report here the analysis of a prospective patient cohort of NSCLC patients harboring BMs treated by gamma knife radiosurgery and investigated whether the primary tumor molecular phenotype had an actual impact on BM radiosensitivity. Materials and methods Two hundred sixty three patients were enrolled between January 2010 and April 2013. Molecular profile was available for 90 patients. Local and distant brain control was determined for these 90 patients harboring 173 BMs. Radiological assessment using MRI-scans was undertaken every 3 months after radiosurgery. Patient-, tumor- and treatment-related data were included. Log-rank test and Cox regression model were used to correlate molecular profile of the primary tumor and other clinical features to intracranial radiological control. Results In total, 48/90 (53.3%) of patients presented molecular alterations, 25/90 (27.8%) had KRAS mutations, 16/90 (17.8%) had EGFR mutations, 3/90 (3.3%) had ALK translocation, and 4 patients other genetic alterations. Overall, local and distant control was achieved in 83/90 (92.2%) and in 39/90 (43.4%) patients respectively. No local treatment failure was observed in EGFR mutant or ALK translocated tumor. One (4%) of the 25 KRAS mutated patients experienced a local failure. In the 42/90 patients (46.7%), local failure occurred in 4 cases (9.5%). Multivariate analysis demonstrated that EGFR mutation status and ALK translocation were independent predictors of better local control in patients treated by gamma knife radiosurgery. Conclusion EGFR mutation and ALK translocation are independent prognostic factor regarding local control after Gama Knife radiosurgery in NSCLC patients with BM. The results provided here suggest that molecular profile of NSCLC patient might be taken in account in treatment decision strategy.

Predictors of treatment response of cystic brain metastasis to gamma knife radiosurgery

Predictors of treatment response of cystic brain metastasis to gamma knife radiosurgery