THER-07. DEVELOPMENT OF A NEW MOLECULAR PREDICTOR FOR RISK OF BRAIN METASTASES AND EFFICACY OF TARGETED THERAPY IN MELANOMA

Abstract Despite therapeutic advances in the treatment of melanoma, development of brain metastases (BM) continues to be a major manifestation of treatment failure. The ability to identify those patients who are at highest risk of developing brain metastases is limited with current methods. Development of sensitive and specific biomarkers to predict which stage II-III melanoma patients are at highest risk of BM would enable initiation of prospective clinical trials focused on both intensive surveillance and therapeutic prevention. To accomplish this goal, we embarked on an effort to optimize a combined molecular/clinical/pathologic predictor of BM risk. We firstanalyzed multiple gene expression datasets including TCGA (n = 437) and an independent series from Australia (n = 183) and identified a list of 60 consensus genes that is robustly predictive of development of melanoma BM (p < 0.05; FDR 5%). Next, we performed a similar analysis of association of miRNAs and melanoma BM risk which identified a set of miRNAs with significant predictive power. An optimized combined set of mRNA and miRNA markers was a better predictor of BM risk than either mRNA or miRNA list alone when applied to the TCGA data set. The combined predictor was most sensitive in separating patients with no metastases from those with either BM or systemic metastases. Current efforts are focused on optimizing miRNA and mRNA separation of patients specifically with BM from those with other mets, and with integrating the expression classifier with other clinical and pathologic predictive factors including: age, stage, thickness, location, histology, ulceration, gender. The sensitivity and specificity of the resulting clinical/molecular predictor will be validated in an independent retrospective cohort, and subsequently implemented in a prospective BM screening trial to determine real-world utility of this approach in preparation for prospective BM adjuvant/chemoprevention trials utilizing both immunotherapy and targeted therapy approaches.

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The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study

Journal of Neuro-Oncology ◽

10.1007/s11060-019-03363-0 ◽

2019 ◽

Vol 146 (1) ◽

pp. 181-193 ◽

Cited By ~ 2

Author(s):

Filipe Martins ◽

Luis Schiappacasse ◽

Marc Levivier ◽

Constantin Tuleasca ◽

Michel A. Cuendet ◽

...

Keyword(s):

Retrospective Study ◽

Targeted Therapy ◽

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Melanoma Patients

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Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery

European Journal of Cancer ◽

10.1016/j.ejca.2017.07.017 ◽

2017 ◽

Vol 84 ◽

pp. 44-54 ◽

Cited By ~ 36

Author(s):

C. Gaudy-Marqueste ◽

A.S. Dussouil ◽

R. Carron ◽

L. Troin ◽

N. Malissen ◽

...

Keyword(s):

Targeted Therapy ◽

Brain Metastases ◽

Melanoma Patients

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Impact of New Systemic Treatment and Radiotherapy in Melanoma Patients with Leptomeningeal Metastases

Cancers ◽

10.3390/cancers12092635 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2635

Author(s):

Pauline Tétu ◽

Lila Sirven-Villaros ◽

Stefania Cuzzubbo ◽

Renata Ursu ◽

Barouyr Baroudjian ◽

...

Keyword(s):

Overall Survival ◽

Targeted Therapy ◽

Brain Metastases ◽

Systemic Therapy ◽

Systemic Treatment ◽

Elevated Serum ◽

Serum Lactate Dehydrogenase ◽

Leptomeningeal Disease ◽

Melanoma Patients ◽

Systemic Therapies

Importance: Few data are available on patients with leptomeningeal disease (LM) from melanoma treated with new systemic therapies. Objective: To gain a better understanding of patients, disease characteristics, and therapeutic interventions in melanoma patients with LM in the era of new systemic treatment. Design: Clinical characteristics, treatments, and survival of melanoma patients diagnosed with LM, isolated or associated with brain metastases, were collected. The Cox regression model assessed the influence of patient and melanoma characteristics on survival. Setting: Monocentric, retrospective, real-life cohort of patients with LM from melanoma. Participants: All patients followed up at Saint-Louis University Hospital and diagnosed with LM between December 2013 and February 2020 were included. For each patient identified, a central review by dermato-oncologist and neuro-oncologist experts was performed to confirm the diagnosis of LM. Exposure: Impact of new systemic therapies and radiotherapy. Results: Among the 452 advanced melanoma patients followed at St Louis Hospital between 2013 and 2020, 41 patients with LM from melanoma were identified. Among them, 29 patients with a diagnosis of LM “confirmed” or “probable” after central neuro-oncologists reviewing were included. Nineteen patients had known melanoma brain metastases at LM diagnosis. Among the 27 patients treated with systemic therapy, 17 patients were treated with immunotherapy, 5 patients received targeted therapy, 1 was treated with chemotherapy, and 4 patients were treated with anti-PD-1 in combination with BRAF inhibitor. The median overall survival (OS) from LM diagnosis was 5.1 months. Median OS was 7.1 months for the 9 patients receiving systemic therapy combined with radiotherapy, and 3.2 months for the 20 patients not receiving combined radiotherapy. Elevated serum lactate dehydrogenase (LDH) (HR 1.44, 95% CI 1.09–1.90, p < 0.01) and presence of neurological symptoms at LM diagnosis (HR 2.96, 95% CI 1.25–6.99, p = 0.01) were associated with poor survival. At the time of data analysis, five patients were still alive with a median follow-up of 47.4 months and had persistent complete response. Conclusion: Targeted therapy and immunotherapy are promising new treatment options in LM from melanoma that can increase overall survival, and may induce long lasting remission in some patients.

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Toxicity and efficacy of Gamma Knife radiosurgery for brain metastases in melanoma patients treated with immunotherapy or targeted therapy—A retrospective cohort study

Cancer Medicine ◽

10.1002/cam4.3021 ◽

2020 ◽

Vol 9 (11) ◽

pp. 4026-4036 ◽

Cited By ~ 2

Author(s):

Brigitte Gatterbauer ◽

Dorian Hirschmann ◽

Nadine Eberherr ◽

Helena Untersteiner ◽

Anna Cho ◽

...

Keyword(s):

Cohort Study ◽

Targeted Therapy ◽

Brain Metastases ◽

Gamma Knife ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Gamma Knife Radiosurgery ◽

Melanoma Patients

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Targeted therapy strategies for melanoma brain metastasis

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab131 ◽

2021 ◽

Vol 3 (Supplement_5) ◽

pp. v75-v85

Author(s):

Chantal Saberian ◽

Paul Sperduto ◽

Michael A Davies

Keyword(s):

Targeted Therapy ◽

Brain Metastases ◽

Targeted Therapies ◽

Cancer Metastasis ◽

Point Mutations ◽

Current Data ◽

High Rate ◽

Driver Mutations ◽

New Therapeutic Approaches ◽

Melanoma Patients

Abstract Melanoma is the most aggressive of the common forms of skin cancer. Metastasis to the central nervous system is one of the most common and deadly complications of this disease. Historically, melanoma patients with brain metastases had a median survival of less than 6 months. However, outcomes of melanoma patients have markedly improved over the last decade due to new therapeutic approaches, including immune and targeted therapies. Targeted therapies leverage the high rate of driver mutations in this disease, which result in the activation of multiple key signaling pathways. The RAS-RAF-MEK-ERK pathway is activated in the majority of cutaneous melanomas, most commonly by point mutations in the Braf serine-threonine kinase. While most early targeted therapy studies excluded melanoma patients with brain metastases, subsequent studies have shown that BRAF inhibitors, now generally given concurrently with MEK inhibitors, achieve high rates of tumor response and disease control in Braf-mutant melanoma brain metastases (MBMs). Unfortunately, the duration of these responses is generally relatively short- and shorter than is observed in extracranial metastases. This review will summarize current data regarding the safety and efficacy of targeted therapies for MBMs and discuss rational combinatorial strategies that may improve outcomes further.

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Management of Melanoma Brain Metastases in the Era of Targeted Therapy

Journal of Skin Cancer ◽

10.1155/2011/845863 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Daniela Gonsalves Shapiro ◽

Wolfram E. Samlowski

Keyword(s):

Targeted Therapy ◽

Brain Metastases ◽

Metastatic Disease ◽

Treatment Options ◽

Whole Brain Radiotherapy ◽

Whole Brain ◽

Brain Radiotherapy ◽

Novel Treatment ◽

Melanoma Brain Metastases ◽

Melanoma Patients

Disseminated metastatic disease, including brain metastases, is commonly encountered in malignant melanoma. The classical treatment approach for melanoma brain metastases has been neurosurgical resection followed by whole brain radiotherapy. Traditionally, if lesions were either too numerous or surgical intervention would cause substantial neurologic deficits, patients were either treated with whole brain radiotherapy or referred to hospice and supportive care. Chemotherapy has not proven effective in treating brain metastases. Improvements in surgery, radiosurgery, and new drug discoveries have provided a wider range of treatment options. Additionally, recently discovered mutations in the melanoma genome have led to the development of “targeted therapy.” These vastly improved options are resulting in novel treatment paradigms for approaching melanoma brain metastases in patients with and without systemic metastatic disease. It is therefore likely that improved survival can currently be achieved in at least a subset of melanoma patients with brain metastases.

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Predictive and Descriptive CoMFA Models: The Effect of Variable Selection

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180212162028 ◽

2018 ◽

Vol 21 (2) ◽

pp. 117-124 ◽

Cited By ~ 4

Author(s):

Bakhtyar Sepehri ◽

Nematollah Omidikia ◽

Mohsen Kompany-Zareh ◽

Raouf Ghavami

Keyword(s):

Variable Selection ◽

Predictive Power ◽

Selection Method ◽

Data Sets ◽

Data Set ◽

Comfa Model ◽

Variable Selection Method

Aims & Scope: In this research, 8 variable selection approaches were used to investigate the effect of variable selection on the predictive power and stability of CoMFA models. Materials & Methods: Three data sets including 36 EPAC antagonists, 79 CD38 inhibitors and 57 ATAD2 bromodomain inhibitors were modelled by CoMFA. First of all, for all three data sets, CoMFA models with all CoMFA descriptors were created then by applying each variable selection method a new CoMFA model was developed so for each data set, 9 CoMFA models were built. Obtained results show noisy and uninformative variables affect CoMFA results. Based on created models, applying 5 variable selection approaches including FFD, SRD-FFD, IVE-PLS, SRD-UVEPLS and SPA-jackknife increases the predictive power and stability of CoMFA models significantly. Result & Conclusion: Among them, SPA-jackknife removes most of the variables while FFD retains most of them. FFD and IVE-PLS are time consuming process while SRD-FFD and SRD-UVE-PLS run need to few seconds. Also applying FFD, SRD-FFD, IVE-PLS, SRD-UVE-PLS protect CoMFA countor maps information for both fields.

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Adverse reactions of targeted therapy in cancer patients: a retrospective study of hospital medical data in China

BMC Cancer ◽

10.1186/s12885-021-07946-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ruofei Du ◽

Xin Wang ◽

Lixia Ma ◽

Leon M. Larcher ◽

Han Tang ◽

...

Keyword(s):

Targeted Therapy ◽

Cancer Patients ◽

Adverse Reactions ◽

Cox Regression ◽

Target Therapy ◽

Skin Damage ◽

Data Set ◽

Patients With Cancer ◽

Number Of Patients ◽

Significant Difference

Abstract Background The adverse reactions (ADRs) of targeted therapy were closely associated with treatment response, clinical outcome, quality of life (QoL) of patients with cancer. However, few studies presented the correlation between ADRs of targeted therapy and treatment effects among cancer patients. This study was to explore the characteristics of ADRs with targeted therapy and the prognosis of cancer patients based on the clinical data. Methods A retrospective secondary data analysis was conducted within an ADR data set including 2703 patients with targeted therapy from three Henan medical centers of China between January 2018 and December 2019. The significance was evaluated with chi-square test between groups with or without ADRs. Univariate and multivariate logistic regression with backward stepwise method were applied to assess the difference of pathological characteristics in patients with cancer. Using the univariate Cox regression method, the actuarial probability of overall survival was performed to compare the clinical outcomes between these two groups. Results A total of 485 patients were enrolled in this study. Of all patients, 61.0% (n = 296) occurred ADRs including skin damage, fatigue, mucosal damage, hypertension and gastrointestinal discomfort as the top 5 complications during the target therapy. And 62.1% of ADRs were mild to moderate, more than half of the ADRs occurred within one month, 68.6% ADRs lasted more than one month. Older patients (P = 0.022) and patients with lower education level (P = 0.036), more than 2 comorbidities (P = 0.021), longer medication time (P = 0.022), drug combination (P = 0.033) and intravenous administration (P = 0.019) were more likely to have ADRs. Those with ADRs were more likely to stop taking (P = 0.000), change (P = 0.000), adjust (P = 0.000), or not take the medicine on time (P = 0.000). The number of patients with recurrence (P = 0.000) and metastasis (P = 0.006) were statistically significant difference between ADRs and non-ADRs group. And the patients were significantly poor prognosis in ADRs groups compared with non-ADRs group. Conclusion The high incidence of ADRs would affect the treatment and prognosis of patients with cancer. We should pay more attention to these ADRs and develop effective management strategies.

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