scholarly journals Targeted therapy strategies for melanoma brain metastasis

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.

scholarly journals Beyond KRAS: Practical Molecular Targets in Pancreatic Adenocarcinoma

2019 ◽  
Vol 12 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Albert Grinshpun ◽  
Yonaton Zarbiv ◽  
Jason Roszik ◽  
Vivek Subbiah ◽  
Ayala Hubert
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Pancreatic Adenocarcinoma ◽  
Targeted Therapies ◽  
Kras Mutation ◽  
Molecular Targets ◽  
Driver Mutations ◽  
Proof Of Concept ◽  
Genomic Analyses ◽  
Variable Success

Pancreatic adenocarcinoma (PDAC) has a grim prognosis. Molecular and genomic analyses revealed that the striking majority of these tumors are driven by KRAS mutation, currently not amenable to targeted therapy. However, other driver mutations were found in a small fraction of patients. Herein we report of 3 cases of patients with metastatic PDAC and wildtype KRAS, found to harbor BRAF or RET pathogenic alterations. The patients were treated with targeted therapies with variable success. In our opinion, those proof-of-concept cases argue in favor of additional research and clinical trials’ effort in this small but significant PDAC population with uncommon driver mutations.

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

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i12-i12
Author(s):  
Howard Colman ◽  
Ken Boucher ◽  
Chris Stehn ◽  
David Kircher ◽  
Sheri Holmen
Keyword(s):  
Targeted Therapy ◽  
Brain Metastases ◽  
Predictive Power ◽  
Data Set ◽  
Multiple Gene ◽  
Methods Development ◽  
Melanoma Patients ◽  
Therapeutic Prevention ◽  
Screening Trial ◽  
Molecular Predictor

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.

TCGA PanCanAtlas Data Analysis Suggests Multiple Possibilities for Personalized Cancer Therapy

2021 ◽  
Vol 7 (1) ◽  
pp. 11
Author(s):  
Aleksey V. Belikov ◽  
Alexey D. Vyatkin ◽  
Danila V. Otnykov ◽  
Sergey V. Leonov
Keyword(s):  
Targeted Therapy ◽  
Tumor Suppressors ◽  
Human Cancer ◽  
Point Mutations ◽  
Driver Mutations ◽  
Primary Tumors ◽  
Cancer Driver ◽  
Significant Difference ◽  
Chromosome Arm ◽  
Personalized Cancer

Personalized cancer medicine holds promise for the future of cancer treatment. One of the keys to success is the knowledge of exact molecular alterations that drive tumorigenesis in a given patient, so that a suitable targeted therapy can be selected. However, the extent of such alterations, i.e., number of various kinds of driver mutations per patient, is still not known. We have utilized the largest database of human cancer mutations—TCGA PanCanAtlas, multiple popular algorithms for cancer driver prediction and several custom scripts to estimate the number of various kinds of driver mutations in primary tumors. We have found that there are on average 12 driver mutations per patient’s tumor, of which 0.6 are hyperactivating point mutations in oncogenes, 1.5 are amplifications of oncogenes, 0.1 have both in the same oncogene, 1.2 are inactivating point mutations in tumor suppressors, 2.1 are deletions in tumor suppressors, 0.3 have both in the same tumor suppressor, 1.5 are driver chromosome losses, 1 is driver chromosome gain, 2 are driver chromosome arm losses, and 1.5 are driver chromosome arm gains. The number of driver mutations per tumor gradually increased with age, from 6.7 for < 25 y.o. to 14.9 for > 85 y.o., and cancer stage, from 10.0 to 15.2. There was no significant difference between genders (12.0 in males vs. 11.9 in females). The number of driver mutations per tumor varied strongly between cancer types, from 1.2 in thyroid carcinoma to 23.8 in bladder carcinoma. Overall, our results provide valuable insights into the extent of driver alterations in tumors and suggest that multiple possibilities to choose a suitable targeted therapy exist in each patient.

Factors associated with time to targeted therapy for patients with metastatic lung cancer with driver mutations.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 120-120
Author(s):  
Suwei Wang ◽  
Hu Huang ◽  
Elisabeth Scheufele ◽  
Yull Edwin Arriaga ◽  
Gretchen Purcell Jackson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liver Disease ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Initial Diagnosis ◽  
Driver Mutations ◽  
Tumor Biomarker ◽  
Metastatic Lung Cancer ◽  
Factors Associated ◽  
Metastatic Lung

120 Background: Targeted therapies are superior to chemotherapy in metastatic lung cancer with driver gene mutations. Delays in initiation of targeted therapies may result in faster symptom progression, decline in quality of life, and shortened survival. We examined factors associated with time to initiation of targeted therapy (TTT) in patients with metastatic lung cancer with selected driver mutations. Methods: In this retrospective cohort study, IBM MarketScan claims data was used to identify patients who had an initial diagnosis of metastatic lung cancer, defined as continuous insurance enrollment 12 months pre- to 6 months post-diagnosis, with tumor biomarker (i.e., EGFR, ALK, ROS1, BRAF V600E, NTRK)-directed targeted therapy performed within 6 months of the initial diagnosis, during the timeframe of 1/1/2013 to 12/31/2018. Trends in TTT were evaluated with Wilcoxon–Mann–Whitney. Quantile regression, a robust model that analyzed factors on different outcome-related quantiles, was used to identify associations among TTT and covariates including age, sex, comorbidity, insurance type, and US region. Results: Among 8977 patients identified with an initial diagnosis of metastatic lung cancer, 710 (7.9%) received targeted therapies within the 6-month timeframe, and 1040 (12%) had tumor biomarker testing performed. The overall median TTT was 21 days (IQR = 36 days). Median TTT decreased from 25 days in 2013 to 18 days in 2018 (p = 0.03). Factors associated with longer TTT (median, 50% quantile) were increasing age (p = 0.04), cardiovascular disease (“CVD”, p = 0.03), HIV (p = 0.04), and mild liver disease (p = 0.05). For the lower quantile ( < = 1 day, 5% quantile), female sex (p = 0.01), HIV (p = 0.04), and mild liver disease (p = 0.002) were associated with longer TTT. Having a PPO health plan extended TTT (p = 0.05) at the upper quantile (79 days, 90% quantile). Conclusions: Our study showed an encouraging 5-year trend of the median TTT decreasing by 28%. Numerous factors associated with longer TTT included increasing age, CVD, HIV, mild liver disease, female sex, and PPO plan. This study provides insights into patient-related factors associated with longer time to initiation of targeted therapies for patients with metastatic lung cancer with driver mutations. Additional research is needed to identify the reasons for longer TTT and to develop strategies to expedite delivery of optimal therapies.

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

2017 ◽  
Vol 84 ◽  
pp. 44-54 ◽  
Author(s):  
C. Gaudy-Marqueste ◽  
A.S. Dussouil ◽  
R. Carron ◽  
L. Troin ◽  
N. Malissen ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Brain Metastases ◽  
Melanoma Patients

Targeted Therapy in Brain Metastases: Ready for Primetime?

2016 ◽  
pp. e123-e130 ◽  
Author(s):  
Vyshak A. Venur ◽  
Manmeet S. Ahluwalia
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Targeted Therapy ◽  
Brain Metastases ◽  
Targeted Therapies ◽  
Future Directions ◽  
Anaplastic Lymphoma ◽  
Cancer Breast ◽  
Current State ◽  
Her2 Mutation

Brain metastasis is a serious complication of cancer that causes significant morbidity for patients. Over the last decade, numerous new driver somatic mutations have been recognized and targeted therapies are changing the landscape of treatment in lung cancer, breast cancer, and melanoma, which are also the three most common cancers that result in brain metastases. The common actionable mutations include the EGFR mutation and anaplastic lymphoma kinase (ALK) translocations in non–small cell lung cancer, the HER2 mutation in breast cancer, and the BRAF mutation in melanoma. However, most of the early trials with targeted agents excluded patients with brain metastases. With a better understanding of the biology, several recent trials of targeted therapy that focus on brain metastases have been reported and others are ongoing. Novel agents with better penetration across the blood–brain barrier are currently being investigated for patients with brain metastases. In this review, we discuss the current state of use and future directions of targeted therapies in brain metastases.

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

Cancers ◽  
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.

scholarly journals Management of Melanoma Brain Metastases in the Era of Targeted Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
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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