Synthetic Lethality between CDK and PARP Inhibition

PARP1/2 are required for single-strand break repair, and their inhibition causes DNA replication fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. The combined disruption of PARP and HR activities thus produces synthetic lethality. Multiple myeloma cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDK), upstream modulators of HR, are dysregulated in multiple myeloma. Here, we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888–induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased H2AX foci. Dinaciclib treatment reduces expression of HR repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosome DSBs. Cotreatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of multiple myeloma cells, but not normal CD19⁺ B cells, and slowed growth of multiple myeloma xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for multiple myeloma therapy. Mol Cancer Ther; 15(2); 241–50. ©2015 AACR.

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Selected Articles from This Issue

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GC1118, with a Distinct EGFR-Binding Epitope and Efficacy

The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR–GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251–63. ©2015 AACR.

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Inhibition of Class I HDACs in Urothelial Carcinoma

Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays; flow cytometry, senescence and lactate dehydrogenase cytotoxicity assays; and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80% and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line– and HDAC-dependently reduced, with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors romidepsin and givinostat, significantly reduced proliferation of all UCCs (IC₅₀, 3.36 nmol/L–4.59 μmol/L). Romidepsin and givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on nontumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and nonapoptotic cell death in UCCs. Thus, although both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation, their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for urothelial carcinoma therapy. Mol Cancer Ther; 15(2); 299–312. ©2016 AACR.

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Inhibition of Endothelial AKT and ERK by 2-DG

Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2-deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity to 2-DG in endothelial cells is not associated with enhanced drug uptake compared with tumor cells, but with time-dependent, endothelial-selective inhibition of AKT and ERK phosphorylation. Downregulation of these critical survival pathways is shown to be due to 2-DG's interference with N-linked glycosylation, leading to alterations in VEGFR2 (and downstream signaling) as well as induction of endoplasmic reticulum (ER) stress, GSK3β activation, and apoptosis. In vivo, periocular administration of 2-DG in LH_BETAT_AG mice was associated with significant reduction of newly formed (CD105⁺) tumor capillaries, ER stress (GRP 78 expression), and endothelial apoptosis (TUNEL). These findings uniquely link N-linked glycosylation inhibition, ER stress, and ERK/AKT downregulation in endothelial cells, and provide a novel drug development strategy to overcome resistance mechanisms to currently available antiangiogenic agents. Mol Cancer Ther; 15(2); 264–75. ©2015 AACR.

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Choline Kinase in Pancreatic Ductal Adenocarcinoma

Choline kinase α (CHKα) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKα in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKα expression, associated with differentiation. CHKα protein expression was directly correlated with sensitivity to MN58b, a CHKα inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKα knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKα inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKα was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKα did not relate to survival, nuclear CHKα distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKα inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC₅₀. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKα inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response. Mol Cancer Ther; 15(2); 323–33. ©2016 AACR.

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Nuclear RON in NHEJ DNA Repair

Tumor hypoxia is associated with radioresistance, chemoresistance, and metastasis, which eventually lead to cancer progression and a poor patient prognosis. RON [also known as macrophage-stimulating protein receptor (MST1R)] belongs to the c-MET [also known as hepatocyte growth factor receptor (HGFR)] receptor tyrosine kinase (RTK) superfamily. To identify the interaction partners of RON nuclear translocation in response to hypoxia, the nuclear extract of TSGH8301 bladder cancer cells was immunoprecipitated for tandem mass profiling analysis. Nuclear RON interacted with adenosine triphosphate (ATP)-dependent DNA helicase 2 (Ku70) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to activate nonhomologous end joining (NHEJ) DNA repair. The interaction was time dependent, extending 3 to 24 hours posthypoxia or until the components had been exposed to the chemotherapeutic drugs doxorubicin and epirubicin. Stable knockdown experiments in vitro suggest the importance of RON for the chemoresistance of cancer cells under hypoxia. In addition, the tyrosine kinase domain of nuclear RON is crucial for interaction with Ku70 under hypoxia. J82 cells transfected with RON showed a survival advantage in the presence of epirubicin and hypoxia. This suggests that nuclear RON activates NHEJ repair by interacting with Ku70/DNA-PKcs and inhibiting RON activity to increase cancer cell chemosensitivity. Mol Cancer Ther; 15(2); 276–86. ©2016 AACR.

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Retraction: Pharmacologic Inactivation of Kinase Suppressor of Ras1 Sensitizes Epidermal Growth Factor Receptor and Oncogenic Ras-Dependent Tumors to Ionizing Radiation Treatment

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ABT-414, an Antibody Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

Targeting tumor overexpressed epidermal growth factor receptor with an antibody drug conjugate is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations including activating mutations and those with the exon 2-7 deletion (EGFR variant III) commonly found in glioblastoma multifome. ABT-414 exhibits potent cytotoxicity against GBM patient-derived xenograft models expressing either wild-type EGFR or EGFR variant III with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard of care treatment of radiation and temozolomide providing significant therapeutic benefit in a glioblastoma multifome xenograft model. Based on these results ABT-414 has advanced to Phase 1/2 clinical trials and objective responses have been observed in patients with both amplified wild-type and EGFR variant III-expressing tumors.

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Targeting Interleukin-11 Receptor-{alpha} Impairs Human Endometrial Cancer Cell Proliferation and Invasion in vitro and Reduces Tumour Growth and Metastasis in vivo.

Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. Interleukin (IL)11 is a cytokine that regulates cell cycle, invasion and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumours and uterine lavage fluid in women with endometrial cancer, alters endometrial epithelial cancer cell adhesion and migration in vitro but its role in endometrial tumourigenesis in vivo is unknown. We injected mice subcutaneously with human-derived Ishikawa or HEC1A endometrial epithelial cancer cells (ectopic), or HEC1A cells into the uterus (orthotopic) to develop endometrial cancer mouse models. Administration of anti-human IL11 receptor (R) α blocking antibody dramatically reduced HEC1A-derived tumour growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared to IgG. Anti-human IL11Rα retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Rα with anti-mouse IL11Rα antibody did not alter tumour growth, suggesting that cancer epithelial cell IL11 signalling is required for tumour progression. In vitro, anti-human IL11Rα antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse IL11Rα antibody reduced STAT3, but not ERK activation in HEC1A cells in vitro and in endometrial tumours in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signalling reduced primary tumour growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo. Our data suggest that therapeutically targeting IL11Rα could inhibit endometrial cancer growth and dissemination.

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Effective concentration of a multi-kinase inhibitor within bone marrow correlates with in vitro cell killing in therapy-resistant chronic myeloid leukemia

Leukemia cells escape BCR-ABL-targeted therapy by developing mutations such as T315I in the p210BCR-ABL fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). While most effort has been focused on development of new tyrosine kinase inhibitors (TKIs), enrichment of these small molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I mutant CML cells to 10 μM of the multi-kinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell cycle arrest at G2/M. Further increase in drug concentration to 17.5 μM blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μM for effective killing of CML cells in vivo. Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapy-resistant CML.

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Intermittent high dose scheduling of AZD8835, a novel selective inhibitor of PI3K{alpha} and PI3K{delta}, demonstrates treatment strategies for PIK3CA-dependent breast cancers

The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα is one of the most frequently mutated oncogenes in human cancer. Hence PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here we report studies with a novel PI3K inhibitor, AZD8835, currently in Phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3K with selectivity vs. PI3Kβ, PI3K and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in ER+ breast cancer cell lines BT474, MCF7 and T47D (sub-µM GI50s). Consistent with this, AZD8835 demonstrated anti-tumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced anti-tumor activity (up to 92% regression). Combination partners were prioritized based on our mechanistic insights demonstrating signaling pathway crosstalk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong anti-tumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation.

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Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

An autocrine driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert hedgehog (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg peroral). Daily treatment with vismodegib efficiently downregulated Hh target genes, Gli1, Hedgehog Interacting Protein (Hhip) and Ptch1, and caused a significant reduction of tumor volume, and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily down regulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh responsive genes such as Fibronectin (Fn1) and Vegf. Primary cells isolated from the rat model cultured in 3%O2 continued to express Dhh but did not respond to vismodegib in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM.

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Combined Effects of Suberoylanilide Hydroxamic Acid and Cisplatin on Radiation Sensitivity and Cancer Cell Invasion in Non-small-cell Lung Cancer

Lung cancer is a leading cause of cancer mortality worldwide, and concurrent chemoradiotherapy has been explored as a therapeutic option. However, the chemotherapeutic agents cannot be administered for most patients at full doses safely with radical doses of thoracic radiation, and further optimizations of chemotherapy regimen to be given with radiation are needed. In this study, we examined the effects of suberoylanilide hydroxamic acid (SAHA) and cisplatin on DNA damage repairs, and determined the combination effects of SAHA and cisplatin on human non-small-cell lung cancer (NSCLC) cells in response to treatment of ionizing radiation (IR), and on tumor growth of lung cancer H460 xenograft receiving radiotherapy. We also investigated the potential differentiation effect of SAHA and its consequences on cancer cell invasion. Our results showed that SAHA and cisplatin compromise distinct DNA damage repair pathways, and treatment with SAHA enhanced synergistic radiosensitization effects of cisplatin in established NSCLC cell lines in a p53-independent manner, and decreased the DNA damage repair capability in cisplatin-treated primary NSCLC tumor tissues in response to IR. SAHA combined with cisplatin also significantly increased inhibitory effect of radiotherapy on tumor growth in mouse xenograft model. In addition, SAHA can induce differentiation in stem cell-like cancer cell population, reduce tumorogenesity and decrease invasiveness of human lung cancer cells. In conclusion, our data suggest a potential clinical impact for SAHA as a radiosensitizer and as a part of chemoradiotherapy regimen for NSCLC.

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Trastuzumab-based photoimmunotherapy integrated with viral HER2 transduction inhibits peritoneally disseminated HER2-negative cancer

Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than human epidermal growth factor receptor 2 (HER2) has hampered the development of treatments for peritoneal dissemination of gastric cancer. We hypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective anti-tumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer.

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The cost of cancer: a retrospective analysis of the financial impact of cancer on young adults

Abstract

Young adult cancer survivors (YAs) are confronted with immense financial challenges in the wake of their treatment. Medical bills and loss of savings may cause YAs to forgo recommended medications or follow-up appointments. Young survivors with financial concerns also report depression, stress and anxiety. The Samfund is a national nonprofit organization that provides financial support to YAs post-treatment. To quantify the financial burden of cancer in YAs, a retrospective analysis was performed of data collected from Samfund grant applications of 334 YA cancer survivors. Grants were awarded between 2007 and 2013 and grant recipients were consented electronically in 2014 for retrospective data analysis. Recipients ranged from 19 to 39 years of age at the time of their grant applications. Descriptive statistics were calculated and compared to the Medical Expenditure Panel Survey (MEPS) and U.S. census data on age-matched peers. Financial indicators of YA cancer survivors are worse in many domains than those of age-matched controls. Furthermore, YA survivors in their 30s report more perilous prefunding financial situations than younger grant recipients. Cancer has a devastating and age-specific impact on the finances of YAs. Philanthropic grants from the cancer support community, in conjunction with healthcare policy reforms, have the potential to break the cycle of financial need and help YAs move forward with their lives after cancer treatment.

Cancer has a devastating and age-specific impact on the finances of young adult (YAs). Dialog between healthcare and survivorship providers and YAs has the potential to empower this population at-risk for adverse financial and psychosocial outcomes, and steer them toward reputable sources of financial support.

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Scenario drafting for early technology assessment of next generation sequencing in clinical oncology

Abstract

Background

Next Generation Sequencing (NGS) is expected to lift molecular diagnostics in clinical oncology to the next level. It enables simultaneous identification of mutations in a patient tumor, after which targeted therapy may be assigned. This approach could improve patient survival and/or assist in controlling healthcare costs by offering expensive treatment to only those likely to benefit. However, NGS has yet to make its way into the clinic. Health Technology Assessment can support the adoption and implementation of a novel technology, but at this early stage many of the required variables are still unknown.

Methods

Scenario drafting and expert elicitation via a questionnaire were used to identify factors that may act as a barrier or facilitate adoption of NGS-based molecular diagnostics. Attention was paid to predominantly elicit quantitative answers, allowing their use in future modelling of cost-effectiveness.

Results

Adequately informing patients and physicians, the latters' opinion on clinical utility and underlying evidence as well as presenting sequencing results within a relevant timeframe may act as pivotal facilitators. Reimbursement for NGS-based testing and accompanying therapies (both general and in case of off-label prescription) was found to be a potential barrier. Competition on the market and demonstrating clinical utility may also be challenging. Importantly, numerous quantitative values for variables related to each of these potential barriers/facilitators, such as such as desired panel characteristics, willingness to pay or the expected number of targets identified per person, were also elicited.

Conclusions

We have identified several factors that may either pose a barrier or facilitate the adoption of NGS in the clinic. We believe acting upon these findings, for instance by organizing educational events, advocating new ways of evidence generation and steering towards the most cost-effective solution, will accelerate the route from bench-to-bedside. Moreover, due to the methodology of expert elicitation, this study provides parameters that can be incorporated in future cost-effectiveness modeling to steer the development of NGS gene panels towards the most optimal direction.

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"Anticancer Res"[jour]; +49 new citations

49 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Anticancer Res"[jour]

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PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Radiothérapie guidée par l’image pour les petits animaux : une nouvelle ère pour les études précliniques

Publication date: Available online 6 February 2016
Source:Cancer/Radiothérapie
Author(s): G. Delpon, A.-M. Frelin-Labalme, S. Heinrich, V. Beaudouin, C. Noblet, M. Begue, C. Le Deroff, F. Pouzoulet, S. Chiavassa




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CLPTM1L polymorphism as a protective factor for lung cancer: a case–control study in southern Chinese population

Abstract

Variants of the cleft lip and palate trans-membrane 1 like (CLPTM1L) gene, located on chromosome 5p15.33, were previously determined to influence lung cancer susceptibility. Here, we performed a case-control study to examine the potential association of CLPTM1L single nucleotide polymorphisms (SNPs) with lung cancer in a Chinese Han population. We selected four SNPs in the CLPTM1L gene that were previously reported to be associated with lung cancer. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to estimate the strength of the relationship between each CLPTM1L SNP and lung cancer risk. Allelic model analysis revealed that the minor alleles of all four SNPs were significantly associated with decreased lung cancer risk. Similar significant results were detected using genetic model analysis. In addition, we observed a protective effect of haplotype "TT" in the CLPTM1L gene. Our results verified that certain CLPTM1L polymorphisms are protective factors against lung cancer in a southern Chinese Han population and may be potential diagnostic and molecular markers for lung cancer patients.

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Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases

Abstract

The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Univariate and multivariate analyses were performed to identify predictors of overall survival. The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

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A Technique for Generating Volumetric Cine MRI (VC-MRI)

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Wendy Harris, Lei Ren, Jing Cai, You Zhang, Zheng Chang, Fang-Fang Yin
PurposeTo develop a technique to generate on-board volumetric-cine MRI (VC-MRI) using patient prior images, motion modeling and on-board 2D-cine MRI.MethodsOne phase of a 4D-MRI acquired during patient simulation is used as patient prior images. 3 major respiratory deformation patterns of the patient are extracted from 4D-MRI based on principal-component-analysis. The on-board VC-MRI at any instant is considered as a deformation of the prior MRI. The deformation field is represented as a linear combination of the 3 major deformation patterns. The coefficients of the deformation patterns are solved by the data fidelity constraint using the acquired on-board single 2D-cine MRI. The method was evaluated using both XCAT simulation of lung cancer patients and MRI data from four real liver cancer patients. The accuracy of the estimated VC-MRI was quantitatively evaluated using Volume-Percent-Difference(VPD), Center-of-Mass-Shift(COMS), and target tracking errors. Effects of acquisition orientation, region-of-interest(ROI) selection, patient breathing pattern change and noise on the estimation accuracy were also evaluated.ResultsImage subtraction of ground-truth with estimated on-board VC-MRI shows fewer differences than image subtraction of ground-truth with prior image. Agreement between profiles in the estimated and ground-truth VC-MRI was achieved with less than 6% error for both XCAT and patient data. Among all XCAT scenarios, the VPD between ground-truth and estimated lesion volumes was on average 8.43±1.52% and the COMS was on average 0.93±0.58mm across all time-steps for estimation based on the ROI region in the sagittal cine images. Matching to ROI in the sagittal view achieved better accuracy when there was substantial breathing pattern change. The technique was robust against noise levels up to SNR=20. For patient data, average tracking errors were less than 2 mm in all directions for all patients.ConclusionsPreliminary studies demonstrated the feasibility to generate real-time VC-MRI for on-board localization of moving targets in radiotherapy.

Teaser

A novel technique has been developed to generate volumetric cine MRI (VC-MRI) using patient prior information. The VC-MRI was generated by deforming the prior MRI images based on the on-board 2D cine MRI and patient respiratory breathing model. The technique was evaluated using both anthropomorphic digital phantom and patient data. Results demonstrated the feasibility of generating VC-MRI for both inter- and intra-fraction verification of moving targets in radiotherapy.


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Trends in Local Therapy Utilization and Cost for Early-Stage Breast Cancer in Older Women: Implications for Payment and Policy Reform

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Shervin M. Shirvani, Jing Jiang, Anna Likhacheva, Karen E. Hoffman, Simona F. Shaitelman, Abigail Caudle, Thomas A. Buchholz, Sharon H. Giordano, Benjamin D. Smith
PurposeOlder women with early-stage disease comprise the most rapidly growing breast cancer demographic, yet it is not known which local therapy strategies are most favored by this population in the current era. Understanding utilization trends and cost of local therapy is important for informing design of bundled payment models as payers migrate away from fee-for-service. We therefore utilized the SEER-Medicare database to determine patterns of care and costs for local therapy among older women with breast cancer.Materials and MethodsTreatment strategy and covariables were determined in 55,327 women age≥66 with Tis-T2 N0-1 M0 breast cancer who underwent local therapy between 2000 and 2008. Trends in local therapy were characterized using Joinpoint. Polychotomous logistic regression determined predictors of local therapy. Median aggregate cost over the first 24 months after diagnosis was determined from Medicare claims through 2010 and reported in 2014 dollars.ResultsMedian age was 75. Local therapy distribution was as follows: 27,896 (50.3%) lumpectomy with external beam radiation; 18,356 (33.1%) mastectomy alone; 6,159 (11.1%) lumpectomy alone; 1,488 (2.7%) mastectomy with reconstruction; and 1,455 (2.6%) lumpectomy with brachytherapy. Mastectomy alone declined from 39.0% in 2000 to 28.2% in 2008 while use of breast conserving local therapies rose from 58.7% to 68.2%. Mastectomy with reconstruction was more common among the youngest, healthiest patients, whereas mastectomy alone was more common among patients living in rural, low income regions. By 2008, cost was $36,749 for lumpectomy with brachytherapy, $35,030 for mastectomy with reconstruction, $31,388 for lumpectomy with external beam radiation, $21,993 for mastectomy alone, and $19,287 for lumpectomy alone.ConclusionsThe use of mastectomy alone in older women declined in favor of breast conserving strategies between 2000 and 2008. Using these cost estimates, price points for local therapy bundles can be constructed to incentivize treatment strategies which confer the highest value.

Teaser

A population-based database of 55,327 older women with early-stage breast cancer treated during 2000-2008 was utilized to determine trends in local therapies and their associated costs. During this interval, the use of mastectomy in the elderly declined in favor of breast conserving strategies. Mastectomy with reconstruction was infrequently utilized. Costs generally grew faster than inflation and varied substantially by chosen local therapy, suggesting that policies encouraging high value care are needed.


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Dose-Escalated Stereotactic Body Radiation Therapy for Patients with Intermediate and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Rupesh Kotecha, Toufik Djemil, Rahul D. Tendulkar, Chandana A. Reddy, Richard A. Thousand, Andrew Vassil, Mark Stovsky, Ryan K. Berglund, Eric A. Klein, Kevin L. Stephans
PurposeTo report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiotherapy (SBRT).Methods and MaterialsBetween 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a three mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in five fractions with a simultaneous dose-escalation to a dose of 50 Gy to the target volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Toxicity Criteria (v4).ResultsThe median follow-up was 25 months (Range: 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute Grade 2 GI toxicity. Two patients (8%) experienced late Grade 2 GU toxicity and two patients (8%) experienced late Grade 2 GI toxicity. No acute or late grade ≥ 3 GU or GI toxicities were observed. The 24-month PSA relapse-free survival outcome for all patients was 95.8% (95% CI: 75.6-99.4%) and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed.ConclusionsA heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy and high-dose: 50 Gy) with a HDAZ provides a safe method of dose-escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.

Teaser

SBRT has demonstrated promising outcomes for patients with low-risk prostate cancer. In this study, we demonstrate a safe method of dose-escalation to a mean dose of 50 Gy in five fractions for patients with higher risk disease, by using a high-dose avoidance zone (around the urethra, bladder, and rectum). This early experience is associated with high biochemical control rates and acceptably low-rates of treatment-related genitourinary and gastrointestinal toxicity.


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A cost analysis of complex radiotherapy for patients with head and neck cancer

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Lionel Perrier, Magali Morelle, Pascal Pommier, Pierre Boisselier, Bernard Coche-Dequeant, Olivier Gallocher, Marc Alfonsi, Etienne Bardet, Michel Rives, Valentin Calugaru, Enrique Chajon, Georges Noel, Hinda Mecellem, David Pérol, Sophie Dussart, Prof Philippe Giraud
PurposeThis cost analysis aimed to prospectively assess the difference in costs between TomoTherapy® and Volumetric-modulated Arc Therapy (VMAT) in patients with head and neck cancer.Materials and methodsEconomic data were gathered from a multicenter study. However, randomization was not possible due to the availability of equipment. Costs were calculated using the micro-costing technique from the hospital's perspective (in Euros, 2013) and the time horizon was radiation therapy. Only resources that entered the hospital production process and which were likely to vary between the strategies being compared were considered. Acute adverse events observed within the time horizon were also assessed.ResultsThe cost analysis was based on a total of 173 patient treatments between 2010 and 2012 in 14 French cancer centers: 73 patients were treated with TomoTherapy®, 92 with VMAT RapidArc® and 8 with VMAT SmartArc®. Estimated costs of SmartArc® were removed from the comparison, due to the small sample size. The mean cost per patient of the treatment planning phase was €314 (SD: 214) for TomoTherapy® and €511 (SD: 590) for RapidArc®. The mean costs per patient of irradiation reached €3,144 (SD: €565) for TomoTherapy® and €1,350 (SD: €299) for RapidArc®. The most sensitive parameter of irradiation was the annual operating time of accelerators. 95% confidence intervals for the mean costs of irradiation were [€3,016-€3,272] for TomoTherapy® and [€1,281-€1,408] for RapidArc®. The number of acute adverse events during radiotherapy was not significantly different between strategies.ConclusionTomoTherapy® appeared more expensive than RapidArc® mainly due to the higher price of the accelerator, the higher costs of maintenance, and the longer duration of the treatment sessions. Since the strategies were not significantly different in clinical effect, RapidArc® appeared to be the strategy to be recommended in this stage of knowledge.

Teaser

Economic evaluations of Intensity-modulated radiotherapy (IMRT) have been conducted in head and neck cancer, but none has compared Helical Tomotherapy with Volumetric-modulated Arc Therapy (VMAT). In this study, we have compared the costs of TomoTherapy® with VMAT RapidArc®. The cost of TomoTherapy® appears to be higher. Since the numbers of acute adverse events during radiotherapy were not significantly different, RapidArc® appeared to be the preferred strategy in the short-term.


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Mild Lung Restriction in Breast Cancer Patients after Hypofractionated and Conventional Radiotherapy : a 3-year Follow-up

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sylvia Verbanck, Shane Hanon, Daniel Schuermans, Hilde Van Parijs, Vincent Vinh-Hung, Geertje Miedema, Dirk Verellen, Guy Storme, Christel Fontaine, Jan Lamote, Mark De Ridder, Walter Vincken
PurposeRadiotherapy treatments for early stage breast cancer patients potentially affect the lung parenchyma. Previous studies have shown acute effects on the lung diffusing capacity, essentially due to lung volume restriction. We aimed to assess the effect of radiotherapy on lung function over the course of 3 years.Methods and MaterialsEvolution of restrictive and obstructive lung function parameters was investigated in 108 breast cancer participants in a randomized controlled trial comparing conventional radiotherapy (CR) and hypofractionated tomotherapy (TT) (age at inclusion ranging 32-81yr). Spirometry, plethysmography and haemoglobin-corrected diffusing capacity was assessed at baseline, after 3 months, 1, 2 and 3 years. Natural ageing was accounted for by considering all lung function parameters in terms of %predicted values using the most recent reference values for women up to 80 years.ResultsIn the patients with negligible history of respiratory disease or smoking (n=77), the greatest rate of functional decline was observed during the initial 3 months, this acute decrease being more marked in the CR vs the TT arm. During the remainder of the 3-year follow-up period, values (in terms of %predicted) were maintained (diffusing capacity) or continued to decline at a slower rate (forced vital capacity). However, the average decline of the restrictive lung function parameters over a 3-year period did not exceed 9%predicted in either TT or CR arm. Obstructive lung function parameters remained unaffected throughout. Including also the 31 patients with a history of respiratory disease or more than 10 packyears showed a very similar restrictive pattern.ConclusionsIn women with breast cancer, both conventional radiotherapy and hypofractionated tomotherapy induce small but consistent restrictive lung patterns over the course of a 3-year period, irrespective of baseline respiratory status or smoking history. The fastest rate of lung function decline generally occurred in the first 3 months.

Teaser

Acute effects of radiotherapy in breast cancer patients include a small but consistent degree of lung restriction and associated decrease in its diffusing capacity. When accounting for the natural decline in lung function over a 3-year period, the restrictive changes observed after 3 months were either sustained or slowly deteriorated. However, the overall decline over the 3-year period never exceeded 9%predicted, irrespective of radiotherapy modality or respiratory status at baseline. There was no airway obstruction following radiotherapy.


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Non-local means denoising of SG-KS-4D-MRI using block matching 3D: Implications for pancreatic tumor registration and segmentation

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jun Jin, Elizabeth McKenzie, Zhaoyang Fan, Richard Tuli, Zixin Deng, Jianing Pang, Benedick Fraass, Debiao Li, Howard Sandler, Guang Yang, Ke Sheng, Shuiping Gou, Wensha Yang

Teaser

Four dimensional MRI (4D-MRI) image sets were denoised with a non-local means filter. The denoised 4D-MRI images were shown to have less noise and better contrast to noise ratio. The 4D image registration was also more consistent on the denoised 4D-MRI compared to the raw 4D-MRI.


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Cost-Effectiveness Analysis of IMRT versus 3DCRT for Preoperative Treatment of Extremity Soft Tissue Sarcomas

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Patrick Richard, Mark Phillips, Wade Smith, Darin Davidson, Edward Kim, Gabrielle Kane
PurposeCreate a cost-effectiveness model comparing preoperative intensity-modulated radiation versus 3D conformal radiation for extremity soft tissue sarcomas.Methods and MaterialsInput parameters included 5-year local recurrence rates, acute wound complication rates, and chronic toxicities (edema, fracture, joint stiffness, and fibrosis). Health-state utilities were used to calculate quality-adjusted life years (QALYs). Overall treatment costs per QALY or incremental cost-effectiveness ratio (ICER) were calculated. Roll-back analysis was performed using average costs and utilities to determine the baseline preferred radiation technique. One-way, two-way, and probabilistic sensitivity analyses (PSA) were performed for input parameters with the largest impact on the ICER.ResultsOverall treatment costs were $17,515.58 for 3DCRT compared to $22,920.51 for IMRT. The effectiveness was higher for IMRT (3.68 QALYs) compared to 3DCRT (3.35 QALYs). The baseline ICER for IMRT was $16,842.75/QALY, making it the preferable treatment. The ICER was most sensitive to the probability of local recurrence, upfront radiation costs, local recurrence costs, certain utilities (no toxicity/no recurrence, grade 1 toxicity/no local recurrence, grade 4 toxicity/no local recurrence), and life expectancy. Dominance patterns emerged when the cost of 3DCRT exceeded $15,532.05 (IMRT dominates) or the life expectancy was under 1.68 years (3DCRT dominates). Furthermore, preference patterns changed based on the rate of local recurrence (threshold: 13%). PSA results demonstrated that IMRT was the preferred cost-effective technique for 64% of trials compared to 36% for 3DCRT.ConclusionsBased on our model, IMRT is the preferred technique by lowering rates of local recurrence, severe toxicities, and improving QALYs. From a third party payer perspective, IMRT should be a supported approach for extremity soft tissue sarcomas.

Teaser

Both IMRT and 3DCRT remain options for the preoperative management of soft-tissue sarcomas. Although IMRT is more costly, our analysis has shown its cost-effectiveness compared to 3DCRT through reducing rates of severe toxicities/local recurrences and improving quality-adjusted life years. Furthermore, IMRT was the preferred technique in 64% of probabilistic sensitivity analyses trials. Third-party payers should support IMRT as a cost-effective option for the pre-operative management of soft-tissue sarcomas.


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Factors Affecting Gender-based Experiences for Residents in Radiation Oncology

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Parul N. Barry, Karen H. Miller, Craig Ziegler, Rosanna Hertz, Nevine Hanna, Anthony E. Dragun
PurposeWhile women comprise approximately half of medical school graduates, an uneven gender distribution exists among many specialties, including radiation oncology where women fill only one-third of residency positions. Although multiple social and societal factors have been theorized, a structured review of radiation oncology resident experiences has yet to be performed.Methods and MaterialsAn anonymous and voluntary survey was sent to 611 radiation oncology residents practicing in the United States. Residents were asked about their gender-based experiences in terms of mentorship, their professional and learning environment, and their partnerships and personal life.ResultsA total of 203 participants submitted completed survey responses. Fifty-seven percent of respondents were men and 43% were women, with a mean age of 31 years (SD = 3.7 years). While residents in general place value in having a mentor, female residents prefer mentors of the same gender (p <0.001), and noted having more difficulty finding a mentor (p=0.042). Women were more likely to say that they have observed preferential treatment based on gender (p≤0.001) and were more likely to perceive gender-specific biases or obstacles in their professional and learning environment (p<0.001). Women select residency programs based on gender ratios (p<0.001), and female residents prefer to see equal number of male and female faculty (p<0.001). Women were also more likely to perceive work related strain than their male counterparts (<0.001).ConclusionsDifferences in experiences for male and female radiation oncology residents exists with regard to mentorship and in their professional and learning environment.

Teaser

Despite the fact that women make up about 50% of medical school graduates, many specialties having an uneven gender distribution. Radiation oncology is no exception, and continues to have a female minority. A survey was sent to radiation oncology residents practicing in the United States evaluating gender-based experiences to further understand why this disparity exists.


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Spatiotemporal fractionation schemes for irradiating large cerebral arteriovenous malformations

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jan Unkelbach, Marc R. Bussière, Paul H. Chapman, Jay S. Loeffler, Helen A. Shih
Purposeand Objectives: We consider fractionation effects in the context of radiosurgery treatments of large cerebral arteriovenous malformations (AVM). In current practice, fractionated treatments divide the dose evenly into several fractions, which generally leads to low obliteration rates. In this work, we investigate the potential benefit of delivering distinct dose distributions in different fractions.Methods and MaterialsFive patients with large cerebral AVMs were reviewed and were replanned for intensity-modulated arc therapy delivered with conventional photon beams. Treatment plans allowing for different dose distributions in all fractions were obtained by performing treatment plan optimization based on the cumulative biologically effective dose (BED) delivered at the end of treatment.ResultsWe show that distinct treatment plans can be designed for different fractions such that high single fraction doses are delivered to complementary parts of the AVM. All plans create a similar dose bath in the surrounding normal brain and thereby exploit the fractionation effect. This partial hypofractionation in the AVM along with fractionation in normal brain achieves a net improvement of the therapeutic ratio. We show that a biological dose reduction of approximately 10% in the healthy brain can be achieved compared to reference treatment schedules that deliver the same dose distribution in all fractions.ConclusionsBoosting complementary parts of the target volume in different fractions may provide a therapeutic advantage in fractionated radiosurgery treatments of large cerebral AVMs. The strategy allows for a mean dose reduction in normal brain that may be valuable for a patient population with an otherwise normal life expectancy.



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Quality of life in women undergoing breast irradiation in a randomized controlled clinical trial evaluating different tumor bed boost fractionations

Publication date: Available online 6 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Morgan A. Finkel, Benjamin T. Cooper, Xiaochun Li, M. Fenton-Kerimian, Judith D. Goldberg, Silvia C. Formenti
Purpose/ObjectiveTo identify differences in breast cancer, patient reported quality of life (QOL) between two radiation tumor bed boost dose regimens.Methods and MaterialsFour hundred patients with Stage 0, I, or II breast cancer who underwent segmental mastectomy with sentinel node biopsy and/or axillary node dissection were treated with either a daily or weekly boost. Patients were treated prone to 40.5 Gy/15 fractions to the whole breast, five days a week. Patients were randomized to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy on Friday. Patients completed six validated QOL survey instruments at baseline, last week of treatment (3 weeks), 45-60 days from the completion of radiation treatment, and at 2-year follow-up.ResultsThere were no statistically significance differences in responses to the six QOL instruments between the daily and weekly radiation boost regimens, even after adjustment for important covariates. However, several changes in responses over time occurred in both arms, including worsening functional status, cosmetic status and breast specific pain at the end of treatment as compared to before and 45-60 days after the conclusion of treatment.ConclusionsWhole breast, prone intensity modulated radiation has similar outcomes in QOL measures whether given with a daily or weekly boost. This trial has generated the foundation for a current study of weekly versus daily radiation boost in women with early breast cancer in which three dimensional conformal radiation is allowed as a prospective stratification factor.

Teaser

This study aimed to identify differences in breast cancer patient reported QOL between two radiation tumor bed boost dose regimens. Patients completed six validated QOL instruments at specified times during and after treatment. We found that whole breast, prone IMRT similarly affects QOL whether given as a daily or weekly boost. This trial has generated the foundation for a current study of weekly versus daily radiation boost using 3D conformal radiotherapy.


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Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases

Abstract

The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Univariate and multivariate analyses were performed to identify predictors of overall survival. The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

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