Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Novel echocardiographic techniques to assess left atrial size, anatomy and function

Three-dimensional echocardiography (3DE) and speckle tracking echocardiography (STE) have recently applied as imaging techniques to accurately evaluate left atrial (LA) size, anatomy and function. 3DE and off-line quantification softwares, have allowed, in comparison to magnetic resonance imaging, the most time-efficient and accurate method of LA volume quantification. STE provides a non-Doppler, angle-independent and objective quantification of LA myocardial deformation. Data regarding feasibility, accuracy and clinical applications of LA analysis by 3DE and STE are rapidly gathering. This review describes the fundamental concepts of LA 3DE and STE, illustrates how to obtain respective measurements and discuss their recognized and emerging clinical applications

Abstract 1352: Genetic susceptibility to immune-related adverse events among melanoma patients treated with ipilimumab

Abstract Background: Ipilimumab is an immune checkpoint inhibitor used to treat melanoma. Although the development of immune-related adverse events (irAEs) among patients treated with ipilimumab is well documented, little is known about factors that may increase risk of irAEs. We conducted a genome-wide association study (GWAS) to examine the genetic susceptibility to irAEs in response to ipilimumab monotherapy. Methods: In partnership with Bristol Myers Squibb BMS, extant genotype data and clinical information were obtained on melanoma patients treated with ipilimumab monotherapy from three clinical trials. Only patients who were treatment naïve were included in our analyses. We defined our outcome as the occurrence of a serious irAE, grade 3 or higher. We first analyzed data from 294 subjects, 79 with severe irAE, enrolled on CA184-169 for whom genotyping was completed using the Affymetrix 6 array. After appropriate quality control, SNP associations were determined using logistic regression models that were adjusted for ancestry, ECOG status, ipilimumab dosage (3 mg/kg vs 10 mg/kg), and number of doses (&amp;lt;4 vs 4+). Next, we analyzed data from 175 subjects, 63 with severe irAE, enrolled on CA209-067 or CA209-069 for whom genotyping was completed using the Illumina MegaEX array; and SNP associations were similarly determined after adjustment for ancestry, trial, and number of doses (&amp;lt;4 vs 4+). Summary statistics from the two analyses were combined using a fixed-effect meta-analysis. Because of the small sample size, we used a sub-genome-wide significance level of 1 × 10-5 to indicate potentially important findings. Results: The most statistically significant marker (rs55981606, p=1.39 × 10-7) and a second independent marker (rs72712605, p=6.33 × 10-6) mapped to a non-coding region on chromosome 9. We identified a marker (rs65949485, p = 9.38 × 10-6) intragenic between the SHQ1 and GXYLT2 genes, both of which are involved in the Notch signaling pathway. Markers proximal to NR2F2 (rs13270533, p=7.8 × 10-6) and within SAMD12 (rs13270533, p = 9.23 × 10-6) were also identified; the latter two genes have been implicated as being oncogenic. Additionally, we identified several markers implicating genes involved in inflammation, specifically macrophage activation, including TLE1 (rs3739581, p = 9.25 × 10-7), SLC16A4 (rs2271885, p=9.23 × 10-6) and CYP2J2 (rs427970, p=2.03 × 10-6). Conclusions: Results from our meta-analysis suggest that genes related to inflammation processes and those with known contributions to oncogenesis may play a role in the development of severe irAEs resulting from ipilimumab monotherapy. If further validated, these findings may provide the foundation to advance models to discriminate patients with a high likelihood of suffering irAE allowing for heightened surveillance of symptom onset or joint decision making for alternative therapies. Citation Format: John Pluta, Lu Qian, Kurt D'Andrea, Chunzhe Duan, Benita Weathers, Megan Wind-Rotolo, Peter Kanetsky, Katherine Nathanson. Genetic susceptibility to immune-related adverse events among melanoma patients treated with ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1352.</jats:p

Abstract 2280: Targeted massively parallel sequencing identifies a limited number of clinically actionable variants in women with early onset breast cancer.

Abstract Approximately 5-10% of breast cancers are likely attributable to single gene mutations. Multiple breast cancer susceptibility genes have been identified; however, there is insufficient information on the clinical benefit of testing for variants in many of these genes outside of BRCA1, BRCA2, TP53 and PTEN. To obtain further information on the spectrum of variants in breast cancer susceptibility genes, we performed massively parallel sequencing using targeted capture of 28 known or proposed breast cancer susceptibility genes in over 250 patients with breast cancer diagnosed under age 40, negative clinical BRCA1 and BRCA2 testing and no personal or family history of ovarian cancer. Sixty-five percent of the patients had a family history of breast cancer. Breast cancers were triple negative in 26% of the patients; 70% of the patients presented with Stage II or greater disease. Positive control mutations in BRCA1, BRCA2, PALB2, CHEK2, MSH2 and BRCC3 were identified using the targeted panel. In analysis of the first 98 study patients, 46+/8 total variants were identified on average per patient with a median read depth of 131. Of the 4,483 total variants identified in the 98 patients, ten variants that are known to be or are likely functionally significant were identified in ten patients (10%). One patient had the CHEK2 1100delC mutation, and another the known deleterious TP53 mutation, P151T. Four of the functionally significant variants are novel frameshift or nonsense mutations in ATM, BRIP1, BARD1 and MRE11A. Four variants predicted to affect splicing, located within the first two nucleotides within the intron, were identified in CHEK2 (3) and MUTYH (1) and are therefore likely to be functionally significant. In addition, 29 patients (29%) were found to carry 27 variants predicted to be deleterious missense variants by multiple variant calling software programs and found at less than 1% frequency in the control population, but are of unclear functional significance as they are either novel or functionally untested. These potentially deleterious variants were identified in ATM (4), RAD50 (3), BRCA2 (3), BARD1 (2), BRCA1 (2), MLH1 (2), NBS (2), BRIP1 (1), CHEK2 (1), MCPH1 (1), MRE11A (1), MSH6 (1), PMS1 (1), and PMS2 (1). These data show that massively parallel sequencing has the ability to identify multiple potentially causative variants in known breast cancer susceptibility genes in patients who present with early onset breast cancer. However, only rare patients, 1% in our initial sample, which will be reported in full, have actionable mutations given current clinical management guidelines. Given the difficulty in determining the functional significance of novel variants, outside of truncating mutations, there is a great deal of uncertainty about how these findings can be translated into improvements in patient care. Citation Format: Kara N. Maxwell, Bradley Wubbenhorst, Richard Letrero, Kurt D'Andrea, Jacqueline Powers, Jill E. Stopfer, Susan M. Domchek, Katherine L. Nathanson. Targeted massively parallel sequencing identifies a limited number of clinically actionable variants in women with early onset breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2280. doi:10.1158/1538-7445.AM2013-2280</jats:p

Abstract 346: Integrative genomic analysis of sporadic clear cell renal cell carcinoma

Abstract Sporadic clear cell Renal Cell Carcinoma (ccRCC) is the most common type of adult kidney cancer. Using high-density copy-number profiling and gene expression profiles, we performed an integrated genomic analysis of 54 sporadic tumor samples. We took a two pronged approach, focusing on 1) all samples and 2) comparing ccRCCs that express both HIF1α and HIF2α (H1H2) and those that express only HIF2α (H2), sub-types of ccRCC that we previously described. For all samples at a frequency over 10%, we identified regions of amplification on 1q, 5q, 7q, 8q, 12p, and 20q, and regions of deletion on 1p, 3p, 6q, 8p, 9p, and 14q, as previously described. We used our integrative analysis to identify target genes that had consistent copy-number and gene expression changes (e.g. amplified and upregulated or deleted and downregulated) within regions on chromosomes 5 and 7. Combining our data with an independent dataset (Beroukhim et al., 2009) and including a literature based analysis, we were able to narrow down to three target genes, which we subsequently validated using a renal cancer cell line. We then compared genomic changes in H1H2 and H2 ccRCCs. Prior data suggested that H2 ccRCCs have increased expression of genes involved in double strand break repair, thus potentially greater genomic stability. Using high-density copy-number data, we have confirmed that H2 tumors have significantly fewer genomic aberrations compared to H1H2 tumors (for amplifications p=0.032 and for deletions p=0.003). In addition, using GISTIC, we found that deletion of chromosome 6 is significantly more common in H1H2 tumors (p&amp;lt;0.001), whereas deletion of chromosome 9 is significantly more common in H2 tumors (p&amp;lt;0.001). Of note, deletion of chromosome 9 previously has been associated with poor prognosis. Thus, correlations between the copy-number data and gene expression profiles indicate that the H1H2 and H2 classes of ccRCC tumors may each have a distinct set of drivers of tumorigenesis; target gene validation for these groups is underway. These experiments provide novel insights into the biology of clear cell Renal Cell Carcinoma (ccRCC). Beroukhim et al. Patterns of Gene Expression and Copy-Number Alternations in von-Hippel Lindau Disease-Associated and Sporadic Clear Cell Carcinoma of the Kidney. Can Res 2009; 69: (11):4674-81. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 346. doi:10.1158/1538-7445.AM2011-346</jats:p

Supplementary Methods from Integrative Genomic Analyses of Sporadic Clear Cell Renal Cell Carcinoma Define Disease Subtypes and Potential New Therapeutic Targets

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