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PDF file - 138KB, Supplementary Table S1. Primers used for site directed mutagenesis of DPYD expression plasmids. Supplementary Table S2. List of missense DPYD variants identified in dbSNP, ESP, and 1000 Genomes databases. Supplementary Table S3. Comparison of in silico predictions of damaging variants and measured enzyme activity of DPD variants.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had DPYD variations could dramatically improve predictive genetic tests for 5-FU sensitivity, especially in individuals of non-European descent. Cancer Res; 74(9); 2545–54. ©2014 AACR.

PDF file - 93KB, DPD enzyme kinetics.

BACKGROUND/AIM Muscle invasive bladder cancer (MIBC) is an aggressive disease with high rates of local recurrence following radical cystectomy (RC). Currently, there are no clinically validated biomarkers to predict local only recurrence (LOR) and guide adjuvant treatment decisions. This pilot study evaluated the role of Ki-67, MRE11 and PD-L1 as predictive biomarkers for recurrence patterns in patients undergoing RC for MIBC. PATIENTS AND METHODS Our institutional cystectomy database containing cases from 1992-2014 was queried for patients with local only recurrence (LOR), and case-matched to patients with distant recurrence (DR) and no recurrence (NR). Clinicopathological data were collected and a tissue microarray was analyzed for presence of Ki-67, MRE11, and PD-L1 using immunofluorescence and immunohistochemistry. RESULTS Pathologic specimens from 42 patients (18 NR, 16 LOR, and 8 DR) were reviewed. Compared to normal bladder tissue, tumors had increased expression of Ki-67 (p

Introduction In surgical series of muscle‐invasive bladder cancer (MIBC), women have higher recurrence rates, disease progression, and mortality following radical cystectomy than men. Similar reports of oncologic differences between men and women following trimodality therapy (TMT) are rare. Our hypothesis was that there would be no difference in overall survival (OS) between sexes receiving TMT. Methods We queried the National Cancer Database (NCDB) for patients diagnosed with clinical stage T2‐T4aN0 M0 MIBC between 2004–2016. We considered patients to have received TMT if they received 55 Gy in 20 fractions or 59.4–70.2 Gy of radiotherapy with concurrent chemotherapy following a transurethral resection of bladder tumor (TURBT). We used multivariable Cox proportional hazard models to determine whether sex was associated with risk of mortality. In addition to OS, we calculated relative survival (RS) to adjust for the fact that females generally survive longer than males. Results Of the patients, 1960 underwent TMT and had survival data. Less than one quarter were female. In the first year following treatment, women had worse OS and RS than men (p = 0.093 and p = 0.030, respectively). However, overall and relative survival differences between sexes were not statistically significantly different in Years 2 and later. Unlike with OS, the RS between sexes remained significant at 9 years; in multivariable analysis based on RS, women were 43% more likely to die than men (p, In surgical series of muscle invasive bladder cancer, females have higher recurrence rates, disease progression, and mortality following radical cystectomy than men. Trimodality therapy (TMT) is an important definitive treatment option in patients seeking bladder preservation. This study examines survival following TMT of women compared with men in a population‐based analysis.

Stereotactic body radiation therapy (SBRT) is a definitive treatment option for early-stage non-small cell lung cancer (NSCLC), but access is not universal. This study evaluated trends in SBRT utilization to identify potential disparities. This was a cancer registry study using the National Cancer Database (NCDB). The NCDB was queried for patients diagnosed with early-stage NSCLC from 2004 to 2016. Patients receiving surgery, chemotherapy, radiation not meeting criteria for SBRT, or other ablative procedures were excluded. SBRT use in treatment facilities over time was evaluated, and patients were analyzed by various socioeconomic factors to determine predictors of SBRT vs no-treatment. Multivariate and Cox regression analyses were performed to determine the extent to which decreased treatment with SBRT may be contributing to worse overall survival. A total of 65,376 patients were included. There was a significant increase in SBRT use from 2004 (n = 80) to 2016 (n = 7948). Patients treated in academic centers were more likely to get SBRT than community programs, but the use in the community has increased in recent years. Covariates associated with decreased use of SBRT included lack of insurance (OR 0.45, p < 0.0001), Hispanic (OR 0.79, p < 0.001), black (OR 0.59, p < 0.0001), or ‘other’ race (OR 0.48 p < 0.0001), and living in a less-educated community (OR 0.83, p < 0.001). On multivariate analysis, use of SBRT was associated with decreased risk of death (HR = 0.48, p < 0.001), and patients treated with SBRT had increased median overall survival compared with patients receiving no treatment (39.6 versus 14.9 months, p < 0.001 by log-rank test). SBRT use is increasing across all treatment facilities but there are notable health disparities based on socioeconomic factors including race that may be contributing to worse survival outcomes.

The prognosis for patients diagnosed with recurrent glioblastoma (GBM) remains poor, with no clear standard of care regarding salvage therapy. Common approaches include chemotherapy, re-resection, tumor treating fields, and reirradiation. However, most studies have shown these to have limited benefits. Reirradiation is particularly difficult due to concern for increased risk of toxicity to surrounding normal brain tissue. A novel intracranial brachytherapy system called GammaTile® (GT Medical Technologies, Tempe, Arizona) involves the placement of Cesium-131 radioactive tiles in the tumor cavity following maximal safe resection. This allows for a highly conformal dose distribution with rapid fall-off to minimize overlap with prior radiation fields and for the application of radiation directly to the high-risk tumor bed. This case report highlights a patient with GBM who survived 11.5 years through multiple recurrences and discusses the many salvage treatments he received, including bevacizumab, irinotecan, and stereotactic radiosurgery (SRS). This case exemplifies that aggressive systemic and local therapies can work well in select patients allowing for long-term survival with a good quality of life. Further efforts should be made to identify which patients may benefit from these therapies. The case study additionally reports on the use of GammaTile therapy. Due to prior external beam radiation therapy and SRS to the treatment site, further external beam radiation options were limited, and the patient was offered GammaTile as local therapy. Although it did not provide a survival benefit in this case due to progressive disease outside of the field of treatment, GammaTile serves as a valuable option in providing local therapy to patients who can no longer receive further radiation. It should be used with careful consideration in lesions characterized by aggressive local invasion.

PURPOSE/OBJECTIVE(S) Multiple myeloma (MM) is a hematologic malignancy that disproportionately affects African Americans (AA) and has a natural history that is often characterized by painful osseous lesions that are amenable to palliative radiotherapy (RT). There are known racial disparities in the definitive treatment of MM and pain management in general in the AA community compared to other racial groups. We sought to determine if racial disparities also exist in use of palliative RT for MM in the United States. MATERIALS/METHODS The National Cancer Database was queried for patients 18 years and older who were diagnosed with MM from 2004-2016 and received radiation. RT dose was limited to between (and including) 4Gy to 30Gy to exclude non-standard doses, incomplete courses, and patients treated for plasmacytoma. The main independent variable under investigation was race/ethnicity, defined as non-Hispanic white (NHW), non-Hispanic black (AA), Hispanic, and other race. Outcomes of interest included receipt of palliative RT within 12 months of MM diagnosis and death within 30 days of initiation of palliative RT. Additional covariates included socioeconomic factors, underlying health, and treatment factors. Multivariable logistic regression analyses were performed to measure the associations of patient race/ethnicity with the odds receiving radiation within 12 months of diagnosis and odds of death within 30 days of receiving the first course of RT. RESULTS Of 23,728 NCDB multiple myeloma patients receiving palliative RT within 12 months of diagnosis, 15.5% of NHW patients, 14.3% of AA patients, 15.8% of Hispanic patients, and 14.4% of other racial/ethnic group patients received palliative RT. The odds of receiving RT were 13% less for AAs compared to NHWs (OR = 0.87, CI = 0.83-0.90, P < 0.0001). Of those receiving radiation, the odds of dying within 30 days of RT were 18% less for AAs compared to NHWs (OR = 0.82, 95% CI = 0.67-1.00, P = 0.046). CONCLUSION This study of the NCDB demonstrates that in addition to previously documented disparities in definitive management of MM, AA patients are also less likely to receive palliative RT within 12 months of diagnosis and at the end of life.

Background Muscle invasive bladder (MIBC) cancer is an aggressive disease with high rates of local recurrence following radical cystectomy (RC). Currently, there are no clinically validated biomarkers to predict local only recurrence (LOR) and guide adjuvant treatment decisions. This pilot study evaluated the role of Ki-67, MRE11 and PD-L1 as predictive biomarkers for recurrence patterns in patients undergoing RC for MIBC. Methods: Our institutional cystectomy database containing cases of urothelial MIBC from 1992–2014 was queried for patients with LOR and case-matched with patients who had distant recurrence (DR) and no recurrence (NR). Clinical and histopathological data were collected from selected patients and a tissue microarray was built and analyzed for presence of Ki-67, MRE11 and PD-L1 using immunofluorescence (IF) and immunohistochemistry (IHC). Univariate, multivariate, and principal component analyses (PCA) were performed to evaluate association of these biomarkers with recurrence pattern. Results: Pathologic specimens from 42 patients (18 NR, 16 LOR and 8 DR) were reviewed. Compared to adjacent normal bladder tissue, tumors had increased expression of PD-L1 on both IHC and IF (p

Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anticancer drug 5-fluorouracil (5-FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA-induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs (miRNA) miR-27a and miR-27b. These miRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells overexpressing miR-27a or miR-27b was 4.4 μmol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 μmol/L; P = 3.3 × 10−5 and P = 1.5 × 10−7, respectively). Mouse liver DPD enzyme activity was inversely correlated with expression levels of miR-27a (R2 = 0.49; P = 0.0012) and miR-27b (R2 = 0.29; P = 0.022). A common variant in the hairpin loop region of hsa-mir-27a (rs895819) was also shown to be associated with elevated expression of the miR-27a in a panel of cell lines (P = 0.029) and in a transgenic overexpression model (P = 0.0011). Furthermore, rs895819 was associated with reduced DPD enzyme activity (P = 0.028) in a cohort of 40 healthy volunteers. Taken together, these results suggest that miR-27a and miR-27b expression may be pharmacologically relevant modulators of DPD enzyme function in the liver. Furthermore, our data suggest that rs895819 may be a potential risk allele for 5-FU sensitivity. Mol Cancer Ther; 13(3); 742–51. ©2014 AACR.

5-Fluorouracil (5-FU) is used to treat many aggressive cancers, such as those of the colon, breast, and head and neck. The responses to 5-FU, with respect to both toxicity and efficacy, vary among racial groups, potentially because of variability in the activity levels of the enzyme dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene). In this study, the genetic associations between DPYD variations and circulating mononuclear-cell DPD enzyme activity were evaluated in 94 African-American and 81 European-American volunteers. The DPYD-Y186C variant was unique to individuals of African ancestry, and DPD activity was 46% lower in carriers as compared with noncarriers (279 ± 35 vs. 514 ± 168 pmol 5-FU min(-1) mg(-1); P = 0.00029). In this study, 26% of the African Americans with reduced DPD activity were carriers of Y186C. In the African-American cohort, after excluding Y186C carriers, homozygous carriers of C29R showed 27% higher DPD activity as compared with noncarriers (609 ± 152 and 480 ± 152 pmol 5-FU min(-1) mg(-1), respectively; P = 0.013).

PURPOSE: To use a linear energy transfer (LET) dependent formula for relative biological effectiveness (RBE) to generate a biological model that can be used to predict toxicity in patients treated with proton therapy for cancer of the head and neck. PATIENTS AND METHODS: Patients treated with protons to a dose of 60 to 70 Gy (RBE = 1.1) for head and neck cancer were eligible to participate in this study. Treatment plans were developed using graphics processing unit Monte Carlo calculations. The equation, RBE = (1.1)[0.08(LET(d))+0.88], was the biological model. The physical model assumes RBE = 1.1. Tumor volumes and organs at risk (OARs) were contoured, and isodose lines were created for 105%–120% of the prescribed dose. Dose to volume of OARs was calculated for both models for comparative purposes. Physician-reported toxicity was graded from 0 to 5 using the Common Terminology Criteria for Adverse Events, version 4.03. Patient-reported outcomes were obtained using the Promis10 and European Organisation for Research and Treatment of Cancer's QLQ-H&N35 instruments. RESULTS: Eleven patients were included in this study. In each case the biological model revealed an increased dose to several OARs compared with the physical model. For selected OARs, the volume receiving >105% of the target dose was 2-fold to 15-fold greater in the biological model than the volume predicted by the physical model. Patients experienced toxicity that was consistent with the dose to OARs predicted by the biological model. Furthermore, 1 patient developed mucosal ulceration and another developed osteoradionecrosis at the location of a biological hot spot. In each case, the biological hot spot was located 2 mm inside the clinical target volume. CONCLUSION: The results suggest that increases in dose predicted by the biological model are clinically relevant and that LET and RBE corrections and optimization should be a component of the treatment-planning process in proton therapy.

In the 45 years since its development, the pyrimidine analog 5-fluorouracil (5-FU) has become an integral component of many cancer treatments, most notably for the management of colorectal cancer. An appreciable fraction of patients who receive 5-FU suffer severe adverse toxicities, which in extreme cases may result in death. Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Clinical studies have suggested that genetic variations in DPYD increase the risk for 5-FU toxicity, however, there is not a clear consensus about which variations are relevant predictors. In the present study, DPYD variants were expressed in mammalian cells, and the enzymatic activity of expressed protein was determined relative to wild-type (WT). Relative sensitivity to 5-FU for cells expressing DPYD variations was also measured. The DPYD*2A variant (exon 14 deletion caused by IVS14+1G>A) was confirmed to be catalytically inactive. Compared with WT, two variants, S534N and C29R, showed significantly higher enzymatic activity. Cells expressing S534N were more resistant to 5-FU–mediated toxicity compared with cells expressing WT DPYD. These findings support the hypothesis that selected DPYD alleles are protective against severe 5-FU toxicity, and, as a consequence, may decrease the effectiveness of 5-FU an antitumor drug in carriers. In addition, this study shows a method that may be useful for phenotyping other genetic variations in pharmacologically relevant pathways. Cancer Res; 73(6); 1958–68. ©2013 AACR.

Understanding the structure and function of the oropharynx is paramount for providing excellent patient care. In clinical oncology, the oropharynx is generally divided into four distinct components: (i) the base of the tongue; (ii) the soft palate; (iii) the palatine tonsillar fossa; and (iv) the pharyngeal wall. The oropharyngeal mucosa is distinct from other mucosal surfaces in the body, as it is composed of a reticulated epithelium with a discontinuous basement membrane, also known as lymphoepithelium. This review describes the anatomy, histology, immunology and surgical resection of the oropharynx as they relate to oncological care.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had

711 Background: For patients with stage IVA rectal cancer with liver metastases treated with curative-intent chemotherapy and surgery, the role of adjuvant pelvic radiotherapy (RT) is unclear. The purpose of this study was to evaluate the impact of pelvic RT on oncologic outcomes in this patient population. Methods: We retrospectively reviewed medical records of all patients with stage IVA rectal adenocarcinoma with liver metastases treated with curative-intent resection of the primary tumor and all liver metastases at our institution between 1991 and 2010. Patient and treatment characteristics were compared between patients who did or did not receive pelvic RT using chi-square and unpaired ttests. Survival and recurrence estimates were calculated from date of initial diagnosis using the Kaplan-Meier method. Local recurrence (LR) was defined as recurrence in the pelvis occurring at or before distant recurrence (DR). Cox regression was used to compare rates of freedom from LR (FFLR), freedom from DR (FFDR), and overall survival (OS) between patients who did or did not receive pelvic RT. Results: The analysis included 65 patients. Median patient age at diagnosis was 59 years (range, 27-87). Tumor stage was T2 (n = 4), T3 (n = 53), or T4 (n = 8). The median number of liver metastases was 2 (range, 1-14). Surgery was low anterior resection (n = 54) or abdominoperineal resection (n = 11). All patients received perioperative fluoropyrimidine based chemotherapy. Pelvic RT was administered to 35 patients (54%), either preoperatively (n = 22) or postoperatively (n = 13). Median RT dose was 50.4 Gy (range 25-58). Patient characteristics were similar for those who did or did not receive pelvic RT. Median follow-up was 3.7 years. The 3-year estimates of FFLR, FFDR and OS were 81% vs 58% (p =.056), 35% vs 29% (p =.75), and 66% vs 71% (p =.81) for RT vs no RT, respectively. Conclusions: In this analysis of patients with stage IVA rectal cancer with liver metastases undergoing curative intent therapy, pelvic RT (vs. no pelvic RT) was associated with a trend to lower rates of LR and similar rates of DR and OS.

Background: Treatment-related AML (t-AML) accounts for 10 to 20% of all AML cases and carries an especially poor prognosis (Kayser et al. 2011, Godley et al. 2008). Patients diagnosed with t-AML are likely to have abnormal cytogenetic profiles with chromosome changes that are predictive of an aggressive malignancy, poor response to therapy, and decreased overall survival(Smith et al. 2003). The simultaneous use of multiple chemotherapeutic agents of different classes makes it increasingly difficult to predict risk for developing t-AML and determining disease course. An updated analysis of predictive factors for t-AML is needed so clinicians can more accurately inform patients of their prognosis. The aim of this study was to classify t-AML according to primary malignancy, previous chemotherapy exposure, and cytogenetic profile. Methods: A retrospective chart review of patients that were diagnosed with AML at Mayo Clinic from 7/1/1990 to 5/13/2015 was performed following IRB approval. AML patients found to have a previous malignancy treated with chemotherapy were classified as t-AML. Chemotherapeutics were classified as alkylating agents, antimetabolites, anti-tubulin agents, and topoisomerase II inhibitors. Patients diagnosed with a myelodysplastic or myeloproliferative disorder prior to development of AML were excluded from this study. Previous chemotherapy exposures, duration of chemotherapy exposure, complete blood count, chromosome abnormalities, and survival data were collected for t-AML cases. Cytogenetic changes were classified as favorable, intermediate, and adverse according to the system used by Kayser et al. 2011. JMP 10.0 was used for statistical analysis. Results: Out of 584 patients, 64 patients (11%) had a primary malignancy that was treated with chemotherapy prior to being diagnosed with AML. The most common primary malignancies were breast cancer (31%), non-Hodgkin lymphoma (27%), colorectal cancer (8%), and Hodgkin lymphoma (8%). Laboratory findings showed median hemoglobin 9.6 g/dL (4.7-13.8), median white blood cells 3.2 x109 (0.6-126), median platelets 50x109 (3-320), median peripheral blood blasts of 8% (0-91), and median bone marrow blasts 38% (1-94). 95% of patients diagnosed with t-AML had been previously treated with an alkylating agent. Additional exposure to an anti-metabolite trended towards a more adverse cytogenetic profile (χ2=5.0, p=0.08) but there was not a statistically significant decrease in overall survival (KM analysis, p=0.31). The median overall survival for patients diagnosed with t-AML was 10.2 months compared to 19.2 months for patients with de-novo AML (KM analysis, p=0.04). Adverse cytogenetic profiles were associated with decreased survival (KM analysis, p Conclusion: Over half of all patients classified as having t-AML in this study received prior chemotherapy for breast cancer or non-Hodgkin lymphoma. Cytogenetic classification of t-AML into favorable, intermediate and adverse groups is useful in predicting disease course. Interestingly, t-AML patients with intermediate risk cytogenetics had similar overall survival to patients with de-novo AML. This suggests that the poor outcomes observed in patients with t-AML is predominantly due to the subset with adverse cytogenetics. Thus, cytogenetic analysis remains the best indicator of overall survival regardless of chemotherapy exposure. Additional work is needed to delineate the risk associated with the aforementioned chemotherapy classes. Disclosures Al-Kali: Celgene: Research Funding.

The pyrimidine analog 5-fluorouracil (5-FU) was developed in the 1950s and remains one of the most widely used chemotherapy drugs in use today. A significant portion of patients who receive 5-FU suffer severe adverse toxicities, and, in extreme cases, death. Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Genetic variations in DPYD have been suggested to increase the risk of 5-FU toxicity. Large-scale sequencing efforts have identified nearly 100 missense and nonsense DPYD variations, however only a handful of alleles have been studied for their association with 5-FU toxicity. Most studies have focused on a single allele (DPYD*2A), which only accounts for a small fraction of DPD deficiencies. Further complicating the interpretation of DPYD alleles, many individuals carry multiple variations within the DPYD gene. The purpose of this study was to identify missense variants that affect the enzyme function of DPD using a mammalian isogenic system of expression. Expression vectors encoding missense DPYD variations were generated by site directed mutagenesis and the expressed protein assayed for enzyme activity. Cells expressing selected variants were also teasted for sensitivity to 5-FU using a novel implementation of electrical impedance based realtime cellular analysis. The results of functional studies are compared to in silico predictions used to classify variants as deleterious or benign. An appreciable fraction of DPD variants showed enzyme activity that was significantly lower than that of wildtype protein. Within the deficient group of variants, a gradient of activities was noted, prompting the grouping of variants as mildly, moderately, and severely impaired. In addition to loss-of-function variations, a few hyperactive DPYD alleles were identified. This novel class of DPYD variants may be protective against 5-FU toxicity at the cost of treatment efficacy. The further evaluation of hyperactive alleles in clinical studies will be necessary to determine their impact on patient outcomes. Overall these data will facilitate the development of predictive tests for 5-FU toxicity by allowing researchers to prioritize variations for association studies. Citation Format: Steven M. Offer, Natalie J. Wegner, Croix Fossum, Robert D. Diasio. Classification of DPYD variations using an isogenic system of expression. [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 2202. doi:10.1158/1538-7445.AM2013-2202