tbuckley/cabot-search huggingface dataset:
Sequencing of cabazitaxel and abiraterone acetate following docetaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ian D. Schnadig, Menaka Bhor, Nicholas J. Vogelzang, Daniel Hennessy, Leonardo V. Nicacio, William R. Berry, Thomas E. Hutson, Mark T. Fleming, C. Lance Cowey, Shanmugapriya Saravanan, Rahul Dhanda, Guru Sonpavde
Journal: Journal of Clinical Oncology (2013)

79 Background: Following docetaxel (D), treatment options for mCRPC include cabazitaxel (CBZ), abiraterone acetate (AA), and enzalutamide. With the introduction of new agents, optimal sequencing is undefined. We evaluated the prevalence of sequencing of AA and CBZ following D in a large community-based cohort to develop a hypothesis for the most optimal sequence. Methods: A retrospective analysis of treatment patterns using the MSH iKnowMed EHR was conducted. Post-D mCRPC patients receiving CBZ and/or AA at full EHR sites with ≥2 visits were included; clinical trial patients excluded. CBZ utilization between Jun’10 and May’12 and sequencing of CBZ or/and AA from Apr’11 and May’12 (when both drugs were available) were examined. OS, time to treatment failure (TTF), and demographics analyses are ongoing. Results: 667 evaluable patients were identified. Overall CBZ (n=359 pts/2 y) utilization declined between Jun’10-May’11 (n=232) and Jun’11-May’12 (n=127). From Apr’11 to May’12: overall AA (n=465 pts/y) utilization increased between Mar-May’11 (n=73) to Jun-Aug’11 (n=164) and subsequently decreased (n=57) from Mar-May’12. Between Apr’11-May’12, 130 patients received both CBZ and AA. More men (P&lt;0.001) received D→CBZ→AA (n=88, 67.7%) compared with D→AA→CBZ (n=42, 32.3%). Median age of patients receiving both CBZ and AA was 67 (44-89) y and their median baseline PSA (111 evaluable) was 84.3 (0.4-7672.2) ng/mL. Conclusions: AA was administered more frequently than CBZ in post-D mCRPC patients. However, the sequence of D→CBZ→AA was more prevalent than D→AA→CBZ in this large community-based cohort. Until predictive biomarkers and outcomes with respective sequences are identified, delivery of all active agents according to patient-specific clinical factors should probably be considered. [Table: see text]
Cardiac dose evaluation in patients undergoing breast radiotherapy in the modern era.
Authors: Christopher A. Peters, Andrew Kaleda, Anthony Manfredo, Elizabeth Tapen, Lawrence Koutcher
Journal: Journal of Clinical Oncology (2014)

78 Background: Breast radiotherapy (RT) after conservative surgery improves overall survival and minimizes locoregional recurrence. The therapeutic ratio of adjuvant RT continues to improve with time. Cardiac toxicity from breast cancer treatment remains a concern, and can result from chemotherapy, biologic therapy, or RT in a dose-dependent fashion. Dose to avoidance structures can be minimized as technological improvements in radiotherapy evolve. We sought to investigate heart and coronary artery dose using modern RT techniques. Methods: We reviewed 164 consecutive non-metastatic breast cancer patients treated with adjuvant breast RT, from 3/2011 to 12/2013. 8 patients were excluded because they did not complete the prescribed dose. Patients were treated on 3 different machines, at 2 centers. Data was extracted using both the treatment planning system and electronic medical records. Univariate analysis was done using t-test and one way ANOVA for variables predicting higher mean heart dose (MHD). Multivariate analysis was performed using multiple linear regression. p values ≤0.05 were considered significant. Results: The median age of our cohort was 63 (range 33-85), and 90% had ≤ stage 2 disease. 53% had left sided RT, 45% right, and 2% had bilateral RT. 18% had breast/chest wall and nodal RT, with 2% dedicated IMN targeting. 22% of patients were treated prone. The median dose, including boost, was 60.4 Gy (range 42.4-66.4). 35% received cytotoxic chemotherapy and 10% received trastuzumab. Mean heart dose was 1.4Gy (SD 2.2), and mean LAD dose was 4.9Gy (SD 4.4). MHD were lower in the prone position compared to supine, but did not reach statistical significance p=0.3. Advanced AJCC stage grouping, left sided or bilateral treatment, breast/nodal target volume, and helical treatment were associated with significantly higher MHD on univariate analysis. On multivariate analysis, only breast/nodal volume and helical technique remained significant, both p&lt;0.001. Conclusions: Modern techniques result in low heart and LAD doses in our series. Because adjuvant breast RT plays a critical role in the definitive management of breast cancer, these data are reassuring to patients, physicians, and payers.
Association of ABCB1 polymorphism and erlotinib toxicity with efficacy in patients with non-small cell lung cancer (NSCLC).
Authors: S. Saeki, J. Sasaki, A. Hamada, N. Iwamoto, M. Inaba, H. Kishi, S. Fujii, S. Ushijima, H. Semba, H. Kohrogi
Journal: Journal of Clinical Oncology (2010)

e18115 Background: Erlotinib demonstrates individual differences in toxicity and efficacy. Last year we reported that patients with homozygous and heterozygous variant for ABCB1 1236C>T, 2766G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type were associated with higher Cmin at steady state and development of skin rush. The aim of this study is to evaluate the relationship between ABCB1 polymorphism and clinical outcome in Japanese patients with NSCLC who received erlotinib. Methods: Thirty-four patients with NSCLC who received erlotinib monotherapy were enrolled. Eligibility criteria included: performance status (PS) < 3, age < 75, stage IIIB-IV, and written informed consent. Plasma levels of erlotinib were measured on stable phase (> day 7) by high-performance liquid chromatography. DNA from plasma was screened for SNPs in the ABCB1 gene using direct nucleotide sequencing or TaqMan assay. Development of skin rush, tumor response and survival data were also collected. Results: Higher Cmin at steady state (> 1.26 μ g/mL) was associated with shorter trend for progression-free survival (51 days vs. 266 days; log-rank test, p = 0.12). Skin rush grade (grade > 2) was correlated with shorter progression-free survival (85 days vs. 332 days; log-rank test, p = 0.003). Patients with homozygous variant for ABCB1 1236TT-2677TT-3435TT showed significant shorter progression-free survival than others (median 34 days vs. 195 days; log-rank test, p = 0.001). The differences of overall survival were not significant. Conclusions: Unexpectedly, skin rush grade and ABCB1 polymorphisms had negative impact on progression-free survival. The reason for this discrepancy was due to heterogeneity of patient background such as EGFR mutation status, previous treatment of EGFR-TKI and histology. In fact, three out of four patients with homozygous variant for ABCB1 1236TT-2677TT-3435TT were refractory to gefitinib before erlotinib treatment. We need further studies to assess the impact of ABCB1 polymorphism on efficacy of erlotinib in particular patients such as EGFR-TKI naïve and EGFR mutation negative. No significant financial relationships to disclose.
Effects of a neurokinin-1 receptor (NK-1R) antagonist on colon cancer through suppression of colon tumor–initiating cells.
Authors: C. Polytarchou, J. M. Bugni, S. Dry, C. Pothoulakis, D. Iliopoulos
Journal: Journal of Clinical Oncology (2011)

3614 Background: Colorectal cancer is the third most common cancer in the United States, accounting for approximately 150,000 new cases and 50,000 deaths per year. The standard chemotherapeutic approaches in colon cancer eliminate the bulk population of tumor cells, however they do not affect the colon tumor initiating cells (TICs) leading to relapse of the disease. Thus, it is essential to identify the colon TICs and develop novel therapeutic strategies by selectively inhibiting their growth. Methods: Flow cytometry for Lgr5, ALDH1, CD133, CD44 markers was used to isolate potential colon TICs derived from 20 human colon cancers and 8 colon cancer cell lines. The tumorigenicity of these subpopulations was tested by limiting dilution xenotransplantation assays in NOD/SCID IL2Rg-/- mice. A chemical library screen (1,204 compounds) was performed in HCT-116 cells to identify drugs that selectively eradicate colon TICs. The effectiveness of these drugs to suppress tumor growth and relapse was tested in xenograft and chemical-induced (azoxymethane) mouse models of colon carcinogenesis. Furthermore, high throughput phospho-kinome assay was performed to identify the signaling pathways affected in the colon TICs by their selective inhibitors. Results: We identified that the colon TICs are Lgr5+/ALDH1+/CD44+ cells, account for the 1.9-4.8% of total colon tumor population and are highly resistant to 5FU and oxaliplatin treatments. The chemical library screen revealed a substance P, NK-1R antagonist to display the highest effectiveness to selectively target the colon TICs. Combinational therapy of a NK-1R antagonist together with oxaliplatin suppressed tumor growth and prevented relapse in the colon cancer mouse models, while oxaliplatin as a monotherapy was not effective in preventing relapse of the disease. Phospho-kinome analysis revealed that the NK-1R antagonist suppressed the NF-κB, AKT and MAPK signaling pathways which were activated in colon TICs. Conclusions: Our study identified colon TICs responsible for colon tumor recurrence and provides the rationale for combining conventional chemotherapy with an NK-1R antagonist, which selectively kills colon TICs, in colon cancer patients.
Effect of enzalutamide on health-related quality of life (HRQoL) in men with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel-based therapy: Results from the AFFIRM study.
Authors: Kurt Miller, Howard I. Scher, Karim Fizazi, Ethan M. Basch, Cora N. Sternberg, Mohammad Hirmand, David Cella, Cristina Ivanescu, De Phung, James Robert Spalding, Cat N. Bui, Stefan Holmstrom, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2013)

17 Background: In the AFFIRM trial, enzalutamide (ENZ), an oral androgen receptor inhibitor, was superior to placebo (PBO) in overall survival (HR=0.63 [0.53, 0.75], p&lt;0.001) [Scher et al. NEJM 2012;367:1187]. This analysis focuses on impact of ENZ on HRQoL. Methods: Men with mCRPC previously treated with docetaxel were randomized (2:1) to receive ENZ (160mg/day) or PBO. HRQoL was assessed at baseline (BL), weeks 13, 17, 21, 25 and every subsequent 12 weeks using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients with BL and ≥1 post-BL evaluable forms were included in this analysis. Change from BL in FACT-P scores over 25 weeks of treatment was analyzed using linear mixed models. HRQoL improvement/deterioration was defined as a 10-point or higher increase/decrease during the study compared to BL on the FACT-P total score. Results: The HRQoL analysis included 938 patients. Changes from BL in FACT-P total score and domains over 25 weeks of treatment were significantly smaller (less decline) with ENZ than PBO (Table). A greater percentage of patients on ENZ reported HRQoL improvement compared to PBO (42.2% vs 14.5%; p&lt;0.001). Median time to first HRQoL deterioration was 9.0 months for ENZ and 3.7 months for PBO (p&lt;0.001). Overall, 46.8% of patients on ENZ and 59.3% on PBO experienced HRQoL deterioration at some point while on treatment (p=0.001). Conclusions: Compared to PBO, therapy with ENZ yields significantly better HRQoL across all domains and delays deterioration. The extent of the HRQoL advantage, along with the previously established overall survival gain of ENZ over PBO, suggest that ENZ confers a significant and meaningful clinical benefit to men with mCRPC. [Table: see text]
What is the prognostic role of bone metastases in ovarian cancer: Results of an analysis of 1,717 patients.
Authors: J. Olschewski, V. Schotters, T. Denecke, J. U. Blohmer, J. Sehouli
Journal: Journal of Clinical Oncology (2011)

e15529 Background: Bone metastases (BM) are a very uncommon site of metastatic spread from ovarian cancer, especially if diagnosed ante mortem.. Information regarding prognostic relevance in this population is very limited. Therefore, the present analysis was initiated. Methods: Patients with histological confirmed epithelial ovarian cancer, carcinoma of the fallopian tube or primary peritoneal carcinoma (EOC) and BM admitted to the university hospital Charité from 2004 to 2009 were analyzed retrospectively. Results: Twenty-six patients with BM were identified, resulting in an incidence of 1.5%. Incidence of BM in patients with EOC in autopsy studies varies around 10.3%. Therefore the estimated number of unknown cases is 9%. The most common localisations of BM were the thoracic and lumbar spine and the pelvic bone. 96% of all BM are located within the margins of the CT abdomen scan. General OS was 55 mo and from diagnosis of BM 13.7 mo. Patients with a single BM had an OS after diagnosis of BM of 24.5 mo vs. patients with multiple BM with 12.1 mo. OS after diagnosis of BM for patients without any further distant metastasis is 27.1 mo in contrast to 9.8 mo for patients with other metastasis. Early onset of BM (within 12 mo from diagnosis of EOC) was associated with a significantly shorter OS of 11.2 mo versus 78.4 mo in the late onset group (BM later than 12 mo after diagnosis of EOC; p=0.000001). Conclusions: Prognosis of BM is poor, especially if the onset of BM is early and if there are multiple lesions and other distant metastasis, whereas late onset and single BM lesions do not seem to alter the overall survival negatively. We would conclude that BM can be either a sign of a fulminant, aggressive disease or a sign of a slow progressive but advanced disease depending on there time of onset. Future studies should aim to elucidate possible backgrounds for these different progression types of EOC in order to utilize this knowledge in future therapeutically approaches.
Proteomic stratification of clear cell renal cell carcinoma utilizing The Cancer Genome Atlas (TCGA) with external validation.
Authors: Samuel D. Kaffenberger, Giovanni Ciriello, Andrew G. Winer, Martin Henner Voss, Jodi Kathleen Maranchie, Pheroze Tamboli, Kimryn Rathmell, Toni K. Choueiri, Robert J. Motzer, Jonathan A. Coleman, Paul Russo, James Hsieh, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2015)

406 Background: Proteomics represents the ultimate convergence of DNA and expression alterations. We therefore sought to leverage TCGA reverse phase protein array (RPPA) data with an independent proteomic platform to identify druggable targets and pathways associated with prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Unsupervised hierarchical consensus clustering was performed and differentially expressed proteins were identified for pathway analysis. Associations with clinicogenomic factors were assessed and Cox proportional hazards models were performed for disease-specific survival (DSS). Results: RPPA clustering of 324 patients from the ccRCC TCGA revealed 5 robust clusters characterized by alterations in specific pathways and divergent prognoses. Cluster 1 was characterized by poor DSS, decreased expression of receptor tyrosine kinases (RTK) and upregulation of the mTOR pathway. It was also associated with mTOR pathway genomic alterations, sarcomatoid histology and the ccb prognostic mRNA signature (all p&lt;0.001). Cluster 2 was characterized by increased expression of RTKs and interestingly, had upregulation of the mTOR pathway with excellent DSS. After accounting for stage and grade, cluster designation remained independently associated with DSS (HR 0.23 for cluster 2, 95% CI 0.08-0.68; p=0.008). External validation was performed on a separate cohort of 189 patients with a different quantitative proteomics platform. A panel of phosphoproteins (pHER1, pHER2, pHER3, pSHC, pMEK, pAKT), highly discriminant between the most divergent RPPA clusters (1 and 2) was evaluated. Those at the highest quartile of activation in &gt; 3 proteins were associated with improved DSS (HR 0.19, 95% CI 0.05-0.082; p=0.03). Patients with mTOR pathway activation segregated to those with coincident RTK activation (n=83) and those without (n=13). Conclusions: We have identified and validated proteomic signatures which cluster ccRCC patients into 5 prognostic groups. Furthermore, two distinct mTOR-activated clusters—one with high RTK activity and one with increased mTOR pathway genomic alterations were revealed, which may have prognostic and therapeutic implications.
Implementation of code status discussion early in the course of treatment for oncology patients.
Authors: Meredith Faggen, Heather Gilchrist, Caitlin C. Donohue, Reanne Burke
Journal: Journal of Clinical Oncology (2014)

88 Background: Having a code status discussion early in the treatment course of patients with advanced stage cancer is important to ensure that patients make decisions about life sustaining treatment in a non-urgent setting. There was not a standardized approach to addressing the code status of patients with stage IV cancer enrolled on the Supportive Oncology (SO) Pathway at Dana Farber Cancer Institute/South Shore. We addressed this problem by implementing a standardized method of documenting code status at or before the 3rd visit in patients with stage IV disease participating in our SO pathway. Methods: A process map highlighted that most patients with advanced cancer discussed their code status the day of hospice enrollment. A fishbone chart detailed the barriers to obtaining code status, and a priority pay-off matrix identified opportunities for improvement, including standardizing the process of the code status discussion and emphasizing the importance of the discussion early in the course of treatment. Physicians were educated on the importance of code status discussions and agreed that documentation should occur by the 3rd visit. Patients enrolled on the SO Pathway were tracked for the first three visits after initial referral to the pathway. We developed a script to assist physicians with code status discussions, which was placed on the encounter form at these visits. To measure the number of discussions, patient charts were reviewed on a weekly basis for documentation of code status. Results: Pre-intervention, during a 1 year period, only 14% (n=42) of patients enrolled on the SO pathway had a code status documented by the 3rd visit. After a 6 week implementation period, 70% (n=10) of patients enrolled on the SO Pathway had a code status documented in the chart by the 3rd visit. Conclusions: Substantial improvement in code status documentation was seen post-implementation of our intervention. We conclude that a script/reminder is a useful tool to prompt physicians to have a meaningful code status discussion in a non-urgent setting. This project has made the often difficult process of obtaining code status a more standardized process, and a more integral part of the culture at the Cancer Center.
Comprehensive genomic profiling of urothelial carcinoma of the kidney and ureter: Comparison with urothelial carcinoma of the bladder and impact on potential for targeted therapy selection.
Authors: Sumanta K. Pal, Julia Andrea Elvin, Siraj Mahamed Ali, Jean H. Hoffman-Censits, Jo-Anne Vergilio, James Suh, Badar Mian, Hugh A.G. Fisher, Tipu Nazeer, Vincent A. Miller, Philip J. Stephens, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2016)

371 Background: Urothelial carcinoma of the upper tract (UTUC) has distinct clinical and pathologic features from UC of the bladder (UCB). We compared the comprehensive genomic profile (CGP) of UTUC with UCB. Methods: DNA was extracted from 40 microns of FFPE sections from 195 consecutive cases of relapsed/metastatic UTUC and 295 cases of UCB. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 627X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), insertions/deletions (INDELs), copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the UTUC patients was 65.7 years (range, 35-86); 74 (38%) were female and 121 (62%) were male. There were 174 (89%) kidney and 21 (11%) ureteral UTUCs assessed. In total, 51 (26%) and 138 (71%) were stage III and IV, respectively, at the time of CGP. Samples for sequencing were obtained from primary tumor in 157 (81%) cases and from metastatic sites in 38 (19%) cases. There were 1,243 total GA (6.4 GA/sample) involving 203 individual genes and 384 CRGA (1.97 CRGA/sample) involving 51 genes. The most frequent GA were non-CRGA mutations in TP53 (46%), CDKN2A (43%) and CDKN2B (36%). The most frequent CRGA were in FGFR3 (28%), PIK3CA (15%) and CCND1 (12%). In comparison with UCB, statistically equivalent CRGA in FGFR3 (28% vs 21%), PIK3CA (15% vs 20%) and total ERBB2 (11% vs 16%) were identified. Of the 14 UTUC with ERBB2 non-amplification alterations, 6 (43%) featured a micropapillary growth pattern virtually identical to the frequency in UCB (40%). Conclusions: CGP of UTUC uncovers a wide variety of CRGA that can respond to targeted therapy including frequent CRGA in FGFR3, PIK3CA and ERBB2. CRGA in UTUC are generally similar to those found in UCB. Further study of targeted therapy for genomically characterized cases in a clinical trial setting for UTUC appears warranted.
Adjuvant therapy for gallbladder cancer: An institutional perspective.
Authors: M. L. Wang
Journal: Journal of Clinical Oncology (2011)

353 Background: Gallbladder carcinoma is a rare malignancy of the gastrointestinal tract. While radical surgery remains the only potentially curative treatment modality, relapse rates are high. Due to the paucity of data on the effectiveness of adjuvant therapy, only patients with high risk factors are referred for adjuvant therapy at our institution. We evaluate the effect of adjuvant chemoradiotherapy on the outcome of this group of patients. Methods: Records of patients who underwent adjuvant radiotherapy at our institution from January 1, 2001, to December 31, 2009, were reviewed. All patients had stage II disease. Patients received adjuvant radiotherapy (dosage 4,500 to 5,040 cGy in 25 to 28 fractions) with concomitant capecitabine or 5-fluorouracil chemotherapy. The effect of adjuvant therapy on disease-free survival (DFS) and overall survival (OS) was evaluated. Results: A total of 11 patients were included in the analysis, of which nine (82%) were females. Patients had stage IIA (27%) or IIB (73%) disease. Surgical margins were clear in 3 (27%), close (&lt;1 mm) in 3 (27%) and positive in 5 patients (45%), including 1 with R2 resection. Ten patients underwent chemoradiotherapy with the exception of one, who received chemotherapy followed by consolidation radiotherapy. With a median follow-up of 46.2 months for surviving patients at the point of analysis, 4 patients were still alive. Eight patients had developed disease recurrence, with the first site being locoregional in 1 (12%), distant in 4 (50%) and both in 3 patients (38%). All relapse occurred within 20 months of surgery, with 88% within 12 months. The median time to relapse was 7.4 months. The estimated disease- free survival rate at 1 and 3 years was 36% and 27%, respectively. The estimated overall survival of the group at 1 and 3 years was 36% and 27%, respectively. Conclusions: Data from numerous studies have shown varied results with regard to the use of adjuvant therapy in gallbladder carcinoma. There are studies where adjuvant therapy have produced 5-year OS rates of up to 70% in patients with negative surgical margins. From our results, patients with high-risk disease may benefit from aggressive adjuvant therapy. A combination of chemoradiotherapy followed by further chemotherapy may be useful. No significant financial relationships to disclose.