tbuckley/cabot-search huggingface dataset:
Trends in prescribing preferences (PPrefs) of U.S.-based oncologists for patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) following docetaxel (DO).
Authors: Charles J. Ryan, Won Kim, Arden Buettner, Susan Lynne Britton, Maria L. Lankford, Doug B. Neely, Mark R. Green
Journal: Journal of Clinical Oncology (2015)

243 Background: PPrefs of 467 US-based medical oncologists (MOs) in post-DO mCRPC pts were studied prospectively. A validated, proprietary, live, case-based market research tool was utilized with a core case scenario and 4 distinct treatment (Rx) outcomes following chemotherapy (CTx). Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case: 59 y/o status post (s/p) radical prostatectomy with PSA failure after 15 months (mo), s/p salvage pelvic radiation (RT) → presents with rise in PSA and 3.5cm pelvic lymph node 16mo following RT→ progresses through multiple Rx over the next 42mo, including combined androgen blockade, anti-androgen withdrawal, sipuleucel-T and abiraterone (ABI). Now starting DO CTx due to increasing bone metastases and bone pain (BP). PPrefs for 4 variant scenarios of DO CTx were probed: (1) DO 75 mg/m 2 Q3wk x 6 cycles (cy) →Resolution of BP/PSA response → DO held due to cumulative myelosuppression/fatigue. Pt more active off CTx, ECOG PS 1. 3mo later →asymptomatic 30% rise in PSA. (2) DO x 4 cy → decrease in PSA, BP, node size. Prior to cy 6, has asymptomatic PSA progression. (3) DO x 4 cy→ decrease in PSA, BP, node size. Prior to cy 6, has both PSA and BP progression. (4) DO x 2 cy → progression with increased BP, PSA, and pelvic nodal disease. Results: See Table. Conclusions: PPrefs after DO CTx were outcome-dependent. In the absence of BP, ENZ is the most common PPref, even in this ABI-refractory pt. PPref for R223 over 2nd line CTx in the acquired symptomatic resistance setting is notable. PPref for 2nd line CTx increases with rapid, symptomatic disease progression. [Table: see text]
Recovery of the Normal B-Cell Compartment in Children Treated for B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Prisca Theunissen, Ester Mejstrikova, Tomasz Szczepanski, Lukasz Sedek, Alita van der Sluijs, Alberto Orfao, Jacques JM van Dongen, Vincent H.J. van der Velden
Journal: Blood (2014)
The proteasome inhibitor PS-341 (bortezomib) in platinum (plat)-treated extensive-stage small cell lung cancer (E-SCLC): A SWOG (0327) phase II trial
Authors: J. Johl, K. Chansky, P. N. Lara, A. M. Davies, R. Bold, D. R. Gandara
Journal: Journal of Clinical Oncology (2005)

7047 Background: The proteasome inhibitor PS-341 inhibits growth of SCLC cell lines through decreased bcl-2 via NFk-B. We conducted a phase II trial of PS-341 in plat-treated E-SCLC patients (pts) to determine the tumor response rate, toxicity and overall survival. Methods: : Pts with histologically-confirmed SCLC, measurable disease, Zubrod performance status 0–1 and prior plat-based therapy were eligible. Pts were stratified by platinum-sensitivity status: sensitive (progression >90 days after plat) or refractory (progression during or ≤90 days after plat). Pts were treated with PS-341 1.3mg/m2 IV on days 1, 4, 8 and 11 q 21 days. Results: Of 60 pts registered, 57 were evaluable for response. Seven pts discontinued treatment due to adverse events or side effects from therapy. Nine pts (16%) had grade (gr) 3/4 platelets. Eight (14%) pts had gr 3/4 fatigue. There was no gr 3/4 neuropathy. Conclusions: Although PS-341 induced a response in a plat-refractory pt, the efficacy is insufficient as a single agent in this heavily-pretreated population. Clinical testing of PS-341 in combination with an apoptotic-trigger such as cytotoxic chemotherapy, as supported by preclinical models, is warranted. A trial of topotecan plus PS-341 has been initiated to test this concept. (This study was supported by SWOG grant CA 30102) No significant financial relationships to disclose.
Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial
Authors: Srdan Verstovsek, Ruben A. Mesa, Jason Gotlib, Vikas Gupta, John F. DiPersio, John V. Catalano, Michael W. N. Deininger, Carole B. Miller, Richard T. Silver, Moshe Talpaz, Elliott F. Winton, Jimmie H. Harvey, Murat O. Arcasoy, Elizabeth O. Hexner, Roger M. Lyons, Ronald Paquette, Azra Raza, Mark Jones, Deanna Kornacki, Kang Sun, Hagop Kantarjian
Journal: Journal of Hematology & Oncology (2017)

The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib—the first myelofibrosis-approved therapy—reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. Patients were randomized (September 2009–April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50–0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. ClinicalTrials.gov, NCT00952289
Carbonic anhydrase IX (CA IX) and pathologic features as predictors of outcome in patients (pts) with metastatic renal cell carcinoma (mRCC) receiving VEGF-targeted therapy
Authors: T. K. Choueiri, M. M. Regan, A. J. Brick, J. M. Clement, C. Kwabi, K. Shah, A. Amato, D. F. McDermott, M. B. Atkins, S. Signoretti
Journal: Journal of Clinical Oncology (2008)

16042 Background: Expression of CAIX (a hypoxia induced protein and potential surrogate for VHL inactivation) and previously defined pathologic features (presence of alveolar features/absence of papillary/granular features) have been reported as independent predictors of outcome in pts with mRCC treated with immunotherapy. We attempted to validate the prognostic and predictive utility of CAIX expression and previously defined pathologic features in pts treated with VEGF-targeted therapy. Methods: We identified 112 pts with mRCC treated with VEGF-targeted therapy between 2001–2007. Paraffin-embedded tumor tissue was obtained on 86 pts: sunitinib (n=30), sorafenib (n=42), bevacizumab (n=12) or PTK787 (n=2) and immunostained with the M75 antibody against CAIX. CAIX expression levels and histologic findings were correlated with response rate (RR), tumor shrinkage (TS), treatment duration (TD) and overall survival (OS). Results: 64% of pts were male. 93% had prior nephrectomy. 71% had ≥2 metastatic sites and 44% had prior systemic, non-antiangiogenic therapies. 34% had poor-risk, 36% intermediate (int)-risk and 28% had good-risk Upton pathologic features. 66% of pts had high CAIX expression (> 85% tumor cells +). Median follow-up was 21 months. High CAIX expression correlated with higher RR, TS, TD and OS, although it did not reach statistical significance (TABLE). Similarly, pts with good Upton pathologic features had higher RR (p=0.24), TS (p=0.27) and TD (p=0.26). OS was significantly better in good-risk pts (p=0.02) compared to pts with int/poor-risk features. Conclusions: Although high CAIX expression is associated with a better outcome in pts with mRCC treated with VEGF-targeted agents, these trends did not meet statistical significance. Pts with good pathologic features had a higher OS than pts with poor/int features. Further analysis of these features will require additional samples and randomized studies. CAIX low (n=29) CAIX high (n=57) P-Value Response Rate (PR) 23% 35% p=0.75 (Fishers exact) Median TS -10% - 16% p=0.58 (Wilcoxon) Median TD 5.1 months 9.1 months p=0.12 (logrank) Median OS 20.5 months 33.2 months p=0.44 (logrank) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Antigenics, Aveo, Bayer/Onyx, Genentech, Novartis, Wyeth Pfizer Bayer/Onyx, Genentech, Novartis
Psychosocial (PS) resilience augmenting strategies (RAS) in patients (PT) with cancer (CA) post-traumatic growth (PTG): A pilot study for personalized survivorship improvement.
Authors: C. A. Presant, S. Hartono, G. H. Upadhyaya
Journal: Journal of Clinical Oncology (2011)

e19718 Background: PS distress is common in CA PTs. Resilience after CA-associated PS trauma requires effective support and coping strategies. In order to increase the information about which strategies are most useful to PTs in achieving PTG, we evaluated PT experiences. Methods: Unstructured interviews were conducted in 10 PTs about their CA experience and RAS (teaching cohort- TC). Based on RAS most often recommended, we then conducted semi-structured interviews and administered surveys to PTs (validation cohort- VC) to determine the frequency and importance of each RAS. We evaluated the relationship between age, gender, and self-perception to the type of strategy used. Results: TC identified four major RAS: family (F), religion (R), self-will (SW) and support group (SG). 34 PTs in the VC were mean age 65, and 59% female. Diagnoses were breast (15), prostate (5), lung (4), colon (3) and miscellaneous CA(7). Time from diagnosis was <1 yr in 5, 1-5 yr in 16, and >5 yr in 9. 79% rated themselves as generally happy, 21% as intermittently happy and worried, and none as worried. PTs rated the following RAS as highly important: F 79%, SW 74%, R 47% and SG 21%. PTs ranked as most important F 53% followed by SW 35%, R 21%, but SG 0%. Mean rankings (scale 1 most important to 5 least important) were F 1.53, SW 2.06, R 2.74, SG 3.73, and other 4.25 (friends, coworkers, blogs, medical staff). F, SW and R were more important than SG (p<0.0001). When asked if CA had changed their attitudes on life, 18% said they had a more positive attitude, 9% said they had a more negative attitude, while 76% said it was unchanged. Analyses indicated no correlation between RAS and gender, age, type of CA, or change in life attitude. Conclusions: RAS identified in order of importance are F, SW, R and SG. Since demographic data does not predict which strategy will be most important to increasing the resilience of the individual PT, PTs should be counseled about all the most commonly used RAS, and monitored to identify their use in managing distress and fostering PTG. Oncologists should not rely solely on SG to increase resilience. These results suggest that promotion of RAS can be more focused and personalized.
Validation of imaging biomarker in a multicentric study to predict PFS in mRCC treated with TKI.
Authors: Nathalie Lassau, Serge Koscielny, Sophie Taieb, Joelle Lacroix, Richard Aziza, Florence Joly, Christine Chevreau, Sylvie Negrier, Gwenaelle Gravis, Bernard J. Escudier
Journal: Journal of Clinical Oncology (2014)

526 Background: Tyrosine kinase inhibitors including sunitinib are the most effective treatments of metastatic renal cell carcinoma (mRCC). A multi-centric study of 539 patients (different tumors treated anti-angiogenic treatments) evaluating dynamic contrast-enhanced ultrasound (DCE-US), showed that a decrease of AUC (Area under the curve) correlated to the blood volume at one month is predictive of response. Our first objective was to validate the correlation between this parameter and the PFS in a sub-group of mRCC treated with Sunitinib The second objective was to study the variability of AUC. Methods: Each Patient had CT-scan every 2 months in order to evaluate the Response assessment using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).DCE-US were performed at baseline and at D30. At each examination, we quantified 7 DCE-US parameters after bolus injection of contrast agent and mathematical modelization of raw linear data recorded during 3 minutes. We also estimated the variation between baseline and D30. The main endpoint was progression free survival assessed according to RECIST. We first selected the best parameters. We studied the trend between the parameter value and freedom from progression. After, the best cut-points were searched through a grid search. The best single cut-point was that with the lowest P-value for progression free survival. We performed this analysis in the sub-group of patients with mRCC treated with sunitinib. Morever, we studied the variability of AUC in 30 other patients treated with TKI . We performed in this group 2 DCE-US the same day before and after lunch. Results: A total of 81 mRCC patients treated with sunitinib were selected. All had DCE-US at baseline and one month. The median of follow-up was 18 months. For DCE-US, the decrease of 90 % of AUC at D 30 was correlated to the PFS (p =0.03). The difference of PFS between the groups defined by this cut-point was 4 months (bad responders) and 14 months (good responders). The results of variability are on-going. Conclusions: The decrease of more than 90% of AUC with DCE-US at one month is a potential predictive biomarker of response in mRCC patients treated with sunitinib. The results of variability of this parameter will be also presented. Clinical trial information: no. 912346.
<i>BTK</i><sup>C481S</sup>-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia
Authors: Jennifer A. Woyach, Amy S. Ruppert, Daphne Guinn, Amy Lehman, James S. Blachly, Arletta Lozanski, Nyla A. Heerema, Weiqiang Zhao, Joshua Coleman, Daniel Jones, Lynne Abruzzo, Amber Gordon, Rose Mantel, Lisa L. Smith, Samantha McWhorter, Melanie Davis, Tzyy-Jye Doong, Fan Ny, Margaret Lucas, Weihong Chase, Jeffrey A. Jones, Joseph M. Flynn, Kami Maddocks, Kerry Rogers, Samantha Jaglowski, Leslie A. Andritsos, Farrukh T. Awan, Kristie A. Blum, Michael R. Grever, Gerard Lozanski, Amy J. Johnson, John C. Byrd
Journal: Journal of Clinical Oncology (2017)

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.
Risk of breast cancer (BC) after BRCA-mutation associated ovarian cancer (BRCA-OC): Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
Authors: K. L. Jhaveri, S. Patil, M. Khasraw, J. Bhatia, Z. K. Stadler, N. D. Kauff, C. Hudis, K. Offit, M. E. Robson
Journal: Journal of Clinical Oncology (2011)

1518 Background: Women (W) with BRCA mutation-associated BC are at significant risk for metachronous OC, ranging from 0.8-1.5% per year. The risk of BC after a diagnosis (Dx) of BRCA-OC is unknown. Methods: MSKCC Clinical Genetics Database was searched to identify patients (pts) with BRCA-OC participating in genetic testing and follow-up studies from 1995 to 2009. Primary objective was to determine the incidence and time to Dx of BC in pts with BRCA-OC. W were censored at last follow-up, date of risk-reducing mastectomy (RRM) or death (any cause) for determination of BC-free survival (BCFS). Overall survival (OS) was determined using Kaplan-Meier with pts being censored at the time of last follow-up. Results: 85 W (57 with BRCA 1 and 28 with BRCA 2 mutation) had BRCA-OC as their first malignancy. 76/85 BRCA-OC pts had OC Dx prior to BRCA testing (median time from OC Dx to testing was 1.4 years (Y), (range 0.29 - 27). Median follow-up from OC Dx for those not developing BC was 6Y (range 0.25 - 28). There were a total of 24 deaths; 21/24 of these were cancer-related (20 OC, 1 BC). 5 and 10 year OS were 86% (95% CI 0.75 - 0.92) and 65% (95% CI 0.51 - 0.76). There were 7 BC diagnoses in W with BRCA-OC (2 synchronous, 5 metachronous). 5 and 10 year BCFS was 95% (95% CI 0.88 - 0.98) and 92% (95% CI 0.81 - 0.97). There were 38 W tested either before developing BRCA-OC or within 12 months after Dx of BRCA-OC. Median follow-up of surviving W from OC Dx was 5 Y (range 0.25 - 13.5). In these W, OS after OC Dx was 69% (95% CI 0.47 - 0.83) at 5Y and 60% (95% CI 0.47-0.83) at 10Y. 5 and 10 year BCFS in this
Combination study of navitoclax with gemcitabine (G) in patients (pts) with solid tumors.
Authors: J. M. Cleary, C. M. S. Rocha Lima, H. Hurwitz, A. J. Montero, G. Shapiro, C. Franklin, J. Yang, A. M. Graham, T. Busman, M. Mabry, K. D. Holen, A. Krivoshik, R. Humerickhouse, H. Uronis
Journal: Journal of Clinical Oncology (2011)

3067 Background: Navitoclax (ABT-263), a novel BH3 mimetic, binds with high affinity and inhibits multiple antiapoptotic Bcl-2 proteins. Preclinical studies show synergy between navitoclax and G in solid tumors. This is the first study of navitoclax with G in solid tumor pts. Dose escalation, pharmacokinetics (PK) interaction and the safety profile of navitoclax plus G, are reported. Methods: Pts with advanced solid tumors, adequate organ function, ECOG status ≤1, for whom G was an appropriate therapy, were eligible. Oral navitoclax was given QD, at escalating doses ranging from 150-425 mg on days (d) 1-3 and 8-10;G was given at 1,000 mg/m2 IV over 30 min on d 1 and 8 following navitoclax; cycle (cy) length was 21d. PK samples were collected for navitoclax and G alone, and in combination. Tumor response was obtained at baseline and the end of every 6 weeks (wks). Adverse events (AE) were graded by NCI CTCAE V3; efficacy was evaluated by RECIST. Results: 35 pts enrolled; 30 discontinued treatment; 11 withdrew consent and 19 had disease progression. 5 remain on study at 3-18+ wks. No dose reductions occurred due to AEs through the 325 mg cohort in the first 2 Cy. DLTs of elevated liver enzymes were seen in 2/5 pts in the 425 mg cohort. Most common grade 1/2 AEs were nausea (43%), anemia (40%), fatigue (37%), & thrombocytopenia (TCP, 30%). Grade 3/4 AEs included TCP (20%) and neutropenia (17%). 12 pts had a best response of stable disease (SD); 4 pts had SD up to 5 months (mths) and 1 pt for 10 mths. 5/12 pts received prior G treatment either alone or with other chemotherapies; duration of SD in these pts ranged from 1-10 mths. Based on limited PK data, there was no apparent PK interaction between navitoclax and G. Conclusions: The maximum tolerated dose, defined as navitoclax 325 mg and G 1,000 mg/m2, was tolerable with no apparent PK interactions. Preliminary antitumor activity with SD in 12/35 solid tumor pts was observed. A weekly schedule of 325 mg navitoclax and 1,000 mg/m2 of G on d 1, 8 and 15 (3/4 wks) is being explored. Navitoclax (150-325 mg, N=14) Cmax/dose (ng/mL/mg)* AUC24/dose (ng*hr/mL/mg)* Navitoclax alone 8.3 ± 6.0 107 ± 98 Navitoclax with G 7.6 ± 3.3 112 ± 55 G (1,000 mg/m2, N=14) Cmax ( µ g/mL)* AUCinf ( µ g*hr/mL)* G alone 26.3 ± 18.4 12.0 ± 7.1 G with navitoclax 28.3 ± 20.4 12.2 ± 7.8 * Mean ± SD
Body mass index, PSA, and prostate cancer risk
Authors: J. Shannon, A. J. Palma, L. Peters, M. Garzotto
Journal: Journal of Clinical Oncology (2008)

5159 Objectives: Body size, assessed by body mass index (BMI), is consistently associated with numerous cancers. However, the relationship between BMI and risk of prostate cancer is not clear. Recent studies have noted an inverse association between BMI and prostate specific antigen (PSA), as well as BMI and prostate cancer incidence, though a direct association between BMI and prostate cancer mortality. These analyses investigate the association between BMI and PSA and prostate cancer incidence, in a population of older veterans enrolled in a case-control study of diet and prostate cancer risk. Methods: Cases and biopsy negative controls were recruited upon referral for prostate biopsy and frequency age-matched; PSA normal controls were identified from VA primary care clinic. BMI was determined from recorded height and weight. Detailed data was obtained regarding risk factors for prostate cancer and dietary intake. BMI was treated as a categorical variable (<25, 25 <30, 30<35, >35). Results: Subjects included 142 incident prostate cancer cases, 249 biopsy negative controls and 232 PSA normal clinic controls. In general linear models, adjusted for age, diabetes, use of non-steroidal anti- inflammatories, family history of prostate cancer, total caloric intake, fat intake, cholesterol intake and race, men with higher BMI had significantly lower PSA values (p=0.008 all subjects, p=0.001 biopsy subjects). Among men having undergone biopsy, BMI was associated with significantly lower PSA density (PSA/ prostate volume; p=0.0008). In logistic regression models adjusted for age, family history of prostate cancer and race, higher BMI was significantly inversely associated with risk of any prostate cancer (OR= for highest vs. lowest BMI category =0.40 (95% CI =0.19–0.87)), and specifically risk of high grade (Gleason ≥7) prostate cancer (OR= for highest vs. lowest BMI category =0.20 (95% CI =0.06–0.64)). Conclusions: Our results suggest that body size, as determined by BMI is inversely associated with PSA and risk of prostate cancer. However, BMI is an imprecise measure of visceral adiposity, perhaps the most important type of adiposity in relation to cancer risk. Our results support those of others and indicate that BMI may reduce risk of prostate cancer among this group of older veterans. No significant financial relationships to disclose.