tbuckley/cabot-search huggingface dataset:
Association of single nucleotide polymorphism in four genes and response to androgen deprivation therapy (ADT) in men with advanced hormone sensitive prostate cancer (aHSPC).
Authors: David Gill, Anitha Alex, James M. Farnham, Tyler Howard Buckley, Shiven B. Patel, Archana M. Agarwal, Craig Teerlink, Frederick S. Albright, Robert A Stephenson, Lisa A Cannon-Albright, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2016)

224 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in aHSPC, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 706 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 59 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to onset of castration resistance prostate cancer (CRPC) in 171 Caucasian men with aHSPC, i.e. those progressing after definitive treatment (biochemical recurrence alone, or onset of metastatic disease), undergoing treatment with ADT. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Five SNPs in four genes showed evidence of association with time to CRPC on ADT while controlling for Gleason Score (p &lt; .0002) (Table). Each of these genes had other nearby SNPs with at least nominal (p &lt; 0.05) significance and so, don’t appear to be false positives. Conclusions: Although none of these SNPs exceeded a strict Bonferoni multiple testing correction (p &lt; 0.00007), that threshold is almost certainly conservative as the SNPs and tests are correlated. These results are being validated in a larger cohort and may serve as predictive markers to ADT in this setting. [Table: see text]
3-year safety follow-up of radium-223 dichloride (Ra-223) in patients (Pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (Mets) from ALSYMPCA.
Authors: Chris Parker, Nicholas J. Vogelzang, A. Oliver Sartor, Robert E. Coleman, Fang Fang, Irene Skjorestad, Sten Nilsson
Journal: Journal of Clinical Oncology (2015)

195 Background: In ALSYMPCA, the first-in-class α-emitter Ra-223 had a highly favorable safety profile and was well tolerated. Safety monitoring of Ra-223 is essential for a complete safety profile. Here are final safety data including long-term follow-up safety 3 years after last pt’s first injection (inj). Methods: Pts received 6 inj and entered designated follow-up from 4 wks after their last inj to 3 years after first inj. Pts were to be evaluated during tx period and 9 follow-up visits. All adverse events (AEs) were collected until 12 wks after last inj; thereafter, only AEs deemed tx-related were collected. Additional long-term safety data were assessed by specific diseases including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and new primary cancer in bone or other organs. Results: Safety population (pts receiving ≥ 1 inj) included 901 pts (Ra-223, n = 600; placebo [pbo], n = 301); 572 pts (Ra-223, n = 405; pbo, n = 167) entered follow-up. 60 pts (Ra-223, n = 49; pbo, n = 11) completed all follow-up visits. Overall, 564 (94%) Ra-223 and 292 (97%) pbo pts had ≥ 1 tx-emergent AE (Table). During long-term follow-up, there were no reports of AML, MDS, or new primary bone cancer. New primary cancers in other organs were reported: 2 Ra-223 (1 bladder, 1 lymph node mets), 3 pbo (2 skin, 1 adenocarcinoma rectum and sigmoideum), and 2 pbo cross-over pts (1 skin, 1 meningioma). Aplastic anemia was reported in 1 Ra-223 pt. Conclusions: Ra-223 remained safe and well tolerated 3 years after the last pt’s first inj. No major safety issues were identified during the ALSYMPCA 3-year long-term follow-up. Clinical trial information: NCT00699751. [Table: see text]
Phase I clinical trial of an allosteric AKT inhibitor, MK-2206, using a once weekly (QW) dose regimen in patients with advanced solid tumors.
Authors: A. Biondo, T. A. Yap, L. Yan, A. Patnaik, I. Fearen, R. D. Baird, K. P. Papadopoulos, L. M. Delgado, A. Taylor, L. Lupinacci, S. C. Blackman, S. Decordova, M. Tall, S. Heaton, M. D. Garrett, D. Sullivan, J. S. De Bono, A. W. Tolcher
Journal: Journal of Clinical Oncology (2011)

3037^ Background: AKT is a key regulator of cellular proliferation, apoptosis and growth. A range of cancers have genetic aberrations that involve the PI3K/AKT pathway, leading to abnormal AKT hyperactivation and tumor progression. MK-2206 is a novel potent investigational AKT inhibitor, which was initially administered orally in a QOD schedule, where the maximum tolerated dose (MTD) was established at 60mg, based on safety and biomarker studies (Yap et al, ASCO 2010). In view of a long half-life (t1/2) (60-80h), a QW schedule was subsequently pursued to explore the potential of less frequent dosing to circumvent feedback activation of alternative signaling pathways in response to sustained and uninterrupted AKT inhibition. Methods: Eligible patients with advanced solid tumors were recruited in a phase I, multi-center, dose escalation study. Patients had regular safety assessments and blood sampling for pharmacokinetic (PK) studies. Pharmacodynamic (PD) and/or predictive biomarker analyses were undertaken on paired tumor samples (mandatory biopsies at MTD), platelet-rich plasma, hair follicles and circulating nucleic acids in plasma. Results: 30 patients (17 M; median age 60 yr; ECOG PS 0/1: 11/19) received MK-2206 at 90, 135, 200, 250 and 300 mg QW. Grade 3 rash was the dose limiting toxicity (DLT) at 300mg (n=3) and 250mg (n=2). Expansion of the 200mg QW resulted in grade 3 rash DLT in 4 of 15 patients. An intermediate dose of 150mg QW is being investigated. Common reversible MK-2206-related toxicities included rash (32.3%), fatigue (9.7%) and nausea, vomiting, diarrhea, pruritus, stomatitis, dry skin and dysguesia, each occurring at 6.5%. No MK-2206-related grade 5 toxicities were observed. PK analysis showed a median Tmax of 6 hr and a mean apparent terminal t1/2 of 78.6 hr. PD analysis of platelet-rich plasma at 200mg QW (n=9) showed suppression of pAKT up to 96 hours post-dose (p<0.001). Biomarker analyses of tumor samples are ongoing. Conclusions: MK-2206 has shown an acceptable toxicology profile, significant and sustained AKT blockade and a PK-PD profile allowing for QW dosing.
Blood neuroendocrine tumor gene cluster analysis to predict somatostatin analog response.
Authors: Mark S. Kidd, Ignat Drozdov, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2016)

276 Background: Defining therapeutic efficacy in NETs is problematic. We have identified circulating NET transcripts that accurately reflect tumor tissue levels and are sensitive measures of tumor biology. We also identified gene clusters that define NET activity e.g., proliferation. We hypothesized that targeted treatment would alter cluster expression and these could predict treatment response. We evaluated this using somatostatin analogs since they effectively ameliorate symptoms and inhibit tumor growth. Methods: We prospectively evaluated GEP-NETs (n=35) [M:F 12:23; median age: 58 years, small intestine: n=29, pancreas n=3, rectum n=3]. Circulating NET gene expression was assessed (qRT-PCR, normalized gene expression) and imaging (CT/MRI: disease status–RECIST criteria) undertaken. Treatments included: sandostatin (n=32), octreotide (n=2) and pasireotide (n=1); median dose 20mg (range 20-60mg). Gene clusters e.g., proliferation (Ki67, NAP1L1, NOL3, TECPR2) were evaluated as predictive “neoplasia hallmarks” using 2-tailed non-parametric and ROC analyses. Cluster expression is expressed as mean±SEM. Results: Imagery identified25 (71%) patients with stable disease; 10 were progressing. Expression of genes associated with secretory regulation, the “secretome” was significantly down-regulated in the disease-stabilized versus progressive group (2±0.5 vs. 30±25, p&lt;0.001). Individuals with disease progression on SSA therapy exhibited both a significantly elevated proliferation-associated gene cluster (65±15 vs. 16±1, p&lt;0.001) and an epigenetic remodeling cluster (44±6 vs. 32±10, p&lt;0.005). ROC analysis confirmed these accurately identified therapy response (AUC: 0.86-0.97, p&lt;0.0001). Other gene clusters e.g., metabolism (10±1.2 vs. 15.4±3) and apoptosis (1.3±0.2 vs. 1.1±0.8) were not different. Conclusions: SSA therapy alters circulating transcript measurements. Disease stabilization is associated with downregulation of genes linked to tumor secretion while progression is associated with elevation in gene clusters that define tumor proliferation and epigenetic reprogramming. Blood transcript measurements provide an accurate tool to predict the efficacy of SSA therapy.
RESPONSE: A randomized, open-label, phase III study of ruxolitinib in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU).
Authors: Srdan Verstovsek, Jean-Jacques Kiladjian, Victor Sandor, Jacek Lukawy, Jingjin Li, Shui He, William M. Garrett, Kamel Malek, Ulrich Pirron, Bijoyesh Mookerjee, Alessandro M. Vannucchi
Journal: Journal of Clinical Oncology (2012)

TPS6643^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, significant morbidity, shortened life span and possible evolution to myelofibrosis and acute myeloid leukemia. Splenomegaly, debilitating constitutional symptoms, and frequent phlebotomy requirements are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers, and other side effects. Control of hematocrit is not always achieved with HU, and many patients are either intolerant of or become resistant to HU. JAK2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F or JAK2 exon 12 mutations. In a phase 2 study in HU-resistant or -intolerant PV patients, ruxolitinib, a potent and selective inhibitor of JAK1/JAK2, was well tolerated and achieved rapid and durable clinical responses, including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) and platelet (PLT) counts and disease-related symptoms. Methods: RESPONSE is a randomized (1:1), open-label, global phase 3 study (NCT01243944) designed to compare the safety and efficacy of ruxolitinib with best available therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (modified European Leukemia Net criteria) and require phlebotomy because of inadequate hematocrit control. Inclusion criteria have been amended to include patients who exhibit palpable splenomegaly with an MRI-confirmed volume of ≥ 450 cm 3 (ie, approximately 2.5 x median normal volume; instead of ≥ 5 cm by palpation) and PLT &gt; 100 x10 9 /L; the requirement for either elevated WBC (&gt; 15 x10 9 /L) or PLT count (&gt; 600 x10 9 /L) was removed. The primary efficacy endpoint is the achievement of both phlebotomy independence and a ≥ 35% reduction in spleen volume after 32 weeks of treatment. Patients will be treated for 80 weeks to assess safety and durability of response. Patients randomized to BAT may be eligible to cross over to receive ruxolitinib after week 32. Enrollment is planned for 145 investigational sites (134 currently open), with a target of 200 patients.
Association of germ-line genetic markers in <i>IL8, HIF1A, VEGFA, and VEGFR2</i> with treatment response to pazopanib in renal cell carcinoma.
Authors: H. A. Ball, C. Xu, C. N. Sternberg, N. Bing, D. Rajagopalan, C. F. Spraggs, V. E. Mooser, R. G. Amado, L. R. Cardon, L. Pandite
Journal: Journal of Clinical Oncology (2010)

4520 Background: Pazopanib (Votrient, P), an oral angiogenesis inhibitor targeting VEGFR-1, -2, and -3, PDGFR-α and -β, and c-Kit, is approved in the US for the treatment of advanced renal cell carcinoma (RCC). No valid biomarker has been identified to predict the response to P treatment, or indeed other agents in this class. This study sought to identify genetic markers associated with efficacy and blood pressure response (a pharmacodynamic marker) to P in RCC. Methods: 40 polymorphisms in 20 candidate genes were evaluated in 370 P-treated RCC patients (pts) from three clinical trials. Association with progression-free survival (PFS), response rate (RR) and average mean arterial pressure (MAP) during P treatment was evaluated using Cox regression, Fisher's exact test, and generalized linear modeling, respectively. No adjustments for multiple comparisons were made. Polymorphisms that met nominal levels of significance (p<0.05) were reported which require confirmation. Results: The IL8 +2767A>T polymorphism was associated with PFS (p=0.03); pts with wild type AA (n=105) and heterozygote AT (n=176) genotypes had longer median PFS (49 and 41 weeks, respectively) than pts with the variant TT genotype (n=59, 28 weeks). The HIF1A +1790G>A (Ala588Thr) polymorphism was associated with RR (p=0.02); pts with the wild type GG genotype (n=323) had better RR (PR+CR, 43%) compared with the variant AG genotype (n=20, 30%). The VEGFR2 +1416T>A (His472Gln) polymorphism was associated with average MAP during P treatment (p=0.005); pts with the variant AA homozygote experienced higher MAP than wild type TT and heterozygote AT genotypes. The mean (SE) MAP change from baseline for the TT (n=208), AT (n=128) and AA (n=26) pts was 4.4 (0.5), 5.7 (0.6) and 9.8 (1.6) mmHg, respectively. Similar findings were observed for the -2578C>A, -1498C>T and - 634G>C polymorphisms in the VEGFA gene (p<0.05). Conclusions: Associations between treatment response to P with variants in the IL8, HIF1A, VEGFA, and VEGFR2 genes were observed in RCC pts. These associations are considered exploratory and require confirmation in an independent dataset. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
What is the health-related quality of life for women with metastatic breast cancer?
Authors: Deepa Lalla, Amye Tevaarwerk, Hans-Peter Goertz, Mary Lou Smith, Preeti S. Bajaj, Elda Railey, Carolina Reyes
Journal: Journal of Clinical Oncology (2016)

70 Background: Metastatic breast cancer (MBC) and its treatments can have a significant impact on patients’ health-related quality of life (HRQoL) and daily functioning. To better assess the impact of MBC on HRQoL, we conducted an online survey among women with MBC. Methods: We developed and administered a cross-sectional, web-based survey, and invited registered members of three advocacy groups currently living with MBC to participate. Respondents completed an informed consent and completed assessments on symptom burden using an overall QOL question (1 item), the MD Anderson Symptom Inventory Survey (MDASI), activities of daily living (ADLs, Rotterdam Scale), and impacts on work productivity. Results: We received 1285 complete responses to the survey. Over half the respondents were between 40-49yrs (37%) or 30-39 yrs (26%). The majority were white (87.7%), well-educated (70.7% had a bachelor’s degree or higher), and working at the time of the survey (55%), with private health insurance (63%). After diagnosis with MBC, most patients had received endocrine therapy (44.2% aromatase inhibitors, 27.3% fulvestrant). The most common chemotherapy agents received after diagnosis with MBC were capecitabine (30.1%) and docetaxel (26.9%). The overall mean HRQoL score was 74 (0-100, higher is better). Mean respondent-reported MDASI scores for symptom severity (SS) and symptom interference (SI) were 4.2 and 4.5 (0-10, higher is worse). Mean Rotterdam scale scores to assess ADLs were 23.7 (0-32, higher better). On average, working women with MBC missed 9.3 hours of work in the past 7 days due to their MBC. As symptom burden increased, respondents reported a lower ability to perform ADLs (p &lt; 0.0001) and lower overall HRQoL (p &lt; 0.0001). The ability to perform ADLs decreased with increase in the total number of agents received (p &lt; 0.0001) and time since diagnosis (p &lt; 0.0001). Conclusions: This survey provides valuable insights into health status, ability to perform ADLs, and lost productivity among patients with MBC. Future analyses will present results by tumor subtypes and drug treatments received.
Why so late? Presentation delay in locally advanced breast cancer (LABC)
Authors: D. M. Kerr-Cresswell, B. Fitzgerald, K. Fergus, J. Gould, M. Lenis, M. Clemons
Journal: Journal of Clinical Oncology (2005)

712 Background: While there have been marked improvements in the prognosis of women with early breast cancer, these gains have not been echoed to the same degree in patients with LABC. Accounting for 10 to 30% of all new primary breast cancers, 5-year survival for LABC remains poor at around 55%. Research suggests that many women with breast cancer have delayed presentation of symptomatic breast cancer, with up to 30% waiting at least 3 months before presenting to a health care provider. Delays may be associated with more advanced lesions & lower survival rates. The characteristics of these patients & reasons for their delaying behaviour are poorly understood. Methods: From October 2001 to September 2004, all new patients referred to our LABC clinic had data collected asking what date she discovered her breast cancer symptom, the type of symptom, her appraisal of that symptom, & the date of initial presentation. Sociodemographic data were also collected. Results: 69 patients were referred with LABC. 98% were female. 62% were Caucasian, 16% Asian, & 13% Black. Median age at presentation 42 years (range 27–83). 55% were married. Initial symptoms were: painless breast lump (59%), axillary mass (9%), breast erythema (9%), nipple inversion (4%), or other symptom (19%). Median time from symptom discovery to presentation to health care provider was 3 months (range 0–416 weeks). Factors that affected a timely diagnosis were: mistaken attribution of symptom as benign process, fear of cancer, belief that breast cancer was unlikely in the absence of a positive family history, belief that it is better “not to know”, decision to pursue complementary therapies first, concern about significant other’s ability to cope, & competing life demands. Conclusions: Late-stage presentation of breast cancer is associated with poor survival. 50% of newly diagnosed LABC patients in this study waited over three months before presenting to a health care provider with their breast cancer symptoms. To reduce morbidity & mortality for all patients with breast cancer, further research is necessary to develop a clear understanding of both the factors influencing when women seek care & whether there are opportunities for earlier intervention. No significant financial relationships to disclose.
Dose-intense preoperative chemotherapy with hypofractionated radiation for high-risk soft-tissue sarcoma (STS)
Authors: C. W. Ryan, A. Montag, S. Undevia, J. R. Hosenpud, B. Samuels, J. B. Hayden, A. Y. Hung
Journal: Journal of Clinical Oncology (2005)

9055 Background: Pathologic necrosis after preoperative (pre-op) chemoradiotherapy is an independent predictor of survival for STS (Eilber JCO 2001;19:3203–9). This is a pilot phase II study of a dose-intense regimen of epirubicin and ifosfamide with pre-op radiation for patients with high-risk STS of the extremities or body wall. The primary endpoint is rate of complete (≥95%) pathologic necrosis. Secondary endpoints include toxicty, disease-free and overall survival. Methods: Eligibility criteria: >5 cm localized STS, intermediate or high-grade, extremity or body wall site. Chemotherapy: epirubicin 30 mg/m2/day D1–4, ifosfamide 2.5 g/m2/day D1–4 with mesna and pegfilgrastim repeated every 21 days for 3 pre-op and 3 post-op cycles. Radiation: 28 Gy over 8 fractions (3.5 Gy/fx) during cycle 2 (epirubicin omitted during radiation) with a post-op boost of 12 Gy over 6 fractions for positive margins. Results: As of December 2004, 22 patients have been enrolled. 15 eligible patients have completed treatment through surgery and are included in this report. Median age: 52 (26–72); surgery: limb-sparing (13), amputation (1), body wall resection (1); margins: negative (14), positive (1); histology: sarcoma NOS (4), liposarcoma (3), leiomyosarcoma (3), MFH (2), PNST (1), synovial cell (1), myxoid chondrosarcoma (1); median size: 9.5 cm (6–35); grade: high (14), intermediate (1); tumor site: thigh (9), arm (2), buttock (2), popliteal fossa (1), body wall (1). Most common grade 3–4 toxicities were leukopenia (12 patients), thrombocytopenia (7), anemia (6), neutropenic fever (5), hypokalemia (3), hypophosphatemia (3), encephalopathy (3). 14/15 patients (93%) completed pre-op therapy, but only 6/10 (60%) completed all post-op chemotherapy due to toxicity or patient withdrawal. 3 patients (20%) have had wound complications requiring surgical intervention. Complete pathologic necrosis was achieved in 8 of 15 tumors (53%). Conclusions: This aggressive neoadjuvant chemoradiotherapy regimen is associated with significant but manageable toxicity. The wound complication rate has been modest. The high rate of complete pathologic response is encouraging. Accural continues to a total of 27 patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Association between weight gain and sarcopenic obesity in patients treated with androgen deprivation therapy.
Authors: Koji Mitsuzuka, Atsushi Kyan, Tomonori Sato, Kazuhiko Orikasa, Takashige Namima, Hiroshi Aoki, Minoru Miyazato, Yoichi Arai
Journal: Journal of Clinical Oncology (2016)

189 Background: Weight gain in response to androgen deprivation therapy (ADT) can be a marker for adverse effects of ADT. However, a concomitant decrease in lean mass in response to ADT may decrease the utility of weight gain in terms of sarcopenia. Therefore, the goal of the present study was to analyze the relationship among weight gain, obesity, and sarcopenia in patients undergoing ADT. Methods: Patients with prostate cancer who were hormone-naïve and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight and results from blood tests of lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat and the psoas muscle before and after 1-year of ADT. ADT was limited to a luteinizing hormone-releasing hormone agonist with or without bicalutamide. Results: CT was performed in 72 patients before and after 1 year of ADT. Median age was 74 years (49-83). Median prostate-specific antigen before ADT was 21.9 ng/ml (0.3-3316). Clinical stage was B (43.1%), C (26.4%), and D (29.2%). Mean increase in weight was 2.7% after 1 year of ADT. Mean increase in the area of subcutaneous and visceral fat was 31.3% and 20.7%, respectively. Mean change in the area of the psoas muscle was -8.4%. When patients were divided into two groups according to weight change during 1 year of ADT (Group A (n = 34): weight gain &lt; 3.0%, Group B (n = 38): weight gain ≥ 3.0%), an increase in subcutaneous and visceral fat was significantly more frequent in Group B, whereas the frequency of a decrease in psoas muscle area was not significantly different between the two groups (Group A: -9.5%, Group B: -7.5%, P = 0.11). Pearson correlation coefficients showed a moderate relationship between weight gain and fat accumulation (r = 0.44-0.52), but little relationship between weight gain and a decrease in psoas muscle area (r = 0.18). Conclusions: Fat accumulation tended to increase in patients who gained weight during ADT, whereas a decrease in psoas muscle area was not related to weight change. Sarcopenia could occur despite weight change during ADT. Clinical trial information: UMIN000018478.