tbuckley/cabot-search huggingface dataset:
Targeting reciprocal feedback inhibition in the clinic: ARN509 and PI3K pathway inhibition in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dana E. Rathkopf, Brett Stewart Carver, Yu Chen, Michael J. Morris, Daniel Costin Danila, Susan F. Slovin, Karen A. Autio, Mia DeNunzio, Charles L. Sawyers, Howard I. Scher
Journal: Journal of Clinical Oncology (2014)

TPS5106 Background: Next-generation androgen receptor (AR) targeted agents provide dramatic benefit to patients with mCRPC, but the durability of response can be limited by intrinsic and acquired resistance to these drugs. (Rathkopf D et al., Cancer J 2013) Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as ARN509 when combined with mTOR or PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) This hypothesis has been validated in breast cancer in the Phase III BOLERO-2 study in which the addition of everolimus to exemestane was able to overcome hormonal resistance in patients with metastatic breast cancer previously treated with tamoxifen and a non-steroidal aromatase inhibitor. (Baselga J et al., New Engl J Med, 2012) The primary hypothesis of this study is that the combination of ARN509 with everolimus in mCRPC will overcome resistance to prior hormonal therapy with abiraterone acetate (AA). We believe that this strategy will effect a major change in the natural history of the disease, with potential to overcome primary resistance and/or delay the development of secondary resistance to AR targeted therapies through inhibition of reciprocal feedback. Methods: The primary endpoint is to determine the safety, pharmacokinetics, and the recommended phase 2 dose (RP2D) of the combination. Approximately 12 patients with progressive mCRPC will be treated with 240 mg/day of ARN509 (RP2D) and 5-10 mg/day of everolimus depending on the safety seen during dose escalation. Dose expansion will include 40 patients with prior AA: 20 with intrinsic resistance (<3 months treatment) and 20 patients with acquired resistance (>6 months treatment). Mechanisms of sensitivity and resistance will be evaluated through exploratory correlative studies such as FDG and FDHT PET imaging, AR allelic status, circulating tumor cells, and tumor biopsies. Supported by Prostate Cancer Foundation Young Investigator Award, Janssen Pharmaceuticals, Novartis (Drug only), and The Experimental Therapeutics Center of MSKCC.
Expression of chemokine (C-C motif) ligand-2 (CCL2) is predictive of response to chemotherapy and overall survival in primary ovarian cancer
Authors: A. Nickles Fader, S. A. Vaziri, L. Rojas-Espaillat, P. W. Faber, P. Elson, C. V. Biscotti, C. M. Michener, P. G. Rose, J. L. Belinson, R. Ganapathi
Journal: Journal of Clinical Oncology (2007)

16013 Background: CCL2, a determinant of macrophage infiltration in tumors, is expressed in normal human ovarian surface epithelium but silenced or down-regulated in ovarian adenocarcinomas (Br J Cancer 92:2024, 2005). We determined the association between quantitative expression of CCL2 with platinum-taxane based chemotherapy response and clinical outcome in patients with primary ovarian cancer. Methods: Tumor samples from chemotherapy-naïve patients with advanced serous ovarian adenocarcinoma were obtained at the time of primary cytoreductive surgery. Gene expression profiles using RNA extracted from tissue enriched for &gt;90% tumor from 2 chemotherapy sensitive (CS) and 8 chemotherapy resistant (CR) patients were performed using the Illumina Sentrix Human-6 Expression Bead-Chip microarray. Gene expression was quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in a larger patient cohort. Statistics were generated using Wilcoxon rank sum tests and Kaplan-Meier survival curves. Results: Clustering analysis of gene expression profiles identified several genes, including CCL2, that were differentially expressed between the CS and CR tumor specimens. Levels of CCL2 were significantly (p&lt;.001) under-expressed in all 8 CR patient tumors as compared to the 2 CS tumors. Quantification of CCL2 gene expression in 9 CS and 16 CR tumors by RT-PCR demonstrated that CCL2 was significantly down-regulated in the CR tumors when compared to the CS tumors (p&lt;.001). Using normalized PCR cycle threshold scores, 22 of the 25 tumors were correctly classified, i.e., 8/9 CS had low CCL2 expression (sensitivity = 89%) and 14/16 CR had high expression (specificity = 88%). For patients with low CCL2 expression, progression free survival was 12 months versus 18.6 months for those with high CCL2 expression (p=.05). Median overall survival (OS) was 20.8 months for patients with low CCL2 expression, while OS was not yet reached for those with high CCL2 levels (p=.01). Conclusions: Results demonstrate that expression of CCL2 correlates with response to chemotherapy and survival in patients with primary ovarian cancer. Expression of CCL2 may be a useful independent biomarker of response to treatment and clinical outcome. No significant financial relationships to disclose.
Phase II study of IV Vinflunine (VFL) as second line treatment of patients (pts) with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum based regimen. Final results
Authors: J. Bennouna, E. H. Tan, M. Obrien, P. Kosmidis, J.-L. Breton, C. Ottensmeier, J.-M. Tourani, F. Carballido, C. Colin, J.-Y. Douillard
Journal: Journal of Clinical Oncology (2004)

7139 Background: Pts with NSCLC who progress on or after 1st line therapy but continue to have a good performance status (PS) may be offered 2nd line chemotherapy. VFL (Javlor) is a novel fluorinated vinca-alkaloid derivative synthesised using superacidic chemistry which has shown high activity in experimental tumour models. Methods: The aim of this trial was to determine the response rate and safety of VFL (320 mg/m2 q 3 weeks) as a single agent in pts with advanced NSCLC, who failed to a previous platinum-based regimen. Results: Sixty-three pts have been treated, 47 males, 16 females, median (m) age 60 years; Karnofsky PS 100 %: 14 pts, 90 %: 21 pts and 80 %: 28 pts. Prior platinum combinations included taxanes (31 % pts), vincas (31 % pts) and other (38 % pts). The total number of cycles administered was 221 (m: 5 [1 - 9]). Of the 62 evaluable pts, 38 (61 %, [95 % CI: 49–73 %]) achieved disease control: 5 pts (8 %, [95 % CI: 1–15 %]) partial response (independent radiological review) lasting 5.8 months (mo) [95 % CI: 4.6–7.9] and 33 pts (53 %, [95 % CI: 41–66 %]) stabilisation. Progression free survival (PFS) was established at 2.6 mo [95 % CI: 1.4–3.8]. In terms of tolerance, grade (G) 3/4 neutropenia was observed in 15.8 % of cycles (25.4 % of pts) and 10.4 % cycles (23.8 % of pts) respectively; G3 anaemia and thrombocytopenia were rare. Two pts suffered from febrile neutropenia and 2 other from neutropenic infection. G ≥3 non-haematological toxicities observed were: myalgia 5 % cycles (15.9 % of pts), fatigue 1.9 % cycles (6.4 % of pts), stomatitis 1.4 % cycles (4.8 % of pts); constipation was present in 2.3 % cycles (7.9 % of pts), abdominal pain and arthralgia were observed in 1.4 % cycles (4.8 % of pts). Neither grade G3/4 peripheral neuropathy nor phlebitis was observed. Conclusions: In NSCLC patients previously treated with platinum containing regimens VFL achieved encouraging efficacy in terms of disease control and PFS. Toxicity was manageable and reversible. Based on these results a phase III is currently ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre (IRPF), France
Cytokine changes in castrate metastatic prostate cancer (CPMC) patients (pts) treated with ipilimumab (Ipi)
Authors: J. Yuan, F. Orlandi, M. Jefferson, H. Li, H. Gallardo, G. Ku, J. Wolchok, H. Scher, J. Allison, S. F. Slovin
Journal: Journal of Clinical Oncology (2009)

e16149 Background: Ipilimumab (Ipi) is a human IgG1 monoclonal antibody that blocks the inhibitory action of the checkpoint molecule CTLA-4. Recent data [Proc Amer Soc Clin Onc, Abstr#5004, 2008] from castrate metastatic PC pts suggested that Ipi was active but was associated with grade 3 autoimmune adverse events (AEs), such as colitis, hepatitis, hypophysitis or rash, which required high dose steroids. We studied pts who were treated on a clinical trial with Ipi 10 mg/kg alone or with radiation to a single site in bone to determine whether there was any correlation between serum cytokine levels and autoimmune AEs. Methods: Thirteen pts were treated, of whom 10 had sufficient specimens for analysis. Of the 10 pts, 8 had ≥1 AE during treatment. Pts were stratified by ascertainment of clinical benefit (CB) vs. no clinical benefit (NCB) based on time-to-PSA-baseline relapse (TTBR) and also by toxicity (tox) using standard NCI tox criteria. TTBR was defined as time from study entry until the time when a PSA measurement reached or exceeded the baseline value. Pts with a TTBR greater than the median value were judged to have CB; those with a TTBR less than the median value had NCB. Pts with grade (gd) 0/1/2 tox were termed “low tox” while those with gd 3/4 tox were “high tox”. Sera at serial time points were analyzed for interferon-gamma (IFN-γ), tumor necrosis factor α and interleukins (IL)-1b, 2, 4, 8, 10, 12, 13 with the Meso Scale Discovery Multiplex Assay (MSD, Gaithersburg, MD). Results: IFN-γ was the predominant cytokine produced in 4 of 5 pts with CB and AEs; it increased at week 4 or 7 after two doses of Ipi, then declined. Four of 5 pts with NCB had minimal IFN-γ production. There was no difference in IL-10 production between those with CB vs. NCB or high vs. low tox. However, there was a suggestion that the IFN-γ /IL-10 ratio may be increased in pts who had high tox and/or CB vs. pts with low tox and NCB. This awaits confirmation. Conclusions: While this experience with Ipi in PC is small, there may be differences between pts with CB vs. NCB and pts with low vs. high tox. Investigation of the immunophenotype of pts who remain in follow- up and continue to be enrolled is ongoing as well as the impact of prior chemotherapy on development of toxicities. [Table: see text]
Phase II study of an epirubicin and docetaxel (ET) combination as pre and post-operative systemic therapy in patients with early stage breast cancer (EBC)
Authors: R. Nishimura, Y. Rai, S. Mitsuyama, S. Toyoshima, H. Iwasaki, I. Ichinose, K. Tamura, F. Matsuo, S. Hara, H. Yano
Journal: Journal of Clinical Oncology (2006)

10660 Background: The goal of chemotherapy (CT) for EBC is to achieve a high pathologic complete response (CR) leading to an increase in the rate of breast conserving surgery (BCS). ET is one of the most active CT regimens for metastatic breast cancer. The primary endpoint of this study was to evaluate clinical response Methods: Eligible patients (pts) were newly diagnosed with EBC and had large primary tumors (stage II-III, &gt; 3 cm). Forty-seven pts were enrolled and received epirubicin 60 mg/m 2 followed by docetaxel 60 mg/m 2 every 3 weeks for 4 cycles before surgery. Within 4 weeks after surgery, 4 additional cycles of ET were given to the pts who responded to ET. Results: Forty-five pts were evaluable for safety and clinical response. The median age was 47 (range, 29–75). The tumor size was T2 in 44% of the pts, T3 in 36%, and T4 in 20%. ER and PgR were both positive in 40% of pts, while both negative in 31%. HER2 was positive in 33% of pts. Four cycles of ET at full dose were given to 96% of pts prior to surgery. The clinical response was 73% including 7% CR (95% CI 58–85%); the BCS rate was 36%. Central pathologic review was performed in 37 pts showing disappearance of all tumor cells (grade 1) in 1 patient (3%) and 2 pts (5%) achieved a grade 2 response (in situ carcinoma in the operated breast) by Chevallier’s criteria. Grade 3–4 toxicities included neutropenia (71%), leukocytopenia (69%), febrile neutropenia (18%) and anorexia (9%). Twenty-four of 33 pts who responded to ET received additional ET after surgery. Conclusions: ET showed a high clinical response in previously untreated EBC with acceptable toxicity. In order to improve pathological CRs further, the doses and treatment schedule of this regimen needs to be improved. Currently, we are following the pts to assess differences in survival between pts with or without additional adjuvant ET. No significant financial relationships to disclose.
Use of long term venous access in cancer patients: Experience from a tertiary cancer centre in South India
Authors: T. Singh, K. V. Sajeevan, C. T. Satheesh, J. Ankith, U. Batra, K. Saini, G. Anupama, K. Govindbabu, K. C. Lakshmiah, D. Lokanatha
Journal: Journal of Clinical Oncology (2008)

20710 Background: The long duration and frequent administration of chemotherapy in cancer patients requires long term venous access. Subclavian central venous catheters (SCVC) and peripherally inserted central venous catheters (PICC) are the most commonly used methods. We hereby present our experience of central venous catheters from a tertiary cancer centre in South India. Methods: A total of 101 patients with various malignancies (hematological and solid tumour malignancy) requiring long term venous access were included in the study. Aim was to review our experience of central venous catheters used over a 2 year period and to analyse the outcome in cancer patients in Indian setting. Intravascular devices like SCVC and PICC were used. A record of all complications and catheter loss and final outcome were analysed and compared with PICC and SCVC. Results: A total of 101 catheters were placed in 101 patients. Of which 15 were PICC and 86 were SCVC. In patients with SCVC, disease distribution included hematologic malignancies (51.1%) and solid tumours (48.8%), whereas for PICC, it was 80% and 20% respectively. Median duration of catheter indwelling period for SCVC was 92 days with range of 1–370 days, whereas, for PICC it was 30 and 1–215 days respectively. Reasons for central catheter removal. Conclusions: Long term venous access using PICC or SCVC is a simple, safe and reliable method for prolonged intravenous administration and blood sampling in patients intensively treated for hematologic and solid malignancies.The incidence of various complications and catheter loss was acceptable and overall patient satisfaction was good. Thus, we conclude that use of central venous catheters is a safe and reliable way of administration of chemotherapy even in developing countries.However, patient needs to be properly counselled and educated as there was a high incidence of accidental removal in our study. SCVC PICC Accidental removal 10 (11.6%) 2 (13.3%) Treatment over 38 (44.2%) 2 (13.3%) Patients death 25 (29%) 5 (33.3%) Suspected infection 9 (10.5%) 2 (13.3%) Leaks 1 (0.1%) 3 (20%) Thrombosis 3 (0.3%) 1 (6.6%) No significant financial relationships to disclose.
Screening mammography rates in women with diabetes.
Authors: Christine Wei-Yin Tran, Amy T. Wang, Ryan Johnson, Karthik Ghosh, Nilay Shah
Journal: Journal of Clinical Oncology (2014)

25 Background: Women with diabetes are at an increased risk of developing breast cancer, present with later stage disease, and experience higher breast cancer-specific mortality compared to nondiabetic women. Thus, it is imperative that diabetic women undergo routine screening mammography. Previous studies have shown conflicting results with smaller studies showing lower screening mammography rates among diabetics while a study using national self-report data showed that diabetic women were equally likely to be screened compared to nondiabetic women. Given the conflicting data and limitations of previous studies, we aimed to study receipt of mammography in diabetic women using a nationally representative administrative claims database. Methods: This was a retrospective study using a nationally representative administrative claims database from January 1, 2010, through December 31, 2012. We compared rates of receipt of mammography within a 2-year time frame in diabetic and nondiabetic women ages 40 to 64. We used Healthcare Effectiveness Data and Information Set (HEDIS) logic to define women with diabetes. We used CPT and ICD-9 codes to identify mammogram services received. We calculated odds ratios with 95% confidence intervals to compare mammogram rates among diabetics compared to nondiabetics. Results: 1,723,674 nondiabetic women and 133,973 diabetic women were identified. Among women ages 40 to 49, diabetic women had significantly decreased mammography rates compared to nondiabetic women (OR 0.84; 95% CI 0.83, 0.85). Rates were also lower in diabetic women ages 50 to 64 (OR 0.88; 95% CI 0.88, 0.91). Despite lower mammography rates among diabetics, diabetic women had 1.78 times more visits than nondiabetic women. Conclusions: Women with diabetes are less likely to undergo routine screening mammography than women without diabetes, despite having more encounters with health care providers. This study serves as a reminder to provide timely preventive health services to all patients regardless of medical comorbidities.
<i>FLT3</i> D835/I836 mutations predict worse disease-free survival (DFS) in younger adults with cytogenetically normal acute myeloid leukemia (CN AML) without <i>FLT3</i> internal tandem duplications (ITD): A Cancer and Leukemia Group B (CALGB) study
Authors: S. P. Whitman, A. S. Ruppert, M. D. Radmacher, K. Mrozek, P. Paschka, J. E. Kolitz, R. A. Larson, M. A. Caligiuri, G. Marcucci, C. D. Bloomfield
Journal: Journal of Clinical Oncology (2007)

10532 Background: The adverse prognostic impact of FLT3 ITD is well-recognized in younger adults with CN AML, whereas the clinical relevance of D835/I836 mutations in the second tyrosine kinase domain of FLT3 (FLT3 TKD), that occur in 5%-14% of patients (pts), remains controversial. We evaluated the prognostic impact of FLT3 TKD, alone and with other prognostic markers, in 139 de novo CN AML adults, aged &lt;60 years, without FLT3 ITD, and treated on similar CALGB protocols (9621 and 19808). Methods: FLT3 TKD was detected by RT-PCR/EcoRV digestion. Affymetrix U133 plus 2.0 gene expression profiles derived from FLT3 TKD+ and FLT3 wild-type (FLT3 WT) pts with available RNA were compared. Results: Relative to FLT3 WT pts, FLT3 TKD+ pts [n=16 (11.5%)] presented with higher white blood cell counts (WBC) (median: 57.2 v 14.6 × 10 9 /L; P&lt;.001), % bone marrow (BM) blasts (median: 75.5 v 63; P=.001), and % blood blasts (median: 62.5 v 46; P=.03). All 16 FLT3 TKD+ pts achieved complete remission versus 85% of FLT3 WT pts (P=.13). With a median follow-up of 4.6 years, FLT3 TKD+ pts had worse DFS (P=.01; 3-year DFS rates: 31% v 60%) and a trend for worse overall survival (OS) (P=.17, 3-year OS rates: 40% v 65%) compared to FLT3 WT pts. Other variables moderately associated with a worse DFS (P&lt;.10) included higher % BM blasts and NPM1 WT. Adjusting for these two variables, FLT3 TKD remained significantly associated with adverse DFS (P=.02; hazard ratio=2.3). A gene expression signature consisting of 333 probe sets (P&lt;.001) differentiated FLT3 TKD+ (n=9) from FLT3 WT (n=50) pts. Genes represented in this signature include those involved in cell motility (e.g., C3AR1, VNN1, VNN2, ADAM8; all over-expressed in FLT3 TKD+), development (e.g., HOXB5, HOXB6; both over-expressed in FLT3 TKD+) and stress response (e.g., MPO; under-expressed in FLT3 TKD+). Conclusions: FLT3 TKD appears to be an independent predictor for DFS among younger CN AML adult pts without FLT3 ITD. Gene expression profiling provides additional insight into the biology of FLT3 TKD+ AML and may lead to identification of additional targets for improved therapy. No significant financial relationships to disclose.
Toxicities associated with chemotherapy followed by craniospinal radiation for adults with poor-risk medulloblastoma/PNET and disseminated ependymoma; a preliminary report of ECOG 4397
Authors: P. L. Moots, A. O'Neill, G. R. Barger, M. P. Mehta, M. R. Gilbert
Journal: Journal of Clinical Oncology (2004)

1573 Background: The treatment of poor-risk medulloblastoma (MED) in adults derives from results in children indicating improved survival with combined modality therapy. In adults, chemotherapy is limited by hematological toxicities when given after craniospinal radiation. ECOG 4397 is designed to assess the toxicities, response rate, and long-term control in poor-risk patients treated with multi-agent chemotherapy prior to craniospinal radiation. This trial represents the collaborative efforts of ECOG and SWOG participants. Methods: Patients greater than 18 years with: 1) poor-risk MED/PNET, or 2) ependymoma with subarachnoid metastases were treated with three cycles of cisplatin (70 mg/m2, day 1), cyclophosphamide (700 mg/m2/d, day 2–3), etoposide (70 mg/m2, days 1–3), and vincristine (1.5 mg/m2 up to 2 mg, days 1 and 14) every 4 weeks. G-CSF was used. Radiation included 36 Gy to the craniospinal axis followed by a boost to 54 Gy to the primary site. MRI scans were performed after each cycle to monitor response. Results: Toxicity data is shown for the first ten patients (8 MED, 1 PNET, 1 ependymoma). Median age is 34 years. Nine of 10 patients received three cycles of chemotherapy. Hematological toxicity predominated with grade 3/4 neutropenia in 6 cycles, and grade 3/4 thrombocytopenia in 4 cycles. Nausea worse than grade 1 was observed in 3 cycles. Other grade 3/4 toxicities included fatigue (1), anorexia (1), dehydration (2), agitation (1), neuropathy (1), hypokalemia (1), hyponatremia (2), and elevated creatinine (1). One patient experienced tumor progression after cycle 2. One patient died of pulmonary emboli after cycle 3. All nine patients who began radiation completed the planned course. Conclusions: This chemotherapy regimen, derived from pediatric experience, can be administered in adults with acceptable toxicities for three cycles. Chemotherapy did not interfere with completion of craniospinal radiation. Response data has not been analyzed because the trial is ongoing, but radiographic progression prior to completing chemotherapy occurred only once. No significant financial relationships to disclose.