tbuckley/cabot-search huggingface dataset:
Relevance of sex and PER2 SNPs for predicting irinotecan tolerability in cancer patients.
Authors: M. Pirovano, D. Fornasari, A. Nasisi, A. Caronno, P. F. Innominato, C. Garufi, M. Moroni, F. Scaglione, F. Levi
Journal: Journal of Clinical Oncology (2011)

416 Background: Advances in understanding the mechanisms underlying diseases and drug responses are creating increasing opportunities to offer safer and more effective treatments to individual patients (pts). Biomarkers are needed for predicting likelihood of therapeutic safety and efficacy in each individual pt. Down-regulation of core clock gene PER2 in tumors predicted for poor survival in pts with metastatic colorectal cancer (Jacobelli. J Clin Oncol. 26: 2008 May 20 suppl; abstr 11032). Methods: A clinical data base and tissue bank involving primary tumor (T) and healthy adjacent colon mucosa (C) from 139 pts treated with circadian-shaped or standard infusion of (A)-single-agent irinotecan (63 pts) or (B) in combination with oxaliplatin and 5FU (76 pts) for previously-treated metastatic colorectal cancer was established and tissues were collected. Clinical relevance of constitutive or acquired single nucleotide polymorphisms (SNPs) for 5 metabolism (ABCB1, ABCB2, CES2, TOP1, UGT1A1) and for two PER2 SNP's (A4572G and C3968T). Results: No acquired mutation in the genes analysed was found (100% T and C concordance). The incidence of grade 3-4 toxic event of any kind was significantly lower in women as compared to men in A population(39% vs 76%, p=0.007) and in A+B population (p=0.05), independently from other factors (p=0.02) this difference is lost if you consider only B population where oxaliplatin is added (p=0.5). No SNP in metabolism genes predicted for toxicity in this cohort. Conversely, SNPs in core clock gene PER2 (1 pt with A4572G and 4 pts C3968T) were significantly associated with higher incidence of G3-4 toxicity (100% in polymorphic pts. vs 17.2% in wild type pts, p=0.01). Conclusions: Irinotecan tolerability is sex dependent and woman has significative low incidence of toxic effects. We demonstrated for the first time an association between constitutive SNPs in a core clock gene and toxicity, further supporting the relevance of the circadian timing system in chemotherapy tolerability. Moreover, our findings are in good agreement with data in mice, supporting the hypothesis that sex determines two chronotoxicity classes in patients with metastatic colorectal cancer. No significant financial relationships to disclose.
A new multimarker panel for circulating tumor cells analysis as an additional tool in the prediction of the clinical outcome in patients with advanced gastric cancer.
Authors: I. Kubisch, A. de Albuquerque, D. Ernst, N. Fersis, S. Kaul, U. Stoelzel
Journal: Journal of Clinical Oncology (2011)

e14655 Background: Despite progress in the treatment of advanced gastric cancer, therapy resistance and high mortality continue to pose major problems in clinical management. This study aims to develop an accurate immunomagnetic assay followed by the validation of a multimarker panel for detection of circulating tumor cells (CTCs) in peripheral blood of gastric cancer patients. Methods: CTCs were isolated with immunomagnetic separation in a training set of 143 peripheral blood samples from 36 gastric cancer patients, using the high affinity antibodies BM7 (MUC1) and VU1D9 (EpCAM) and subsequently analyzed by RT-qPCR for the expression of CK19, MUC1, EpCAM, CEA and Survivin. Specificity and sensitivity of the assay were defined by analysis of blood from 40 healthy volunteers and tumor cells spiking experiments. Progression-free survival was estimated by Kaplan-Meier product limit and compared between groups according to CTCs detection (positive vs negative) by log-rank test. Results: Overall positivity of the training set was 55.9% while specificity was 100%. Positivity rates for each individual marker were as follows: 21.0% for CK19, 35.7% for MUC1, 32.9% for EpCAM, 14.0% for CEA and 22.4% for Survivin. Patients analysed before therapy with CTCs positivity compared with CTCs negative patients had a significant shorter median progression-free survival (PFS; 133.6 vs 239.2; P =0.011). Conclusions: Our results indicate that the molecular detection of circulating tumor cells before treatment is an independent predictor of PFS in patients with gastric cancer. Identification of CTCs using a multimarker panel may give information about the malignant biological properties of the tumor cells and be helpful in the selection of clinical treatment and judgment of prognosis.
DERMA phase III trial of MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) as adjuvant therapy in patients with MAGE-A3-positive resected stage III melanoma.
Authors: J. M. Kirkwood, B. Dreno, A. Hauschild, D. Schadendorf, A. Testori, P. Hersey, C. Jamoul, O. Peeters, P. Therasse
Journal: Journal of Clinical Oncology (2011)

TPS232 Background: Clinical activity of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) was observed in a Phase II study in patients with metastatic melanoma (NCT00086866) and in a Phase II study in patients with completely resected non-small cell lung cancer (NSCLC) (NCT00290355). Based on these positive signals for the activity of MAGE-A3 ASCI, a Phase III trial is currently ongoing in patients with resectable regionally advanced melanoma (DERMA Phase III trial, NCT00796445). Methods: DERMA is a double-blind, placebo-controlled, 2:1 randomized trial of MAGE-A3 ASCI vs. Placebo. Eligible patients must have cutaneous melanoma expressing MAGE-A3 with histologically proven macroscopic nodal disease (AJCC Stage IIIB-C). Central randomization uses an internet-based algorithm accounting for the following factors: Stage of the disease (IIIB, IIIC and IIITx), TNM nodal category (N1, N2 and N3), primary category (Tx-0 or T1-2 or T3 or T4), extracapsular extension (Yes, No), study center, prior treatment with IFN or anti-CTLA-4 (Yes, No). Patients must have had complete surgical resection of all tumor. Disease-Free Survival (DFS) in the overall patient population is the primary endpoint, while overall survival, safety and health-related quality of life (EQ-5D) are secondary endpoints. A previously-defined gene signature associated with MAGE-A3 ASCI benefit is also being validated as a secondary endpoint of this trial (Louahed et al., EORTC-NCI-AACR 2009). The MAGE-A3 ASCI combines the tumor-specific antigen MAGE-A3, delivered as a recombinant protein, with the immunostimulant AS15. A maximum of 13 doses are administered by intramuscular injection over 27 months; the first 5 are given at 3-week intervals followed by 8 at 12-week intervals. This Phase III trial is designed to enroll 1300 patients from 250 centers worldwide. Since Dec 1, 2008, 2426 patients have been screened. From 1917 tumor samples valid for testing the expression of MAGE-A3, 1265 express MAGE-A3 (MAGE-A3 expression rate of 66%). 832 patients are currently enrolled to this study.
High throughput screening to assess urothelial cancer lines and their metastatic derivatives for assessing changes in sensitivity in therapeutics.
Authors: Louis Spencer Krane, Reema Railkar, Iawan Hsu, Cathy Vocke, Paul S. Meltzer, Craig Thomas, Marc Ferrer, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2016)

407 Background: Chemotherapy for urothelial cancer (UC) is less effective in patients with large volume metastatic disease, likely due to acquired driver mutations. Driver mutation may lead to differences in sensitivity between primary cell lines and metastatic clones. Quantitative high throughput screening (qHTS) assesses large drug libraries to evaluate in vitro effectiveness. We utilized this modality to compare effectiveness of cell inhibition in two bladder cancer cell lines with their metastatic lines. Methods: We screened T24 and UMUC-3 bladder cancer cell lines against 1,912 oncology-focused drugs using a 48 hr cell proliferation assay with an ATP-based readout (CellTiterGlo), and determined the activity and potency of the compounds in a dose response manner. We compared the results of their activity with known metastatic lines for reach of these primary lines: T24T, SLT3 and FL3 for T24 and LUL2 UMUC3 and UMUC3-luc (LUC3). We identified candidate drugs based on two parameters: 1) more than 70% inhibition at 48 hours and 2) a curve class of -1.1 or -1.2 indicating curve class with good fit (r2 &gt; 0.9). We used a custom capture next generation DNA sequencing chip for exonic regions of 229 known cancer related genes to compare primary and metastatic tumor cell lines. Results: The qHTS compounds, are demonstrated in figure 1a for T24 cell lines and figure 1b for UMUC cell lines. Amongst 1912 drugs tested, only 141 (7.4%) met inclusion criteria for T24. However, only 79 of these drugs (56%) met criteria for all cell lines derived from T24. 160 (8.4%) compounds were found to be active in the UMUC line. Only 32 (20%) of the UMUC3 detected compounds remained active in all UMUC3 derived cell lines. Genomic comparison between cell lines identified several mutations which were found only in the derived cell lines (RAC1 and CDH1 in UMUC3) and (AR, CDK12, GATA1, GUCY1A2 in T24). Conclusions: qHTS of a library of potential therapeutic interventions can produce a list of targets and therapies for bladder cancer. This data reinforces the differences between primary and metastatic tumors as compounds identified active in the primary cell lines were inactive in known metastatic cancer cell lines .
Biochemotherapy for metastatic melanoma: The importance of dose intensity
Authors: D. R. Minor, M. Madland, M. Kashani-Sabet, S. Denny, W. Harvey
Journal: Journal of Clinical Oncology (2005)

7547 Background: Despite a decade of study, the utility of biochemotherapy for metastatic melanoma remains controversial, as the favorable single-institution phase II results have not been confirmed by phase III studies. Dose intensity has been recognized as an important determinant of response and survival in the chemotherapy of several malignancies, but has not been studied in biochemotherapy. In this study we describe the relationship between achieved dose intensity and response rate of inpatient decrescendo biochemotherapy at our center. Methods: A retrospective study of 38 consecutive patients with metastatic melanoma treated between September 2002 and July 2004 was undertaken. The planned doses were dacarbazine 800 mg/m2 on day 1 or temozolomide 150 mg/m2 d 1–4, cisplatin 20 mg/m2 d 1–4, vinblastine 1.5 mg/m2 d 1–4, interferon-alpha-2a 5 million IU (MIU)/m2 d 1–5, & interleukin-2 36 MIU IV on day 1, 18 MIU d 2, and 9 MIU d 3 & 4. Six cycles at 21-day intervals were planned. Results: Of 38 patients that received a total of 204 cycles of therapy, 8 (21%) complete responses and 14 (37%) partial responses were observed for an objective response rate of 58%. The number of responses at 18 weeks (22/38, 58%) was higher than the number of responses at 9 weeks (14/38, 37%) suggesting that six cycles of therapy may be necessary for maximum response. The median overall survival was 13.6 months. Eleven patients received less than six cycles of therapy, three because of toxicity and eight because of disease progression. 85% of cycles 2–6 began on time. Achieved dose intensity (actual dose/planned dose) was high with patients receiving 98.7% interleukin-2, 87.1% interferon, 90.7% DTIC, 94% temozolomide, 87.2% cisplatin, and 89.7% vinblastine. Conclusion: Six cycles of inpatient decrescendo biochemotherapy can be given with a high administered dose intensity and acceptable toxicity. This is the first study, to our knowledge, of biochemotherapy to report detailed data on the dose intensity achieved for all administered drugs for each cycle and the number of cycles administered on time. High response rates with biochemotherapy for melanoma may correlate with dose intensity, dose density, and the number of cycles given on time. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron, Schering-Plough Chiron, Schering-Plough
Prediction of patient-reported bowel quality of life (QOL) after dose-escalated radiation therapy (RT) for prostate cancer by rectal dosimetry.
Authors: Matthew H. Stenmark, Anna S.C. Conlon, Stephanie Daignault, Michael Frederick Bassetti, Sean Vance, Robin Marsh, Dale Litzenberg, Timothy Ritter, Felix Yi-Chung Feng, Howard Mark Sandler, Martin G. Sanda, Daniel A. Hamstra
Journal: Journal of Clinical Oncology (2013)

84 Background: Rectal dose-volume histogram (DVH) parameters and a consensus normal tissue complication probability (NTCP) model predict physician scored toxicity but have not been well studied for patient reported outcomes (PRO) following external beam RT for prostate cancer. Methods: PRO were prospectively collected at baseline and 12 month intervals by expanded prostate cancer index composite (EPIC) for 98 patients from 2004-2009. Linear regression modeling for bowel score at 1 and 2 years was performed using pre-treatment bowel score and DVH parameters [V 80 (% of rectal volume &gt;80 Gy), V 75 , V 70 , V 50 , V 25 , and NTCP]. Results: Median RT dose was 78 Gy with image-guidance in 81%, intensity-modulation in 72%, and pelvic RT in 11%. Rectal DVH parameters are presented in the Table. Pretreatment and 2 year PRO were available for 92% of patients. The mean pretreatment bowel summary score declined from 96.0 (sd 8.0) to 91.8 (13.5) at 2 years. Acute proctitis (grade 1-2) during RT was associated with a decline in 2 year bowel QOL, while acute diarrhea (grade 1-2) was not. At 2 years 63% of patients had a decline &lt;4 points while the remainder had a mean decline of 15.9 (14.2) with 4-6 points having been defined as the minimal clinically significant change. Linear regression modeling, adjusted for pretreatment bowel function, revealed an association between increasing V dose , NTCP and bowel QOL (Table). Akaike information criterion analysis followed by leave-one-out cross validation, indicated that V 75 provided the best predictive model for 2 year bowel QOL followed by NTCP and V 70 . Conclusions: Most previous studies have highlighted V 70 for toxicity (such as rectal bleeding). The association with V 75 and rectal QOL has not been previously reported and supports potential changes in how prostate plans are designed to maintain QOL. This is also the first validation of a consensus NTCP model for bowel QOL. [Table: see text]
Risk of lung cancer in Hodgkins (HL), non-Hodgkins (NHL) lymphoma and chronic lymphocytic leukemia (CLL) patients (pts): Analysis of the Surveillance Epidemiology and End Results (SEER) data
Authors: S. K. Arunselvan, A. Schwartz, C. Schiffer, F. Vigneau, M. Islam, S. M. Gadgeel
Journal: Journal of Clinical Oncology (2008)

8611 Background: Development of lung cancer(LC) in pts with lymphoma and CLL has been observed, although the risk of LC in these pts is not well characterized. We conducted an analysis of the SEER data to assess the risk of LC and risk of other second primary cancers (SPC) in these pts and define the pts likely to develop LC. Methods: Pts with HL, NHL and CLL diagnosed between 1973–1997 with follow up through 2002, in the SEER data were included. Standardized Incidence Ratios (SIRs) were calculated to assess the risk of developing LC and SPC in these pts compared to the general population. The demographics of pts with subsequent LC were also analyzed. Results: 83,423 pts with HL, NHL and CLL were identified, of whom 1825 (2%) pts developed LC. A 300% increase in LC incidence was observed in HL (SIRs - 3.01; Males- 2.88, Females- 3.32), 30% increase in NHL (SIRs- 1.31; Males- 1.23, Females- 1.44) and 60% increase in CLL pts (SIRs- 1.59; Males-1.60, Females- 1.54), whereas the incidence of other SPC was increased by 92%,8% and 6% in HL, NHL and CLL pts respectively. LC occurred more often than expected in pts < 50 years in each of the lymphoma categories (SIRs for HL- 4.57; NHL- 2.25; CLL- 3.42) but not in pts 70 years or older at lymphoma/CLL diagnosis. The median time to development of LC was HL- 9 years, NHL- 6 years and CLL- 5 years. 92% of LCs were non-small cell and 8% were small cell in NHL and CLL pts, while in HL pts it was 85% and 15%. The median survival of pts following diagnosis of LC ranged from 5–9 months. Conclusions: The risk of LC is significantly higher in pts with HL, NHL and CLL compared to the general population, especially in pts < 50 yrs. The biological factors underlying this increased risk are unclear. These data have important implications regarding screening for LC in these pts. No significant financial relationships to disclose.
Clinical features of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.
Authors: Y. Yamamoto, N. Tomita, H. Takasaki, E. Ogusa, Y. Hattori, S. Matsuura, C. Matsumoto, S. Takemura, H. Kuwabara, H. Fujita, Y. Ishigatsubo
Journal: Journal of Clinical Oncology (2011)

e18534 Background: The clinical manifestations of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) remain unclear. We studied patients with MALT lymphoma by our group. Methods: The Yokohama City University hematology group newly diagnosed 133 patients with MALT lymphoma between 1998 and 2010. We retrospectively studied 124 for whom complete clinical data were available at presentation, and who had undergone tumor staging at least by physical examination; computed tomography (CT) from cervix to pelvis (or positron emission tomography/CT); bone marrow aspiration; and biopsy. Results: Slight female predominance (men, 58; women, 66) was observed in the study population; the median age was 67 years (range: 37-81 years). The primary dominant locations at presentation were the stomach (39%), orbita (20%), lung (13%), intestinal tract (8%), thyroid gland (6%), others (12%), and unknown (2%). Most patients had localized disease (stage 1, 65%; stage 2, 19%; stage 3, 6%; stage 4, 10%). The soluble interleukin -2 receptor level was over 1,000 U/ml in 10 patients (8%), and the serum lactate dehydrogenase level was elevated in 20 patients (16%). Of the 124 patients, 14 (11%) had lymph node involvement; 5 (4%), bone marrow involvement; and lung and gastric involvement. Four of 8 patients with primary thyroid MALT lymphoma had regional lymph node involvement. According to the International Prognostic Index criteria, 66%, 24%, 9%, and 1% of the patients were in the low-, low-intermediate, high-intermediate, and high risk groups, respectively. Chromosomal analysis was performed for 28 patients; 5 (18%) had cytogenetic abnormalities, including t(11;18) in 1 patient. The 5-year overall survival rate for all 124 patients was 96.1%. Conclusions: MALT lymphoma had slight female predominance, and most patients had localized disease stage. The vital prognosis was excellent. Gastro-intestinal fiberscopic examination is essential especially in cases with lung involvement at presentation.
Phase III study of APF530 versus ondansetron with a neurokinin 1 antagonist + corticosteroid in preventing highly emetogenic chemotherapy-induced nausea and vomiting: MAGIC trial.
Authors: Ian D. Schnadig, Richy Agajanian, Shaker R. Dakhil, Nashat Y. Gabrail, Robert E. Smith, Charles W. Taylor, Sharon Wilks, William Cooper, Michael Mosier, Yvette Payne, Michael Klepper, Jeffrey L. Vacirca
Journal: Journal of Clinical Oncology (2015)

68 Background: Managing chemotherapy-induced nausea and vomiting (CINV) associated with delayed ( &gt; 24-120 h) highly emetogenic chemotherapy (HEC) is an unmet need. APF530, extended-release granisetron, provides sustained release over ≥ 5 days to prevent acute (0-24 h) and delayed CINV. This trial compared the efficacy and safety of APF530 in preventing CINV after HEC in a 3-drug regimen vs a standard 3-drug regimen with ondansetron (Ond). Methods: In this double-blind, multicenter study (NCT02106494), patients (pts) receiving single-day HEC (2011 ASCO guidelines) were randomized 1:1 to APF530 500 mg SC (10 mg granisetron) or Ond 0.15 mg/kg IV and stratified by cisplatin ( ≥ 50 mg/m 2 , yes/no). Pts were scheduled to receive concomitant dexamethasone (Dex) 12 mg IV + fosaprepitant (Fos) 150 mg IV on day 1 + PO Dex on days 2-4. The primary end point was delayed-phase complete response (CR) (no emesis, no rescue medication). Secondary end points included CR in acute and overall phases and complete control (CC; CR and no more than mild nausea) in acute, delayed, and overall phases. Treatment (tx) comparisons used chi-square test controlling for cisplatin. Adverse events (AEs) and injection-site reactions (ISRs) were assessed. Results: Modified intent-to-treat analysis included 902 pts (APF530, n = 450; Ond, n = 452) with baseline demographics balanced between tx groups. A significantly higher % of APF530 (65%) vs Ond (57%) pts had delayed-phase CR (P= .014). A significantly higher % of APF530 (61%) vs Ond (53%) pts had delayed-phase CC (P= .022, Table). CR and CC rates in acute and overall phases were numerically higher with APF530 vs Ond, but not statistically significant. APF530 was well tolerated. Most common AEs were ISRs, mostly mild or moderate. Conclusions: APF530 with Fos+Dex led to statistically higher CR and CC rates in delayed-phase CINV with HEC vs a standard 3-drug regimen of Ond with Fos+Dex. Clinical trial information: NCT02106494. [Table: see text]
Updating data about a first-line modified schedule of gemcitabine with a lower dose than standard in very elderly or PS 2 patients with advanced non-small cell lung cancer.
Authors: A. Nacci, D. Galetta, E. Mazzoni, P. Rizzo, N. Calvani, L. Orlando, F. Sponziello, P. Schiavone, P. Fedele, C. Chetri, M. D' Amico, A. Marino, M. Cinefra, M. Criscuolo, S. Cinieri
Journal: Journal of Clinical Oncology (2011)

e18031 Background: Monochemotherapy with gemcitabine (Gem) is often the treatment of choice in elderly or poor performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Our study was aimed to assess the efficacy and tolerability of a modified schedule of Gem using a lower dose than standard. Methods: From May 2009 through December 2010, fifty patients (43 males and 7 females with a median age of 76 years (64 to 85) with advanced NSCLC (stage IIIB 34,0% and IV 66,0%) were enrolled. Histology were: squamous 39,6%, adenocarcinoma 31,2%, large cell 6,2 %, undifferentiated 4,2 %, undetermined 18,8%. Only eight patients (16,0%) had a WHO PS 0 whereas nineteen (38,0%) were PS 1 and eleven (46,0%) PS 2. All patients received first-line chemotherapy with 6 cycles of Gem 1000 mg/sq on days 1 and 8 every 4 weeks. Results: At the time of analysis 35 patients were evaluable for response. Partial response (PR) was achieved in 7 patients (20,0%), stable disease > 12 weeks (SD) in 16 (45,7%) whereas 12 had progressive disease (34,3%). Importantly, the clinical benefit rate (PR + SD) was 65,7%. Quality of life was mesured with EORTC QoL 3.0 Questionary. Both pain and PS improved in 6 patients (17,1%) whereas 19 (54,2%) had an improvement in pain with no worsening of PS. We observed only grade 2 NCCTs version 3 haematological toxicities including anemia, leucopenia, neutropenia and trombocytopenia. Not febrile neutropenia occurred in 4 patients (11,4%). Overall, we did not observe any not-haematological treatment-related event. Conclusions: Our data show that a modified schedule of Gem with a lower dose intensity than standard may be beneficial in terms of both disease control and tolerability when employed in elderly or PS 2 patients with advanced NSCLC. These data are similar to published data in elderly. At ASCO meeting we present all data about 50 pts enrolled.