tbuckley/cabot-search huggingface dataset:
Trends in the use of adjuvant anthracycline- and taxane-based chemotherapy regimens in early-stage breast cancer, by surgery type.
Authors: Shuling Li, Anne Hudson Blaes, Jiannong Liu, Yan Hu, Rohini Khorana Hernandez, Scott Stryker, Alexander Liede, Allan J Collins
Journal: Journal of Clinical Oncology (2014)

e12017 Background: Anthracyclines (A) and taxanes (T) are widely used in adjuvant chemotherapy (chemo) treatment for early-stage breast cancer (BC). Recent changes in chemo regimen choice have been documented. This study examined, by surgery type, trends in adjuvant chemo regimen use. Methods: We identified women in the MarketScan database with BC as their only cancer at age 18-64 in 2005-2009, completing initial treatment(s), and with ≥1 claim for a chemo agent. Regimens of interest included A+T, A-based (A+other agents without T), or T-based (T+other agents without A). Trends in regimen use by surgery type were examined for all pts and pts receiving trastuzumab and endocrine therapy (ET) used as proxy for HER2+ and hormone receptor positive BC. Differences between breast-conserving surgery (BCS) and mastectomy (MST) were tested using a logistic model. Results: 4,058 pts underwent BCS and 4,014 MST. A+T use fell from 2005 to 2009 at similar rates between BCS and MST (p=0.93) and was consistently lower in BCS than MST pts (p<0.001). Regardless of surgery type, there was an observed decrease in A-based regimens and a marked increase in T-based regimens, with 5% of pts in 2005 and 48% in 2009 receiving T-based regimens. The decline of A-based regimens in tandem with the increase in T-based regimens was more pronounced in BCS than MST (BCS vs. MST: p=0.007 for A-based regimens; p<0.001 for T-based regimens). Similar trends were observed for pts receiving ET (n=4805). In pts receiving trastuzumab (n=1562), trends were similar between BCS and MST (p>0.10 for all comparisons) and, by 2009, nearly 60% of pts received T-based regimens and few pts received A-based regimens. Conclusions: We observed differences in trends from 2005 to 2009 in the adjuvant use of A- and T-based regimens between BCS and MST in younger, early-stage BC pts, with consistent findings observed for pts receiving ET, but not for pts receiving trastuzumab. Further studies are warranted to better understand these differences. A+T regimens, % A-based regimens, % T-based regimens, % 2005 2007 2009 2005 2007 2009 2005 2007 2009 All MST 63 52 47 23 12 4 6 28 42 BCS 51 48 39 37 15 4 4 31 54 Trastuzumab MST 66 37 18 4 4 1 4 34 59 BCS 63 42 26 4 5 4 9 36 59
A phase I trial of riluzole and sorafenib in patients with advanced solid tumors and melanoma.
Authors: Janice M. Mehnert, Neha Semlani, Yvonne Wen, Antoinette R. Tan, Rebecca Anne Moss, Shari Adams, Mark N. Stein, Mikel Ross, Michael P. Kane, Darlene Gibbon, John Joseph Wright, Joseph Aisner, Suzie Chen, James S Goydos
Journal: Journal of Clinical Oncology (2012)

TPS3112 Background: Metabotropic glutamate receptor 1 (GRM1) has been identified as a potential therapeutic target in melanoma. Over 60% of human melanomas express this cell surface glutamate receptor and excitation of GRM1 results in the activation of MAPK and PI3K/AKT pathways. Riluzole, an oral GRM1 blocking agent, results in growth arrest of melanoma cells in vitro and in vivo. We previously reported that administration of riluzole to melanoma patients suppressed activity of the PI3K/AKT and MAPK pathways in paired tumor samples (Yip Clin Cancer Res 2009). In preclinical studies, the efficacy of riluzole was attenuated in melanoma cells harboring BRAFV600E mutations, but sorafenib, a RAF kinase inhibitor, enhanced the effect of riluzole on these cells. The combination of riluzole and sorafenib was additive or synergistic in both BRAF mutant and BRAF wildtype melanoma cells in vitro and in BRAF wildtype cells in a xenograft model (Lee HJ Clin Cancer Res 2011). We thus designed a phase I trial to test the combination of riluzole with sorafenib in patients with solid tumors and advanced melanoma. Methods: The primary objective of this trial is identification of the maximum tolerated dose (MTD). An expansion cohort at the MTD is planned for patients with advanced melanoma to examine the correlation of clinical or radiographic response with signaling through the MAPK and PI3K/AKT pathways and with GRM1 receptor status of individual tumors. Eligible patients must have advanced solid tumors (phase I) or stage III unresectable/stage IV melanoma with biopsiable tumor (expansion cohort) and ECOG PS ≤ 2. Riluzole will be administered at 100 mg twice daily combined with sorafenib beginning at 200 mg daily and escalating in subsequent cohorts at 200 mg increments. Correlative studies: Tumors will be assessed for BRAF and NRAS mutational status. Pretreatment tumor blocks will be examined for GRM1 receptor status by immunohistochemistry. Pre and post treatment levels of pERK and pAKT will be measured in paired tumor samples to assess effects of treatment on MAPK and PI3K signaling. Limited sampling pharmacokinetic studies will be performed. Progress: Accrual to three cohorts is complete without DLT. Accrual to the final planned cohort is in progress.
Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or <i>PIK3CA</i> mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C.
Authors: Barbara Burtness, Ju-Whei Lee, Donghua Yang, Fang Zhu, Joaquin J. Garcia, Arlene A. Forastiere, Christine H. Chung
Journal: Journal of Clinical Oncology (2013)

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.
Mutation enrichment next-generation sequencing for quantitative detection of KRAS mutations in urine cell-free DNA from patients with advanced colorectal and other cancers.
Authors: Filip Janku, Afsaneh Barzi, Andrea Sartore-Bianchi, Takeo Fujii, Andrea Cassingena, Giulia Siravegna, Daniel D. Karp, Sarina Anne Piha-Paul, Vivek Subbiah, Apostolia Maria Tsimberidou, Helen J. Huang, Silvio Veronese, Federica Di Nicolantonio, Mark G. Erlander, Rajyalakshmi Luthra, Scott Kopetz, Funda Meric-Bernstam, Salvatore Siena, Heinz-Josef Lenz, Alberto Bardelli
Journal: Journal of Clinical Oncology (2017)

602 Background: Molecular testing of cell-free (cf) DNA from urine is a completely non-invasive approach for detection of actionable mutations in cancer. Methods: A quantitative mutation enrichment next-generation sequencing (NGS) urine cell-free (cf) DNA KRAS G12/G13 mutation test was developed and results compared to clinical testing of archival tumor tissue and research testing of plasma cfDNA from patients with advanced colorectal (n=56, 79%) and other advanced cancers (n=15, 21%). Results: The analytical sensitivity of the KRAS G12/G13 cfDNA test was 0.002%-0.006% mutant copies in wild-type background. In 71 patients, the agreement between urine cfDNA and tumor was 73% (sensitivity 63%; specificity 96%); the agreement increased to 89% for patients with recommended 90-110mL of urine. In 33 patients with available plasma samples, the agreement with tumor was 94% (sensitivity 92%; specificity 100%). In patients treated with systemic therapy there was lower number of KRAS G12/G13 copies in urine and plasma cfDNA on therapy compared to baseline and progression ( P&lt;0.003). Decrease in urine and plasma cfDNA KRAS G12/G13 copies on therapy compared to no change/increase was associated with longer median time to treatment failure ( P&lt;0.05). Conclusions: Mutation enrichment NGS detection of KRAS G12/G13 mutations in urine cfDNA has good concordance with archival tumor tissue. Changes in urine cfDNA correspond with time to treatment failure.
In vitro priming of tumor-specific cytotoxic T lymphocytes from healthy donors using allogeneic dendritic cells derived from the MUTZ-3 cell line (NMDC)
Authors: Saskia J. Santegoets, Marco W. Schreurs, Allan J. Masterson, Hans Baumeister, Steffen Goletz, Esther W. Kueter, Sinead M. Lougheed, Alfons J. Van Den Eerthwegh, Rik J. Scheper, Erik Hooijberg, Tanja D. De Gruijl
Journal: Cancer Research (2004)

1285  We have recently shown that dendritic cells can be generated from the HLA-A2+ CD34+ human acute myeloid leukemia cell line MUTZ-3. Upon stimulation with GM-CSF, IL-4 and TNF-α, MUTZ-3 precursor cells acquire a dendritic cell phenotype consistent with conventional interstitial DCs, displaying the full range of functional antigen processing and presentation pathways. These DC are hereafter referred to as NMDC. In our current experiments, the capacity of NMDC to induce tumor-specific CTL in vitro was examined and compared to the induction capacity of autologous monocyte-derived dendritic cells (MoDC). To this end, HLA-A*0201+/CD8β+ CTL precursors from healthy donors were weekly stimulated with either autologous MoDC or NMDC, both pulsed with the tumor-associated A2-binding peptides hTERT988Y or CEA571-579 (Cap-1). Equivalent CTL priming efficiencies were observed for MoDC and NMDC. After isolation by CD8/tetramer-guided flow sorting and cloning by limiting dilution, the functional capacity of the obtained CTL clones generated was determined. CTL clones could be identified with CEA571-579 specific cytolytic activity. With an intracellular IFN-γ staining procedure we were able to show that these clones recognized the naturally processed epitope on KATO-3, an HLA-A*0201+/CEA+ tumor cell line. We conclude that functional tumor-specific CTL can be primed by NMDC with equivalent efficiency to autologous MoDC. Our data indicate that NMDC represent a ready and standardized source of semi-allogeneic DC for immunotherapeutic approaches aiming at augmented CTL functions.
An analysis of early molecular testing, time to treatment initiation, and medical resource use in metastatic NSCLC.
Authors: Craig H. Reynolds, David A. Smith, Debra A. Patt, Gregory Smith, Menaka Bhor, Ruslan Horblyuk, Debra Rembert, Josephine A. Sollano, Debajyoti Bhowmik, Jack Mardekian, Mark Yap, Leonard Philip James
Journal: Journal of Clinical Oncology (2014)

e19031 Background: Evidence-based treatment and Lung Cancer Biomarker guidelines recommend molecular testing for appropriate patients with advanced NSCLC at the time of diagnosis of adenocarcinoma. This study evaluated uptake of early molecular testing (EMT) over time, explored predictors of EMT, associated time to treatment initiation and rates of medical resource utilization (MRU) in patients with metastatic NSCLC who were tested early vs. later in their disease progression. Methods: Retrospective analysis of electronic medical records from a large community-based oncology group practice in the US. Patients with a diagnosis of metastatic NSCLC between March 2011 and June 2012, ≥2 visits and ≥6 months of follow-up were eligible. EMT and non-upfront molecular testing (NMT) was defined as occurring <45 days and ≥45 days of diagnosis, respectively. Rates of molecular testing were assessed on quarterly basis during the study period. Logistic regression was applied to explore predictors of EMT. Time to treatment initiation and rates of MRU were compared between EMT and NMT cohorts. Results: A total of 350 patients were eligible. Average age was 64, majority were female (55%) with stage IV disease (90%). Demographic characteristics were well balanced between EMT and NMT cohorts, but EMT patients exhibited significantly poorer performance status as measured by ECOG (p<0.05). EMT rates increased from 41% to 84% (p<0.0001) during the study period. Regression analysis did not reveal significant predictors of EMT, although younger patients were slightly less likely to be tested early. EMT was associated with significantly shorter time to treatment initiation (30 vs. 43 days, p<0.05) while there were no significant differences in MRU rates between the two groups, except for use of inpatient services, which was higher for EMT (2.8 vs. 2.4 per patient per month, p<0.05). Conclusions: Rates of EMT in advanced NSCLC increased over time. Absence of significant predictors of EMT may indicate that no specific demographic criteria are used in real-world practice for referring patients for early molecular testing, which is associated with significantly reduced time to treatment initiation without increase in MRU.
Race-specific differences in mucosal sulfidogenic bacteria modify colon cancer risk
Authors: James Kinross
Journal: Gut (2017)

Over the past 10 years, the incidence and mortality of colorectal cancer (CRC) in the USA has steadily declined. However, this fall has been less dramatic among African-Americans (AA), who continue to have the highest rates of mortality from CRC when compared with other ethnic subgroups.1 The reasons for the health disparities are multifactorial and represent socioeconomic factors and barriers to effective screening. The gut microbiome is increasingly implicated as a critical cometabolic engine that mediates the impact of environmental modifiers such as diet in high-risk cohorts.2 Despite the emergence of several theories for the role of the gut microbiome in colon cancer initiation, a precise mechanism has yet to be definitively elucidated.3 ,4 A major challenge is deciphering the huge range of molecular signalling languages the microbiome uses to influence human health. The intestinal microbiota plays a central role in digestive biochemistry and element cycling, which has largely been under-reported in CRC studies.

The study by Yazici et al 5 is important because it provides compelling evidence that the gut microbiome plays a significant part in defining cancer risk in AAs by modifying sulfur metabolism. Hydrogen sulfide (H2S) is a regulator of gut health linked with multiple GI diseases, and …
Mass spectrometry-based serum and plasma peptide profiling for prediction of treatment outcome in patients with cancer.
Authors: Mariette Labots, Lisette M. Schutte, Johannes C. Van der Mijn, Thang V. Pham, Connie R. Jiménez, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2014)

e22221 Background: Treatment selection tools are needed to enhance efficacy of targeted treatment in patients with solid malignancies. Providing a read-out of aberrant signaling pathways and proteolytic events, mass-spectrometry (MS) based peptidomics enables identification of predictive biomarkers. The serum or plasma ‘peptidome’ may provide easily accessible signatures associated with response to treatment. We have systematically reviewed literature on MS-based peptide profiling in blood for prompt clinical implementation. Methods: A syntax-based search was consecutively performed in Pubmed and Embase for studies employing blood-based MALDI- or SELDI-TOF-MS peptide profiling in patients with solid malignancies prior to initiation of any treatment modality, with availability of outcome data in terms of response, progression-free or overall survival. Titles, abstracts and full-text articles of potentially relevant studies were independently reviewed by 2 investigators. Results: Thirty-seven out of more than 1,200 studies were eligible for review; the majority of included studies were performed in patients with non-small cell lung cancer (NSCLC) and breast cancer. Median classification prediction accuracy was 80% in 11 models from 14 studies reporting a MS-based peptide signature. A pooled analysis of 16 treatment arms and retrospective cohorts from 10 NSCLC studies revealed a clinically significant median progression-free and overall survival in ‘poor’ classified patients of 1.95 (± 1.07) and 4.27 (± 1.48) months, respectively. Conclusions: Pre-treatment MS-based serum and plasma peptide profiling has shown promising results for prediction of treatment outcome in patients with solid tumors. Limited sample size and absence of signature validation in most studies have prohibited its clinical implementation thus far. However, our pooled analysis indicates that this blood-based profiling approach is feasible for treatment selection in patients with cancer and needs robust prospective evaluation to determine its clinical value.
Evaluating the Response to Imatinib In Philadelphia-Positive Chronic Myeloid Leukemia (Ph+ CML): The Value of Major Molecular Response (MMolR) at 12 Months
Authors: Michele Baccarani, Gianantonio Rosti, Giovanni Martinelli, Fausto Castagnetti, Francesca Palandri, Gabriele Gugliotta, Marilina Amabile, Nicoletta Testoni
Journal: Blood (2010)
A study of ERG, PTEN, and ki-67 in a phase III trial assessing docetaxel and estramustine in high-risk localized prostate cancer (GETUG 12).
Authors: Shanna Rajpar, Philippe Vielh, Agnes Laplanche, Francois Lesaunier, Remy Delva, Gwenaelle Gravis, Frederic Rolland, Frank Priou, Jean-Marc Ferrero, Nadine Houede, Loic Mourey, Christine Theodore, Ivan Krakowski, Jean Francois Berdah, Marjorie Baciuchka, Muriel Habibian, Stephane Culine, Laura Faivre, Anne Chauchereau, Karim Fizazi
Journal: Journal of Clinical Oncology (2014)

5063 Background: High-risk localized prostate cancer (CaP) is a heterogeneous disease and only a minority of patients (pts) ultimately die of their cancer. GETUG 12 is a phase III trial assessing androgen deprivation therapy (ADT) with or without docetaxel-estramustine (DE) in pts with high-risk localized CaP (Eur J Cancer 2012; 48:209-17). Progression free survival (PFS) data will be reported at the ASCO 2014 meeting. The aim of this study was to investigate the prognostic and predictive value of Ki-67, PTEN, and ERG expression in GETUG 12. Methods: Pre-treatment prostate core biopsies were collected from 255 of the 413 pts (62%) who were enrolled in GETUG 12. Immunohistochemistry analysis was performed for Ki-67, PTEN and ERG. PTEN and ERG expression were defined as positive if there was a staining (1+ or 2+) in any core. Ki-67 was characterized as low and high according to the cut-off based on the observed median value (1%). PFS differences were compared using the Logrank test and multivariate analysis was conducted with established prognostic factors using the Cox model. Results: In the overall population, the median age was 63 (46-77) years. 72/174 pts (41%) had Ki-67 >1%, 106/178 pts (60%) were negative for PTEN and 103/191 pts (54%) were negative for ERG. ERG negative expression (p=0.03) and high Ki-67 (p=0.02) predicted for unfavorable PFS. In multivariate analysis, pN+ (p<0.0001), ERG negative expression (0.0003) and PTEN negative expression (p=0.05) were independent prognostic factors of poor PFS. DE improved PFS in pts with a ERG positive expression (HR=0.56 [0.28-1.15]) but not in pts without ERG expression (HR=1.12 [0.65-1.91]), interaction test: p=0.02. In contrast no PFS benefit was associated with DE in subgroups defined according to Ki-67 and PTEN expression. Conclusions: Docetaxel-estramustine is associated with an improved PFS in pts treated for a high-risk localized CaP with ERG expression.
Combination of eribulin (E) and capecitabine (C) in elderly metastatic breast cancer (MBC): Update of a new option suitable in older elderly.
Authors: Ignazio Ugo Carreca, Giuseppe Bronte, Anna Paola Carreca, Viviana Bazan, Dario Cova, Antonio Russo
Journal: Journal of Clinical Oncology (2015)

9540 Background: E mesylate, a nontaxane microtubule dynamics inhibitor is widely prescribed for MBC pts pretreated with at least 1-2 lines of chemotherapy, including anthracyclines and taxanes (A&T). Elderly Patients (EP) develop rapid and sometimes fatal toxicity during standard treatments because of their pharmacokinetic features. We designed a new combination schedule (E+C) to evaluate its suitability for elderly MBC patients. Methods: Treatment plan: E 0.96 mg/sqm IV on d1 every 21d - C 900 mg/sqm bid d1-14 every 28d (Dose-adjustement if necessary was according to Kintzel-Dorr’s formula for EP), schedule would be continued until progression or intolerable toxicity. Eligibility criteria: histologically confirmed diagnosis of MBC, written informed consent, at least 1 measurable lesion, at least 1 site of visceral mts (not brain mts), age > 70 years, previous treatment with A&T, Comprehensive Geriatric Assessment evaluation (CGA) permissive for chemotherapy, adequate renal, bone marrow and liver function. Charlson's Score Comorbidity Scale was also considered. Evaluations tools: Clinical Benefit (CB) as Stable Disease + Objective Response Rates according to WHO criteria, toxicity profile using NCI-CTC v2.0 and Quality of Life (QoL) score through EORTC QLQ-C30 questionnaires. Results: From 2013 jan to 2014 dec 39 metastatic EP, mean age 80.5 (range 71 - 90) were treated and 37 are still under maintenance therapy (2 pts discontinued treatment for personal reasons). A total of 599 cycles were delivered to the 37 pts without G4 toxicity. No delay in therapy delivery was needed. QoL score shows no worsening with improvement in about 55% (72-78 y/o group) after treatment in comparison with baseline. Total CB was 80%. Conclusions: A further period of monitoring allowed to confirm our previous report in this setting with this combination schedule. It appears more fit with comorbidity or frailty than other standard chemotherapy regimens for MBC. In this updated analysis this schedule has showed non-inferiority vs standard treatments and more suitability for older EP. This study will be extended to confirm these outcomes in order to validate a schedule devoted to EP.