bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of PIK3CA mutation-associated gene expression signature (PIK3CA-GS) with deactivation of the PI3K pathway and with prognosis within the luminal-B ER+ breast cancers
Authors: Loi S. , Haibe-Kains B. , Lallemand F. , Pusztai L. , Bardelli A. , Gillett C. , Ellis P. , Piccart-Gebhart M. J. , Phillips W. A. , McArthur G. A. , Sotiriou C. 
Published: August 2020

533 Background: The phosphathidylinositol-3-kinase (PI3K) signaling pathway is frequently deregulated in tumor biology and is an attractive target for cancer therapy. Our aim was to characterize the molecular and clinical outcome effects of PIK3CA mutations in breast cancer (BC). Methods: We analyzed 173 BC samples for PIK3CA mutations. Corresponding gene expression profiles were used to understand its effects on the PI3K pathway. We validated a PIK3CA-GS in 2 independent BC cohorts (n = 183) with known PIK3CA mutation status and evaluated its correlation with clinical outcome in 1748 BC samples stratified by treatment and subtype. Results: 26% of BCs had a PIK3CA mutation. Tumors with PIK3CA mutation demonstrated a distinct gene expression signature (p = 0.03 after 1000 perm). In 2 datasets it could discriminate PIK3CA mutation carriers from wild-type (ROC 0.68, 0.71, p = 0.001for both). However, the PIK3CA-GS was correlated with deactivation of the PI3K pathway probably through a negative feedback loop. This observation was supported by: 1) the PIK3CA-GS was significantly correlated with gene expression changes induced by PI3K inhibitors (Connectivity Map, Gene set enrichment analyses) and 2) the PIK3CA-GS was anti-correlated with a GS of PTEN loss (R = -0.3; Saal et al, 2007). Higher levels of the PIK3CA signature were observed in HER-2+ and estrogen receptor positive (ER+), luminal BC subtypes. Whilst there was no association with mutation status alone and prognosis, increasing expression of the PIK3CA-GS (suggesting deactivation) was significantly associated with better clinical outcome in both untreated (p = 0.04) and particularly ER+, luminal-B, tamoxifen only-treated (p = 0.004) BC. Multivariate analysis (HR: 0.4; 95%CI: 0.3–0.7; p = 0.002) confirmed that the PI3KCA-GS provided independent prognostic information. Conclusions: Paradoxically, the PIK3CA-GS correlates with inhibition of the PI3K pathway in ER+ BC and identifies a subgroup of luminal B BCs with a favorable outcome. The PIK3CA-GS may be a better indicator of PI3K pathway dysfunction than mutation status, potentially indicating patients who may benefit from combined endocrine therapy and PI3K inhibition. No significant financial relationships to disclose.
Underuse of breast cancer adjuvant treatment: Patients' knowledge, beliefs, and medical mistrust
Authors: Bickell N. , Weidmann J. , Fei K. , Leventhal H. 
Published: August 2020

6521 Background: We surveyed breast cancer patients in New York City to understand why women did not receive radiotherapy (RT) following lumpectomy, chemotherapy, or hormonal therapy for hormone receptor negative or positive tumors >1 cm, respectively. Methods: 258 New York City women recently surgically treated for a new primary stage I or II breast cancer were surveyed about their experience of care, knowledge and beliefs about breast cancer and its treatment. Adjuvant treatment data were obtained from in and out-patient chart abstraction. Principal components factor analysis was used to create scales of adjuvant treatment beliefs and knowledge, medical mistrust, physician communication about treatment and social support. Scales were scored to 100. Bivariate and multivariate analyses were conducted to determine differences between treated and untreated women; odds ratios were converted to adjusted relative risks. Results: Compared to treated women, untreated women were less likely to know adjuvant therapies increase survival (66 vs 75; p < 0.0001), had greater mistrust (64 vs 53; p = 0.001), and less self efficacy (92 vs 97; p < 0.05); there was no association between physician communication of treatment information and patient knowledge and beliefs about adjuvant treatment (r = 0.8; p = 0.21). Multivariate analysis found that compared to those who were treated, untreated women were more likely to be 70 years or older (OR = 4.46; 95%CI: 1.9–10.7), more likely to have a comorbidity (OR = 3.39;1.5–7.9), more likely to express mistrust in the medical delivery system (OR = 1.03;1.0–1.1), and less likely to believe adjuvant treatments beneficial (OR = 0.91; 0.87–0.96) (model c = 0.84; p =< 0.0001). Conclusions: Patient knowledge and beliefs about treatment and medical mistrust are mutable factors associated with underuse of adjuvant therapies. Despite physicians' discussion of treatment, patients do not have a clear understanding of treatments' benefits and risks. This disconnect between what is said and what is heard may be mediated and addressed by dealing with patients' trust in and concerns about the medical delivery system. No significant financial relationships to disclose.
Adjuvant trastuzumab for breast cancer outside of clinical trials: Cardiotoxicity and economic evaluation
Authors: Snow S. , Skedgel C. , Rayson D. , Thompson K. , Sellon M. , Barnes P. , Jeyakumar A. , Younis T. 
Published: August 2020

6585 Background: Clinical and economic evaluations of adjuvant trastuzumab (aTZ) in breast cancer (BC) are based on clinical trial outcomes. Population based studies however provide unique opportunities to examine outcomes in a real world setting. We previously examined aTZ uptake in all patients diagnosed with stage I-III BC over one year in Nova Scotia, Canada (Snow et al SABCS 2007). We now report cardiotoxic events (CE) and an economic evaluation based on our previous cohort. Methods: A retrospective chart review of all patients treated with aTZ was conducted to abstract clinical-pathological characteristics, treatment details, CEs/significant LVEF declines, and associated medical resource utilization (MRU). Cardiac risk scores (CRS) (Rastogi et al ASCO 2007) were also computed for all patients. Biserial correlation was performed to detect differences in CRS scores among subgroups. Costs associated with aTZ were based on MRU; unit costs were derived from the literature and local resources. A probabilistic model (Skedgel et al ASCO 2008) was utilized to examine the cost per quality adjusted life year gained (QALYG) at a 25-year horizon with budget impact calculated in 2009 Cdn $. Results: Of a total population of 630 patients with stage I-III BC, 37 (5.9%) received aTZ as per HERA trial treatment schedule; two (5.4%) had a CE (one death) and five (13.5%) experienced significant LVEF decline. CEs and LVEF declines were higher in patients with baseline LVEF 50–55% vs. > 55% (10% vs. 4% and 20% vs. 11%, respectively). CRS accurately predicted the observed CE rate, and was also predictive of significant LVEF decline (p = 0.056). Compared to previous estimates, the mean cost per patient of $46,070 (95%CI: $38,541-$54,422) was lower and the cost-utility of $60,439/QALYG was more favourable. Based on the observed aTZ utilization rate, a budget impact of $59.9m (95%CI: 42.5 m-79.9 m) for 2009 in Canada is expected. Conclusions: CEs and significant LVEF declines in this population based cohort appear comparable to that reported in clinical trials. Based on the aTZ costs per patient in this study, the cost-utility of aTZ is more favourable than previous estimates although the associated budget impact remains substantial. No significant financial relationships to disclose.
Growth hormone deficiency and cardiovascular risk factors in childhood cancer survivors
Authors: Gujral K. , Petryk A. , Steffen L. , Baker K. , Perkins J. , Kelly A. S. , Zhou X. , Sinaiko A. , Moran A. , Steinberger J. 
Published: August 2020

6614 Background: Childhood cancer survivors (CCS) have a high frequency of growth hormone deficiency (GHD) and risk of early cardiovascular disease (CVD). This study examined the relations between GHD and risk factors for CVD in CCS. Methods: Anthropometrics, blood pressure, lipids, growth hormone (GH) stimulation test, dual-energy x-ray absorptiometry, abdominal CT, and insulin resistance (IR) (euglycemic, hyperinsulinemic clamp - low M/lbm signifies IR) were obtained in 174 CCS, mean age 15±2 years and 89 healthy sibling controls, mean age 13.5±3 years. Linear regression evaluated the relations between GHD and CVD risk factors, adjusted for sex, age, pubertal stage, and body mass index (BMI) or visceral fat. Results: 62 CCS (36%) had GHD. There were no significant measurement differences between non-GHD CCS and controls. Compared to controls, GHD CCS who never received GH (N = 34) had greater BMI (24.8 vs 20.8 kg/m2, p < 0.0001), percent body fat (36.1% vs 25.8%, p < 0.0001), visceral fat (34.8 vs 19.6 cm2, p < 0.0001), and triglycerides (TG) (120.2 vs 83.8 mg/dL, p = 0.001) and were more IR (M/lbm 11.1 vs 14.2 mg/kg/min, p = 0.0006). Adjustment for BMI and visceral fat did not change the IR or TG results. GHD CCS currently on GH had lower BMI (21.9 kg/m2, p = 0.02), percent body fat (31.2%, p = 0.08), and visceral fat (26.5 cm2, p = 0.03) compared to those not treated. IR and TG were not different between treated and not treated GHD CCS. Conclusions: GHD is a common finding in CCS and is significantly associated with adiposity, IR, and elevated TG.There is a suggestion that GH treatment had a positive impact on adiposity, but not IR and TG levels. These study findings imply that CVD risk factors are present in CCS with GHD independent of body fatness, suggesting that the cancer diagnosis or treatments received may lead to early cardiovascular disease in childhood cancer survivors. No significant financial relationships to disclose.
A comparison of patient-reported outcomes (PROs) in National Cancer Institute-sponsored cancer treatment trials conducted during two time periods: 1999–2003 and 2003–2008
Authors: O'Mara A. M. , Denicoff A. M. , Reeve B. , Burns R. , Trimble T. 
Published: August 2020

6618 Background: Over the past decade, the U.S. National Cancer Institute (NCI) support for incorporating Patient-Reported Outcomes (PROs) into disease treatment clinical trials has grown considerably, both in the number of trials, as well as the types of research questions being addressed and the measures used to answer the questions. This presentation will compare the breadth of NCI supported Phase III treatment trials in breast, colo-rectal, lung, and prostate cancers that include PRO secondary endpoints activated during two time periods: 1999–2003 and 2003–2008. Both time periods will be compared to identify the number and type of PRO measures; in addition the targeted PRO domain will be examined by cancer site. Methods: For this study, PRO was broadly defined to include any self-report questionnaire that gathered data on the potential impact that disease treatment might have on patient functioning, quality of life, or symptoms. Using the terms, 'protocol title, lead disease, phase III, quality of life, and instrument name,’ a search was conducted of the NCI database containing breast, colo-rectal, lung, and prostate Phase III treatment trials activated during the two time periods. If a scale was used more than once or if different versions of the scale were used, i.e., FACT-G and FACT-BR, it was only counted once. Results: Between 1999 and 2003, 42 phase III trials in the four major cancers were activated, with 15 trials having one or more PROs as secondary endpoints. Between 2003 and 2008, 50 phase III trials in the four major cancers were activated, with 28 trials having one or more PROs as secondary endpoints. Although the data reveal a 20% increase in the number of phase III trials in the 4 diseases between the two time periods, the number of trials with PRO endpoints has doubled. Conclusions: This significant increase in the use of PROs in phase III trials gives investigators additional data to fully analyze the impact of new treatments. These PRO data will provide researchers, clinicians, and future patients with a more in-depth understanding of the potential for new cancer therapies and technologies to extend both the quantity and quality of life. No significant financial relationships to disclose.
Subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients (Pts) with the T315I mutation: Data from an ongoing phase II/III trial
Authors: Cortes J. E. , Khoury H. J. , Corm S. , Nicolini F. , Schenk T. , Jones D. , Hochhaus A. , Craig A. R. , Humphriss E. , Kantarjian H. 
Published: August 2020

7008 Background: Omacetaxine (OM), a first-in-class cetaxine shows clinical activity against Ph+ CML with a mechanism independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have no activity against T315I. Methods: Adult Pts with T315I+ CML following TKI failure received OM induction at 1.25 mg/m2 subcutaneous (SC) twice daily (BID) for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 66 pts (39 chronic [CP], 16 accelerated [AP] and 11 blast phase [BP]) have been enrolled. All had failed prior imatinib and 80% failed ≥2 prior TKIs. Median age is 58 yrs. Median disease duration is 58 mos. OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are diarrhea (2%) and fatigue (4%). Efficacy data are available for 44 Pts. In CP Pts, the median number of cycles is 4 (1–22) with 39% having received ≥ 6 cycles of therapy; 64% of Pts have had the T315I clone reduced to below detection limits; the 2-year progression free survival is 70%. Conclusions: Omacetaxine in T315I+ CML Pts results in de-selection of the T315I clone and induces hematologic and cytogenetic responses. [Table: see text] [Table: see text]
Prognostic significance of leukopenia at the time of diagnosis in acute myeloid leukemia (AML)
Authors: Arellano M. L. , Winton E. , Pan L. , Souza L. , Sunay S. , Lima L. , McLemore M. , Heffner L. T. , Langston A. , Khoury H. J. 
Published: August 2020

7070 Background: In contrast to the poor prognosis associated with hyperleukocytosis, the prognostic significance of leukopenia at the time of diagnosis of AML is unknown. Methods: Single institution retrospective analysis of 225 consecutive, newly diagnosed AML patients (pts), homogeneously treated between July 1996 and February 2005; and divided into 2 groups based on presenting WBC: < 2,000/uL (30) and > 2,000/uL (195). Simultaneously obtained peripheral blood and marrow blasts were analyzed for cell surface expression of CD34, cKit, CXCR4, PCAM, VLA-2, VLA-3, VLA-4, VLA-5, and FLT3 using flow cytometry. Results: Patients’ characteristics (gender, secondary vs. de novo, and cytogenetic [CTG] risk) were comparable between the 2 groups. Leukopenic AML pts were older (median 56 vs. 53 years, p = 0.02), and had lower induction complete remission [CR] rates: 63% vs. 81% (p = 0.03) by univariate analysis. Induction mortality was 0% for leukopenic and 5% for non-leukopenic pts. In primary refractory pts, median survival was longer for leukopenic (11) vs. non-leukopenic (34) pts: 137 vs. 81 d (p = 0.026). Median follow-up was 22 mos. Event-free (EFS), disease-free (DFS), and overall survivals (OS) were lower in the leukopenic group: 12 vs. 14; 14 vs. 17; and 17 vs. 19 mos, respectively; but did not reach statistical significance. By multivariate analysis, age (p < 0.0001) and CTG risk group (p < 0.0001) were independent predictors of OS, while CTG risk group predicted RFS (p < 0.0001). The level of expression of cell surface adhesion molecules on blood and marrow blasts was comparable for the 2 groups. Conclusions: AML pts presenting with leukopenia have comparable outcomes to those presenting with normal or high WBC despite a lower likelihood of achieving remission. Leukopenic AML did not have over-expression of cell surface adhesion molecules. No significant financial relationships to disclose.
Insulin-like growth factor receptor 1 (IGF1R) protein expression, mRNA expression and gene copy number in operable non-small cell lung cancer (NSCLC)
Authors: Dziadziuszko R. , Merrick D. T. , Witta S. E. , Mendoza A. D. , Szostakiewicz B. , Rzyman W. , Jassem J. , Bunn P. A. , Varella-Garcia M. , Hirsch F. R. 
Published: August 2020

7524 Background: IGF1R is a promising target for NSCLC therapy. We have evaluated IGF1R protein expression, mRNA expression and gene copy number in primary tumors from surgically treated NSCLC patients (pts) as a reference for correlative biomarker studies in trials using IGF1R inhibitors. Methods: The study included 189 consecutive NSCLC pts who underwent curative pulmonary resection. There were 24% females, 54% squamous cell carcinomas (SCC), 29% adenocarcinomas (AC), 3% large cell carcinomas, 14% other histologies; p stage I: 41%, pII: 22%, pIII: 32% and pIV: 4%. IGF1R expression was evaluated in tissue microarrays by immunohistochemistry (IHC) with Ventana CONFIRM (N=179) and Novus (#NB600–559) anti-IGF1R Ab scored by two observers (H score 0–400). IGF1R gene copy number was assessed by FISH using customized probes (N=181). IGF1R gene expression was evaluated using qRT-PCR from 114 corresponding fresh-frozen samples. Results: Patterns of IHC staining were different for the Ventana and the Novus Ab (inverse correlation, r=-0.16, p=0.04, N=177). IGF1R protein expression detected by Ventana Ab (> median score) was more frequent in SCC (76%) than AC and other histologies (14%, p<0.001) and in pts with higher stage (p=0.03) but was not associated with survival (p=0.46). IGF1R H score by Ventana Ab, but not by Novus Ab, correlated with mRNA expression (r=0.37, p<0.001). IGF1R mRNA expression tended to be higher in SCC than in other histologies (p=0.089), but did not associate with other clinical features or survival (p=0.73). According to criteria previously established for EGFR, IGF1R gene copy number by FISH showed 5 tumors with gene amplification (2.8%), 43 tumors - high polysomy (23.8%), 87 tumors - low polysomy (48.1%), and 46 tumors - trisomy/disomy (25.4%). Pts with gene amplification/high polysomy had 3-yr survival of 60% (95% CI 47% - 74%) vs. 48% (38% - 59%) for low polysomy and 35% (21% - 49%) for trisomy/disomy pts (p=0.016). Prognostic value of IGF1R gene copy number was confirmed in the multivariate analysis. Conclusions: IGF1R protein expression is higher in SCC. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number associates with better prognosis in operable NSCLC. [Table: see text]
Effects of immediate compared with delayed gefitinib after front-line chemotherapy in Chinese with advanced non-small cell lung cancer
Authors: Wang J. Z. , An T. T. , Yang L. , Bai H. , Zhao J. , Duan J. C. , Li P. P. , Wu M. N. , Sun H. , Yang P. , Wang J. Z. 
Published: August 2020

8069 Background: To compare therapeutic effects of immediate vs. delayed gefitinib used for advanced non-small cell lung cancer (NSCLC) patients who obtained disease control (DC) after front-line chemotherapy in Chinese population. Methods: The study included 121 Chinese with advanced NSCLC treated with standard chemotherapy and obtained DC followed by either immediate gefitinib (66 cases) or delayed gefitinib, i.e. when tumors progressed (55 cases). The disease control rate (DCR), median progression-free survival time (PFS), median overall survival time (OS) of the two groups were analyzed. The impact of EGFR mutation status on the treatments was also evaluated. Results: The median PFS of patients treated in the immediate treatment setting was significantly longer than that of patients without gefitinib treatment (15.23 months versus 8.13 months,P<0.001). However, the overall median PFS was similar in patients treated with either immediate or delayed settings (15.23 months and 16.23 months respectively, P=0.450). There was no significant difference in OS between the two groups. Although patients whose tumors had EGFR mutation showed a longer median PFS compared to those without the mutation in both treatment groups, similar overall PFS was observed between the groups for patients with EGFR mutation (18.75 months and 18.30 months for maintenance and second-line groups, respectively). Conclusions: Immediate gefitinib use may improve PFS for Chinese patients with advanced NSCLC after front-line chemotherapy. However, similar PFS may be achieved by delayed use of gefitinib. No significant financial relationships to disclose.
Continued high activity of figitumumab (CP-751,871) combination therapy in squamous lung cancer
Authors: Karp D. D. , Novello S. , Cardenal F. , Haluska P. , Blakely L. J. , Garland L. , Paz-Ares L. G. , Dolled-Filhart M. P. , Johnson E. D. , Gualberto A. 
Published: August 2020

8072 Background: Figitumumab (CP-751,871) is a fully human, IgG2monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR). We reported in a randomized phase II study (ASCO 2008), preliminary evidence of high activity of the combination of paclitaxel (T), carboplatin (C) and figitumumab (F) in advanced treatment-naïve NSCLC of squamous cell histology (n=11 pts). A single arm trial extension cohort was conducted to confirm those findings. Methods: Fifty-six pts with non-adenocarcinoma NSCLC were enrolled. Pts received T (200 mg/m2), C (AUC of 6) and F (20 mg/kg) q3weeks for up to 6 cycles; pts with response (PR) or stable disease were eligible to continue F as single agent until disease progression. Statistical hypotheses were 30% (null) versus 50% (response of interest). Protein expression of the IGF-IR in core tumor biopsies was quantified using automated quantitative analysis (AQUA) technology. Results: Pts were 72% male, 28% >70 years old and 91% stage IV. Median number of treatment cycles was 4, with 46% of pts receiving single agent F beyond cycle 4. TCF was well tolerated. The most common all-causality grade 3, 4 CTCAE adverse events were neutropenia (21%), hyperglycemia (14%) and fatigue (14%). Hyperglycemia adverse events almost always occurred within the first treatment cycle and were manageable with standard measures. Responses in squamous pts are currently 25 out of 40 pts according to RECIST, with final response assessment still pending for 7 additional pts (≥53%, p<0.001). One complete response and 7 striking PRs (50–80% tumor size reduction at cycle 2) were observed. Tumor size reductions with F maintenance treatment were also seen in 2 pts. Median progression free survival has not been yet reached at 4 months follow up. A trend (p=0.1) for higher IGF-IR expression in patients responding to TCF was observed in a small data set (n=12). Median tumor IGF-IR expression in pts responding to TCF therapy and non-responders were respectively 6287 and 4131 AQUA scores. Analysis of IGF-IR and other members of the IGF-IR pathway continues. Conclusions: These data further support the activity of figitumumab combination therapy in pts with squamous NSCLC. [Table: see text]