tbuckley/cabot-search huggingface dataset:
Health-related quality of life of pre-menopausal breast cancer survivors
Authors: M. J. Naughton, J. A. Petrek, E. Ip, E. D. Paskett, E. Naftalis
Journal: Journal of Clinical Oncology (2005)

636 Background: Longitudinal studies examining the health-related quality of life (HRQL) of premenopausal breast cancer patients are sparse, and are needed to identify survivorship issues among younger women. Methods: 627 premenopausal women were recruited to the Menstrual Cycle Maintenance and Quality of Life Study between 1998 and 2001 and are still receiving follow-up. Patients were ≤ 45 years old with regular menstrual cycles at the time of diagnosis with a stage 1–3 breast cancer. Multivariate regression techniques were used to investigate which demographic (age, race, education, marital status, number of children), clinical (stage at diagnosis, type of surgery, treatments received, menstrual bleeding status at follow-up), and lifestyle variables (body mass index, cigarette use, alcohol use, exercise and social support) were predictive of HRQL, as measured by the FACT-B total score, at 1, 2, and 3 years post-breast cancer diagnosis. Results: FACT-B total scores improved as the time from diagnosis increased (105.5, SD 19.2 at baseline vs. 113.4, SD 19 at year 3, p<.001). At one year post-diagnosis, Caucasian race (p=.0477), patients’ satisfaction with appearance (p<.0001), greater social support (p<.0001), and greater time since diagnosis (p=.0038) were significant predictors of better HRQL. Longitudinal analyses at 2 and 3 years post-diagnosis indicated that HRQL was lower among those who were non-Caucasian (p=.0006 year 2; p=.0016 year 3), those with lower education (p=.0341 year 2; p=.0233 year 3), and those who received adjuvant chemotherapy (p=.0150 year 2; p=.0174 year 3). HRQL was better for those who were more satisfied with their appearance (p<.0001 at both years 2 and 3), engaged in moderate weekly exercise (p=.0081 year 2; p=.0006 year 3), had higher social support (p<.0001 at both 2 and 3 years), and as time from diagnosis increased (p=.0007 year 2; p<.0001 year 3). Conclusions: The HRQL of breast cancer survivors is improving as time from diagnosis increases. Interventions focused on increasing satisfaction with appearance, regular physical exercise, and improved social supports may be of benefit to young survivors. No significant financial relationships to disclose.
Using whole-genome sequencing to implicate the androgen receptor as the predominant driver of DNA breakpoints and fusion events in prostate cancer.
Authors: Niall Corcoran, Geoff Macintyre, Matthew Hong, Clare Slogget, Haroon Naeem, Marek Cmero, John Pedersen, Izhak Haviv, Andrew Ryan, Pramit Phal, Anthony Costello, Christopher Hovens
Journal: Journal of Clinical Oncology (2014)

67 Background: Structural rearrangements in cancers genomes have the potential to disrupt normal gene function and result in a selective growth advantage, either by inactivating tumour suppressors or creating novel gene fusions with oncogenic gain-of-function. Specific fusion genes identified to date are found in particular tumor types rather than being present in all cancers suggesting there are tissue-specific mechanisms underlying these events. The most well-known fusion event in prostate cancer is TMPRSS2-ERG. Recent studies have suggested that androgen receptor may play a role in the formation of TMPRSS2-ERG fusions, bringing the two loci in close proximity in the nucleus and facilitating DNA strand break and repair along with AR associated enzymes. Methods: To explore this mechanism more comprehensively, we performed whole-genome sequencing of 14 prostate cancers from seven patients as well as paired whole blood controls. Results: Across the cancer genomes we identified approximately 4,500 high confidence DNA breakpoints and found that a large proportion of these breakpoints were in close proximity to curated androgen receptor binding sites. Furthermore, when we examined breakpoints in 11 other cancers from the TCGA and ICGC projects, we identified a similar association with androgen (and estrogen) receptor binding sites specifically in hormone-dependent tumour types, suggesting a role for steroid hormone receptors in the formation of cancer driving structural rearrangements. In addition, in at least one patient, the formation of a novel gene fusion contributed directly to the lethal evolution of his tumour. Conclusions: These data suggest that the androgen receptor drives genome wide breakpoints and novel fusion events in prostate cancer.
Increased gene copy number and amplification of FGF2 and FGFR1 in metastatic colorectal cancer.
Authors: Christopher Hanyoung Lieu, Marileila Varella-Garcia, Liang Guo Xu, Zhi-Qin Jiang, S. Gail Eckhardt, Wells A. Messersmith, Dipen M Maru, Scott Kopetz
Journal: Journal of Clinical Oncology (2013)

402 Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration, and angiogenesis in cancers. However, gene copy number and amplification of FGF2 and FGFR1 have not been extensively evaluated in patients with metastatic colorectal cancer (CRC). Methods: Two tissue microarrays (TMA) were constructed with resected CRC liver metastases from 120 patients. The TMAs included duplicated intratumoral regions and the invasive margin between tumor and normal hepatic parenchyma. Patients were either untreated, or previously treated with FOLFIRI or FOLFOX +/- bevacizumab. The TMA slides were subjected to a two-color FISH assay using a mixture of FGF2 and FGFR1 in-house developed probes. Results: Results were obtained from 118 patients. The analysis detected an average of 1.90 copies of FGF2 signal per cell (range, 1.10-3.46 copies) and an average of 2.27 copies of FGFR1 signal per cell (range, 1-12-7.14 copies). Three control specimens from each slide were also scored, with an average of 1.74 copies of FGF2 and 1.73 copies of FGFR1. High copy number per cell (mean &gt; 2.5 copies) was detected in 9.3% of specimens for FGF2 and 27.9% for FGFR1, including 2 patients (1.7%) for FGF2 and 5 (4.2%) for FGFR1 with focal amplification, defined by ≥ 10% cells with &gt; 4 copies. Additionally, duplications of gene signals in the same locus were detected in 10 samples (8.5%) for FGF2 and 19 (16.1%) for FGFR1. Intratumoral heterogeneity was rare (detected in 3 patients). There was no statistically significant correlation between FGF2 or FGFR1 gene copy number and prior treatment, pathologic response, relapse free survival, or overall survival, though there was a trend towards higher FGFR1 gene copy number in patients previously receiving bevacizumab (p=0.07). Conclusions: Both FGF2 and FGFR1 display variable copy number among resected CRC liver metastases, with larger variability detected for FGFR1. Gene amplification was rare but detected in several patients for both FGF2 and FGFR1. Follow up studies will investigate higher FGFR1 gene copy number in patients previously treated with bevacizumab, perhaps reflecting a potential escape or resistance mechanism.
A non-comparative phase II study of pemetrexed in patients with pretreated soft tissue sarcoma: German Sarcoma Group/AIO 005
Authors: J. T. Hartmann, S. Bauer, S. Schaedel, I. Meisinger, B. L. Bruecher, B. Kasper, H. Kopp, L. Kanz, F. Mayer, V. Gruenwald
Journal: Journal of Clinical Oncology (2008)

10575 Background: To assess the efficacy and safety of pemetrexed, a multi target enzym inhibitor with antitumor activity in epithelial and mesenchymal tumors, in patients with adult type soft tissue sarcoma (STS) who have failed anthracycline-based chemotherapy. Methods: Pts with ECOG 0–2, measurable disease and adequate organ functions were eligible. All patients had metastatic disease and had progressive disease during or after first-line chemotherapy prior to study entry. Pemetrexed was administered at a dose of 500 mg/m2 i.v. applied over a period of 10 minutes (day 1), repeated on day 22. Supplements consisted of oral folic acid 350–1,000 μg beginning at least 5 days prior to the first application of pemetrexed, continuing for 21 days, as well as Vitamin B12 1,000 μg i.m. 1–2 weeks prior to the initial application and following every third treatment cycle. Dexamethasone was prescribed 4 mg orally b.i.d. 1 day prior to, on the day of and one day after each application of pemetrexed. The primary endpoint was overall response rate as defined by RECIST. The secondary endpoint was toxicity. A two-stage design was used (1st step: 14 pts, at least 1 PR in order to succeed with 2nd step; p0 = 5+, p1 = 25+, alpha = beta = 0.1). Results: 37 patients, median age 59 yrs (range, 20–81) with STS were recruited. To date, 30 pts are evaluable for toxicity and 24 pts for efficacy analysis after cycle 2. In general, the drug was well tolerated. Hematologic CTC grade 3 toxicity consisted of granulocytopenia in 10+, anemia in 13+ and febrile neutropenia/fever in 3+ of pts. No toxic death was seen in a total of 104 cycles administered. CTC grade 3 non- hematologic toxicity consisted of elevated ASAT/ALAT in 10+, fatigue in 7+ and mucositis in 3+ of pts. Summary of anti-tumor activity: 1 confirmed partial response (4+). Four further pts had minor responses (>20+ shrinkage), and progression arrest after cycle 2 was seen in 6 additional pts (46+). Conclusions: The confirmed objective response rate is low; however, 4 additional pts showed tumor shrinkage >20+ from baseline. Preliminarily, the progression-free rate of 46+ after two cycles of treatment in pretreated adult type STS appears promising. The observed toxicity profile is favorable. Supported by Lilly Germany, ClinicalTrials.gov ID NCT00427466. No significant financial relationships to disclose.
The hotspot mutational landscape of upper tract and bladder urothelial cancers and correlation to survival.
Authors: Matthew T. Campbell, David James McConkey, Surena F. Matin, Ashish M. Kamat, Colin P. N. Dinney, Jennifer Wang, Jianjun Gao, Arlene O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2016)

466 Background: The prevalence of potentially targetable molecular mutations in urothelial carcinoma of the upper tract and bladder carcinoma are beginning to emerge. Important differences of molecular alterations may exist between upper tract and bladder primary tumors necessitating different treatment approaches and drug development strategies for these patients. Methods: All patients with urothelial carcinoma at UT MD Anderson who had undergone the CLIA-certified 50 gene panel utilizing next generation sequencing for detection of hotspot mutations were retrospectively reviewed. The prevalence of mutations was tabulated and compared between upper tract and bladder primary tumor locations using the Fisher’s exact test. Survival comparisons were calculated using the Kaplan-Meier technique and the Log Rank Test. Results: 136 patients with urothelial carcinoma were included in the analysis of which 41 were upper tract and 95 had bladder primary tumors. Of the 136 patients, 132 had de novo or developed metastatic/recurrent disease. The most prevalent mutations in the upper tract primary cohort included FGFR3, TP53, EGFR, FBXW7, PIK3CA, and KRAS. The most prevalent mutations in the bladder primary tumors were TP53, PIK3CA, RB1, FGFR3, HRAS, KRAS, BRAF, and FBXW7. In both upper tract and bladder tumors, a mutation in FGFR3 was nearly mutually exclusive for having a TP53 mutation. Compared to bladder primary tumors, upper tract tumors were more likely to have an FGFR3 mutation (36.5% vs. 7.4%, p &lt; 0.0001), while the prevalence of TP53 (34% vs. 49%) and or a mutation in PIK3CA, HRAS, or KRAS (12.2% vs. 20.8%) was not significantly different. In the 132 patients with metastatic disease, the presence of a mutation in PIK3CA, HRAS, or KRAS was associated with inferior survival (HR 2.342, 95% CI: 1.32-8.67, p = 0.012), while the presence of an FGFR3 or TP53 mutation was not associated with a statistically different survival when compared to patients with wild type mutational status. Conclusions: Patients with upper tract and bladder primary sites have different molecular mutation rates. Understanding how these mutations in differing sites affect tumor biology may have important clinical implications.
Potential mechanisms for the anti-myeloma properties of bisphosphonates
Authors: K. M. Swanson, H. Tong, A. J. Wiemer, S. Murthy, R. J. Hohl
Journal: Journal of Clinical Oncology (2005)

6586 Background: For cell membrane association, small GTPases such as Ras, Rap1A, Rab, and Rho must undergo post-translational isoprenylation modification. Isoprenoid intermediates of the mevalonate pathway, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), are substrates for farnesylation or geranylgeranylation modifications, respectively. It is reported that nitrogen-containing bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit isoprenylation through inhibition of FPP synthase, the enzyme that catalyzes the synthesis of FPP. A more significant target could be GGPP synthase, the enzyme that catalyzes the synthesis of GGPP. This study was designed to more precisely identify mevalonate pathway targets of BPs. Methods: Human-derived myeloma cell lines, RPMI-8226 and ARH-77 were incubated for 24 hours with either 50μM of ZOL, or 50μM LWS-138, a novel non-nitrogen containing BP found to be a selective GGPP synthase inhibitor. Levels of FPP and GGPP were measured using methods recently reported (Tong, H. et al. Analytical Biochemistry, 336:51, 2005). Isoprenylation status of Rap1A and Rab6 were analyzed by Western blot. Results: In RPMI-8226 cells, baseline levels for FPP and GGPP were 0.115+/- 0.009 pmol/ 106 cells and 0.270 +/- 0.010 pmol/106 cells, respectively. In ARH-77 cells these values were 0.144 +/- 0.009 pmol FPP/ 106 cells and 0.250 pmol GGPP/ 106 cells. When treated with ZOL, GGPP levels decreased by 54%, while FPP levels increased by 297%. When treated with LWS-138 GGPP levels decreased by 95%, while FPP levels increased by 121%. Both ZOL and LWS-138 impaired isoprenylation of Rap1A and Rab6. The addition of 10μM GGPP, but not 10μM FPP restored isoprenylation of these proteins. Conclusions: GGPP synthase is a more likely target of inhibition by BPs in human myeloma cell lines than FPP synthase. Increased FPP levels after treatment with ZOL suggest that ZOL may have multiple sites of activity on the isoprenoid pathway, while LWS-138 is specific for GGPP synthase. No significant financial relationships to disclose.
Knowledge-based planning for stereotactic body radiation therapy (SBRT) of the liver.
Authors: Hunter C Gits, Janell Dow, Martha Matuszak, Mary Uan-Sian Feng
Journal: Journal of Clinical Oncology (2016)

375 Background: SBRT is emerging as a treatment option for patients with unresectable liver tumors. However, generating high quality liver SBRT plans is technically challenging and user-dependent. Aiming for high tumor doses and low normal tissue doses can demand lengthy planning times and result in plans of inconsistent quality. This study investigates knowledge-based planning (KBP) as a standardized method to ensure efficacy, safety, and efficiency for SBRT plans and allow for broader use of this therapy. Methods: SBRT treatment plans were manually optimized for 55 liver cancer cases by an expert liver dosimetrist in a commercial treatment planning system (Varian Eclipse v13.6). Each volumetric modulated arc therapy plan was approved by a physician using strict criteria for target coverage and normal tissue sparing. The plans were used to create a custom model in a KBP system (RapidPlan, Varian Eclipse v13.6) designed to improve both efficiency and standardization of quality. To validate the model, 15 new cases were optimized manually by an expert liver dosimetrist and then semi-automatically using the KBP model. The validation plans were compared based on target coverage, normal tissue sparing, and planning time. Results: Compared to manual plans created by an expert liver dosimetrist, KBP-generated plans showed similar target coverage and improved normal tissue sparing with similar planning times. Mean and minimum target doses were similar, as was D98, p &gt; 0.2 for all. Normal tissue complication probability for liver damage was marginally lower with KBP, mean 3 vs. 1%, p = 0.07. Doses to adjacent organs including stomach, heart, and bowel were similar. Manual planning required a median and mean time of 15 and 20 minutes, respectively, range 8-55 min. KBP required similar times of 12 and 19 min, range 8-50 min. 9 of 15 KBP cases were automated, while 6 plans required dosimetrist improvement. Conclusions: Using KBP, high quality plans for liver SBRT can be created automatically or semi-automatically. These plans are comparable to those generated by an expert liver dosimetrist. KBP could be used to standardize treatments between institutions, particularly when experience with liver SBRT is limited.
Cosmetic outcome within one year of breast-conserving surgery, after external beam or intraoperative radiotherapy for early breast cancer: Objective assessment of patients from a randomized controlled trial.
Authors: Norman R. Williams, Frederik K. Wenz, Grit Welzel, Nikolaos Michalopoulos, Mohammed R. Keshtgar
Journal: Journal of Clinical Oncology (2014)

1088 Background: The international randomised controlled TARGeted Intraoperative radioTherapy (TARGIT) trial demonstrated non-inferiority between the technique of TARGIT (Intra-Operative RadioTherapy (IORT) with Intrabeam) and whole-breast external beam radiotherapy (EBRT) in women with early breast cancer. We have shown in a sub study of 342 patients that cosmesis at one year or later is better after TARGIT than EBRT; a significant component was cX2b (“redness”, a surrogate for radiation induced erythema grade I or II). The aim of this study was to determine if the single high dose of TARGIT leads to impaired cosmesis within the first year after surgery. Methods: Frontal digital photographs were taken of women participating in the TARGIT Trial at a single centre and analysed, blinded to treatment received, by BCCT.core software which produced Harris scores for symmetry, colour and scar; scores for cX2b were also recorded, a high score indicating “redness.” Results: 17 women (9 EBRT, 8 IORT), median age 65 years (range 50 to 79) had photographs taken at baseline (up to 5 days prior to surgery), then at one month (median 31d), at 6m if given EBRT (median 87d from first fraction), and at 12m (median 332d). All images scored Excellent, Good or Fair with no differences apparent over time or between treatment groups. At 6m there was a significant change from baseline in cX2b in the women given EBRT (see Table); this change persisted to 12m. No change was seen after IORT. Conclusions: This objective assessment of aesthetic outcome in patients from a randomised trial demonstrates that “redness” associated with EBRT is significantly worse within 90d of commencement; this change was not seen in women treated with IORT. This study provides further evidence that the objective scoring of cosmesis using BCCT.core is feasible and may be an approach for standardisation, and shows an early beneficial effect of TARGIT on cosmesis. Increase in cX2b from baseline mean (SEM). 1 month 6 months 12 months EBRT -0.04(0.09) +0.18(0.06)* +0.18(0.17) IORT +0.02(0.03) +0.04(0.10) * Significant increase from baseline P = 0.0247, paired t-test.
Assessment of fetal radiation dose during maternal sentinel lymph node mapping for breast cancer
Authors: L. Montgomery, L. Dauer, I. Doddamane, J. St. Germain, P. Zanzonico, H. Cody, P. Borgen, C. Divgi
Journal: Journal of Clinical Oncology (2005)

541 Background: Pregnancy is considered a contraindication to sentinel lymph node (SLN) mapping due to the possible detrimental effects of technetium-99m sulfur colloid (TSC) radiation and isosulfan blue dye on the developing fetus. As a result, pregnant women with breast cancer must undergo complete axillary lymph node dissection for axillary staging. The U.S. Nuclear Regulatory Commission has established an occupational dose limit of 500 mrem over the gestation period (recommended at the rate of no more than 50mrem/month) for a declared pregnant woman. The purpose of this study was to assess the amount of radiation exposure to the fetus during breast surgery involving SLN mapping using TSC and to compare this exposure to federal regulatory limits. Methods: A review was performed of a prospective SLN database of 1,021 patients who underwent SLN mapping using unfiltered TSC from January 2000 to April 2001. Two separate techniques were used with respect to isotope SLN mapping: either 0.1 mCi TSC particles were injected intradermally superficial to the tumor site on the same day as surgery or 0.5 mCi TSC particles were injected on the day before surgery. Standard, FDA-reviewed, dose assessment methodologies (OLINDA-EXM 1.0) were applied to a standard reference model and to the median patient characteristics from this database to develop a patient-population phantom (non-pregnant and at 3 stages of pregnancy: 3 mos, 6 mos, and 9mos). It was assumed that the injection site remained in the breast until complete decay of the technetium-99m, regardless of the definitive breast procedure. Results: See Table. Conclusions: Based on these conservative estimates, the maximal fetal doses during breast surgery involving TSC for SLN mapping are small and well below levels associated with risk concerns. At these activity levels (0.1 mCi and 0.5 mCi), pregnancy should not be considered a contraindication for SLN mapping in breast cancer utilizing TSC. No significant financial relationships to disclose.
Prognositic value of suppressed markers of bone turnover (BTO) after 6 months of androgen deprivation therapy (ADT) in prostate cancer.
Authors: J. Sharma, C. T. Yiannoutsos, N. M. Hahn, C. Sweeney
Journal: Journal of Clinical Oncology (2011)

4594 Background: Elevated markers of bone turnover at baseline are prognostic for poorer cancer outcomes. Suppressed levels on therapy may be prognostic for better ADT efficacy in controlling prostate cancer. Methods: Markers of bone turnover were assessed at baseline and 6 months in a prospective prostate cancer trial of patients with bone metastases commencing ADT. Association with time to castration resistant prostate cancer (CRPC) and skeletal related event (SRE) was evaluated using a MVA model with a Cox regression analysis with covariates of treatment assignment to 30 mg/day of risedronate versus placebo and known prognostic variables, PSA nadir < 0.2 ng/ml vs. > 0.2 ng/ml and extent of metastases. Results: Between 12/03 and 8/05, 63 patients were enrolled with median follow-up of 39.7 months. BTO markers were available for 50 patients at baseline and 40 patients at 6 months. The median values at baseline and 6 months were urine n-telopeptide (nmolBCE/mmol Creat) - 42.65/27.40; urine total DPD (nmol/mmol Creat) - 9.84/8.30; bone specific alkaline phosphatase (ng/mL) - 20.35/9.77 and serum osteocalcin (μg/mL) -19.43/16.82. On MVA, 6 month BTO markers which were all below the baseline median BTO marker level (p=0.014), nadir PSA below 0.2 ng/ml (p=0.042) and lower volume of metastases at baseline (p=0.033), were associated with longer time to SRE. 6 month BTO biomarkers below the baseline median and PSA nadir < 0.2ng/ml were the factors associated with longer time to CRPC (p=0.026 and p=0.058 respectively) and 6 month BTO markers below the baseline median was the only factor weakly associated with OS (p=0.092) in this study in men on ADT for metastatic prostate cancer with bone involvement. Conclusions: Lower bone turnover markers at 6 months of ADT is prognostic for better outcomes with ADT.