tbuckley/cabot-search huggingface dataset:
Vitamin D levels among patients with colorectal cancer (CRC) from the San Francisco Bay area.
Authors: Marissa Barbara Savoie, Alan T Paciorek, Li Zhang, Nili Sommovilla, Chloe Evelyn Atreya, Hueylan Chern, Robin Kate Kelley, Andrew H. Ko, Ankit Sarin, Madhulika G. Varma, Donald I. Abrams, Alan P. Venook, Katherine Van Loon
Journal: Journal of Clinical Oncology (2017)

793 Background: A growing body of literature suggests that 25-hydroxyvitamin D [25(OH)D] levels are inversely related to the risk of developing CRC and that deficiency is associated with CRC-specific mortality. Due to the unique racial-ethnic diversity and UV exposure patterns of the San Francisco Bay Area, we aimed to evaluate vitamin D levels among our CRC patients at time of diagnosis and during treatment. Methods: Permanent residents of the SF Bay Area with a new diagnosis of CRC of any stage were recruited between 2011 and 2015 prior to initiation of therapy. Self-reported data on sun exposure, diet, and exercise patterns were collected. Clinical data including disease stage and primary tumor location were abstracted from charts. Serum 25(OH)D levels at time of diagnosis and at 6-month follow-up were batched and measured using the Liaison XL assay (Heartland Assays). Supplement use was not restricted. Kruskal-Wallis and Pearson correlation tests were used for categorical or continuous variables, respectively, to evaluate the associations of patient characteristics with 25(OH)D levels. Results: Among 94 patients with a new diagnosis of CRC, median 25(OH)D level at baseline was 27.0 ng/mL (range 7.2-59.0); 26% had deficient levels (&lt;20 ng/mL), 39% had insufficient levels (&lt;20 and &lt;30 ng/mL), and 35% had sufficient levels (&lt;30 ng/mL). Race, multivitamin use, vitamin D supplementation, and disease stage were associated with baseline serum 25(OH)D levels (p&lt;0.05). The median change in 25(OH)D from baseline to six months was -0.6 ng/mL (range -19.4-51.7) for patients treated with chemotherapy (n=60) and 1.6 ng/mL (range -6.4-33.2) for patients who did not receive chemotherapy (n=19) (p=0.51). Conclusions: Among patients with a new diagnosis of CRC in the San Francisco Bay area, vitamin D insufficiency was seen in more than half of patients, consistent with reports from other geographic areas. Allowing for vitamin D supplementation, serum 25(OH)D levels did not decrease significantly after 6 months of chemotherapy. We are routinely screening CRC patients for 25(OH)D insufficiency at time of diagnosis and during treatment.
Population-based analysis of treatment toxicity among men with castration-resistant prostate cancer.
Authors: Robert Nam, Christopher J.D. Wallis, Refik Saskin, Symron Bansal, Urban Emmenegger, Raj Satkunasivam
Journal: Journal of Clinical Oncology (2017)

252 Background: There is little phase 4 data regarding the toxicity and effectiveness of contemporary metastatic castrate-resistant prostate cancer (mCRPC) treatments. We examined hospital admissions and emergency room (ER) visits and survival among patients in the Province of Ontario treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel for mCRPC. Methods: We performed a population-based, retrospective cohort study of 2439 men over the age of 65 treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel for mCRPC from 2003-2015 in Ontario, Canada. Outcomes were toxicity (hospitalizations and ER visits) and overall survival. We used multivariable Cox proportional hazards models with time-varying exposures to calculate hazard ratios (HR). Results: Among 2439 patients, cumulative exposure was greatest for docetaxel (n = 1886 (77.3%); 11,436 person-months), followed by abiraterone (n = 893 (36.6%); 5143 person-months), enzalutamide (n = 52 (2.1%); 351 person-months) and cabazitaxel (n = 18 (0.7%); 61 person-months). Abiraterone exposure was not significantly associated with any-cause (HR 0.88, 95% CI 0.72-1.07) or treatment-related (HR 1.09, 95% CI 0.87-1.37) hospitalizations or ER visits. Enzalutamide was not significantly associated with any-cause (HR 1.20, 95% CI 0.69-2.07) or treatment-related (HR 0.85, 95% CI 0.43-1.68) toxicity. Docetaxel exposure was associated with a significantly increased risk of any-cause (HR 1.29, 95% CI 1.15-1.44) and treatment-related (HR 1.52, 95% CI 1.33-1.74) toxicity. Cabazitaxel exposure was also associated with treatment-related (HR 5.94, 95% CI 1.87-18.92) but not any-cause (HR 2.37, 95% CI 0.59-9.63) toxicity. Patients who began CRPC treatment after the introduction of oral therapies had improved overall survival compared with those treated prior to their introduction (aHR 0.70, 95% CI 0.64-0.77). Conclusions: Among patients with metastatic CRPC, treatment with chemotherapy (docetaxel or cabazitaxel) is associated with an increased risk of hospitalizations and emergency room visits. We failed to show a significantly increased risk for patients treated with oral agents (abiraterone or enzalutamide).
Pre-treatment 5-methyltetrahydrofolate levels and response to pemetrexed in stage IV adenocarcinoma of the lung.
Authors: Stephen Joseph Bagley, Corey J. Langer, Charu Aggarwal, Tracey L. Evans, Evan W. Alley, Roger B. Cohen, Suhong Zhang, Lynn Werner, Ian A Blair, Alexander Steven Whitehead, Anil Vachani
Journal: Journal of Clinical Oncology (2015)

8037 Background: The anti-folate drug pemetrexed (PMX) is used in treatment regimens for non-small cell lung cancer (NSCLC). Recent evidence suggests that differences in cellular folate metabolism may confer variation in tumor response to PMX. We investigated whether the pre-treatment intra-erythrocyte (RBC) level of 5-methyltetrahydrofolate (5-MTHF), a key component of folate metabolism, is associated with response to PMX-based chemotherapy in stage IV lung adenocarcinoma. Methods: We conducted a single-center, prospective cohort study of patients with newly diagnosed stage IV lung adenocarcinoma receiving first-line chemotherapy with a PMX-containing regimen. RBC 5-MTHF levels were quantified using a mass spectrometry-based method from blood drawn prior to initiation of chemotherapy. Clinical response was assessed by determining radiographic tumor response after 4-6 cycles of PMX-based chemotherapy and categorized as partial response, stable disease, or progression. We explored the relationship between pre-treatment RBC 5-MTHF levels and response to PMX-based chemotherapy. A log-binomial model was used to adjust for age and sex. Results: 54 patients were enrolled; the median age was 61 (IQR 55-68) and 29 (54%) were female. RBC 5-MTHF ranged from 37 to 1,667 nM (mean 588, median 518). Following 4-6 cycles of chemotherapy, 23 patients (43%) had an objective radiographic response and 15 (28%) had stable disease. The remaining 16 patients (29.6%) had progression (7 during cycles 1-3, 9 during cycles 4-6). Patients with 5-MTHF levels in the lowest quartile were significantly less likely to achieve radiographic response compared to patients in the highest three quartiles (response rate 8% vs. 54%; risk difference 0.46, 95% CI 0.25-0.67). After controlling for age and sex, there remained a significantly higher likelihood of lack of response to PMX for patients in the lowest 5-MTHF quartile (RR 6.86, 95% CI 1.01 – 46.92). Conclusions: Low pre-treatment RBC 5-MTHF levels are associated with an inferior response to PMX-based chemotherapy in stage IV lung adenocarcinoma. Multicenter prospective studies are needed to validate RBC 5-MTHF as a predictive marker of response to PMX in NSCLC.
BRAF mutation as a pejorative marker in metastatic melanoma.
Authors: Sophie Brissy, Caroline Gaudy-Marqueste, Stéphanie Mallet, Sandrine Monestier, Sylvie Hesse, Marie-Christine Koeppel, Marie-Christine Rojat-Habib, Isabelle Nanni, Anderson Loundou, L'houcine Ouafik, Nathalie Bonnet, Marie-Aleth Richard, Jean Jacques Grob
Journal: Journal of Clinical Oncology (2012)

8555 Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p&lt;0.05) were histopathologic subtype (SSM), high mitotic rate (≥1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, p=0.016), truncal location and location on occasionally exposed at sun site.The interval from diagnosis of first ever melanoma to first distant metastasis was not significantly different in BRAF-mutant and wild-type patients. The median overall survival (OS) from diagnosis of primary melanoma was 6.5 years for BRAF wild-type patients. Median OS was not reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, but also in those not treated (p=0.24, and p=0.06 for treated BRAF-mutant vs BRAF wild-type). The overall survival from diagnosis of first distant metastasis was not significantly different (p=0.75). These results remained unchanged in a multivariate analysis. Conclusions: Our results confirm the characteristics of BRAF-mutant metastatic patients, and the efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is per se a pejorative predictive marker.
A phase II, single-arm, feasibility study of dose-dense doxorubicin and cyclophosphamide (AC) followed by eribulin mesylate for the adjuvant treatment of early-stage breast cancer (EBC).
Authors: Tiffany A. Traina, Clifford Hudis, Robert Lehman, Jessicca Rege, Wenquan Wang, David Cox, Andrew David Seidman
Journal: Journal of Clinical Oncology (2012)

TPS1145 Background: Randomized trials have confirmed the benefit of the combination of an anthracycline (A) and cyclophosphamide (C) for the adjuvant treatment of EBC. The addition of taxane therapy to AC therapy has further improved survival. Despite the improvement in adjuvant therapies for BC, new approaches for improving outcomes are of significant importance and may involve developing improved combination regimens. Eribulin mesylate has demonstrated antitumor activity and significant improvement in overall survival (OS) in patients with heavily pretreated locally advanced or metastatic breast cancer (MBC) and may improve outcomes in EBC as well. Methods: This study will determine the feasibility of eribulin as adjuvant therapy following dose-dense AC for HER2 normal EBC. A completion rate of &gt;80% was set as a threshold for feasibility as established adjuvant regimens have shown feasibility rates ranging from ~65% for trastuzumab to &gt;80%. This is a phase 2, single-center, feasibility study of dose-dense adjuvant chemotherapy in patients with EBC. Dose-dense AC (Doxorubicin 60 mg/m 2 IV plus C 600 mg/m 2 IV) on day 1 of every 14-day cycle is given for 4 cycles, followed by 4 cycles of eribulin mesylate at 1.4 mg/m 2 over 2-5 minutes IV on days 1 and 8 every 21 days. Growth factors are given on day 2 of AC cycles and only for neutropenia events with eribulin treatment. Feasibility is determined by the ability to complete the eribulin portion of the regimen without a dose delay or reduction. Exploratory objectives include efficacy endpoints of 3-year disease-free survival (DFS) and OS. Patients have histologically confirmed HER2 normal stage I-III invasive disease and adequate bone marrow, liver, and renal function. Thirty two of approximately 80 planned patients are currently enrolled. Feasibility rates will be calculated with growth factor support (ie, the successful use of growth factor support following a neutropenia event is not considered a dose delay)and without growth factor support (ie, where need for growth factors is considered a delay). Secondary endpoints include DFS and OS and will be estimated by Kaplan-Meier method.
Use of platinum-based neoadjuvant chemotherapy (NACT) in patients (pts) with hormone receptor-positive breast cancer.
Authors: Christos Kyriakopoulos, Tadeu Frantz Ambros, Alberto J. Montero, Judith Hurley
Journal: Journal of Clinical Oncology (2012)

e11038 Background: NACT is used for the treatment of locally advanced breast cancer. Evaluation of breast cancer subtypes and their responses to specific chemotherapy regimens is important. Methods: Retrospective review of medical records from University of Miami/Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital from 1998-2011. Complete pathologic response (pCR) was classified as absence of malignant tissue both in the breast and the lymph nodes in the surgical specimen. Results: One hundred ninety-one women with ER-positive breast cancer received platinum based NACT. Mean age was 52 years (range 31-83). One hundred eleven (58.1%) women were premenopausal and 80 (41.9%) postmenopausal. The clinical stage at presentation: IIA (6.3%), IIB (26.7%), IIIA (31.9%), IIIB (30.9%), IIIC (4.2%). Sixty one (31.9%) pts had her-2/neu positive tumors. pCR occurred in 17 patients (8.9%), premenopausal vs. postmenopausal (9.9% vs. 7.5%, p=0.56), white race vs. black (9.9% vs. 4.9%, p=0.32), Hispanic vs. non-Hispanic (9.4% vs. 6.8%, p=0.6), tumor size &lt;=4 cm vs. &gt;4 cm (14.7% vs. 7.6%, p=0.19), her-2/neu positive vs. her-2/neu negative (13.1% vs. 6.9%, p=0.16), T4 vs. T1-T3 (4.8% vs. 10.9%, p=0.19). Conclusions: pCR rates with platinum based NACT in pts with hormone receptor-positive tumors were low. The pCR rate did not appear to be influenced by her2/neu, tumor size, race, ethnicity or menopausal status.
Abstract #2301: Combined Bcl2 /mTOR inhibition leads to enhanced radiosensitization via autophagy and apoptosis in non-small lung numor nenograft model
Authors: kwang Woon kim, Dae Kwang Jung, Bo Lu
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Purpose: Radiotherapy has a central role in the treatment of locally advanced non-small cell lung cancer. The effectiveness of this modality, however, is often limited, in part due to the presence of defects in cell death pathways. In this study, we hypothesized that combination of an apoptosis-induced agent and an inducer of autophagy with radiation could potentially act in additive or synergistic cytotoxicity in vitro or in vivo. Methods: Clonogenic assay was used to determine radiosensitivity. H460 lung cancer xenografts was generated and immunohistochemistry (IHC) was performed on tumor sections for tumor cell proliferation (Ki67 staining), angiogenesis (von Willebrand Factor staining), and apoptosis (cleaved caspase-3 antibody staining). Autophagy was determined by p62 protein, which is named sequestosome 1(SQSTM1) and links polyubiquitinated proteins to the autophagic machinery in vivo and punctuate localization of GFP-LC3 fusion protein, which observed under a confocal fluorescence microscope in vitro. Apoptosis measured using the Annexin V-fluorescent isothiocyante apoptosis detection kit I (Pharmingen) with flow cytometry in vitro. Autophagy was induced by rapamycin, an mTOR inhibitor, and apoptosis was induced by AT-737, a Bcl2 inhibitor. Results: The combination of ABT-737 and rapamycin markedly enhanced sensitivity of H460 cells to radiation (DER=2.47, p=0.002) in clonogenic assay. This enhanced radiosensitization was associated with an increase in characteristic punctuate localization of GFP-LC3 and in cleaved caspase-3, suggesting that both apoptosis and autophagy were induced simultaneously. We found that the combination of ABT-737 and rapamycin with radiation showed a dramatically tumor growth delay in a mouse hind limb xenograft model in vivo , and was well tolerated compared to control. In addition, the concurrent administration of ABT-737, rapamycin and radiation in vivo significantly decreased cell proliferation by 77% (P=0.001) and vascular density by 67.5% (p=0.09) compared to radiation alone. Consistent with the in vitro results, the tri-modality treatment showed a dramatically 14-fold increase in caspase-3 activity as a marker for apoptosis and a significant 8-fold decrease in p62 protein level for detecting autophagic flux in the lung tumor xenograft model. Conclusions: These results suggest that concurrent up-regulation of autophagy and apoptosis may be utilized as a novel strategy to enhance radiation therapy in lung cancer . 

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2301.
Treating patients with colorectal liver metastasis: A national decision-making analysis to understand choice of therapy.
Authors: Timothy M Pawlik, Hari Nathan, David Cosgrove, Dan Laheru, Luis A. Diaz, Joseph M. Herman, Barish H Edil, Kenzo Hirose, Christopher Lee Wolfgang, Michael A. Choti, Richard D. Schulick
Journal: Journal of Clinical Oncology (2012)

3596 Background: Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. Methods: Physicians completed a national web-based survey that consisted of varied CLM case scenarios. Respondents choose among 3 treatment strategies: immediate liver resection(LR), preoperative chemotherapy followed by surgery(C→LR), or palliative chemotherapy (PC). Data were analyzed using multinomial logistic regression, yielding relative risk ratios (RRR). Results: Of 219 respondents, 79% practiced at academic centers and 63% were in practice ≥10 years. Median number of cases evaluated was 4/month. Surgical training varied: 51% surgical oncology (SO), 44% hepatobiliary/transplant (HB/LT), 5% no fellowship. While each factor impacted choice of CLM therapy, the relative impact differed (p&lt;0.01). Synchronous CLM presentation increased the choice of C→LR (OR 4.27) and PC (OR 3.10) versus LR (p&lt;0.001). For patients with more extensive intrahepatic disease (i.e., 5 tumors, both lobes) respondents strongly favored C→LR (OR 5.12) and PC (OR 9.60) versus LR (p&lt;0.001). The presence of hilar lymph-node disease was associated with a strong aversion to LR with surgeons more likely to choose C→LR (OR 8.92) or PC (OR 49.9) (p&lt;0.001). Interestingly, even the presence of a resectable solitary lung metastasis strongly deterred choice of LR with respondents favoring C→LR (OR 4.43) or PC (OR 6.97) (p&lt;0.001). While other factors such as patient age, tumor size, and extent of resection impacted choice of therapy, the relative size of these effects was modest. After controlling for clinical factors, surgeons with more years in practice were more likely to choose LR (RRR 1.4). SO-trained surgeons were more likely than HB/LT-trained surgeons to choose C→LR (RRR 2.5) or PC (RRR 4.15)(p&lt;0.001). Conclusions: This is the first study to define the relative impact of key clinical factors on choice of therapy for CLM. While clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.
A phase Ib dose-escalation study of TRC105 in combination with bevacizumab for advanced solid tumors.
Authors: David S. Mendelson, Lee S. Rosen, Francisco Robert, E. Gabriela Chiorean, Jonathan Wade Goldman, Ben K. Seon, Delia Alvarez, Bonne J. Adams, Charles P. Theuer, Bryan R. Leigh, Michael S. Gordon
Journal: Journal of Clinical Oncology (2012)

3034 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is a human/mouse chimeric anti-CD105 monoclonal antibody that completed phase I testing and is being studied in multiple phase II trials. Methods: Pts with advanced solid tumors (non-CNS), ECOG PS 0-1, and normal organ function were treated with escalating doses of intravenously administered TRC105 plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk and assessed for safety, PK, and response. Results: Twelve pts were treated (3 with TRC105 at 3 mg/kg q1wk + BEV at 15 mg/kg q3wk, 5 with TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk, and 4 with TRC105 at 6 mg/kg q1wk + BEV at 10 mg/kg q2wk), and 10 have completed the DLT evaluation period. TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk resulted in grade 1-3 headaches with sinus congestion following the cycle 1 day 1 (C1D1) dose in 5 of 5 pts that improved with continued dosing. Treatment with BEV 10 mg/kg q2wk and sequential dosing with Bev starting on C1D1 and TRC105 on C1D8 resulted in decreased frequency and severity of headaches, allowing dose escalation to continue. TRC105 serum concentrations that saturate CD105 binding sites (&gt;200 ng/mL) were achieved continuously at 6 mg/kg q1wk. At 3 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV, one pt with BEV-resistant ovarian cancer had stable disease for 6 cycles and one pt with refractory hepatocellular cancer who failed sorafenib and sunitinib had an AFP decrease from 1578 at baseline to 179 at the end of cycle 3. Two of three evaluable pts at 6 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV with VEGF-refractory tumors (HCC and CRC) are ongoing in C4 with stable disease. Dose escalation continues and TRC105 dose levels of 8 and 10 mg/kg are planned. Conclusions: The combination of TRC105 and BEV was tolerated with early evidence of activity in VEGF-refractory pts by sequential administration during initial dosing in C1.