tbuckley/cabot-search huggingface dataset:
A prognostic score for patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate post chemotherapy.
Authors: Arnoud J. Templeton, Aurelius Gabriel Omlin, Carmel Jo Pezaro, Thian San Kheoh, Raya Leibowitz-Amit, Francisco Emilio Vera-Badillo, Ian Tannock, Gerhardt Attard, Eitan Amir, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2014)

70 Background: We aimed to establish a simple prognostic score for men with mCRPC treated with abiraterone following docetaxel and explored incorporation of the neutrophil/lymphocyte ratio (NLR), a marker of host inflammation with prognostic value in many solid tumors. Methods: To develop the model, clinical and laboratory factors for 185 men treated at Royal Marsden were included in a univariable Cox regression analysis. Statistically significant variables were dichotomized using an optimal cut-off chosen by selecting the highest c-index among three potential cut-offs with high Hazard Ratios (HR). All significant variables in univariable analysis were analyzed using multivariable Cox analysis. One risk point was assigned for each variable with a P value of &lt;0.05 in multivariable analysis and the risk points were used to establish three prognostic groups of similar prevalence. The validity of the model is being examined using the large data-set from the abiraterone registration trial (COU-AA-301). Results: Median age was 69 years, 41% had both bone and lymph node metastases (BLN), 15% had visceral disease. Involvement of BLN or visceral disease (HR 1.6, P=0.013), ALP &gt;2.0 x ULN (HR 1.7, P=0.005), LDH &gt;1.5 x ULN (HR 3.4, P&lt;0.001), Hgb &lt;12 g/dL (HR 2.1, P&lt;0.001), and NLR &gt;5 (HR 1.5, P=0.033) were associated with worse OS in the multivariable analysis. Outcomes for three risk groups using these 5 factors are presented in the table. The c-index was 0.73 (95% CI 0.65 - 0.80) for the prognostic score. Patients with NLR &gt;5 at baseline and whose NLR was ≤5 within four weeks of treatment also had longer median survival (15.1 months) than those with NLR &gt;5 at baseline that remained high (median OS 7.6 months, HR 0.48, 95% CI 0.25-0.93, P=0.029). Conclusions: This initial simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC. Data from the validation cohort will be presented. [Table: see text]
Impact of metformin on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: Lana Hamieh, Rana R. McKay, Suzanne S Mickey, Xun Lin, Ronit Simantov, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2016)

531 Background: Metformin has been shown to confer anti-neoplastic properties in several tumor types. Its effect on outcomes in mRCC patients has not been completely characterized. In this study, we evaluated the role of metformin on survival outcomes in pts with mRCC. Methods: We conducted a retrospective study of pts with mRCC treated on several phase II and III clinical trials from 2003-2013. We analyzed overall survival (OS) in the metformin users versus non-users using the Cox regression model and the Kaplan-Meier method. Results: We identified 4,736 pts with mRCC including 486 diabetic pts of whom 218 (4.6%) were metformin users. The majority were &lt;65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to IMDC risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. Pts received treatment with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon (IFN)-α (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560); overall 3,044 (64%) received first-line therapy. In the total cohort, metformin use did not impact OS when compared to users of other anti-diabetic agents (p=0.17) or non-diabetics (p=0.69). In diabetic pts, metformin use did not confer a survival advantage when stratified by type of therapy and IMDC risk group. However, in the cohort of diabetic pts receiving sunitinib (n=128), metformin use was associated with an improvement in OS when compared to users of non-metformin anti-diabetic agents (29.3 versus 20.9 months, respectively, p=0.0008, HR 0.051, 95% CI 0.009, 0.292). Conclusions: This is the largest study to date investigating the role of metformin on outcomes in mRCC pts. In this analysis, we demonstrate that concomitant use of metformin may improve survival in diabetic pts with mRCC treated with sunitinib. Based on preclinical data, we hypothesize that the mechanism underlying this survival benefit may be related to synergistic inhibition of the MAPK pathway. However, the study is limited by the small number of diabetic patients. Larger prospective studies are warranted to validate these results.
Qatar experience of standard risk breast cancer screening program (BCSP).
Authors: Salha M. Bujassoum, Reena Alassam, Hekmat Bugrein
Journal: Journal of Clinical Oncology (2014)

18 Background: Qatar has one of the highest age-adjusted breast cancer incidences in the Arab world. Although this is much lower than the incidence in the West. Breast-cancer incidence in Qatar was 45 per 100,000 in 2003 to 2007.These higher incidence rates in Qatar are mainly due to the growing population. The prevalent age group, for Qatari and non-Qatari patients, was age 40 to 50. This suggests that the age-specific incidence of breast cancer in Qatari women is unlike the pattern usually seen in Western nations where median age at diagnosis is 61 years, moreover the diagnosis is often at advanced stages of breast cancer. These factors led to establishment the first hospital based (BCSP) in Qatar. It uses a distributed model of mammography service. The program launched 2008, accepts eligible asymptomatic women at ages 40 to 69. Methods: Retrospective study was done during the period from April 2008 to December 2013. Our aim is to describe our experience of (BCSP) in Qatar and to monitor performance indicators. Our (BCSP) includes an office call and recall as well as triple assessment. We also discuss positive cases in multidisciplinary meeting. Results: Total number of screened women was 4,264 with an increasing participation, year by year. Out of these, Qatari patient’s accounts for 1,145, and non Qatari for 3,119. The age group of cases was (43 to 51). Total breast biopsies were 82, of which 45 were positive of breast carcinomas, (37) invasive ductal carcinoma, (8) noninvasive ductal carcinoma. The invasive cancer detection rate was 8.2 %. The positive predictive value (PPV) was 46%. Sensitivity value has improved from 51% in 2008 to 70% in 2012 as well as specificity value that has increased from 77% in 2008 to 83% in 2012. Conclusions: Public acceptance of (BCSP) in Qatar gradually increased and detection rates are higher than western countries. We’re detecting biologically aggressive tumors at younger age groups. We’ve a unique population and we need to utilize our data and evidence based medicine to guide policy makers and women to make the correct decision towards (BCSP).
Baseline and long-term cognition and neuroimaging in patients with primary CNS lymphoma (PCNSL) treated with enhanced chemotherapy (CHT) delivery.
Authors: N. D. Doolittle, M. A. Lubow, D. F. Kraemer, E. Dosa, N. A. Hedrick, R. M. Tyson, C. Lacy, L. M. Maron, R. W. Butler, E. A. Neuwelt
Journal: Journal of Clinical Oncology (2011)

2085 Background: Delayed treatment-related neurotoxicity in PCNSL is a significant problem since improved treatments have increased survival rates. The purpose is to describe neuropsychological and neuroimaging outcomes in patients (pts) treated with methotrexate (MTX)-based intra-arterial CHT with blood-brain barrier disruption (BBBD) who are in complete remission (CR), and correlate baseline and long-term neuropsychological and neuroimaging indicators of neurotoxicity. Methods: PCNSL pts treated with MTX-based CHT with BBBD and in CR for 2 yrs or more were evaluated with a standardized neuropsychological test battery and brain MRI. The battery, developed for prospective trials, evaluates attention, processing speed, motor skills, verbal memory, and quality of life (Correa et al, 2007). Results: Data from 25 pts (14M/11F) are summarized. At diagnosis, median age was 49 yrs; median KPS was 80; all had brain parenchyma disease. The pts had completed 12 (median) monthly courses of MTX-based CHT with BBBD. In addition to follow-up (f/u, from diagnosis to study testing), baseline neuropsychological scores were available on 24 of 25 pts, and end of treatment scores on 11 pts. Median f/u was 12 yrs (min 2.4, max 26 yrs); 9 (36%) were more than 15 yrs since diagnosis. Comparisons of baseline and f/u scores showed improvement in attention (Digit Span Forward: p=.0305; Digit Span Total: p=0.0487), and processing speed (Trail Making Test A: p=0.0057; and B [complex set shifting]: p=0.0304). There was no change in working memory (Digit Span Backward: p=0.190), and motor skills (Grooved Peg Board: p>0.20). There was no evidence of any significant correlation between a change from baseline to f/u in any neuroimaging parameter with any change from baseline to f/u in any neuropsychological parameter among pts. Conclusions: In this series of PCNSL pts with the longest reported median f/u of 12 yrs, comparisons of baseline and f/u scores indicate pts remained stable or improved in cognitive domains including auditory attention, working memory, processing speed, and motor skills, after enhanced CHT delivery with BBBD.
A retrospective analysis of Merkel cell carcinoma in Alberta from 1980 to 2006.
Authors: V. Prajapati, A. Mazurek, J. Haws, K. Joseph, J. G. McKinnon
Journal: Journal of Clinical Oncology (2010)

e19016 Background: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin tumor with high mortality rate and no definitive management guidelines published in the literature. Methods: A retrospective analysis was performed on 133 MCC patients identified by the Alberta Cancer Registry from 1980-2006. Patient demographics, disease presentation, histopathology, treatment, recurrence and follow-up data was collected. The objective was to create MCC database to identify trends in incidence, treatment and survival. Results: Ninety-eight (n = 98) patients analyzed thus far. Median age at diagnosis: 77.8 years (range 45-96). There was no gender predilection and only whites were affected. Median follow-up time was 26.1 months. Overall survival at 2 and 5 years was 61% and 36%, respectively. Median disease-free and overall survival was 13.4 and 27.5 months, respectively. Population-controlled annual incidence per 100,000 was 0.05, 0.14 and 0.30 in 1985, 1995 and 2006, respectively. Primary tumor found in 91/98 (93.8%) patients and 7/98 (6.2%) with unknown primary. Location of known primary: 48/91 (52.7%) head/neck, 35/91 (38.5%) extremities and 8/91 (8.8%) trunk. At diagnosis, 61/98 (62.2%) patients were AJCC stage 1, 21/98 (21.4%) stage 2, 12/98 (12.2%) stage 3 and 1/98 (1.0%) stage 4. Primary surgical treatment varied: 55/98 (56.1%) local excision, 30/98 (30.6%) wide local excision, 7/98 (7.1%) Mohs surgery and 6/98 (6.1%) involved lymph node dissection as the sole treatment. Nodal assessments were infrequently undertaken with only 5/98 (5.1%) patients having SLNB and 16/98 (16.3%) having LN dissections. Radiotherapy was delivered in 35/98 (35.7%) patients with statistically significant 5-year survival benefit of 56% for treated vs. 27% for non-treated patients (p = 0.0936). After treatment, 60/98 (61.2%) patients were free of recurrence, while 38/98 (38.8%) had local, nodal or metastatic recurrence. Conclusions: The most striking results are increasing incidence of MCC and significant survival benefit offered by radiotherapy. Further statistical analysis will be performed including subgroup analysis for each treatment modality's effect on disease-free and overall survival. No significant financial relationships to disclose.
Effect of PIK3CA and KRAS mutations on sensitivity to ATP-competitive mTOR inhibitors in a primary xenograft model of colorectal carcinoma.
Authors: Gregory S. Ducker, Chloe Evelyn Atreya, Jeffrey Simko, Eric K. Nakakura, Emily K. Bergsland, David B. Donner, Kevan M. Shokat, Robert S. Warren
Journal: Journal of Clinical Oncology (2012)

483 Background: The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and has been strongly implicated in cancer. Mutations in KRAS and the PI3K pathway are upstream of mTOR and are common in colorectal carcinoma (CRC). Currently approved mTOR inhibitors are derivatives of the natural product rapamycin and have shown little clinical efficacy in CRC. A new and potentially more efficacious class of ATP-competitive mTOR inhibitors has now entered clinical trials. Methods: Seeking a more representative preclinical model of CRC, we generated primary xenografts in nude mice of surgically resected specimens of human hepatic colorectal cancer metastases. We then treated xenograft tumors with the selective ATP-competitive mTOR inhibitor PP242 and monitored response by inhibition of tumor growth, changes in histopatholgy, and alterations in signaling pathways. Cell line experiments were performed to support observations made in the patient derived xenografts. Results: We demonstrate that in contrast to rapamycin, the mTOR inhibitor PP242 is highly effective at inhibiting tumor growth in both the primary xenograft model and in colorectal cancer cell lines. The inhibition of tumor growth in the xenografts and cell lines depended upon the strong inhibition of phosphorylation of mTOR substrate eIF4E binding protein 1 (4EBP1) but was not correlated with inhibition of phosphorylation of S6 kinase (S6K). Cells with mutant KRAS were relatively resistant to PP242 induced growth inhibition and this correlated with reduced inhibition of 4EBP1 phosphorylation. However, these effects were partially rescued in cells in which a co-mutation in PIK3CA resulted in AKT activation. Conclusions: Our studies reveal the first mTOR inhibitor resistant cell line, the genetic basis for its resistance and most importantly, these findings were revealed through the use of a primary xenograft mouse model which recapitulates morphologically the features of the tumors isolated from patients. We believe ATP-competitive inhibitors may be of limited clinical utility in mutant KRAS tumors, except for those that have concomitant activation of AKT.
Can grade 2 neutropenia predict the risk of grade 3 neutropenia in metastatic colorectal cancer patients treated with chemotherapy?
Authors: Yoichiro Yoshida, Seiichiro Hoshino, Naoya Aisu, Masayasu Naito, Syu Tanimura, Yuichi Yamashita
Journal: Journal of Clinical Oncology (2013)

562 Background: Neutropenia is a major factor affecting the continuation of chemotherapy for colorectal cancer. In many clinical trials, a neutrophil count of more than 1500 is targeted for the continuation of chemotherapy; for a count of less than 1500, medication is commonly discontinued. However, there is no definite evidence for setting the targeted neutrophil count at 1500. In our department, chemotherapy is discontinued when the neutrophil count is less than 1000 (Grade 3); for a count of 1000 to 1500 (Grade 2), chemotherapy is continued. We examined the neutrophil count during continuation of chemotherapy in patients with a count of 1000 to 1500, and verified whether these neutrophil counts warrant discontinuation of medication. Moreover, we examined the neutrophil count during the previous course of chemotherapy when it fell below 1000. Methods: The study included 104 patients who received XELOX + bevacizumab (BV) therapy, XELOX therapy, and XELIRI + BV therapy for advanced or recurrent colorectal cancer. Results: The patients with a neutrophil count of 1000 to 1500 were 26 (23.1%) of the total. Two (7.7%) of 26 patients had a neutrophil count of less than 1000 during the following course of chemotherapy. Moreover, among the patients with a neutrophil count of less than 1000, 25% had a count of 1000 to 1500 during the previous course of chemotherapy and 75% had a count of more than 1500. Conclusions: According to these results, Grade 2 neutropenia cannot predict the risk of the Grade 3 neutropenia. Continuation of chemotherapy in patients with a neutrophil count of 1000 to 1500 may be appropriate, and discontinuation of therapy is not always required.
Treatment benefit of tivozanib hydrochloride versus sorafenib on health-related quality of life (HRQoL) among patients (pts) with advanced/metastatic renal cell carcinoma (mRCC): TIVO-1 study results.
Authors: David Cella, Cristina Ivanescu, Konstantina Skaltsa, Montserrat Casamayor, Andrew Louis Strahs, Brooke Esteves, Anna Berkenblit, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

355 Background: Tivozanib hydrochloride (T) was superior to sorafenib (S) in progression-free survival (medians of 11.9 vs. 9.1 months, respectively; 12.7 vs. 9.1 months, respectively, for metastatic treatment-naïve pts) in the phase III TIVO-1 study in pts with mRCC. T showed a differentiated safety profile with lower rates of dose interruptions/reductions v S (18/12 vs. 35/43, respectively; p&lt;0.001). TIVO-1 also evaluated patient self-reported HRQoL. Methods: Pts with mRCC were randomized 1:1 to receive T (1.5 mg PO once daily for 3 weeks on, 1 week off) or S (400 mg bid, continuously). HRQoL was assessed on Cycle 1/Day1 (baseline [BL]) and at the beginning of each cycle, using the Functional Assessment of Cancer Therapy–General (FACT-G), FACT–Kidney Symptom Index Disease Related Symptoms (FKSI-DRS), and EuroQol 5-dimensional (EQ-5D) questionnaires; EQ-5D scores are not reported here. Pts with BL and ≥1 post-BL evaluable forms were analyzed. Changes from BL in FACT-G and FKSI-DRS scores over 18 treatment cycles were analyzed using repeated measures mixed-effects models. QoL improvement/deterioration was defined as an increase/decrease from BL of ≥3 points for FACT-G subscales and FKSI-DRS total score and 7 points for the FACT-G total score during the study. Results: In the mixed effects analyses, no significant differences in HRQoL (FACT-G and FKSI-DRS) were noted between T and S. More pts receiving T vs. S experienced a significant improvement during the study in physical well-being (PWB) (25.7% vs. 16.4%; p=0.011) and a favorable trend in all other FACT-G and FKSI scores (p values: 0.078–0.405). FKSI improvement was greater with T than S in treatment-naïve pts (34.1% vs. 23.6%; p=0.023), pts with ≥2 metastases (32.9% vs. 24.7%; p=0.054), or pts &lt;65 years old (33.0% vs. 22.8%; p=0.022). Median time to QoL deterioration was usually longer with T (3.75-7.66 months) than S (2.04-8.80 months). Conclusions: HRQoL was generally similar for T and S. Non-significant numeric differences usually favored T over S, and PWB improvement occurred significantly more often with T. These results support the previously-reported PFS advantage of T over S. Clinical trial information: NCT01030783.
Disseminated tumor cells in primary breast cancer: Evaluation of the percentage of breast cancer stem cells in bone marrow aspirates of patients receiving neoadjuvant chemotherapy
Authors: J. M. Reuben, B. Lee, A. Lucci, H. Gao, E. N. Cohen, C. Li, S. Krishnamurthy, G. N. Hortobagyi, W. A. Woodward, M. Cristofanilli
Journal: Journal of Clinical Oncology (2009)

505 Background: Disseminated tumor cells (DTC) in the bone marrow (BM) are related to poor prognosis of primary breast cancer (PBC). Cancer-initiating stem cells (CSC) have been detected in BM of PBC patients. Downregulation of the Notch pathway leads to murine mammary stem cell expansion and its expression is an early event in breast cancer. We enumerated CSC in BM mononuclear cells (BMC) and assessed the expression of Notch-1, ER, and HER-2 to study the differences between untreated patients and those treated with neoadjuvant chemotherapy. Methods: BM was collected from 90 PBC patients at time of surgery to assess DTC (CD326 + CD45 - ) and CSC (CD326 + CD45 - CD44 + CD24 - ) by FACS analysis. BM samples were also interrogated for the presence of CSC with ALDH activity using the Aldefluor® detection kit. RNA extracted from 61 BMC was analyzed for Notch-1, ER, and HER-2 transcripts by RT-PCR; the level of each transcript was normalized to that of the housekeeping gene, GAPDH. Results: The median age of patients is 51 years old (range, 27–77 years). A total of 29 patients (32%) received neoadjuvant chemotherapy, including 8 patients with anti-HER-2 targeted therapy. BMC of neoadjuvant-treated patients had a significantly higher median percentage of CSC in BMC (P= 0.046) and a significantly higher proportion of CSC cells within the Aldefluor + population (P= 0.013) than those of untreated patients. Median level of Notch-1 transcripts in BMC was lower in neoadjuvant-treated patients compared with that of untreated patients (P= 0.07). There was an inverse correlation between the level of Notch-1 transcripts and the percentage of CSC in BMC of untreated (Spearman's rho= -0.519, P &lt; 0.001), but not in neoadjuvant treated (Spearman's rho= -0.483, P= 0.058) patients. Conclusions: Neoadjuvant chemotherapy is associated with expansion of CSC in the BMC of patients with PBC. Untreated patients with higher level of Notch-1 transcripts in the BMC tend to have lower percentages of CSC and suggest that Notch signaling may be crucial for differentiation of CSC. The prognostic value of this finding is under investigation and gene expression profile of CSC may provide indications for novel neoadjuvant therapies. No significant financial relationships to disclose.