tbuckley/cabot-search huggingface dataset:
Overall survival (OS) and baseline disease characteristics in MDS patients with primary HMA failure in a randomized, controlled, phase III study of rigosertib.
Authors: Pierre Fenaux, Aref Al-Kali, Maria R. Baer, Mikkael A. Sekeres, Gail J. Roboz, Gianluca Gaidano, Lewis R. Silverman, Bart L Scott, Peter Greenberg, Uwe Platzbecker, David P. Steensma, Karl A Kreuzer, Lucy A. Godley, Robert Collins, Ehab L. Atallah, Nozar Azarnia, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2015)

e18079 Background: ONTIME was a randomized (2:1) study of rigosertib (RIG) vs best supportive care (BSC, including optional low-dose ARA-C) in 299 pts with higher-risk MDS who had relapsed after, failed to respond to, or progressed during treatment with hypomethylating agents (HMAs). For MDS patients who fail HMAs, there are no FDA-approved therapies. Thus an unmet medical need exists for effective second-line therapies. ONTIME showed a significant treatment effect with RIG in the subgroup of patients with “primary HMA failure” (Garcia-Manero et al, Blood 2014). Methods: We evaluated the correlation between baseline disease characteristics and OS in pts with primary HMA failure (RIG N=117; BSC N=52) as ascertained by a centralized, blinded reader. Results: Pts with primary HMA failure were generally male (69%), age 50-86 years (median 73), at high or very high risk per IPSS-R (80%), with 5-19% bone marrow blast count (92%). A meaningful difference in median OS between RIG and BSC was observed not only in the overall population of pts with primary HMA failure, but also in several subgroups (see Table). Overall, adverse events (AEs) were reported in 99% of RIG pts and 88% of BSC pts. The following AEs >=Grade 3 were reported by ≥10% of pts: anaemia (16% RIG vs 10% BSC), thrombocytopenia (15% vs 6%), neutropenia (15% vs 8%), febrile neutropenia (13% vs 10%), pneumonia (12% each). Conclusions: Patients with primary HMA treatment failure and certain subgroups identifiable on the basis of baseline disease characteristics randomized to RIG showed an improvement in OS compared to BSC. Such characteristics should be considered in the design of future trials in second-line in primary HMA failure patients. Clinical trial information: NCT01241500.Median (months) OS by baseline disease characteristics in Pts with primary HMA failure. Characteristic RIG BSC Log-rank p-value Hazard ratio (RIG/BSC) (95% CI) N OS N OS All patients with Primary HMA Failure 117 8.6 52 4.5 0.011 0.63 (0.44-0.90) IPSS-R category of high or very high 97 8.6 38 4.1 0.0015 0.52 (0.35-0.79) Bone marrow blast = 5%-19% 93 10.1 36 4.7 0.0079 0.58 (0.39-0.87) Duration of prior HMA treatment < 9 months 79 8.6 37 4.5 0.0014 0.49 (0.31-0.76)
Predicting chemotherapy response in invasive breast cancer.
Authors: David Harrison, Emad Rakha, Andrew R. Green, Ian H. Kunkler, Susanne Wagner, Darl D Flake, Alexander Gutin, Jerry S. Lanchbury, Steve Chan, Ian O. Ellis
Journal: Journal of Clinical Oncology (2014)

1084 Background: The care of patients with estrogen receptor positive (ER+), node negative early breast cancer has been revolutionized by first generation mRNA signatures that have improved the identification of patients with low risk of recurrence following adjuvant hormone therapy who may be spared chemotherapy. Additionally, a signature may be of value in predicting response to chemotherapy in high-risk individuals. We developed a second generation prognostic signature in ER+ breast cancer consisting of a weighted combination of cell division (CCP), immune and receptor genes (molecular score) and clinical parameters (combined score). Here, we aimed to understand the capacity our signature to predict chemotherapy effectiveness regardless of ER status. Methods: The first cohort consisted of 247 ER+ patients treated pre-operatively with TFEC or TFAC. Association of the signature with complete pathological response (pCR) was evaluated by logistic regression. The second data set was a population cohort of 431 adjuvant chemotherapy treated and 599 untreated invasive breast cancer patients. The interaction between chemotherapy treatment and CCP, molecular and combined scores was individually tested in a Cox proportional hazards model with distant metastasis free survival as outcome. Results: CCP and molecular scores were predictive of pCR in the pre-operatively treated cohort (CCP score p=0.015; molecular score p=0.029). In the population cohort, the test for interaction with adjuvant treatment was highly significant with p-values of 0.000016, 0.000020 and 0.00012 for CCP, molecular score, and combined score, respectively. In all cases higher scores were associated with response or improved outcome. Conclusions: A second generation prognostic tool for ER+ invasive breast cancer predicts pre-operative chemotherapy response in an ER+ breast cancer cohort. Molecular and clinical combined components predict outcome in adjuvant chemotherapy treated cohort regardless of ER status. After further studies to validate prognostic and predictive efficacy, the second generation prognostic signature may offer enhanced discrimination for the care of breast cancer patients.
Patterns of disparities in breast cancer care.
Authors: Michael J. Hassett, Deborah Schrag, Kun Chen, Patrick R. Roohan, Francis P. Boscoe, Maria J. Schymura
Journal: Journal of Clinical Oncology (2013)

6565 Background: Studies have documented disparities in breast cancer care for decades, but disparities in outcomes have not improved. Previous disparity investigations included relatively small, potentially biased samples of disadvantaged populations, or focused only on selected aspects of care. We sought to describe the relative importance of race/ethnicity versus Medicaid insurance status as determinants of suboptimal quality across the spectrum of care using two population-based samples of women with non-metastatic breast cancer. Methods: From two state registry datasets (NY and CA), we identified adult women diagnosed with stage 0-III breast cancer from 2004-2009. To these data, we merged enrollment and claims files from Medicaid and Medicare. Quality was assessed relative to 35 underuse and overuse measures derived from clinical practice guidelines. We compared measures across race/ethnic and Medicaid enrollment groups, and used logistic regression models to assess the relationships between race/ethnicity, Medicaid status, and quality relative to surgery, chemotherapy, radiation, and endocrine measures. Analyses were conducted in parallel for NY and CA, and for women &lt;65 and ≥65 years old. Results: The sample, which comprised 80,079 from NY and 121,098 from CA, included 14%/6% blacks, 8%/15% Hispanics, 5%/12% API’s, and 19%/14% Medicaid enrollees, respectively from NY/CA. There was moderate-high correlation in measure performance across states and race/ethnic groups. Multivariable models demonstrated that blacks had lower odds of receiving recommended surgery versus whites, and whites had lower odds of receiving chemotherapy, whether recommended or not, versus other race/ethnic groups. Medicaid status was associated with lower odds of receiving recommended surgery, radiation therapy, and anti-estrogen therapy, but not chemotherapy, for patients &lt;65 and ≥65. Conclusions: Medicaid status, a surrogate for socio-economic status, was associated with lower odds of receiving recommended care across a broad spectrum of breast cancer treatments. Understanding patterns of disparities will facilitate efforts to design and disseminate real world solutions that foster improvements in outcomes for the most disadvantaged populations.
Early-stage ovarian cancer: Clinical outcome and analysis of prognostic factors—Results from a prospective registry of GEICO (Spanish Group for Ovarian Cancer Research).
Authors: Belen Ojeda, Cristina Maria Churruca, Ignacio Romero, Andrés Redondo, Elisa Calvo, Ana Santaballa, Josep M. del Campo, Ana Sebio, Nuria Laínez, Isabel Bover, Margarita Romeo, Cristina Caballero, Elena García-Martínez, Jeronimo Martinez, Ana Herrero, Ana Beatriz Sánchez, Ana De Juan, Susana Hernando Polo, Nuria Ruiz, Andres Poveda
Journal: Journal of Clinical Oncology (2014)

5582 Background: Early stage ovarian cancer (ESOC) represents 10-15% of all Ovarian Cancer (OC) cases and the reported experience is limited. Methods: A centralized prospective register of ESOC (I-IIb) patients treated at GEICO centers was initiated on January 1998 and updated up to November 2013. Description of cases as well as correlation with Relapse Free Survival (RFS) and Disease Specific Survival (DSS) and an exploratory multivariate analysis was undertaken. Results: A total of 1179 cases with a median age of 48 (17-66) have been included: 983 (83.4%) Stages I, of which 369 (31.3%) were stage Ia, 49 (4,2%) stage Ib and 565 (47.9%) stage Ic, 169 (14,3%) were Stage II and 27 (2.3%) unknown. The most frequent histological type was Endometrioid (E) (n: 320, 27.1%), followed by Serous (S) (n: 297, 25.2%), Clear-cell carcinoma (CCC) (n: 244, 20.7%) and Mucinous (M) (n: 176, 14.9,%). Among E histology grade 1-2 vs grade 3 were present in 19.3% and 5.9% respectively while S grade 1 vs grade 2-3 were 5.9% and 15.2%. Surgical staging was categorized as complete surgery (22%), modified surgery (50%) and inadequate (28%). 1010 patients (88.3%) received adjuvant chemotherapy (ACT). With a median follow-up of 69 months (1-250), 16% of cases have relapsed and 8.1% were dead due to OC. Five-years RFS and DSS are 83% and 92% respectively. M and low grade E together have a 5-years RFS of 91% compared to other subtypes 79% (p<0.0001) and CCC a 5-years RFS 77%, compared to other subtypes RFS 85% (p<0.035). Prognostic factors including histology, histology and grade, stage and ACT were included in the multivariate analysis showing that stage (p=0.0001), low grade E (p=0.004) and ACT (p=0.005), remained of prognostic importance. Conclusions: In this large prospective cohort of ESOC, surgical staging remains inadequate in one fourth of cases according to current guidelines. E subtype is the most reported. Better prognosis is observed in low grade E, low stage and patients treated with ACT.
Exploratory analysis of left- versus right-sided colorectal carcinoma in RAISE: A randomized, double-blind, phase 3 trial of ramucirumab (RAM) + FOLFIRI versus placebo (PBO) + FOLFIRI.
Authors: David Craig Portnoy, Radka Obermannova, Gyorgy Bodoky, Jana Prausová, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, Pilar Garcia Alfonso, Allen Lee Cohn, Eric Van Cutsem, Kentaro Yamazaki, Takayuki Yoshino, Sara Lonardi, Tae Won Kim, Kensei Yamaguchi, Axel Grothey, Juan Manuel O Connor, Yanzhi Hsu, David Ferry, Federico Nasroulah, Josep Tabernero
Journal: Journal of Clinical Oncology (2017)

668 Background: Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2. Overall survival (OS) and progression-free survival (PFS) in 2 nd line FOLFIRI based treatment for metastatic colorectal cancer (mCRC) were improved with RAM therapy versus PBO in the RAISE trial. Recent work suggests mCRC primary tumor location is both prognostic and predictive; with improved OS and therapy-specific sensitivity observed in left (L)- vs right (R)-sided tumors. Given these findings, the RAISE trial data was subjected to post-hoc analysis to determine if sidedness influenced RAM efficacy. Methods: Primary tumor site was obtained. L-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum, while R-CRC included transverse, ascending colon and cecum. OS/PFS in L and R subgroups were analyzed via Kaplan-Meier method and unstratified log-rank test (treatments within subgroup), unstratified Cox proportional hazards model (estimate hazard ratio [HR] and 95% CI), and Wald test (treatment-by-subgroup interaction). Results: Tumor location was available for 1012/1072 (94%) patients, 699 L- and 313 R-CRC. Baseline characteristics were balanced between arms. RAM treatment enhanced L-CRC median OS by 2.5 mo (median 14.5 vs 12.0 mo) with a HR (95% CI) = 0.807 (0.675, 0.965), P = 0.019; compared to a 1.1 mo increase in median OS in R-CRC vs PBO (12.7 vs 11.6) with a HR (95% CI) = 0.971 (0.750, 1.258), P = 0.823; and, RAM enhanced L-CRC median PFS by 1.6 mo (6.0 vs 4.4 mo) and HR (95% CI) = 0.776 (0.664, 0.906), P = 0.001 compared to a 1.1 mo increase in median PFS R-CRC vs PBO (5.6 vs 4.5) with a HR (95% CI) = 0.855 (0.674, 1.084), P = 0.197. The treatment-by-subgroup interaction for both OS and PFS was not significant ( P = 0.276, 0.578, respectively). Conclusions: Despite L-CRC patients having longer OS/PFS and a seemingly stronger RAM treatment effect than R-CRC, the non-significant interaction test cannot verify sidedness as being predictive of RAM efficacy. The current study confirms ramucirumab benefits mCRC patients regardless primary tumor location. Clinical trial information: NCT01183780.
A study on the prevalence of HER2 genetic heterogeneity and its impact on breast cancer survival.
Authors: Jingshan Ho, Daniel Boon Yeow Chan, Soo-Chin Lee, Evelyn S. C. Koay
Journal: Journal of Clinical Oncology (2013)

586 Background: HER2 heterogeneity (GH) has been described in breast cancer that has conventionally been labeled as HER2 negative (FISH score &lt;2.2). We aimed to ascertain the prevalence of GH in HER2 negative breast cancers and to investigate for any impact on survival. Methods: We reviewed HER2 FISH (Vysis) data for 158 primary breast cancer specimens from 2006-2010 which were 0 – 2+ on immunohistochemistry. HER2:CEP17 ratios were calculated for each of the 60 cells scored and cases were classified as HER2 GH according to the ASCO/CAP guidelines (GH = 5-50% tumor cells with a ratio &gt;2.2). Results: 67% (106/158), 7% (11/158) and 26% (41/158) were HER2 negative, equivocal (FISH ratio 1.8-2.2) and positive respectively. GH was found in 43% and 100% of Her2 negative and HER2 equivocal patients respectively. Of the 117 cases (with FISH score &lt;2.2), HER 2 GH was associated with higher histologic grade (grade 3: 81.8%, 52.3% and 33.3% in HER2 equivocal, negative with GH and negative without GH (p = 0.007). There were no significant associations with ER status or the presence of lymphovascular invasion. The mean overall survival was 63 months (95% CI 43-87), 118 months (95% CI 96-141) and 148 months (95% CI 148-168) for HER 2 equivocal, negative with GH and negative without GH patients respectively (p=0.017). In a subset analysis of HER2 negative (with FISH score &lt;2.2), non metastatic patients, with at least a 4 year follow up period (n=63), mean overall survival was 79 months (95% CI 60-98), 119 months (95% CI 96-143) and 159 months (95% CI 139-180) for HER2 equivocal, negative with GH and negative without GH patients (p=0.034). GH remained a significant factor in the multivariate analysis irrespective of grade, stage and ER status (p=0.046). Conclusions: HER2 GH occurs in 100% of HER2 equivocal and 43% of HER2 negative breast cancers and is associated with higher histologic grade and poorer overall survival, irrespective of grade, stage or hormonal status.
Combination therapy with ipilimumab and electrochemotherapy: Preliminary efficacy results and correlation with immunologic parameters.
Authors: Ester Simeone, Lucia Benedetto, Giusy Gentilcore, Corrado Caraco, Gianluca Di Monta, Antonio M Grimaldi, Assunta Esposito, Marilena Capone, Ugo Di Marone, Marcello Curvietto, Gabriele Di Madonna, Marialuisa Di Cecilia, Stefano Di Mori, Nicola Mozzillo, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2013)

e20031 Background: Ipilimumab is the first agent approved for the treatment of advanced melanoma that showed a survival benefit in randomized phase 3 trials. Despite the survival benefit, due to its mechanism of action it is associated with a slow onset and low rate of responses and, in many cases, responses occur after other therapies, like chemotherapy, targeted therapy and radiotherapy. Electrochemotherapy (ECT) has been shown to be effective and well tolerated for local control of metastatic melanoma with superficial lesions. The current challenge is to improve ipilimumab efficacy by combination/sequence with other therapies. We performed a pilot study of combination with ipilimumab and ECT in order to verify the possible increase of response rate. Furthermore, due to the lack of predictive markers, we evaluated the possible predictive role of circulating T-regulatory cells (T-Reg) variations in peripheral blood mononuclear cells (PBMC) of treated patients. Methods: We collected data from 10 patients (pts) with advanced melanoma (6 stage IIIc and 4 stage IV M1c) treated with ipilimumab at 3 mg/kg every 3 weeks for 4 cycles (day 1) and ECT with bleomycine at 15 mg/m2 (day 2) on superficial lesions. Blood draws were collected on day 0, 1 and 2, then on day 15 and 30 from ECT, at each cycle of ipilimumab and at every tumor evaluation (every 12 weeks). PBMC were thawed and labeled with anti-CD4-Pe-Cy-5, CD25-Pe and anti-FoxP3-AlexaFlour488 for T-Reg. Results: 10/10 (100%) pts showed local objective responses (4 CR and 6 PR). 7/10 (70%) pts showed local response (6 PR and 1 CR) after the second ipilimumab dose and 3/10 showed response (3 CR) at week 12. Two pts with PR (28%) out of the group of 7 showed response on distant lesions at week 24 (abscopal effect). All pts are still alive with a median follow up of 11 months (range 6-18). We found in all pts a decrease of T-Reg of 0.10% (range 0.50-2.6%) per cycle and no variation of CD4+ and CD25+ lymphocytes. Conclusions: Our preliminary results show that a combination approach with ipilimumab and ECT may increase responses to ipilimumab. T-Reg decrease in PBMC could be associated with response to treatment. Further studies about this combination are warranted.
An evaluation of pharmacologic costs of complete liver resections in unselected advanced colorectal cancer patients.
Authors: Andrea Bonetti, Silvia Muraro, Jacopo Giuliani, Anna Mercanti, Lara Furini, Emilia Durante, Filippo Greco, Anna Rita Trolese, Paolo Piacentini, Giacomo Moratello, Michele Tognetto
Journal: Journal of Clinical Oncology (2013)

e17551 Background: The aim of this study is to evaluate the pharmacological costs of conversion chemotherapy in an unselected population of advanced colorectal cancer patients. Methods: Phase III studies evaluating chemotherapy regimens for advanced colorectal cancer patients were considered. The percentage of reported complete liver resection in each arm was used to calculate the number of patients needed to treat (NNT) to get a complete liver resection. This number was multiplied by the number of cycles administered before the resection (assuming 6 cycles for biweekly chemotherapy or 4 cycles for chemotherapy given every three weeks). Calculation is based on an “ideal patient” (BSA 1.8 sqm; weight 70 Kg).The costs of drugs are at the Pharmacy of our hospital and are expressed in €. Results: Results are summarized in the Table. Conclusions: The pharmacological costs to obtain a complete resection of liver metastases from colorectal cancer varies widely across the different chemotherapy regimens commonly used and is influenced by the efficacy of the treatment and by the costs of drugs used. Schemes containing a “biological” are associated with an increased of costs. [Table: see text]
Importance of HPV involvement and FOXP3+ T-cell status as prognostic factors in tonsilar squamous cell carcinoma.
Authors: Kwonoh Park, Kyung-Ja Cho, Dok Hyun Yoon, Jiyoun KIM, Sang Yoon Kim, Soon Yuhl Nam, Seung-Ho Choi, Myung Woul Han, Sang-wook Lee, Si Yeol Song, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2012)

5586 Background: Human papillomavirus (HPV) status is a strong and independent favorable prognostic factor for survival in tonsilar squamous cell cancer (TSCC). The reason for the improved survival in HPV associated TSCC is unclear. Recently, activation of immune surveillance mechanism against non-self Ag is postulated to one of reasonable causes as favorable prognosis of HPV associated with TSCC. Methods: We reviewed the medical records of histologically confirmed locally advanced TSCC patients, curatively treated in Asan Medical Center from January 2000 to December 2008. The immunohistochemistry (IHC) assays for p16 and FOXP3 were done in TSCC pafaffin-embedded samples. Results: We identified 79 patients who met the inclusion criteria. The median age was 54 years (range 32-76) and 16 (20%) patients were stage III and the others were all stage IV. With the median follow up of 62.9 months (95% CI, 59.2 - 66.7), sixty three (80%) were HPV-positive with p16 overexpression, and 38 (48%) were Treg-positive with FOXP3. Treg involvement was significantly related to HPV positive status (P=0.011). The result was the same after adjustment of age, T &amp; N stage, smoking exposure and alcohol consumption. (Odd ratio = 6.54, 95% CI 1.58-27.1, P=0.01) Five-year overall survival (OS) rate in HPV-positive group was significantly higher than that of HPV-negative group (78% and 63%, Hazard Ratio (HR)=0.347, 95% CI 0.14-0.87, P=0.025), and 5-year OS of Treg-positive group was also higher than that of Treg-negative group (89% and 61%, HR=0.158, 95% CI 0.05-0.53, P=0.003). In multivariate analysis, the Treg status was an independent prognostic factor (HR=0.11, 95% CI 0.03-0.40, P=0.001), as well as HPV status. (HR=0.28, 95% CI 0.10 - 0.78, P=0.016). Conclusions: HPV positivity was associated with Treg positivity in TSCC and both were found to be favourable prognostic factors for survival.
Gene expression biomarkers to predict overall survival of prostate cancer patients.
Authors: Chunde Li, Zhuochun Peng, Lambert Skoog, Henrik Hellborg, Gustaf Jonstam, Inga-lill Wingmo, Marie Hjelm-Eriksson, Ulrika Harmenberg, Lars Ährlund-Richter, Setia Pramana, Yudi Pawitan, Monica Nistér, Sten Nilsson
Journal: Journal of Clinical Oncology (2012)

4561 Background: Current clinical parameters are not accurate in the prediction of overall survival of prostate cancer patients. Methods: Driven by cancer stem cell hypothesis and by using a simple bioinformatics analysis, we identified 641 genes with either consistently high or low level of expression in human embryonic stem cells. We showed that these 641 genes had strong power to classify cancers into different biological subtypes and named them as embryonic stem cell gene predictors (ESCGPs). Nineteen selected ESCGPs and five control genes were analyzed by multiplex quantitative PCR in prostate fine needle aspiration (FNA) samples taken at diagnosis. The cohort included 189 patients diagnosed during 1986-2001. Of these patients, 97.9% had overall and cancer specific survival data and 77.9% were treated by medical or surgical castration as the primary treatment. The cohort was divided into a discovery and two validation subsets. The univariate and multivariate Cox proportional hazards and Kaplan-Meier plots were used in the survival analysis. A published dataset was used for an external validation. Results: Ten gene markers F3, WNT5B, VGLL3, CTGF, IGFBP3, c-MAF-a, c-MAF-b, AMACR, MUC1 and EZH2, showed a significant correlation to overall or cancer specific survival. Four of these genes, F3, IGFBP3, CTGF and AMACR, were independent of all clinical parameters. An expression signature of F3, VGLL3 and IGFBP3 characterized patients into three subtypes. The median overall survival was 2.60 years in the high risk, 3.85 years in the intermediate risk and 7.98 years in the low risk subtype, corresponding to a HR of 5.86 (95% CI 2.91-11.78, p&lt;0.001) for the high risk and 3.45 (95% CI 1.79-6.66, p&lt;0.001) for the intermediate risk over the low risk subtype. Two gene markers, F3 and EZH2, were further verified by the external validation. Conclusions: The new ESCGP gene markers and the expression signatures can be used to predict the overall and cancer specific survival of prostate cancer patients.