tbuckley/cabot-search huggingface dataset:
Metronomic therapy for heavily pretreated relapsed/refractory multiple myeloma (RRMM).
Authors: Xenofon Papanikolaou, Jackie Szymonifka, Alan Mitchell, Jason Keller, Christoph Johann Heuck, Sarah Waheed, Saad Zafar Usmani, Bijay Nair, Frits Van Rhee, Stephen Charles Medlin, Clyde Bailey, Nathan Petty, Antje Hoering, John Crowley, Bart Barlogie
Journal: Journal of Clinical Oncology (2012)

8041 Background: RRMM represents a true challenge in MM therapy. Based on the effectiveness of metronomic therapy in solid tumors, we developed a treatment of metronomically scheduled therapy (MT) for RRMM (Hollmig, ASH 2004). We are now updating our experience with a median follow up of 25.6 months. Methods: We identified 187 patients treated with MT from 03/2004 to 11/2011. Results: The median age was 61 years (range 36-83); the median number of prior therapies was 14 (range 1-51). 79% of patients had prior HDT, 99% had a prior exposure to bortezomib, 98% to an IMiD, and 95% to their combination . The median number of completed MT cycles was 1 (range 1-5). 63% of patients had a response of MR or better (6% CR ,7% VGPR, 36% PR, 16% MR). The median overall (OS) and progression free (PFS) survivals were 11.3 and 3.7 months respectively. 91 of 187 patients had gene expression profiling (GEP) prior to initiation of MT, of which 53% were high risk according to the 70-gene (GEP70) risk model. OS was affected by elevated CRP (&gt; 8mg/L, HR=1.71, p=0.009) and cytogenetic abnormalities within 6 months of initiation of MT (HR=2.45, p&lt;0.001). For the 91 patients with GEP data available, OS was correlated with elevated CRP &gt; 8mg/L (HR=2.11, p=0.009) and GEP70 high-risk (HR=2.65, p&lt;0.001), which also showed a trend towards shorter PFS. Hematological toxicity grading was difficult as 69% of patients presented with grade &gt;=3 thrombocytopenia within 90 days prior to starting MT. Grade 4 leucopenia , anemia thrombocytopenia due to MT occurred in 74%, 17%, 89% of patients respectively. Incidence of grade 4 neutropenic fever was 1%. Grade 4 or worse incidence of all non-hematological toxicities was below 9%. Most patients were treated in the outpatient setting (95%) and secondary admissions due to regimen toxicity occurred in 20%. Conclusions: MT is an effective salvage treatment in RRMM, with a high ORR and a favorable toxicity profile. [Table: see text]
<i>BRCA</i>-mutation status combined with BCL2 protein in prediction of relapse in triple-negative breast cancer (TNBC) treated with adjuvant anthracycline-based chemotherapy.
Authors: Katerina Bouchalova, Marek Svoboda, Gvantsa Kharaishvili, Jana Vrbkova, Lenka Radova, Jan Bouchal, Radek Trojanec, Vladimira Koudelakova, Karel Cwiertka, Marian Hajduch, Zdenek Kolar
Journal: Journal of Clinical Oncology (2014)

1132 Background: The role of BRCA mutation status as a predictor in TNBC is unclear. Data show an association of high BCL2 expression and resistance to anthracyclines. BCL2, size and nodal status are independent predictors for both relaps and death in TNBC treated with adjuvant anthracyclines (Bouchalova et al. ASCO 2012). The objective of this study was to determine whether combination of BCL2 and BRCA1 status predicts outcome in TNBC patients treated with adjuvant anthracycline-based therapy. Methods: The study included 187 patients with TNBC, 178 of whom were treated with adjuvant chemotherapy (164 had anthracyclines). BCL2 analysis was performed using IHC. BRCA1 was obtained from patients records: mutation (mut), wildtype (wt) and unknown status were present in 21.39, 19.25, and 59.36 %, respectively. The data were analysed with software Statistica and R. Results: Among six BCL2/BRCA1 TNBC subtypes, BCL2high/BRCA1wt predicts the worst, while BCL2low/BRCA1mut the best RFS (logrank p<0.05). BCL2high protein expression predicts poor relapse free survival (RFS) in BRCA1wt TNBC patients treated with adjuvant anthracycline-based regimens (logrank p=0.007, hazard ratio, HR 13.24, 95%CI 1.19-147.93). Interestingly, there was no significant difference in RFS between BCL2low/BRCA1mut and BCL2high/BRCA1mut, but between BCL2low/BRCA1mut and BCL2high/BRCA1wt (logrank p=0.009) TNBC patients treated with adjuvant anthracycline-based therapy. BCL2high/BRCA1wt predicts trend to the worst overall survival (OS) analyzed together with other subtypes treated with adjuvant anthracycline-based regimens (logrank p=0.065). Conclusions: Dividing TNBC into subtypes according BCL2 protein expression and BRCA1 mutation status predicts good, vs. poor outcome in patients treated with adjuvant anthracycline-based chemotherapy. BCL2 expression together with BRCA1 status could facilitate decision making on adjuvant therapy. Underlying mechanisms could be revealed by further research. In patients with BCL2high/BRCA1wt other types of adjuvant therapy should be considered.
Inflammatory breast cancer in Morocco: Experience of Hassan II University Hospital.
Authors: Khaoula Daoudi, Sami Aziz Brahmi, Lamie Boudahna, Fatima Zahra Hijri, Nezar Bouyahia, Karima Oulla, Hafida Benhammane, Amine Mohammed Chad, Fatima Zahra El mrabet, Samia Arifi, Mellas Nawfel, Omar El Mesbahi
Journal: Journal of Clinical Oncology (2012)

e11516 Background: Inflammatory breast cancer (IBC) is the most virulent type of breast cancer. It represents 1 to 6% of all the breast cancer in Western countries. It is speculated that the incidence of IBC is greater in emerging countries especially in North Africa. The management of this disease requires a multidisciplinary. Methods: We recorded the cases of 80 patients with IBC admitted in the Medical Oncology Unit between January 2007 and August 2011. We included patients with IBC classified as T4d using criteria based on the tumor-node-metastasis (TNM) classification . The aims of this study is to evaluate the epidemiological, clinical, histopathological and therapeutic aspects of this disease. Results: The median age of our patients was 44.5 years ranged from 24 to 88 years. The incidence of IBC in our study was 7.8%. The lymph node involvement was noted in 60% distributed as following: N0 in 40%, N1 in 30%, N2 in 19%, N3 in 11%. For histology, ductal carcinoma represents 96% of all cases. Human epithelial receptor 2 (HER 2) was positive in 32% of the cases. Hormonal receptors were negative in 22% of the cases. The grade of the tumor according to the Scarff Bloom Richardson classification was as following: grade I ( 2.5%), grade II (52%), grade III (45.5%). All patients received neoadjuvant chemotherapy. 45% received chemotherapy with anthracyclines, 35% were treated with docetaxel and anthracycline and 10% with the association chemotherapy Trastuzumab. According to RECIST classification, a partial or total clinical response was noted in 80% of cases, 10% of patients had stability, and 10% clinical progression. According to Sattalof classification, a histological response greater than 50% in the tumor (TB) was noted in 45%. A complete pathological response (TANA or TANB) was obtained in 15% of cases. After a median follow up of 2 years 35% of the patients had a metastatic or locoregional reccurence, 45% of the cases remain in complete remission. Conclusions: The result of our study is concordant with the litterature. The incidence of IBC was greater than the incidence in western countries. The IBC was also associated with high grade and younger age. Despite a good clinical and pathological response to chemotherapy, outcomes were poor.
Long-term safety profile of palbociclib (P) in combination with letrozole (L) as first-line treatment for postmenopausal patients with ER+ and HER2- advanced breast cancer (ABC) (PALOMA-1/TRIO-18).
Authors: Dennis J. Slamon, John Crown, Istvan Lang, Sergey O. Kulyk, Marcus Schmidt, Ravi Patel, Anu Thummala, Nataliya L. Voytko, Sophia Randolph, Sindy Kim, Xin Huang, Cynthia Huang Bartlett, Patrick Schnell, Richard S. Finn
Journal: Journal of Clinical Oncology (2015)

570 Background: P is a selective and reversible oral CDK4/6 inhibitor. In a randomized phase (ph) I/II trial comparing P plus L (P + L) to L alone in patients (pts) with ER+ and HER2– ABC who had not received any prior systemic therapy for their ABC (Study 1003), P + L demonstrated significantly longer progression-free survival (PFS) vs L (20 vs 10 m; HR = 0.488, P=0.0004). Methods: We analyzed reported Adverse Events (AE) from Study 1003 by time interval (0-6m, 6-12m, 12-24, and >24m), cumulatively (12 m, 24 m time points) and assessed latency (event onset) of pertinent Adverse Drug Reactions (ADRs). Results: As of Nov 2013, 95 pts received P + L. The median duration of treatment for P was 374 d (range: 63-1682) for Ph1 (n=12) and 420 d (range: 7-1242) for ph2 (n=83). The 6 m interval analysis of the most common (>15%) ADRs (Table 1) indicated that ADRs tend to occur with greater frequency within the first 6 m with some decrease in incidence over time. Comparison of the cumulative incidences between the end of the 2nd year and 1st year shows that the cumulative event rates of the most common ADRs such as neutropenia (76% vs. 76%), fatigue (45% vs 40%), leucopenia (45% vs. 39%) and anemia (34% vs. 30%) were stable. The cumulative event rates for Grade 3/4 events were also stable except for a slight increase in fatigue (5% vs. 3%). The median time to onset of neutropenia was (20d), leucopenia (36d), anemia (168d), and thrombocytopenia (140d). Conclusions: Long term safety analysis suggests no evidence of any specific cumulative or late onset of toxicity with the prolonged treatment with P + L as first-line treatment for ER+ and HER2- ABC. Clinical trial information: NCT00721409.Summary of treatment emergent all causality ADRs by 6-m intervals (>15%). Adverse Events P + L Treatment Duration (M) 0-< 6 N = 95 % 6-< 12 N = 77 % 12-< 18 N = 59 % 18-< 24 N = 40 % ≥24 N = 29 % Any AE 97.9 88.3 81.4 72.5 79.3 Neutropenia 69.5 54.5 44.1 40.0 51.7 Leucopenia 33.7 27.3 16.9 20.0 13.8 Fatigue 33.7 14.3 13.6 10.0 10.3 Nausea 23.2 6.5 5.1 2.5 6.9 Anemia 22.1 19.5 15.3 15.0 13.8 Diarrhea 18.9 0 5.1 2.5 10.3 Alopecia 16.8 2.6 1.7 0 3.4
Patterns of management of rash associated with epidermal growth factor receptor inhibitors (EGFRIs): A national practice survey
Authors: M. E. Lacouture, S. Lai, A. W. Rademaker, D. Liu, C. Pfeiffer, D. Mauro
Journal: Journal of Clinical Oncology (2007)

14081 Background: Dermatological toxicities are frequent in patients receiving epidermal growth factor inhibitors (EGFRIs), which significantly affect health and quality of life. No current consensus or guidelines exist for the management of these manifestations. In order to gain insight on actual management approaches, a retrospective survey was conducted across oncology practices in the US. Methods: A survey in person was carried out that included 51 questions to 110 practitioners administering EGFRIs in the US, during which time erlotinib, cetuximab and gefitinib were FDA-approved. Open- and closed-ended questions relating to frequency and CTC-graded (G) severity of rash observed, management patterns, and impact on continued EGFRI therapy were evaluated. Statistical testing for correlations was done using Fisher’s exact test. Results: Respondents (resp) included MDs (72%), nurses (23%), NPs (4%), and pharmacists (1%). Majority (&gt;50%) of rash events observed were mild/moderate (G1 in 39% + G2 in 34%). Interventions against rash by resp was based on severity, with G1 treated by 47%, G2 (71%), G3 (87%), G4 (80%). Treatments for G1/2 included only topical agents (TA) by 30% of providers, and combined TA + systemic agents (SA) for G3 (G4) by 48% (30%) of providers. Interestingly, 84% of resp indicated G2 rash improved with TA+SA therapy and only 44% with SA only. Although severe events were reported infrequently (4% and 3% of resp see &gt;50% of G3 and 4 events, respectively), EGFRIs were frequently dose modified (76%) or discontinued (32%) due to rash. Conclusions: Rash is frequent and its management heterogeneous across the US, which increases with rash G. These findings suggest that combined therapy (TA + SA) is more effective than single-agent. Therefore, the high frequency of dose EGFRI modification/discontinuations reported may be minimized by proactive interventions. Trials evaluating proactive and reactive combined TA + SA against rash are currently underway. No significant financial relationships to disclose.
A randomized, open label, multicenter comparative phase II trial of ipilimumab after isolated limb perfusion (ILP), versus ILP alone in patients with in-transit metastases melanoma stage IIIB and IIIC.
Authors: Andrea Cavalcanti, Caroline Robert, Christine Mateus, Jane Muret, Celeste Lebbe, Caroline Dutriaux, Eve Maubec, Jean-Philippe Arnault, Sandrine Mansard, Carole Templier, Jean Philippe Lacour, Emilie Lanoy
Journal: Journal of Clinical Oncology (2015)

e20107 Background: : The management of IT-mets remains a challenge because it is dictated by the biologic behaviour of melanoma. In-transit metastases are a manifestation of melanoma at an advanced stage, with an associated 5-years survival rate range from 40 – 59%. ILP is effective on limb in-transit metastases with a response rate of more than 50%, however, this regional treatment has no effect on distant melanoma metastases. Ipilimumab is approved for the treatment of patients with advanced metastatic melanoma at the dose of 3 mg/kg for 4 infusions with a low response rate of about 15 to 20%. Some studies suggest that the induction of autoimmunity in patients with metastatic melanoma treated with Ipilimumab could be a marker of objective and durable tumoral responses. The rational of this association, ILP + ipilimumab is to obtain an abscopal effect, combining tumor destruction with release of tumor-associated-antigens with an immune stimulation by ipilimumab. Methods: Melanoma patients with regional limb disease (stage IIIB/C) are treated by ILP with TNF-alpha and melphalan for bulky melanoma or after failure of a prior ILP with melphalan alone; while the others patients are treated with melphalan alone. The patients are randomized 4 weeks after ILP, and for the combination arm, receive ipilimumab at the dose of 3mg/kg, q3wx4 doses, in the 28 days following the randomization. Fifty patients are going to be treated in each arm. The primary endpoint is to compare the PFS between the two treatments groups; ILP alone versus ILP followed by ipilimumab. Secondary endpoints are OS, local progression free survival (LPFS), distant progression free survival (DPFS), limb response, safety and quality of life. Translational research with sequential biopsies and immuno monitoring is also performed. Results: As of March 2014, 4 patients have been enrolled, one patient was stage IIIB and 3 patients were stage IIIC. Wieberdink grade I-II limb toxicity was seen in all patients. Two patients received ipilimumab. Conclusions: The combination was overall well tolerated and responses are promising. . The trial is actively recruiting. Clinical trial information: CA184-316 (France).
Adjuvant chemoradiotherapy versus chemotherapy for resectable gastric cancer: A systematic review and meta-analysis.
Authors: Yu Yang Soon, Cheng Nang Leong, Jeremy Chee Seong Tey, Ivan Weng Keong Tham, Jiade Jay Lu
Journal: Journal of Clinical Oncology (2013)

4066 Background: The benefits of adjuvant chemo-radiotherapy (ChRT) over chemotherapy (Ch) for resectable gastric cancer are currently unclear. We performed a systematic review and meta-analysis (direct and indirect) of published randomized controlled trials (RCT) to compare the effects of adjuvant chemo-radiotherapy with chemotherapy on overall and disease-free survival for patients with resectable gastric cancer. Methods: We searched MEDLINE and CENTRAL from the date of inception and annual meeting proceedings of ASCO and ASTRO from 1999 to November 2012 for RCTs comparing adjuvant ChRT with Ch, adjuvant ChRT with surgery alone and adjuvant Ch with surgery alone. The primary outcome was overall survival (OS); secondary outcomes included disease-free survival (DFS) and toxicity. Hazard ratios (HR), confidence intervals (CI) and p values (p) were estimated with fixed effects models using Revman 5.1. Results: We found five trials comparing adjuvant ChRT with Ch (n = 1110), three trials comparing adjuvant ChRT with surgery alone (n = 651) and 31 trials comparing adjuvant Ch with surgery alone (n = 8273). Meta-analysis of direct comparison trials showed that adjuvant ChRT significantly improved both OS (HR 0.79, 95% CI 0.64-0.98, p = 0.03) and DFS (HR 0.76, 95% CI 0.64-0.92, p = 0.004) when compared with Ch. Subgroup analyses showed that the effects on OS and DFS were similar regardless of use of D2 nodal dissection, intensity modulated radiotherapy techniques, fluorouracil or platinum-based chemotherapy. There were no significant differences in toxicity between the two groups. The results for the direct and indirect comparisons were statistically consistent. Conclusions: There was a significant survival benefit of adjuvant chemo-radiotherapy over chemotherapy, with no increase in toxicity for patients with resected gastric cancer. Future efforts should also focus on predictive markers, and toxicity or quality-of-life assessments, to individualize adjuvant therapy and optimize the therapeutic ratio.
Characterising phenotypically relevant intratumoural heterogeneity in high grade serous ovarian cancer.
Authors: Christina Fotopoulou, Paula Cunnea, Nona R Rama, Ratri Wulandari, Tommy Gorgy, Hani Gabra, Euan A Stronach
Journal: Journal of Clinical Oncology (2015)

e16569 Background: High-grade serous ovarian cancer is characterized by high degrees of genomic instability and heterogeneity, with the majority of patients eventually acquiring resistance to platinum chemotherapy. Platinum resistant tumour cells can be resensitised to platinum chemotherapy using targeted agents such as inhibiting DNA-PK, however matching best treatment options to patient tumour remains problematic due to diverse platinum resistance mechanisms and limited effective predictive biomarkers. The objective of this study is to understand the extent of intratumoural heterogeneity (ITH) in advanced stage HGSC, at presentation, and to define the link between ITH at the molecular and phenotypic levels. Methods: Advanced ovarian cancer patients (n = 17) receiving radical upfront debulking surgery underwent a tumour mapping of their tumour dissemination patterns. Biopsies from tumour deposits were taken from predefined anatomical regions. Tumour cells were extracted from multiple tumour deposits, placed in short-term culture and treated with cisplatin alone and in combination with a DNA-PK inhibitor. Apoptotic response and cell viability was measured after 24hrs. Cellularity was assessed using immunofluorescent microscopy for common tumour and stromal cell markers. Results: Cellularity was assessed for each deposit and tumour cell content > 70% was accepted for phenotypic assay analysis and subsequent exome-SEQ and proteomic analysis. Preliminary data from phenotypic assays exhibit clear differences in platinum and DNA-PK inhibitor response between the tumour deposits in each case examined, visibly demonstrating phenotypic heterogeneity in therapeutic response within different tumour deposits. Conclusions: This data coupled with future proteomic and genomic analysis of tumour deposits from each case will provide a definitive description of ITH and clonally evolved chemoresistance in HGSC.
Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neoadjuvant androgen deprivation therapy (ADT).
Authors: Anna C. Ferrari, Ying Chen, Hatem E. Sabaawy, Mark N. Stein, David Foran, Srinivasan T. Yegnasubramanian
Journal: Journal of Clinical Oncology (2017)

88 Background: Although androgen deprivation therapy initially decreases PC tumor burden, resistance to further androgen receptor (AR)-directed treatments or chemotherapy is inevitable once CRPC is established. We postulated that the stress of ADT triggers widespread alterations in expression that renders a metastable physiologic state conditioned by epigenetic changes that might be initially reversible by targeting non-androgen pathways. We conducted a pilot study to explore genome-wide expression alterations in PC foci surviving 3 months ADT (eADT). Methods: mRNA from 7 frozen microdissected PC foci and normal counterparts (NC) were processed for RNA-seq. RNA-seq changes in eADT specimens were compared first with NC and the untreated PC in the TCGA PRAD (TCGA) database to castrate resistant (mCRPC) specimens in the dbGAP study phs000915.v1.p1database. The raw data (fastq files) was quantified using kallisto, normalized by TMM using R package edgeR, batch effects corrected using R package SVA. Analysis of differential gene expression by R package sleuth. Pathway and gene set by GSEA, GAGE/pathview packages for Gene Ontology (GO) and KEGG. Results: TMPRSS2-ERG+, 5/7. Highest DEG in eADT vs. TCGA vs mCRPC were non-coding RNA’s. Among 17431 differentially regulated paths; GSEA of eADT vs TCGA or mCRPC: 341 (1.95%) and 1366 (7.84%) up- vs 46 (0.26%) and 59 (0.34%) down-regulated. KEGG paths, eADT vs. TCGA or mCRPC, 11 and 53 up vs. 2 and 3 down- respectively. Highly down- path in eADT vs TCGA (log q &lt; 10 -17 ) was ribosomal vs. cell cycle and DNA replication in mCRPC. Six paths significantly up- in eADT vs TCGA or mCRPC: Wnt, adherence junction, steroid biosynthesis, unsaturated fatty acids, citrate cycle, ErbB. Calcium, MAPK, insulin, GnRH and Hedgehog were also up- in eADT vs mCRPC. AR full-length was marginally higher in eADT than TCGA and lower than mCRPC, no differences in gene targets. Conclusions: This pilot data shows that ADT triggers a wide range of gene expression alterations that support PC cell survival and may be vulnerable to therapeutic targeting in addition to the androgen pathway. Validation of these findings is planned in a larger set of samples from the same bank.