tbuckley/cabot-search huggingface dataset:
Irinotecan/5-FU/FA (I-FU) or 5-FU/FA (FU) first-line therapy in older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials
Authors: G. Folprecht, M. T. Seymour, L. Saltz, J. Y. Douillard, R. J. Stephens, E. Van Cutsem, P. Rougier, T. S. Maughan, C. H. Köhne
Journal: Journal of Clinical Oncology (2007)

4071 Background: Irinotecan containing first line therapy has been shown to improve efficacy in first line therapy. Pooled analyses demonstrated that elderly patients benefit in a similar way as younger patients if 5-FU or 5-FU/oxaliplatin is administered as palliative or adjuvant treatment within clinical trials (Sargent, NEJM 2001, Folprecht, Ann Oncol 2004, Goldberg JCO 2006). Methods: We present an updated metaanalysis using source data of randomized trials (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986] and Seymour 2005 [FOCUS]) and compared the efficacy and toxicity in older (=70 years) and younger (&lt;70 years) patients receiving first line 5- FU/FA with or without irinotecan. Randomized patients who did not receive treatment were excluded. Results: A total of 2,691 pts. was enrolled into the analysis ( table 1 ). There was no imbalance regarding risk factors (ECOG PS, WBC, No. of tumor sites, alkal. phosphatase, LDH) between elderly and younger patients. Older and younger patients had significantly improved response rates and PFS with I-FU compared to FU. Younger patients had significantly longer OS with I-FU, older patients a trend to longer OS with I-FU ( table 1 ). I- FU was associated with more grade &gt;= 3 toxicity in the general population, but there were no significant differences regarding toxicity between older and younger patients ( table 1 ). Conclusion: Patients over 70 yrs who are selected for inclusion in phase III trials derive similar benefits from irinotecan-containing chemotherapy, and with similar risks of toxicity, compared with younger patients. [Table: see text] [Table: see text]
A retrospective analysis of the prevalence of <i>EGFR</i> or <i>KRAS</i> mutations in patients (pts) with crizotinib-naïve and crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC).
Authors: Justin F. Gainor, Anna M. Varghese, Sai-Hong Ignatius Ou, Sheheryar Kabraji, Mark M Awad, Ryohei Katayama, Amanda Pawlak, Mari Mino-Kenudson, Beow Y. Yeap, Gregory J. Riely, Anthony John Iafrate, Maria E. Arcila, Marc Ladanyi, Jeffrey A. Engelman, Dora Dias-Santagata, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2013)

8083 Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC. Recently, several studies have reported that ALK+ pts occasionally harbor concomitant mutations in other oncogenic drivers. Methods: We retrospectively analyzed tumor genotyping data from 1,683 pts with NSCLC seen at 3 U.S. centers from 2009 – 2012 to determine rates of overlapping alterations in EGFR, KRAS and ALK. Mutations in EGFR and KRAS were mainly identified using the SNaPshot multiplexed assay (&gt;95% of cases). ALK FISH was performed in all cases. To determine if this prevalence is impacted by crizotinib, we also updated our earlier analysis (Katayama et al., Sci Transl Med, 2012) of a series of repeat biopsy specimens from 34 crizotinib-resistant, ALK+ pts. Resistant specimens were examined using ALK FISH, SNaPshot, and direct sequencing of the ALK tyrosine kinase domain (TKD). Results: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. 4 pts with KRAS mutations also had abnormal ALK FISH patterns, involving isolated 5’ green probes (3/4 cases) and an isolated 3’ red probe that was unusually small (1/4 cases). Sufficient tissue was available for confirmatory ALK immunohistochemistry (clone 5A4, Novacastra, UK) in 3 of these cases, all of which were negative for ALK expression. Among pts with ALK+ NSCLC and acquired crizotinib resistance, repeat biopsy specimens remained ALK fusion positive in 28/28 (100%) cases. Secondary mutations in the ALK TKD (1151Tins, L1196M, G1202R, S1206Y, and G1269A) were identified in 7/34 (20.6%) cases. L1196M was the most common secondary mutation (3/34, 8.8% cases). ALK gene amplification was present in 3/28 (10.71%) pts. No EGFR or KRAS mutations were identified in 23 crizotinib-resistant, ALK+ pts with sufficient tissue for testing. Conclusions: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK+ pts with acquired resistance to crizotinib.
A phase II study of the anti-programmed death ligand-1 antibody durvalumab (D; MEDI4736) in combination with PARP inhibitor, olaparib (O), in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fatima Karzai, Ravi Amrit Madan, Helen Owens, Amy Hankin, Anna Couvillon, Nicole D. Houston, Farhad Fakhrejahani, Marijo Bilusic, Marc Robert Theoret, Lisa M Cordes, Jane B. Trepel, Daniel C. Edelman, Paul S. Meltzer, James L. Gulley, William L. Dahut, Jung-min Lee
Journal: Journal of Clinical Oncology (2017)

162 Background: Recent data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition. Immune checkpoint blockade is a promising avenue in mCRPC treatment. We hypothesize that increased DNA damage by O will complement anti-tumor activity of immune checkpoint inhibitor, D, in mCRPC (NCT02484404). Methods: Eligible pts have mCRPC with adequate end organ function and biopsiable disease (bone or soft tissue). Prior treatment with enzalutamide and/or abiraterone is required. D is administered at 1500 mg iv q28 days with O at 300 mg po q12 h. Primary endpoint is PFS. Secondary endpoints include PSA responses, safety and ORR. Single arm pilot study with a total accrual of 25 pts. On-study core biopsies undergo mutational analysis. Results: 6 pts have enrolled (median age 67 yr [range 60-79], median ECOG PS 1 [1-2]). Median baseline PSA: 258.1 (54.1-809.9 ng/mL). 4 pts have Gleason score (GS) &gt; 8 and 2 pts have GS of 7. Grade 3/4 adverse events include anemia 2/6 (33%), thrombocytopenia, lymphopenia, nausea, febrile neutropenia, aspiration pneumonia [1 each, (17%)]. Conclusions: Exploiting synergy of D+O is a treatment option for heavily pre-treated pts. Preliminary data shows D+O is tolerable and active in mCRPC pts without germline BRCA mutation. Paired tumor biopsies and blood samples including ctDNA are being collected. Accrual is ongoing. Clinical trial information: NCT02484404. [Table: see text]
KIF5B-RET fusion gene and oncogenic mutations of EGFR or KRAS gene in lung adenocarcinomas.
Authors: Jin Hyoung Kang, Jeong-Oh Kim, Jieun Lee, Jung-Young Shin, Ji-Eun Oh, Chan-Kwon Jung, Jae Gil Park, Sook-Whan Sung, Sang-Ju Bae, Hyun-Jung Min, Dowon Kim
Journal: Journal of Clinical Oncology (2014)

7537 Background: The KIF5B-RET rearrangement is detected with the frequency of 1~2% in ‘triple marker’-negative lung adenocarcinomas, i.e., EGFR, KRAS and EML4-ALK wild type. These mutational changes are known to be mutually exclusive, but the co-existence of ALK rearrangement with activating mutations of EGFR is rarely found. Methods: We examined the KIF5B-RET fusion gene in frozen tissues from 156 surgically resected lung tumors using RT-PCR with direct sequencing and the mutation status of EGFR and KRAS genes using PNA clamping (PANAGENE, KOREA). We tested KIF5B-RET translocation in FFPE (Formalin Fixed Paraffin Embedded) using fluorescence in situ hybridization (FISH) with Zytolight Spec RET dual color break-apart probe (zytovision) and KIF5B-RET SY translocation FISH probe (abnova). We also measured c-RET mRNA and protein expression by qRT-PCR and immunohistochemistry (IHC), respectively. Results: The existence of KIF5B-RET fusion gene was identified in 11 pts (7.1 %). The mean age was 64.8(52~82) and M: F ratio 5:6. Of 11 pts, 3 pts (27.3 %) harbored wild type of EGFR and KRAS gene. However, KIF5B-RET fusion gene coincided with EGFR or KRAS mutation in 8 pts (72.7 %). These eight pts were also positive for both KIF5B-RET fusion (41.9%, 22.2~72.4 %) and RET break-apart probes (23.7%, 14.3~37.8 %). However, there were no correlations between RET mRNA and protein expression in the KIF5B-RET-positive pts. The median DFS and OS were 23.0 months (8.0~111) and 27.8 months (2.6~114.5), respectively. Conclusions: Taken together, our data suggest one-step screening platform for KIF5B-RET as well as EGFR, K-RAS, ALK oncogenic mutations be necessary for lung adenocarcinoma pts because EGFR or KRAS mutation are not infrequently found in KIF5B-RET-positive pts. Now, we are undergoing the clinical study for combined treatment of EGFR TKIs with RET inhibitors for lung adenocarcinoma pts harboring both KIF5B-RET rearrangement and EGFR mutation.
Racial variations in upgraded gleason scores of active surveillance candidates.
Authors: Krishna Pandya, Allison H. Feibus, Andrew B. Sholl, Jonathan L. Silberstein
Journal: Journal of Clinical Oncology (2017)

e548 Background: Currently, active surveillance is an appropriate option for patients who have low risk PCa as determined by the NCCN as Gleason Score (GS) ≤ 6 and a PSA &lt;10. Methods: Following IRB approval, we determined that 141 men from our database had low risk PCa and were eligible for AS, but underwent radical prostatectomy (RP). We performed a retrospective review of these patients examining GS upon RP. Disease upgrading on RP was considered Gleason score ≥ 7. A two-tailed t-test was performed to examine whether African American (AA) patients had greater incidence of upgrading on RP than non-African American patients. Results: Of the 141 patients identified (36 AA, 105 non-AA) there were no significant differences in age at RP (59 AA, 59 non-AA), median PSA (5.5 ng/dL AA, 5.4 ng/dL non-AA), and number of positive cores (3 AA, 3 non-AA) at biopsy when stratified by race. A total of 85 patients (19 AA, 66 non-AA) were found to have an upgraded GS at the time of RP; again without significant difference with respect to age (60 AA, 61 non-AA), serum PSA (5.3 AA, 5.35 non-AA), total cores taken at biopsy (12 AA, 12 non-AA) and median positive cores (3.5 AA, 3 non-AA). Of the 85 patients upgraded, 66 (12 AA, 54 non-AA) were 3+4 and the remainder were ≥ 4+3. There was no significant racial variation for patients upgraded to Gleason 3+4 (p&gt;0.05). Next we reviewed the presence of tertiary pattern 5 within these 3+4 patients and found it present in 1 patient who was AA. For the 19 patients with ≥ 4+3 upgrading, with respect to race (7 AA, 12 non-AA, p = .08) there were no significant differences in age, serum PSA, median positive and total cores taken at biopsy. However, when comparing these 19 upgraded ≥ 4+3 patients to the total cohort, they had a higher median serum PSA (6.16 ng/dLvs 5.4 ng/dL) and higher positive cores (4 vs 3) on biopsy. For these 19 patients, upgrading resulted in reclassification from low to high-grade (GS ≥ 8) PCa in 7 patients. Conclusions: African American patients with low risk PCa have do not have an increased risk of significant upgrading at RP when compared with other races, and further investigation is needed to identify factors that contribute to upgrading.
Potential predictive and prognostic factors for sequential treatment with abiraterone acetate and cabazitaxel in metastatic docetaxel-refractory castration-resistant prostate cancer (mDR-CRPC).
Authors: Sergio Bracarda, Alketa Hamzaj, Michele Sisani, Giuseppe Di Lorenzo, Francesca Marrocolo, Sabrina del Buono, Valeria de Simone, Verena De Angelis
Journal: Journal of Clinical Oncology (2013)

e16093 Background: in recent years Abiraterone Acetate (AA) andCabazitaxel (Cbz) were shown to be efficacious agents in patients with mDR-CRPC. However, no data exist for patients treated with both these drugs in terms of best sequencing evaluation and potential predictive and prognostic factors for different treatment sequencies. Aim of our study was to analyze these data in a real world scenario. Methods: intention-to-treat (ITT) analysis of activity data deriving from all consecutive patients with mDR-CRPC treated in our unit with prednisone plus Cbz, AA or both drugs. Data analyzed were, median Progression Free Survival (mPFS) for the two single agents and their sequencies (evaluated according to PCWG2, Prostate Cancer Working Group 2, criteria) and their possible correlations with median age, Gleason score, baseline PSA, ECOG PS, visceral metastases and number of previous chemotherapy lines. Results: here we report characteristics and activity data of the initial 62 patients, 7 treated with Cbz, 32 with AA and 16 with both drugs. The median age of our study population was 71.5 years (range, 55-87), median Gleason Score 8 (4-9) and median ECOG PS 0 (0–3); visceral disease was present in 37 cases (59.7%). The mPFS, according to Kaplan Meier method (KM), was 4.7 months (m) for patients treated with Cbz, 8.6 months for cases treated with AA and 8.2 m for cases treated with both agents. Of the 16 patients treated with both drugs, 12 received a sequence Cbz-AA and 4 a sequence AA-Cbz for an overall median PFS of, respectively, 5.6 and 4.0 m. Any of the analyzed prognostic or predictive factor was found to be significant. Conclusions: in our experience AA and Cbz were showed to be effective agents in the mDR-CRPC setting also when used sequentially. No clear indication of a preferred treatment sequence was identified such as eventual prognostic/predictive factors, also because of the limited number of treated patients. These data should be analyzed in large size prospective trials.
Patients’ perceptions of caregivers’ preference for comfort care at the EOL: Impact on DNR completion.
Authors: Kalen Michele Fletcher, Holly Gwen Prigerson, Paul K Maciejewski
Journal: Journal of Clinical Oncology (2013)

9521 Background: Research has shown that informal caregivers provide substantial psychosocial and material support to advanced cancer patients. Few studies have examined how family caregivers influence patients’ advance care planning. Here we test whether patients’ perceptions of their caregivers’ preference for comfort (vs. life-extending) end-of-life (EOL) care is associated with DNR order completion. We also evaluated whether caregivers’ actual agreement with patients on preference for comfort EOL care was associated with their rates of DNR order completion. Methods: Coping with Cancer II is an NCI –funded, multi-site, prospective cohort study of patients with advanced cancer and their informal family caregivers. Patients are interviewed after receiving restaging scan results and asked if they would prefer a plan of EOL care focused on life-extension or one focused on relieving pain. Patients are also asked what type of EOL care they think their family caregivers would prefer for them and whether or not a DNR order has been completed for them. Caregivers are interviewed separately after patients receive restaging scan results and asked what type of EOL care they would want for the patient. Results: Based on patient data alone (N=72), patients who preferred comfort care at the EOL and who believe that their family caregiver agrees with them on this were significantly more likely than others to report DNR order completion (OR=3.67, p=0.013). Based on data from both patients and caregivers, patients’ perception of agreement with their caregivers on desire for comfort EOL care was more strongly associated with patients’ reports of DNR completion (r s =0.51, p=0.004) than was actual agreement with their caregivers on desire for comfort EOL care (r s =0.36, p=0.045). Conclusions: Patients who prefer comfort care to life-extending care at the EOL, and who think that their caregivers also want them to pursue comfort care, are more likely to have a DNR order completed. Interestingly, patients’ perception of this agreement had a stronger influence on DNR completion than the caregivers’ actual agreement with patients’ preference for comfort EOL care. DNR completion is influenced by patients’ perceptions of family support.
High Predictive Value of Pre Transplant Minimal Residual Disease Assessment By Combining WT1 Expression and Flow Cytometry in Acute Myeloid Leukemia
Authors: Fabio Guolo, Federica Galaverna, Paola Minetto, Livia Giannoni, Chiara Ghiggi, Marino Clavio, Carmen Di Grazia, Anna Maria Raiola, Nicoletta Colombo, Raffaella Grasso, Maurizio Miglino, Adalberto Ibatici, Roberto Massimo Lemoli, Marco Gobbi, Andrea Bacigalupo
Journal: Blood (2015)
The E3 ubiquitin ligase Cbl-b to improve the prognosis of RANK positive breast cancer patients by inhibiting RANKL-induced cell migration and metastasis.
Authors: Lingyun Zhang, Yunpeng Liu, Xiujuan Qu, Yibo Fan, Yan Wang, Yuee Teng, Jing Shi, Yanju Ma, Ce Li, Xiaonan Shi
Journal: Journal of Clinical Oncology (2015)

e22196 Background: The receptor activator of nuclear factor κ-B ligand (RANKL)/RANK pathway plays an important role in breast cancer progression. However, the prognostic value of RANK expression in breast cancer remains unclear. Despite the known role of Casitas B-lineage lymphoma (Cbl)-b as an essential regulator of the RANKL/RANK pathway, its effect on RANK in breast cancer remains unclear. The present study investigated the effect of Cbl-b on RANKL-triggered migration and metastasis of breast cancer cells as well as on the prognosis of RANK-expressing breast cancer patients. Methods: RANK and Cbl-b expression was examined by immunohistochemistry in 300 breast cancer tissues. Survival analysis was done to explore the effect of RANK and Cbl-b expression on prognosis. Flow cytometry was used to examine RANK expression in breast cancer cell lines MDA-MB-231 and MCF-7. RANKL- induced cells migration was examined by transwell migration assay. RANKL/RANK pathway was examined by western blot. Animal experiment was used to investigate the effect of Cbl-b on tumor metastasis. Results: RANK and Cbl-b expression was separately detected in 154 ( 51.3%) and 165 ( 55.0%) breast cancer tissue samples. RANK expression was not a predictor of poor disease-free survival (DFS) and disease-specific survival (DSS) (P = 0.538 and P = 0.857, respectively) for breast cancer populations. However, in RANK-expressing patients, Cbl-b expression was correlated with better DFS and DSS (P = 0.004 and P = 0.036, respectively). In addition, multivariate analysis showed that Cbl-b expression was an independent predictor of DFS in RANK-expressing breast cancer patients. Animal experiment results demonstrated that silencing Cbl-b expression in MDA-MB-231 cells increased the incidence of lung metastasis in nude mice. Further mechanism investigation revealed that Cbl-b down-regulated RANK protein expression and inhibited RANKL-induced breast cancer cell migration by negatively regulating the Src-Akt/ERK pathway. Conclusions: Cbl-b improves the prognosis of RANK-expressing breast cancer patients by inhibiting RANKL-induced breast cancer cell migration and metastasis.
Differences in disease characteristics, treatment patterns, and outcomes between men (M) and women (W) with follicular lymphoma (FL): Prospective evaluation of 2,650 U.S. patients (pts).
Authors: Chadi Nabhan, Michelle Byrtek, Keith Lamont Dawson, Xiaolei Zhou, Ryan Ziemiecki, Andrew David Zelenetz, Jonathan W. Friedberg, James Robert Cerhan, Christopher Flowers
Journal: Journal of Clinical Oncology (2014)

8550 Background: Differences in disease presentation, characteristics, treatment patterns, and outcomes between sexes among pts with FL have not been well-described. Methods: Using the National LymphoCare Study, a prospective registry sponsored by Genentech, that enrolled newly diagnosed FL pts (2004–2007), we analyzed differences in baseline characteristics and outcomes by gender. Associations of gender with disease characteristics, treatment, R dose intensity, and overall response (OR) were assessed using Pearson χ2tests. For pts receiving R-based induction, median progression-free survival (PFS), overall survival (OS), and lymphoma related mortality (LRM) by gender, age, and treatment regimen were estimated using Kaplan-Meier method. Adjusted Cox modeling for baseline factors and treatment regimens assessed gender differences in PFS, OS, and LRM. Results: 1,276 M and 1,374 W were prospectively enrolled (median F/U 6.9 yrs). More W had poor-risk FLIPI (36% vs 32%; P=0.05), which was likely due to anemia (27% vs 15%; P<0.0001) without other differences. Treatment varied by gender (P=0.002) with more W receiving R-monotherapy (15% vs 11%). R-containing regimens were given to 62% M and 61% W respectively with no differences in dose intensity (P=0.428). ORs were similar for M and W across regimens and age groups but in M and W, R-chemotherapy provided superior OR to R-monotherapy. After adjusting for baseline factors and treatment, W receiving R-based induction had superior PFS (HR 0.82, 95% CI 0.71–0.95; P=0.009) and OS (HR 0.73, 95% CI 0.58–0.90; P=0.003). Comparisons to pts who did not receive R-treatment were not performed due to low pt numbers. There were no significant difference in LRM overall (HR 0.86, P=0.35), but W had superior LRM in the pts ≤60. W had superior PFS and OS across all age categories (Table). Conclusions: This is the first prospective report to show that PFS and OS of W with FL are superior to M in the modern era. Clinical trial information: NCT00097565. W vs M ≤60 yrs 61–80 yrs >80 yrs PFS 0.79 (0.62–1.00) 0.91 (0.73–1.12) 0.58 (0.37–0.91) OS 0.61 (0.38–0.99) 0.87 (0.66–1.14) 0.47 (0.29–0.78) LRM 0.41 (0.20–0.87) 1.07 (0.71–1.61) 0.90 (0.39–2.07)