tbuckley/cabot-search huggingface dataset:
Identifying <i>ALK</i> rearrangements that are not detected by FISH with targeted next-generation sequencing of lung carcinoma.
Authors: Siraj M. Ali, Sai-Hong Ignatius Ou, Jie He, Nir Peled, Juliann Chmielecki, Mary Colleen Pinder, Norma Alonzo Palma, Wallace L. Akerley, Kai Wang, Julian R. Molina, Jeffrey S. Ross, Roman Yelensky, Garrett Michael Frampton, Lyudmila Bazhenova, Gary A. Palmer, Deborah Morosini, Doron Lipson, Phil Stephens, Ravi Salgia, Vincent A. Miller
Journal: Journal of Clinical Oncology (2014)

8049 Background: Genomic rearrangements of ALK are the defining feature of a subset of lung non-small cell carcinomas (NSCLC), and predict response to ALK-targeted therapies. We reviewed our experience with ALK rearranged lung carcinomas (LC) as detected by a clinical next generation sequencing (NGS)-based assay. Methods: Genomic profiling of 1,070 lung carcinomas was performed on >50 ng of DNA extracted from formalin fixed, paraffin embedded specimens, from either primary tumors or metastatic sites. Libraries constructed from such DNA were subjected to hybrid capture of all exons of 236 cancer related genes and 47 introns of 19 genes frequently rearranged in cancer, and followed by clinical NGS with high uniform coverage to a median exon coverage depth exceeding 700x. Data regarding prior diagnostic studies for genomic alterations and response to targeted therapies was provided by treating physicians. Results: Of 1.070 total lung carcinomas profiled, 47 harbored ALK rearrangements (4.4%); including lung adenocarcinomas (n=39/724), NSCLC (n=4/146), adenosquamous carcinomas (n=2/12), and mucoepidermoid and large cell neuroendocrine carcinomas (n=1/3 and n=1/23). The median age of the patients was 52 years, with an equal sex ratio, and 38 patients had Stage IV disease. Of the 28 ALK rearranged specimens also tested by ALK FISH, 9 (32%) were negative, and 19 were positive. Of the 47 ALK rearranged cases, all fusions had a breakpoint in intron 19 of ALK. Six cases harbored non-EML4 5' partners. Of the 41 EML4-ALK fusions, there were 17 cases with a breakpoint in intron 13 of EML4 (variant1), 2 cases in intron 18, 2 cases in intron 2(v5), 4 cases in intron 20 (v2), and 16 cases in intron 6 (v3). Twenty-two patients were treated with crizotinib and had response data available; 19 responded by investigator assessment. Of the 9 cases negative by FISH, 5 patients responded to crizotinib, 2 patients did not, and the response data for the remaining 2 patients is unavailable. Conclusions: Targeted NGS may be more sensitive for the detection of ALK rearrangements than FISH. In light of the responsiveness of ALK NGS+/FISH- tumors to crizotinib, the use of FISH as the gold standard for ALK detection in LC warrants prospective study.
Safety data on adjuvant treatment of cutaneous melanoma patients with interferon-alpha2b and pegylated interferon-alpha2b: An interim analysis of 285 patients treated in Germany
Authors: T. K. Eigentler, R. Gutzmer, A. Hauschild, T. Vogt, R. Linse, C. Garbe
Journal: Journal of Clinical Oncology (2007)

8561 Background: A multicenter, prospective randomized, phase III trial (EADO 2002/CMII) evaluating efficacy of interferon-a2b (IFNa) and of pegylated interferon-a2b (PEGIFNa) was carried out in cutaneous melanoma patients. Patients were eligible for this trial after local excision of an intermediate risk cutaneous melanoma (tumor thickness &gt;1,5mm) &amp; the absence of regional nodal macrometastases). Methods: Interferon-a2b (IFNa) for 18 months (3x3MIU sc/week), and pegylated interferon-a2b (PEGIFNa) for 36 months (100 μg sc/week) were evaluated in 285 patients treated in Germany; 141 pts treated with PEGIFNa and 144 pts with IFNa. Safety data was analyzed and adverse events of the IFN-a treatment were monitored. Results: All relevant AEs appeared within the first year of treatment. The leading clinical adverse events observed in both arms were fatigue (27.7%) &amp; myalgia (19.7%) (NCI-CTC2–3). There were no significant differences between both treatment arms in frequency and intensity for depression, fever, weight loss, erythema at injection site, nausea, constipation, hair loss, pain, cardiovascular function, pulmonal &amp; nervous status (NCI-CTC2–3). There were no significant differences in terms of anemia, thrombocytopenia, bilirubinaemia, SGOT, SGPT, BUN &amp; proteinaemia (NCI-CTC3). Leukocytopenia (NCI-CTC3) occurred in 2.4% of all cases, and was observed more frequently in the PEGIFNa arm (3.1% vs. 0.8%; p=0.09). Granulocytopenia (NCI-CTC3) was present in 6.7% of all treated patients, appearing more frequent in the PEGIFNa arm (11.0% vs. 2.3%; p=0.05), also. One patient in the PEGIFNa arm developed a grade 4 leuko- and granulocytopenia. In another case in the IFNa arm a grade 4 increase of the SGPT was observed. In 23.7% of all treated patients a dose reduction was performed. Conclusions: Both PEGIFNa and IFNa are well tolerated using these regimens for these treatment durations. There were few differences in the tolerability between PEGIFNa 100 μg sc/week and IFNa 3x3MIU sc/week. Only an increased myelosuppressive effects such as leuko- and granulocytopenia have been observed. A prolongation of PEGIFNa treatment to 3 years was not associated with an increase in AEs. No significant financial relationships to disclose.
Phase II trial of sorafenib in advanced thyroid cancer: A disease site analysis.
Authors: Aaron Benjamin Cohen, Mark Yarchoan, Andrea B. Troxel, Kanchan Puttaswamy, Kathleen Harlacker, Laurie A. Loevner, Marcia S. Brose
Journal: Journal of Clinical Oncology (2014)

e17000 Background: Sorafenib has demonstrated efficacy in a phase III trial for patients with progressive, radioactive iodine-refractory, differentiated thyroid carcinoma (rrDTC) and was recently FDA approved for this indication. This analysis aimed to characterize the relative efficacy of sorafenib by disease site in patients from the prior phase II study. Methods: Eligible patients with rrDTC received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2–3 months. In this analysis, we measured response rates separately for pulmonary and lymph node target lesions (PTL and LNTL), visceral organs, and bone. We used Wilcoxon rank-sum or t-test when indicated to compare average time to best response (aTBR), average progression-free period (aPFP), and average best response (aBR) in size by target lesion disease site. Results: Forty-two patients with rrDTC and evaluable target lesions between February 2006 and August 2009 were included. Thirty-eight (91%) had PTL, 24 (57%) had LNTL, and 3 (7%) had visceral or bone target lesions. Sixteen (38%) had only PTL, 4 (10%) had only LNTL, and 20 (48%) had both PTL and LNTL. Thirteen (34%) PTL and 11 (46%) LNTL progressed by Response Evaluation Criteria in Solid Tumors (RECIST). The aTBR in days for PTL was 316 (95% CI, 215–419) compared to 217 (95% CI, 110–326) for LNTL (p=0.059). The aPFP in days for target lesions that progressed was 648 (95% CI, 465–832) for PTL compared to 421 (95% CI, 281–560) for LNTL (p=0.024). This relationship also held for patients with only PTL (856, 95% CI, 600–1113) compared to patients with only LNTL (404, 95% CI, 36–772; p=0.045). Together these data suggest that lymph nodes respond more quickly but the responses are less durable than pulmonary lesions. Furthermore, the aBR for PTL was a 34% decrease (95% CI, 28%–41%) from baseline PTL compared to a 23% decrease (95% CI, 17%–28%) for LNTL (p= 0.013). Conclusions: In patients with rrDTC, sorafenib is effective in decreasing both PTL and LNTL size. However, our results show that PTL had a higher aPFP and aBR than LNTL. These findings offer clinicians important guidance on what to expect when treating rrDTC patients with sorafenib and also suggest how underlying disease heterogeneity may influence results. Clinical trial information: NCT00654238.
Evaluation of soluble mesothelin-related peptide as a marker additional to cytology for diagnosing malignant pleural mesothelioma effusions.
Authors: Antonella Vigani, Paola Ferro, Pier Aldo Canessa, Enrico Battolla, Paolo Dessanti, Carmen Manta, Carlo Aschele, Maria Cristiana Franceschini, Vincenzo Fontana, Franco Fedeli, Silvio Roncella
Journal: Journal of Clinical Oncology (2012)

e17533 Background: Detection of soluble mesothelin-related peptide (SMRP) levels in serum has been proposed to help the diagnosis of malignant pleural mesothelioma (MPM). In this study we evaluated the SMRP levels in pleural effusions of MPM (MPM-PE), the clinical importance and usefulness of SMRP detection in MPM-PE and whether it can have an additional value to cytological analysis (Cyt). Methods: We studied 52 MPM-PE, 129 benign PE (B-PE) and 94 non-MPM pleural metastasis PE (Mts-PE). In all PE samples, both cytology and SMRP detection were performed. SMRP levels were estimated by means of the MesoMark ELISA kit (Fujirebio Diagnostic, Malvern, PA). Diagnostic performance parameters were estimated through the ROC analysis, Youden's index was applied to obtain the best cut-off level and the degree of correlation was estimated by Diagnostic Odds Ratio (DOR) and by P-value (P) with Chi-square test. Results: The median SMRP levels were significantly higher in MPM-PE (28.2 nM) than in B-PE (3.2 nM) or Mts-PE (3.8 nM). MPM-PE vs B-PE yielded an AUC of 84.5 (P&lt;0.001) whereas MPM-PE vs Mts-PE yelded an AUC of 79.6 (P&lt;0.001). The cut off level in MPM-PE was estimated in 9.30 nM at which value we established Se=75%, Sp=93% for MPM-PE vs BPE and SP=81% for MPM-PE vs Mts-PE. We found SMRP positive cases (≥ cut off) in 38/52 (73%) MPM-PE, in 9/129 (7%) B-PE (DOR=40, P&lt;0.001) and in 18/94 (19%) Mts-PE (DOR=13, P&lt; 0.001).Cyt was negative in 29/52 (56%) of MPM-PE, among which SMRP was positive in 20/29 (69%) cases. Cyt was positive in 15/52 (29%) of MPM-PE, among which SMRP was negative in 4/15 (27%) cases. Finally, in 8/52 (15%) MPM-PE Cyt diagnosis was suspicious and SMRP was found positive in 7/8 (88%) cases. Conclusions: Our results demonstrate that SMRP levels in PE are significantly higher in MPM-PE than in PE from other pathologies. However the test cannot be alternative to cyt but it may provide additional diagnostic value to Cyt. SMRP detection in MPM-PE can be applied in the workup of patients with a PE of unknown origin.
Tumor burden kinetics and estimation of TTP for the evaluation of response and resistance to therapy in phase II clinical trials.
Authors: Nadine Houede, Nicolas Penel, Thomas Filleron, Andrew Kramar
Journal: Journal of Clinical Oncology (2014)

e13516 Background: In phase II clinical trials, the primary endpoint for the evaluation of drug activity is almost always based on a categorized version of change in tumor burden (TB), more specifically time to progression (TTP). TTP is increasingly used as a primary endpoint to evaluate the efficacy of targeted therapies because of their cytostatic effects. Since the actual dates of nadir and disease progression is never known precisely, most TTP reported in the literature are overestimated. The objective of this study is to evaluate this imprecision under four hypothetical tumor kinetic settings and two frequently used assessment schedules. Methods: A two component tumor growth model is used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression (Wang 2009). From an initial TB=100mm, four scenarii were generated with this model, corresponding to two by two combinations of fast and slow rates of tumor shrinkage and resistance, respectively. The effect of evaluations on the classification of response was estimated with a variable number of assessment schedules. The objective of this analysis was to evaluate the difference between the estimated TTP assessed every 6-wks (6-TTP) or every 8-wks (8-TTP) and the true-TTP (t-TTP). Results: Depending on the relative frequency of the four different tumor kinetic models, t-TTP could vary between 11.2 and 46 wks. The estimate of t-TTP was overestimated up to 4.6 and 4.8wks for 6-TTP and 8-TTP respectively. Compared to t-TTP, estimated TB was increased up to 18.6% and up to 34.4% for 6-TTP and 8-TTP respectively. According to whether or not the true nadir is detected and depending on the number and spacing of intermediate evaluations, simulation results show that treatment effect can be classified as either a partial response or progressive disease according to RECIST criteria. Conclusions: TTP is used as a surrogate endpoint for survival in several situations. Depending on the tumor evaluation schedule and the underlying model, treatment effect can be incorrectly classified. Optimization rules should be recommended to avoid failure in further development of the therapy in phase III clinical trials.
A prospective study on the incidence of postoperative venous thromboembolism in Korean gastric cancer patients: An inquiry into the application of western guidelines to Asian cancer patients.
Authors: Keun Wook Lee, Jin Won Kim, Eun Ju Chun, Sang Il Choi, Do Joong Park, Soo-Mee Bang, Jeong-Ok Lee, Yu Jung Kim, Jee Hyun Kim, Jong-Seok Lee, Hyung-Ho Kim
Journal: Journal of Clinical Oncology (2013)

e15129 Background: Several Western guidelines recommend the routine use of pharmacologic thromboprophylaxis for cancer surgery patients to prevent venous thromboembolism (VTE). However, the necessity of routine pharmacologic perioperative thromboprophylaxis in Asian gastric cancer (GC) patients has not been clearly determined. Methods: To determine the necessity of routine perioperative pharmacologic thromboprophylaxis in Korean gastric cancer patients, the incidence of postoperative VTE was prospectively evaluated in gastric cancer patients receiving surgery. Among 610 GC patients who had received surgery, 375 patents prospectively underwent routine duplex Doppler ultrasonography (DUS) on days 5-12 following surgery to detect VTE and then VTE-related symptoms and signs were checked at 4 weeks after surgery (cohort A). The 235 patients that declined DUS were registered to cohort B and the occurrence of postoperative VTE was retrospectively analyzed. Results: In cohort A, symptomatic or asymptomatic VTE until 4 weeks after surgery was detected in 9 patients [2.4%; 95% confidence interval (CI); 0.9-3.9]. Tumor stage was a significant factor related to VTE development [stage I, 1.4%; stage II/III, 2.4%; stage IV, 9.7% (P = 0.008)]. In multivariate analysis, patients with stage IV had a higher postoperative VTE development [odds ratio, 8.18 (95% CI, 1.54-43.42)] than those with stage I. In cohort B, a low incidence of postoperative VTE was reaffirmed; only one postoperative VTE case (0.4%) was observed. Conclusions: The incidence of postoperative VTE in Korean GC patients was only 2.4%. Risk-stratified applications of perioperative pharmacologic thromboprophylaxis are thought to be more appropriate than the routine pharmacologic thromboprophylaxis in Korean GC patients receiving surgery.
Sources of information and influence on surgical decisions regarding contralateral prophylactic mastectomy: A prospective study.
Authors: Katharine Yao, Kristen Wroblewski, Martha Van Haitsma, Sarah Rabbitt, Jordan Williams, Swati Kulkarni
Journal: Journal of Clinical Oncology (2014)

e17628 Sources of Information and Influence on Decisions Regarding Contralateral Prophylactic Mastectomy: A Prospective Study Background: Little is known about what influences a woman's decision to undergo a contralateral prophylactic mastectomy (CPM). We hypothesized that different types of information influence women diferently depending on the patient's age, race and type of surgical procedure. Methods: A 55-item survey validated with breast cancer survivors was administered to 82 patients before surgery. Women were asked about the influence of medical personnel, individuals outside of medicine, and other sources of information on their decision to keep or remove their healthy breast. Results: The median age was 59 years; 29.2% were African American, 68.1% were White, and 2.8% were Asian; 8.3% had a CPM, 33.3% had a unilateral mastectomy(UM), and 58.3% had a lumpectomy(LU). Among the 66 women who perceived they had a choice to have a CPM, 62.7% stated that their surgeon had strong influence on their decision, compared to 37.5% for their oncologist and 20.4% for their plastic surgeon. Women reported that breast cancer survivors (66.1%), spouses(53.7%), and friends/relatives(43.9%) had a strong/some influence on their decision. Furthermore, 39.7% of women responded that websites/literature recommended by their doctor had strong/some influence on their surgical decision making, compared to 26.7% for websites/literature not recommended by their doctor, and 14.0% for television. Women >50 years old reported that the mammographer had a stronger influence on their decision to undergo a CPM than women < 50 years old(p=0.03). Oncologists(p=0.008), nurses and trained counselors(p=0.06-0.07), had more of an influence for African Americans compared to Whites while the reverse was true of the plastic surgeon(p=0.05). The plastic surgeon(p<0.001) had more influence on women choosing a mastectomy(CPM or UM) while the mammographer (p=0.05) had more influence on those choosing a LU. Conclusions: Medical personnel, particularly surgical, strongly influence a woman's decision to undergo a CPM. These findings present an opportunity for surgeons to educate women about the utility of CPM.
The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.
Authors: John C. Byrd, Richard R. Furman, Steven E. Coutre, Jan Andreas Burger, Kristie A. Blum, Jeff Porter Sharman, Ian W. Flinn, Barbara W. Grant, Nyla A. Heerema, Amy J Johnson, Tasheda Navarro, Danelle Frances James, Eric Hedrick, Susan Mary O'Brien
Journal: Journal of Clinical Oncology (2012)

6507 Background: Fludarabine based therapy, while effective, carries significant risk of morbidity and mortality in the elderly pts. As such, older CLL pts represent a high priority for new therapeutic approaches. PCI-32765 (P) an oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts is reported. Methods: Pts &gt;65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until disease progression (PD). Response was evaluated according to 2008 IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort was terminated after comparable activity and safety between doses was shown in R/R pts. Median age 71 yrs (range 65-84) with 74% of pts &gt;70 yrs. 19/31 (61%) had baseline cytopenias (Hgb &lt; 11g/dl or plts &lt;100,000). Unmutated IgVH was present in 43% of pts. The majority of AEs have been Gr&lt;=2 in severity, most commonly diarrhea, nausea, and fatigue. Gr &gt;3 non-heme AEs potentially related to P in 19% of pts. 10% of pts experienced Gr &gt;3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial responses (PR) and 8% complete remissions with no morphologic evidence of CLL on marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high ORR, including marrow clearance and very low PD rate with the single agent suggests that P warrants further study as a first-line treatment approach in elderly pts.
Correlation of insulin-receptor expression with efficacy of axitinib in patients with advanced renal cell carcinoma.
Authors: Masayuki Takahashi, Kei Daizumoto, Megumi Tsuda, Yoshito Kusuhara, Hidehisa Mori, Terumichi Shintani, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Tomoharu Fukumori, Hiroomi Kanayama
Journal: Journal of Clinical Oncology (2017)

442 Background: Axitinib has demonstrated high efficacy with well-controlled adverse events (AEs) for advanced renal cell carcinoma (RCC). Recently, nivolumab has been approved for advanced RCC. However, it is very expensive in Japan and may cause severe immune-related AEs. There is no clue to choose axitinib or nivolumab as the second-line for advanced RCC. Previously we identified the gene set which may predict poor prognosis of RCC patients (Takahashi m et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001) and have sought to elucidate whether insulin receptor (INSR) expression in the gene set may predict the resistance for axitinib as a biomarker. Methods: Axitinib was administered in 36 patients in our department between January 2008 and April 2015. Median age was 70 (36-84) years old with 22 males and 14 females. Histological subtype included clear cell RCC (n=27, 75.0%), clear cell + sarcomatoid component (n=3), collecting duct carcinoma (n=2), papillary, sarcomatoid, mucinous tubular and spindle cell carcinoma (MTSCC), and unknown in each one. Axitinib was administered in two patients as the first line, 21 patients as the second line, and 13 patients as ≥ the third line. Tissue of primary tumor was available in 20/36 patients, including 16 clear cell RCC and 4 other subtypes. Immunohistochemical INSR expression was examined and correlated with survival of the patients with axitinib. Results: Objective response rate was 27.6%, progression-free survival (PFS) was 16.3 months, and overall survival (OS) was 41.9 months in clear cell RCC patients. Patients with low INSR expression (n=7) had significantly shorter PFS (68 vs. 586 days, p&lt;0.001) and OS (169 vs. 1027 days, p=0.004) compared with those with high INSR expression (n=13). If only clear cell RCC was evaluated, patients with low INSR expression (n=3) had significantly shorter PFS (77 vs. 586 days, p=0.008) and OS (294 vs. 1027 days, p=0.016) compared with those with high INSR expression (n=13). Conclusions: Axitinib was highly effective for advanced clear cell RCC. However, immunohistochemically low expression of INSR in the primary tumor may predict the resistance for axitinib and those patients may be more suitable for immune checkpoint inhibitors.