tbuckley/cabot-search huggingface dataset:
Somatic mutation profiling in ovarian Brenner and associated mucinous tumors.
Authors: Christopher S. Potter, Susan M. Mockus, Sara E. Patterson, Vanessa Spotlow, Talia Mitchell, Roger Liu, Guruprasad Ananda, Eric B. York, Gregory J. Tsongalis, Laura J. Tafe
Journal: Journal of Clinical Oncology (2015)

e16585 Background: Benign ovarian Brenner tumors are often associated with mucinous cystadenomas (MCA) or mucinous borderline tumors (MBT) and hypothesized to share a histogenic origin and progression, yet limited molecular characterization has been conducted that might support this. Here, we describe targeted next generation sequencing of Brenner and ipsilateral mucinous tumors to identify molecular mechanisms linking these tumor types which may contribute to pathogenic progression. Methods: DNA from histologically diagnosed tumor FFPE samples (7 Brenner, 3 MCA, and 2 MBT (including 4 sets of paired samples)) was sequenced using a 358-gene next-generation sequencing assay. Sequenced samples were subjected to an in-house bioinformatic pipeline, partially annotated using SnpEff/SnpSift, and interpreted by mapping high/medium impact variants to an in-house manually curated clinical knowledgebase. Variant calls were compared within tumor groups to assess somatic mutation profiles. Results: 213 different high/medium impact variants were detected across all samples with a 76% overlap between Brenner and MCA-MBT samples. Within Brenner tumors, exon-coding mutations in GLI1 (7.5%), BRCA1 (7.0%), ERBB2 (4.6%), and AURKB (4.4%) represented the highest frequency variants. Variants in BRCA1 (8.6%), GLI1 (5.9%), AURKB (4.2%), PGR (4.1%) were most frequent in MCA-MBT tumors. Twenty variants were common to all (7/7) Brenner samples, while 21 variants were found in all (5/5) MCA-MBT samples. Mutations in RAS were noted in 4 of 5 MCA-MBT samples, but no Brenner samples. Pathway analysis of mutated genes noted a common association with Hedgehog signaling in both groups. However, genes highly mutated in Brenner tumors were more commonly linked to epithelial-mesenchymal transition pathways, while those in MCA-MBT tumors impact regulation of MYC mediated apoptosis. Conclusions: The high degree of overlap in gene variants between Brenner and mucinous (MCA-MBT) tumors observed in our analysis supports the idea of a shared origin or progression. Differences observed in affected genes and pathways, particularly involving KRAS and MYC, may point to molecular drivers that support the divergent phenotype and progression of these ovarian tumors.
Oral bisphosphonates fail to prevent bone loss from androgen deprivation therapy in men with prostate cancer
Authors: R. Y. Lam, M. Scholz, B. Guess, T. Trilling
Journal: Journal of Clinical Oncology (2006)

14643 Background: Androgen deprivation therapy (ADT) is a widely administered treatment for prostate cancer. However, ADT is associated with accelerated bone loss, osteoporosis, and fractures (Shahinian, NEJM 2005; 352:154). According to Smith et al, annual bone loss on ADT approaches 9% (Smith, NEJM 2001;345:948), using QCT densitometry, a highly sensitive test for the detection of osteoporosis in men. Intravenous bisphosphonates (pamidronate, zolendronate) have been shown to prevent ADT-related bone loss in randomized phase III trials. We performed a retrospective analysis to determine if oral bisphosphonates effectively prevent bone loss in men receiving ADT. Methods: Twenty two men, ages 60–80, were placed on alendronate or risendronate at the initiation of ADT. Baseline and follow-up bone mineral densitometry (BMD) studies were performed with QCT densitometry. Repeat BMD was performed 12- 27 months (mean = 17mo) after the baseline BMD. Percentage change in bone density was annualized. Within each treatment group, the hypothesis of no mean change from baseline was analyzed using a paired t test. Results: Mean baseline bone density was 122.6mg/cc. Mean follow-up bone density was 112.7mg/cc. For the whole group, the annualized mean change in BMD was negative 7.77%/yr (p = 0.0003). Of note, 9/22 men maintained or gained bone density (-1.26% to +5.95%). 13/22 men lost at least 6.03% (-6.03% to -23.2%). There was no unexpected toxicity or fractures. Conclusions: In this retrospective study, prophylactic oral bisphosphonates do not protect against accelerated ADT-induced bone loss in men with prostate cancer. No significant financial relationships to disclose.
Application of next-generation sequencing (NGS) for evaluation of advanced epithelial cancers: A single institution experience.
Authors: Patrick McKay Boland, Alan P. Skarbnik, Massimo Cristofanilli, R. Katherine Alpaugh, Anthony J. Olszanski
Journal: Journal of Clinical Oncology (2013)

11092 Background: The use of molecular targeted therapeutic agents may require the application of sophisticated diagnostic technologies for patients’ selection. Next generation DNA sequencing (NGS) has the ability to identify genetic alterations (GA) including mutations, copy number alterations, insertions/deletions, and rearrangements in tumor specimens. We sought to evaluate patients with advanced and refractory epithelial tumors to detect potentially actionable molecular abnormalities. Therapeutic intervention driven by GA findings was determined solely by the patient’s treating physician. Methods: Tumor samples from 77 patients ≥ 18 years old with any solid malignancy were sequenced. NGS of 186 genes was performed by FoundationOne through funding from Foundation Medicine using archival or newly acquired tumor tissue. Results: Seventy-four patients had specimens with adequate material for DNA extraction and analysis. Characteristics: 74% female, median age 55 years (19-82). Tumor sites included inflammatory breast (50%), colon (12%), unknown primary (5%) and other (33%). At least one genetic alteration was seen in 71 (96%) patients. The most common GA included mutations in 65 (60%) samples revealing TP53 (32%), KRAS (10%), PIK3CA (8%), and APC (6%) and amplifications in 38 (35%) samples which included MYC (18%), MCL1 (14%), CCND1 (12%), and ERBB2 (7%). Copy number loss (4%), fusion (1%) and deletions (2%) were also discovered. An actionable GA was seen in 46 of 74 patients successfully tested (62%), with 54% of GAs being amplifications and 43% mutations. Patients had a median of 3 GA (range 0-7). One patient with anal cancer had a concomitant PIK3CA mutation and amplification. NGS in association with immunohistochemistry helped identify site of origin for one patient with an occult primary. Conclusions: NGS identified GAs in the majority of patients with advanced epithelial cancers, including actionable abnormalities in a large fraction of this heterogeneous population. NGS shows promise in the diagnostic evaluation of advanced malignancies. Future studies should include the potential prognostic implications of genomic-driven personalized therapy.
Colorectal cancer patient follow-up following surgery with curative intent: The GILDA trial
Authors: F. E. Johnson, K. S. Virgo, E. M. Grossmann, W. E. Longo, R. Fossati
Journal: Journal of Clinical Oncology (2004)

3645 Background: Surgery is the mainstay of treatment for colorectal cancer. In western industrial societies most patients are treated with curative intent and enter some type of follow-up regimen. Surgeons often follow their own patients after colorectal cancer surgery but the optimum surveillance strategy has not been defined. There are no active adequately powered trials dealing with this topic originating in North America, as far as we are aware, but one based in Milan, Italy, is open (Gruppo Italiano di Lavoro per la Diagnosi Anticipata - GILDA). Methods: After primary curative-intent treatment, stratification, and randomization at GILDA headquarters, colon cancer patients are followed according to a more intensive or less intensive surveillance regimen. Rectal cancer patients are also followed according to a more intensive or less intensive regimen; these arms are similar to the arms for colon cancer patients but focus more on local-regional recurrence. To ensure adequate statistical power, the target number of patients is 1,500. Health-related quality of life and cost-effectiveness measures are incorporated in the trial. Results: The trial opened in 1998; 940 patients from 41 centers had been enrolled as of November 2003. The trial opened to North American centers in 2002. The mean duration of follow-up was 13 months as of November 2003. Sixty-six relapses, 31 deaths, and 5 second primary cancers had been documented in the two more intensive follow-up arms; 52 relapses, 21 deaths, and 9 second primary cancers had been observed in the two less intensive arms as of November 2003. Conclusions: This trial should provide the first evidence based on an adequately powered randomized trial to determine the optimal follow-up strategy for colorectal cancer patients. The authors will provide information packets at the meeting for individuals and institutions interested in participating in this trial. No significant financial relationships to disclose.
Neoadjuvant chemotherapy plus trastuzumab in stage II/III breast cancer with low HER2 expression.
Authors: Qamar J. Khan, Anne O'Dea, Carol J. Fabian, Carol Sue Connor, Marilee McGinness, Joshua Matthew Varghise Mammen, Jamie Lynn Wagner, Stella Baccaray, Michelle Springer, Henry Yeh, Priyanka Sharma
Journal: Journal of Clinical Oncology (2015)

1039 Background: Adjuvant trials have demonstrated that addition of trastuzumab (T) to chemotherapy reduces risk of recurrence and death in women with HER2 overexpressed or gene amplified early breast cancer (BC). Central testing of specimens from patients in NSABP B-31 demonstrated that ~ 10% of patients without overexpression/gene amplification of HER2 had similar benefit from adjuvant T. Aim of this study was to assess pathologic complete response (pCR) when T is added to neo-adjuvant (NA) chemotherapy in women not exhibiting HER2 FISH amplification but had low level of protein (IHC) expression (1+ or 2+). Methods: Single arm phase II trial of clinical stage II/III operable BC with HER2 expression of 1+ or 2+ by IHC and FISH negative (Ratio < 2). All clinically suspicious axillary nodes were biopsied. Eligible women received 12 weeks of weekly nab-paclitaxel (100mg/m2) + weekly T (4mg/kg LD then 2mg/kg) followed by 4 cycles of dose dense AC (60/600), followed by surgery. Women with + axillary nodes at diagnosis had ALND. Results: 32 subjects were enrolled between 7/2009-9/2013. Median age was 53. 59% were postmenopausal. 6% had grade 1, 41% grade 2 and 53% had grade 3 tumor. All but 1 were ER + (97%) with average ER expression of 85% (range 50-99%). 22 tumors (70%) were 1+ by IHC; 10 (30%) were 2+. Median tumor size was 4.1 cm (range 1.5 to 8cm). 17 (53%) had biopsy proven + axillary nodes. 14 subjects had clinical CR after 12 weeks of nab-paclitaxel/trastuzumab. 18 had cCR at completion of AC. 8 (25%) patients had pCR in breast. 7 (22%) had pCR in breast + axilla. Of 17 biopsy proven node + patients at diagnosis, 9 (53%) were rendered node negative at surgery. 14 (44%) had one or more grade 3 toxicity. Neuropathy was noted in 23 (72%) subjects (53% grade 1, 19% grade 2). No cardiac events observed. 29/32 women completed all therapy. Conclusions: Neo-adjuvant T/nab-paclitaxel followed by AC in HER2 negative, ER + BC resulted in pCR rates higher than expected for this population. Among patients with positive axillary nodes, a very high (53%) complete response rate was noted in axilla. Correlative studies are underway to identify biomarkers of response. Benefit of T in BC with low HER2 expression should be studied in a randomized neo-adjuvant trial. Clinical trial information: NCT00944047.
The efficacy and safety of gemcitabine + nab-PTX for recurrence and refractory pancreatic cancer.
Authors: Kei Saito, Yousuke Nakai, Hiroyuki Isayama, Naminatsu Takahara, Suguru Mizuno, Hirofumi Kogure, Saburo Matsubara, Minoru Tada, Kazuhiko Koike
Journal: Journal of Clinical Oncology (2017)

485 Background: Gemcitabine + nab-Paclitaxel (GnP) is considered as one of the standard first-line chemotherapy for advanced pancreatic cancer (PC), but its efficacy and safety of GnP in patients with refractory or recurrent (Ref/Rec) PC has not been fully reported. Therefore, we conducted this retrospective analysis of GnP in patients with Ref/Rec PC. Methods: Consecutive patients with PC who received GnP at the University of Tokyo Hospital were retrospectively studied. Clinical outcomes in patients with Ref/Rec PC were compared with those in patients with PC receiving GnP as 1 st line therapy. Dose intensity was calculated as the total amout of drug given in eight weeks. Tumor response was evaluated using RECIST 1.1 and adverse event using CTCAE ver 4.0. Progression free survival (PFS) were evaluated using the Kaplan-Meier method and compared by long-rank test. Cox regression models were used to calculate hazard ratios (HRs) to evaluate the prognostic factors in patients with Ref/Rec PC and in patients receiving GnP as 1 st line therapy. Results: A total of 80 patients (37 as 1 st line, 18 refractory and 25 recurrent) received GnP between January 2015 and July 2016. There were no significant differences in patient characteristics between 1 st line therapy group and Ref/Rec group other than sex (Male in 41 vs. 67%). In relative dose intensity (RDI), there were no significant difference (75 vs. 72%). AE rates, both hematologic and non-hematologic, did not differ significantly between two groups. RDI was 75 vs. 72% for gemcitabine and 80 vs. 79% for nab-Paclitaxel. Response rate and disease control rate were 23 and 93% vs. 11 and 86%. The median PFS were 9.0 (95%CI: 4.9-13.9) vs. 5.5 (95%CI: 3.5-8.0) months (p = 0.06) and 1-year survival rate were 42.9 vs. 14.3% (p = 0.16). In the multivariate analyses, HRs of RDI &lt; 70 were 2.44 (95%CI: 1.07-5.49, p = 0.04) in Ref/Rec group, while the association was not significant in the 1 st line group (HR 1.70 [95%CI: 0.63-4.25], p = 0.28). Conclusions: GnP was safely administered in patients with Ref/Rec PC with DI comparable to 1 st line therapy. However, PFS in refractory and recurrent group tended to be short compared to those receiving GnP as 1 st line therapy. DI was associated with the prognosis only in Ref/Rec PC.
Phase I/II study of brentuximab vedotin in pediatric patients (pts) with relapsed or refractory (RR) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL): Interim phase (ph) I safety data.
Authors: Kathleen Neville, Lia Gore, Christine Mauz-Körholz, Angelo Rosolen, Judith Landman-Parker, Jose Sanchez de Toledo, Auke Beishuizen, Anna Rachel Keating Franklin, Adedigbo Fasanmade, Jingyuan Wang, Dirk Huebner, Franco Locatelli
Journal: Journal of Clinical Oncology (2013)

10028 Background: Brentuximab vedotin (ADCETRIS) is a novel antibody-drug conjugate that targets CD30, a cell surface antigen expressed by HL and sALCL. The ph 1 portion of this study evaluated safety, pharmacokinetics (PK), and recommended ph 2 dose (RP2D) of brentuximab vedotin in pediatric pts with RR CD30-expressing tumors. Methods: Ph 1/2, open-label, multicenter study in pts aged 2 to &lt;18 years with RR HL or sALCL (5 to &lt;18 years for HL). Pts received brentuximab vedotin by IV infusion once every 21 days (Q3wk). Ph 1 start dose was 1.4 mg/kg escalated to 1.8 mg/kg in a traditional 3+3 design. Results: 12 pts (median age 14.5 y; 10 HL; 2 sALCL) received brentuximab vedotin in the ph 1 portion (mg/kg/dose [n]: 1.4, [3]; 1.8 [9]). 1.8 mg/kg cohort was expanded from 6 to 9 pts to raise the ph 1 pediatric experience to 12 pts before the ph 2 portion. At data cut, pts had received a median of 3 cycles (range, 1–8). 11 pts (92%) had ≥1 treatment-emergent adverse event (TEAE): 2 at 1.4 mg/kg, 9 at 1.8 mg/kg. 6 pts (50%) had Gr ≥3 TEAE: 1 at 1.4 mg/kg, 5 at 1.8 mg/kg. The most frequent (≥15%) TEAE were nausea (50%), abdominal pain, diarrhea (25% each), upper abdominal pain, cough, fatigue, hypokalemia, leukopenia, decreased lymphocyte count, pain, paresthesia, vomiting, weight loss (17% each). 1 pt (8%) discontinued due to TEAE (Gr 3 hepatotoxicity). 7 serious AE (SAE) were reported in 4 pts at 1.8 mg/kg: Gr 2 supraventricular tachycardia unrelated to treatment in 1 pt; Gr 3 febrile neutropenia, Gr 3 hepatotoxicity and Gr 3 cardiac failure (not a cardiac event per later analysis) in 1 pt; Gr 3 bronchospasm and Gr 2 laryngeal edema in 1 pt; 1 cardiac arrest resulting in death, unrelated to treatment. 2 dose limiting toxicities were reported in 1 pt in the 1.8 mg/kg cohort (SAE: prolonged Gr 3 liver event, Gr 3 febrile neutropenia). PK data will be presented. Conclusions: Brentuximab vedotin is generally well tolerated in pediatric pts with RR CD30-positive HL or sALCL up to 1.8 mg/kg Q3wk. For the majority of pts, toxicities were generally mild to moderate and did not lead to discontinuation. 1.8 mg/kg is the RP2D for pediatric and adult pts. The ph 2 portion is ongoing. Clinical trial information: NCT01492088.
C-jun N-terminal kinase dependent autophagic cell death in cancer cells induced by Zanthoxylum fruit extract from Japanese pepper.
Authors: Toru Kono, Reo Nozaki, Hiroki Bochimoto, Tsuyoshi Watanabe, Kaori Oketani, Yuichi Sakamaki, Naoto Okubo, Koji Nakagawa, Hiroshi Takeda
Journal: Journal of Clinical Oncology (2017)

653 Background: Natural products constitute a promising resource for drug development including an anticancer drug. Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) is an important component of Daikenchuto, which is a form of Japanese traditional medicine. Recently, we have reported that Daikenchuto has an anticancer activity in vivo, however precise mechanism is still unclear. Therefore, we investigated the potential anticancer activity of ZFE as an inducer of autophagic cell death (ACD). Methods: ZFE powder was provided by Tsumura (Japan). We investigated the effect of ZFE on the morphology of six types of human cancer cells and normal cells by using phase contrast microscopy and electron microscopy. Knockdown of autophagy-related gene 5 (ATG5), which is an essential gene for autophagy, by transfecting small interfering RNA was performed and confirmed by quantitative RT-qPCR and Western blot analysis. Effect of bafilomycin A1 (Baf A1), an inhibitor of vacuolar type H+-ATPases, on the anticancer activity of ZFE was investigated. Western blot analysis revealed LC3-II levels, a marker of autophagy. Results: ZFE caused remarkable autophagy-like cytoplasmic vacuolization with the inhibition of cell proliferation and subsequent induction of cell death in human cancer cell lines, DLD-1, HepG2 and Caco-2 cells but not in A549, MCF-7 or WiDr cells. ZFE increased LC3-II protein levels. Suppression of an ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, ZFE increased the phosphorylation of c-jun N-terminal kinase (JNK) in cancer cells which can be induced cell death by ZFE and JNK inhibitor SP600125 attenuated both vacuolization and cell death induced by ZFE. Instead, ZFE-induced cell death was neither apoptosis nor necrosis according to the morphological perspective and the marker of apoptosis or necrosis. And normal intestinal cell was not affected by ZFE. Conclusions: ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.
Phase I trial of the hedgehog (Hh) inhibitor, LDE225, in combination with etoposide and cisplatin (EP) for initial treatment of extensive stage small cell lung cancer (ES-SCLC).
Authors: Maria Catherine Pietanza, Lee M. Krug, Anna M. Varghese, Martin Fleisher, Jerrold B. Teitcher, Andrei Holodny, Camelia S. Sima, Anna Maria Litvak, Kenneth K. Ng, Payal R. Patel, Fawzia Ibrahim, Anne Haughney-Siller, Dorothy Dulko, Grace Monger, Melanie Albano, Clare M Moran, Mark G. Kris, Charles M. Rudin
Journal: Journal of Clinical Oncology (2014)

7602 Background: SCLC relies on the Hh developmental pathway for tumor initiation and progression. Pharmacologic blockade with Hh inhibitors blocks these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of LDE225, a selective, oral smoothened antagonist, in combination with EP in newly diagnosed ES-SCLC patients. Methods: Untreated patients with measurable disease, Karnofsky performance status ≥70, and asymptomatic brain metastases were eligible. All patients received 4 to 6 21-day cycles of EP (E, 120mg/m2 D1-3; P, 60mg/m2 D1) with daily LDE225. Patients with response or stable disease were continued on LDE225 until disease progression or unacceptable toxicity. Prophylactic cranial irradiation was performed after EP + LDE225, and LDE225 was held during that therapy. Two dose levels of LDE225 were planned: 400mg and 800mg daily, with 200mg daily de-escalation if necessary. Circulating tumor cells were quantified by Veridex Cell Search Platform at baseline and with disease evaluation. Results: 14 patients with ES-SCLC were enrolled (median age 56 (range, 46-68); 57% male). Patients were treated as follows: 200mg (n=2); 400mg (n=7); 800mg (n=5). The first 3 patients were enrolled at 400mg, and 2 experienced a dose limiting toxicity (DLT) (nausea, n=1; febrile neutropenia (FN), n=1), leading to dose de-escalation (200mg). The definition of DLT was changed to exclude FN. The 400mg dose level was expanded with 4 additional patients without any further DLTs. 800mg has been established as the recommended phase II dose in combination with EP. Toxicity led to removal of one patient from study (grade 3 colitis and acute kidney injury). Grade 3 toxicities included: anemia (n=1), thrombocytopenia (n=1), CPK elevation (n=1), fatigue (n=2), and fever (n=1). 3 patients had grade 4 neutropenia. One patient died of an unrelated myocardial infarction. 5 patients actively are being treated. Partial responses were confirmed in 50% (7/14; 95% CI: 27-73%); 3 received maintenance LDE225 ≥4 months. Conclusions: LDE225 800mg daily was the MTD when administered with EP. The phase II dose expansion of this regimen is underway. Clinical trial information: NCT01579929.