bluuebunny/crossref_metadata_2025_split huggingface dataset:
KIT gene molecular analysis distinguishes multiple primary GIST from metastatic disease
Authors: Dei Tos A. P. , Rossi S. , Gasparotto D. , Bearzi I. , Gallina G. , Maestro R. 
Published: March 2020

10048 Background: The occurrence of multiple primary GIST (MPG) has been reported exclusively in children and in NF1 patients. However, sometimes adult GIST patients present at onset with double lesions raising the problem of the differential diagnosis between metastatic and MPG. Morphologic features might help in recognizing MPG. A clear cut distinction is much less obvious when dealing with simultaneous high risk lesions. Molecular analysis of KIT gene may represent an important tool to discriminate among these two possibilities, allowing proper therapeutic strategies. Methods: From a series of 200 GIST we selected 5 non NF1 adult GIST patients, presenting double lesions at onset. Genomic DNA was extracted from both the nodules of each patients and exons 9, 11, 13, 14 and 17 of KIT gene were sequenced. Cases were also investigated for KIT exon 10 and intron 10 and PDGFRA exons 12 and 18. Results: Age ranged from 48 to 82 years. Four patients had a dominant nodule, ranging in size between 3 and 10 cm, and a peritoneal/hepatic nodule ranging in size between 0.8 and 3 cm. One patient had one gastric and one small intestinal nodules of 6 cm. No significant differences in mitotic rate and morphology were seen between the two nodules in each case. In two cases, both nodules showed same molecular profile, confirming the metastatic nature of the disease. In one case, the same KIT mutation was detected in both lesions, but an additional mutation was present only in the intestinal tumor. In contrast, in one case, different KIT mutations were found, suggesting the occurrence of two synchronous GIST. In an additional case, while a PDGFRA mutation was found in the tumor located in the stomach, no mutations were detected in the tumor located in the liver. Conclusions: 1. Molecular analysis proves the existence of exceptional cases of multiple primary GIST in non children, non NF1 patients. 2. Since discrimination between metastatic disease at onset and multiple primaries impacts over therapeutic strategies, it might be useful also in the routine practice to perform molecular analysis of both nodules in cases of double GIST. No significant financial relationships to disclose.
The outcomes of imatinib therapy of advanced gastrointestinal stromal tumors (GISTs) originating from the small bowel
Authors: Rutkowski P. , Nowecki Z. I. , Debiec-Rychter M. , Grzesiakowska U. , Michej W. , Wozniak A. , Limon J. , Osuch C. , Switaj T. , Ruka W. 
Published: March 2020

10052 Background: The aim of the study was to assess the outcomes of imatinib (IM) therapy in subgroup of patients with advanced CD117(+) GIST originating from small intestine. Methods: In the group of 245 consecutive patients with inoperable and/or metastatic GIST CD117(+) treated with imatinib in the dose of 400–800mg daily and enrolled into prospectively collected Clinical GIST Registry between 09/2001 and 10/2006 we identified 123 patients (50.2%) with GIST originating from small bowel. There were 43 primary unresectable/metastatic tumors and 80 recurrent (after primary surgery) tumors. Median follow-up time was 31 months (range: 3–63). Results: The estimated 3-year progression-free survival (PFS; calculated form the date of the start of IM) and overall survival (OS) were 61% and 80%, respectively. The best responses observed during IM therapy according to RECIST criteria were as follows: complete responses (CRs) - 9 cases (7%), partial responses (PRs) - 66 cases (54%), stable disease SD - 29 cases (24%) and progressive disease (PD) - 19 (15%). In 42 analyzed specimens 29 GISTs (69%) had exon 11 KIT mutations, 9 (21%) - exon 9 KIT mutations and 4 (10%) other genetic abnormalities. We identified three factors negatively affecting PFS statistically significant (p<0.05) in multivariate analysis: baseline poor WHO performance status = 2, tumor genotype with other than exon 11 KIT mutant and primary tumor mitotic index >10/50HPF. Two more additional factors had negative impact on PFS in univariate analysis only: baseline high neutrophil count (p=0.04) and low baseline hemoglobin level (p=0.01). Conclusions: In analysis of the subset of patients with advanced GIST originating from the small bowel we confirmed long-term benefit from IM therapy. We identified three independent biological factors influencing the progression-free survival during imatinib therapy in this group of patients. [Table: see text]
Perifosine (P) as an active agent in the treatment of patients with advanced sarcoma
Authors: Birch R. , Chawla S. , Nemunaitis J. , Savage P. , Kaiser P. , Spira A. , Cervera A. , Middleman E. , Sausville E. , Knowling M. , Henderson I. 
Published: March 2020

10059 Background: Clinical benefit rate (CBR), defined as complete or partial responses (RECIST) or stable disease > 4 months, has been taken as evidence for the activity of mTOR inhibitors in sarcomas, (Chawla ASCO 2006). P is a novel oral alkylphosphocholine that targets the PI3K pathway upstream from mTOR by inhibiting the phosphorylation of Akt. (Kondapaka, Mol Cancer Ther 2003). P's activity against sarcomas has now been evaluated in 121 patients enrolled in one of 3 phase (ph) I trials or 4 ph II studies. Five of these studies have been published. All of the data are in the Keryx database from which this analysis was performed. Methods: Dose-schedules in the ph I trials were weekly (wkly) 100–800 mg; loading dose (LD) 300 - 1,800 following by daily (d) 50 - 21 every 21 days; LD 400 - 900 & d 50 - 100 continuously. In the ph II trials doses were LD 900 & d 150 every 21 days, LD 900 and d 100 continuously, d 50 mg continuously; wkly 900, wkly1200 & wkly 1,500. Regimens that included a wkly or LD of 1,200 mg or more or a d dose of ≥ 150 mg were more toxic and are defined as “higher dose” for this analysis. Results: 121 pts with sarcoma were entered on studies prior to 9/1/2006 and could be assessed for CBR. CBR is shown in the table below. Toxicities were mainly gastrointestinal and/or fatigue. The percentage of pts with grade 0 nausea (N), vomiting (V), diarrhea (D) and fatigue (F) for lower dose P was 40, 60, 45 and 57% respectively compared to 29, 38, 24 and 66% for higher dose P. The proportion of patients with grade 2+ N, V, D and F was 19, 15, 17 and 21% for lower dose P and 46, 31, 40 and 21% for higher dose P. Conclusions: In the ph I/II studies of P the CBR was 50%. This compares favorably with the activity of the mTOR inhibitors. There was no suggestion of greater activity in those given higher doses of P, but there was substantially more toxicity and greater earlier withdrawal from therapy with the higher doses. [Table: see text] No significant financial relationships to disclose.
P16 as a marker to differentiate atypical lipomatous tumor/well-differentiated liposarcoma from deep seated lipoma: An immunohistochemical analysis of 51 cases
Authors: He M. , Aisner S. , Benevenia J. , Patterson F. , Aviv H. , Hameed M. 
Published: March 2020

10070 Background: Atypical lipomatous tumor (ALT)/well-differentiated (WD) liposarcoma is a locally aggressive malignant mesenchymal neoplasm characterized by supernumerary ring and giant marker chromosomes with amplification of MDM2 gene. These cytogenetic characteristics can be very helpful to distinguish ALT from deep-seated lipomas. As ALTs have only rare presence of lipoblasts, they can resemble benign lipomas rendering difficulty in morphological diagnosis. P16INK4 is a specific inhibitor of CDK4/CDK6. CDK6 gene is often found co-amplified with MDM2 gene in ALTs. P16 overexpression is a hallmark of cervical dysplasia. Our study investigates the value of p16 expression in cytogenetically confirmed ALTs and deep-seated lipomas. Design: Fifty-one (51) cases of lipomatous neoplasms, with cytogenetic results, from forty-three (43) patients were collected for the study from the archives in department of pathology, UMDNJ/NJMS during 1998 - 2005. These include 18 cases of deep-seated lipoma, one hibernoma, and 32 cases of ALT / well-differentiated liposarcoma (24 patients, five patients with recurrence, and four cases with de-differentiation). Immunohistochemical staining for p16 was performed on representative paraffin blocks. Staining results were scored according to intensity (negative 0, weak 1+, intermediate 2+, and strong 3+) and percentage of positive cells. Results: Twenty-eight cases (28/32, 87.5%) of ALT/WD liposarcoma, including all four cases of dedifferentiated liposarcoma, showed strong nuclear p16 expression. In cases of recurrence, the primary and recurrent tumor showed the same pattern of p16 staining. Four cases (4/32, 12.5%) of ALT/WD liposarcoma showed negative p16 expression. All cases of deep-seated lipoma (18/18, 100%) and single hibernoma showed negative p16 staining except focal positivity in areas of fat necrosis in two cases (p16 positivity, 87.5 vs. 0%, P <0.00001, Fisher's exact test). Conclusion: 1). P16 appears to be a valuable marker to differentiate ALT and deep-seated lipomas. 2). P16 expression remains unchanged in progression and transformation of ALT. 3). P16 related signal transduction pathway most likely is an early event in tumorogenesis of ALT. No significant financial relationships to disclose.
EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT)
Authors: Lin N. U. , Dieras V. , Paul D. , Lossignol D. , Christodoulou C. , Laessig D. , Roché H. , Zembryki D. , Oliva C. R. , Winer E. P. 
Published: March 2020

1012 Background: CNS disease is a major problem among pts treated with H for stage IV HER2+ breast cancer with a reported incidence of 28–43%. This study was designed to characterize further the activity reported with lapatinib in an initial phase II trial in women with HER2+ disease metastatic to brain (Lin et al ASCO ‘06). Methods: Eligible pts had HER2+ breast cancer, prior H therapy and cranial RT, ECOG PS 0–2, and radiographic evidence of progressive brain metastases with at least one measurable (LD = 10mm) brain lesion. Pts received lapatinib 750 mg PO BID. Brain MRIs were obtained at 3.0 mm slices without gaps in the axial dimension. The primary endpoint was CNS response as defined by a = 50% volumetric (vol) reduction of CNS lesions in the absence of: new lesions, need for increased dose of steroids, progressive neurological signs/symptoms (NSS), or progressive extra-CNS disease. CNS disease progression was defined as either a = 40% vol increase from nadir, increase in steroid requirements, or progression of NSS. Results: The study exceeded its accrual goal of 220 pts in < 1 year; 238 pts were enrolled from Jan-Nov 06. Preliminary data from the initial 104 pts have undergone independent radiology review. 8 pts (7.7%) met vol criteria for partial response with a median absolute vol reduction of CNS disease of 3.6 cm3 (range 0.4 to 29.7 cm3). Exploratory analysis revealed that 17 of the initial 104 pts (16.3%) experienced a = 20% vol reduction of CNS disease with a median absolute vol reduction of 3.3cm3. The median time to vol progression in these 17 pts was 16 wks (range 12 -24 wks). Analysis of efficacy and tolerability based upon protocol defined criteria from all 238 pts will be presented. Conclusions: Preliminary data from this large multicenter trial provides evidence that lapatinib has activity based on vol reductions in pts with progressive HER2+ CNS disease following prior H-based systemic therapy and cranial RT. Definitive conclusions will be based on the entire database. Additional studies are warranted incorporating lapatinib in combination with other therapies and/or in a less refractory setting to optimize its use in HER2+ CNS disease. [Table: see text]
Absence of brain metastases in late relapse of HER2-overexpressed breast carcinoma
Authors: Tomasevic Z. I. , Jovanovic D. , Jelic L. Radosevic , Tomasevic Z. M. , Vasovic S. , Stamatovic L. , Jelic S. , Spasic J. 
Published: March 2020

1014 Background: The incidence of brain metastases (BM) in HER2 3+ breast carcinoma (BC) reported in the literature is between 20–34%, usually during first 2 years of metastatic disease. However, there are limited data about BM as a late relapse in HER2 over expressed BC. Therefore, the aim of this paper is to analyze BM as a late relapse in patients with HER2 over expressed and non over expressed BC. Late relapse is defined as relapse at least five years after initial diagnose. Methods: Medical documentation of all patients with late relapse was analyzed for DFI and development of BM at any time point during metastatic disease. IHH (Herceptest DAKO) HER-2 status was determined on the archived pathological specimens of the primary BC Results: Among 1,256 BC patients diagnosed during 6 months period (June-November, 2005 at the Institute for Oncology and Radiology of Serbia), 111 (8,8%) were diagnosed with late relapse. Median age at the initial diagnose was 50 years (33–74), median time to relapse was 7 years, (range 5–29). Archived pathological specimens is identified for 64% of patients and HER-2 status of the primary BC was: 76,3% 0 or1+; 9,5% 2+; and 14,2% 3+; Only 5 patients have been treated with trastuzumab in metastatic setting. None of the patients with HER2 3+ BC had BM either as a first relapse site or later during metastatic disease. Two patients who had late relapse of HER2 0+ BC, developed BM as a first site of relapse, after 5 and 7 years of the initial diagnose. Conclusions: Although the number of presented patients is small, the absence of BM in late relapse of HER2 3+ BC, could represent the specific biological characteristic of HER 2 3+ carcinomas to develop BM mostly in the early course of metastatic disease. No significant financial relationships to disclose.
HER2-neu status as a predictor of survival in patients with brain metastases from primary breast adenocarcinoma
Authors: Sawrie S. M. , Meredith R. F. , Spencer S. A. , Markert J. M. , Fiveash J. B. 
Published: March 2020

1016 Background: Recent data suggests that Her2-neu positivity predicts for development of brain metastases in patients with breast cancer. However, there now exists a targeted agent, trastuzumab, that provides excellent systemic control of Her2-positive (Her2 +) disease. We therefore explore the course of this disease as a function of Her2 status in patients with primary breast cancer who have developed brain metastases. Method: We retrospectively analyzed data from 50 consecutive patients with primary breast cancer who subsequently developed brain metastases. Factors evaluated included Her2-neu, ER/PR, T stage, nodal stage, use of whole brain radiotherapy (WBRT) as initial management of CNS disease, initial number of metastases, hormonal therapy, use of trastuzumab, and Karnofsky Performance Status (KPS). Overall survival (OS) was modeled using Cox proportional hazard. Kaplan-Meier analysis was used for significant predictors. Results: Median age was 49 years (28–78 y). Fifty-four percent of patients were Her2 +, whereas only 15% were ER +. All but one Her2 + patient received trastuzumab. Seventy-two percent were node positive, and only 5 patients were metastatic at time of diagnosis. T stage was as follows: T1 = 24%, T2 = 36%, T3 = 8%, and T4 = 16%. Adjuvant chemotherapy was administered to 90% of the sample, and 94% underwent radiation to the primary site. Sixty-six percent had <= 3 initial brain metastases, and 38% underwent WBRT as part of their initial CNS management. Median followup was 55 weeks. A Cox multivariate model of OS yielded two independent predictors. Her2 positivity (p = 0.007) and <= 3 initial brain metastases (p = 0.003) were associated independently with OS from time of initial diagnosis of CNS disease. Median survival and actuarial one year survival for Her2 + patients were 65 weeks and 87%, respectively, versus 33 weeks and 44% for Her2 negative patients (Mantel Cox p = 0.025). Conclusions: Although Her2 + patients appear to have a greater risk of developing brain metastases, overall survival from time of initial diagnosis of brain metastasis appears to be better in this cohort. This may be a function of the improved extracranial control provided by trastuzumab in patients with Her2+ disease. No significant financial relationships to disclose.
HER2 gene amplification (HER2) and hormone receptor expression (ER/PR) in early (EBC) and metastatic breast cancer (MBC) in the same patients
Authors: Wilking U. , Skoog L. , Elmberger G. , Wilking N. , Bergh J. 
Published: March 2020

1023 Background: HER2 and ER/PR expression are used as predictors of response to trastuzumab and hormonal treatments, respectively. In most institutions these markers are only analyzed in EBC and any later treatment decisions are based these analyses. At our institution, it has been the routine to verify the breast cancer diagnosis, as well as HER2 and ER/PR status in MBC, if ever possible. We focus this report on data obtained for double testing during the time period 2000–2005. Methods: HER2 and ER/PR in MBC (metastatic site = 43% cutaneous or lymph node; 17% liver; 29% bone, 3% CNS and 8% GI tract) were compared to EBC results. Any result with IHC 3+/FISH amplification was regarded as HER2 +. Any ER/PR expression was regarded as ER/PR +. Results: HER2 testing: We identified sixty one (61) patients who had their tumor analyzed for HER2 in both EBC and MBC. Thirty-seven (61%) of these tumors were negative in both EBC and MBC. One (2%) had a positive EBC and negative MBC; 20 patients (32%) had both positive EBC and MBC testing and 3 patients (5%) had negative EBC testing and positive MBC testing. ER/PR testing: One hundred and four (104) patients underwent both EBC and MBC testing for ER/PR. Forty nine (47%) remained ER/PR +, 7 (7%) had EBC- and MBC+ test; 22 patients (21%) had ER/PR EBC+ test and MBC- test; 26 patients (25%) remained negative from EBC to MBC. Conclusions: Breast cancer tumor characteristics are not constant as the disease progresses. In this study we found that 7% have a change in their HER2 expression and 28% had a change in their ER/PR expression based on analyses of both primary and metastatic disease. It is therefore important that, whenever possible, not only to morphologically verify MBC, but also to analyze HER2 and hormone receptors (ER/PR) to be able to offer the best possible treatment to all patients. [Table: see text]
Lapatinib (L) plus capecitabine (C) in HER2+ advanced breast cancer (ABC): Genomic and updated efficacy data
Authors: Geyer C. E. , Martin A. , Newstat B. , Casey M. A. , Berger M. S. , Oliva C. R. , Rubin S. D. , Stein S. , Cameron D. 
Published: March 2020

1035 Background: EGF100151 demonstrated L+C improved TTP relative to C alone in women with HER2 positive, trastuzumab- exposed ABC (Geyer, NEJM;355(26):2006). We report updated efficacy data and results of correlative studies to determine if gene expression levels in the 5-FU and HER pathways are associated with clinical benefit in L+C. Methods: Tumor blocks are available on 217/399 patients, and so far sufficient mRNA has been extracted from 64/217 blocks using qRT-PCR. Tumors were evaluated for expression of HER1–4, TS, TP, PTEN, c-MYC. In addition to univariate and multivariate analyses, a SpotFire™ DecisionTree analysis was performed to determine the genes most significantly associated with RR; these genes were further analyzed for association with TTP. Results: Updated efficacy results through April 3, 2006 demonstrate: TTP L+C (27 wks)vs C (19 wks) HR 0.57 [0.43,0.77] p=0.00013; ORR L+C (24%)vs C (14%), Odds Ratio 1.9[1, 1.34] p=0.017; OS L+C vs C HR 0.78 [0.55,1.12] p=0.177; progression in CNS L+C (2%)vs C (11%) p=0.0445. Preliminary analysis of the first 64 samples indicates that elevated baseline mRNA expression of HER2 is associated with a higher RR and longer TTP (p<0.0001) with L+C. The opposite was seen in the C arm, where elevated HER2 mRNA expression seemed to predict for a poorer outcome. Analyses of ErbB3,4, PTEN and MYC as well as TS did not correlate with RR. Conclusion: The updated efficacy results confirm the prior demonstrated benefit of L+Cvs C and provide the first evidence for a systemic anti-HER2 therapy to have an effect on the development of CNS metastases. This preliminary analysis suggests a correlation between elevated HER2 mRNA levels and RR/TTP. Further investigation, including full genome microarray analysis of samples is ongoing. [Table: see text]
Phase II study of the farnesyl transferase inhibitor tipifarnib plus fulvestrant in postmenopausal patients with hormone receptor-positive breast cancer: New York Cancer Consortium Trial P6205
Authors: Li T. , Christos P. , Sparano J. A. , Hershman D. L. , O’Brien K. , Hoschander S. , Wright J. , Vahdat L. T. 
Published: March 2020

1037 Background: Tipifarnib and fulvestrant both have single agent activity in hormone receptor-positive (HR+) metastatic breast cancer (MBC), and tipifarnib enhances the activity of anti-estrogens in HR+ breast cancer cell lines. Methods: Eligibility criteria: measurable HR+ MBC, postmenopausal status, ECOG PS of 0–2, and no prior chemotherapy for MBC. Treatment: fulvestrant 250 mg IM on day 1 plus oral tipifarnib 300 mg BID on days 1–21 every 28 days (defined as one cycle). Response was evaluated by RECIST criteria every 3 cycles. The study was suspended for efficacy/futility analysis after 33 of 46 patients were accrued. It was designed to detect an improvement in clinical benefit rate (CBR; defined as objective response or stable disease for at least 24 weeks) from 50% to 70% (90% power, type I error 10%), and would require at least 26 of 42 eligible/evaluable patients to have clinical benefit (CB). The expected CBR for fulvestrant alone is 30% in aromatase inhibitor (AI) resistant disease (Ingle, 2006), 45% in tamoxifen (tam)-resistant disease (Osborne, 2002), and 60% when used as first line endocrine therapy (ET) (Howell, 2004). Results: Of 33 patients enrolled, 28 are currently assessable for CBR (2 were ineligible, and 3 have stable disease for < 6 months and remain on treatment). Grade 3/4 toxicity: neutropenia (15%), pain (11%) and gastrointestinal toxicity (11%). Tipifarnib was either reduced in dose (N=10) or discontinued (N=8) due to toxicity or non-compliance. The overall CBR is shown; should accrual continue, all 14 evaluable patients must have CB in order to meet the pre-specified efficacy objective. For the ET-resistant group, 18 were resistant to AI therapy (or AI plus tam in 5) and 2 to tam. * Number eligible/evaluable for CBR. Conclusions: The tipifarnib-fulvestrant combination is not likely to produce a CBR of at least 70%. The 45% CBR in ET-resistant disease may merit further evaluation in this setting. [Table: see text] No significant financial relationships to disclose.