bluuebunny/crossref_metadata_2025 huggingface dataset:
A multiplex assay for detection of common pediatric sarcoma tumor markers
Authors: Bender R. A. , Liu J. Y. , Li H. , Qu K. Z. , Sferruzza A. D. , Sanders H. R.
Published: March 2020

10041

Background: Molecular assays for tumor markers have become an important component in diagnosing pediatric sarcomas and small round cell tumors. We developed a multiplex assay to detect 7 common translocations associated with synovial sarcoma (SYT/SSX1, SYT/SSX2), Ewing's sarcoma (EWS/FLI1, EWS/ERG), rhabdomyosarcoma (PAX3/FKHR, PAX7/FKHR), and small round cell desmoplastic tumors (SRCDT) (EWS/WT1). Methods: 27 samples were analyzed with the multiplex assay: 13 formalin-fixed paraffin-embedded tumor samples, 5 fresh frozen tumor samples, 2 commercial RNA samples (SYT/SSX1, SYT/SSX2), 3 cell line samples (EWS/FLI, EWS/ERG, PAX3/FKHR), 1 synthetic control (PAX7/FKHR), and 3 negative controls. After RNA extraction, RT-PCR was performed using the SuperScript III One-Step RT-PCR System with Platinum Taq DNA Polymerase (Invitrogen, Carlsbad, CA). 12 primers were added to a single master mix to amplify all 7 translocations and an internal control; 1 primer from each pair was fluorescently labeled. After RT-PCR, the PCR products were separated on a genetic analyzer and the translocations identified based on the size of the PCR products and their signal intensity. Samples were also analyzed by our current assay (real-time RT-PCR or standard RT-PCR/gel electrophoresis). Results: The results of our current and multiplex assays were positive for all synthetic controls, cell lines, and commercial RNA samples and were concordant for 15/18 tumor samples: 2/7 synovial sarcoma samples were positive for SYT/SSX1 and 3/7 for SYT/SSX2; 2/6 Ewing's sarcoma samples were EWS/FLI1-positive; 1/1 SRCDT sample was EWS/WT1-positive; and 4/4 rhabdomyosarcoma samples were negative. The 3 discordant samples tested negative with our current assay; the new multiplex assay detected EWS/FLI1 in 1 of these and SYT/SSX2 in 2, in agreement with the histological classification. Conclusions: This multiplex assay can detect 7 translocations commonly found in pediatric soft tissue tumors in a single-tube reaction, with increased clinical sensitivity relative to our current methods.

No significant financial relationships to disclose.
Kit-stem cell factor (kit ligand) axis in GIST patients treated with imatinib
Authors: McAuliffe J. C. , Lazar A. , Steinert D. , Patel S. , Benjamin R. , Trent J. C.
Published: March 2020

10046

Background: Gastrointestinal stromal tumors (GISTs) represent the majority of GI mesenchymal neoplasms. Imatinib (Gleevec; STI571; Novartis, Basel, Switzerland) has marked efficacy in the management of GIST; however, little is known of its exact mechanism in GIST. We sought to elucidate expression patterns of stem cell factor (SCF, Kit ligand) and the Kit receptor tyrosine kinase in GIST and tumor-associated endothelial cells (TECs) from patients treated with imatinib. Methods: We constructed a 54 GIST specimen tissue array from patients with GIST surgically resected who received 400–800 mg/day adjuvant imatinib. Arrays were stained for SCF by immunohistochemistry and scored for expression as 0 (none), 1 (weak), or 2 (strong). Expression was correlated to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. In a second study we collected pre-imatinib core needle biopsies from 15 patients on a phase II prospective, randomized clinical trial of neo-adjuvant and adjuvant imatinib (600mg/day) for the treatment of primary or advanced, resectable GIST. Specimens were stained for phosphorylated-Kit and CD31 and visualized by immunofluorescence and confocal microscopy. Co-localization of markers was correlated to radiographic response by positron emission tomography (PET) and dynamic computed tomography (dCT). Results: 47 of 54 tumors (87%) expressed SCF but there was no significant correlation between SCF expression or intensity with PFS and OS. Interestingly, the majority of GIST tissue from patients on the prospective clinical trial contained pre-imatinib TECs expressing phosphorylated-Kit. 69% and 79% of patients receiving 3–7 days of imatinib responded by PET scan or dCT, respectively. Conclusions: The majority of GISTs express SCF while pre-imatinib TECs were found to express phosphorylated-Kit. Therefore, our results suggest that within the tumor microenvironment there may be Kit/SCF crosstalk between tumor cells and TECs. Whether disruption of this crosstalk plays a role in tumor response or anti-vascular efficacy requires additional investigation.

No significant financial relationships to disclose.
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.
Gemcitabine plus paclitaxel and gemcitabine plus docetaxel in first- or second-line metastatic breast cancer: A phase II randomized trial
Authors: Boccia R. V. , Vaughn L. , Zeigler H. , Wang Y. , Gill J. , Melemed A. , Shonukan O.
Published: March 2020

1046

Background: The combination of gemcitabine (G) with paclitaxel (P) has proven efficacy in the first-line treatment of metastatic breast cancer (MBC). In addition, the combination of G with docetaxel (D) has shown activity in several nonrandomized, Phase II, MBC trials. This randomized Phase II trial was conducted to assess the efficacy and safety of G plus P and G plus D combination regimens in previously treated patients with MBC. Methods: Patients with locally advanced or metastatic breast cancer were randomized equally into two groups to receive either GP (G 1,250 mg/m2 IV on Days 1 and 8 plus P 175 mg/m2 IV on Day 1) or GD (G 1,000 mg/m2 IV on Days 1 and 8 plus D 75 mg/m2 IV on Day 1). Treatment was administered every 21 days and continued until disease progression or undue toxicity. Planned enrollment was 112 patients (56 per group). The primary study objective was tumor response assessed using RECIST criteria. Toxicities were assessed using the NCI Common Toxicity Criteria, Version 2.0. Results: Twenty-five patients were enrolled in each treatment group and accrual was stopped due to slow enrollment. In the GP group, only 23 patients were evaluable for response and 24 patients were monitored for safety. One patient did not receive study medication and was not assessed for efficacy or safety. A second patient was determined to have nonmeasurable disease at baseline and was not assessed for response. Overall response rate was 39% (95% CI 20, 61) for the GP group and 40% (95% CI 21, 61) for the GD group. The median number of cycles administered was 6.5 in the GP group and 6.0 in the GD group. Detailed study results are summarized in the table below. Conclusions: These results show that GP and GD combination regimens are both efficacious in the treatment of MBC, with similar response rates and manageable toxicity profiles.

[Table: see text]

No significant financial relationships to disclose.
Elevated stem cell marker CD133 mRNA in peripheral blood predicts colon cancer recurrence
Authors: Lin E. H. , Hassan M. , Li Y. , Zhao H. , Nooka A. , Xie K. , Champlin R. , Wu X. , Li D.
Published: March 2020

10504

Background: CD133 is a specific stem cell marker that enriches cancer stem cells of many tumor types including colon cancer as well as circulating endothelial progenitors (CEP). CEP is vital in postnatal angiogenesis and elevated CEP is a proven favoable prognositic marker for heart disease but a potentially poor prognostic marker for cancer. We examined whether elevated CD133 mRNA expression levels in peripheral blood mononuclear cells (PBMC) predict recurrence in colon cancer patients. Methods: We developed and validated a semi-quantitative real-time RT-PCR to quantify CD133 mRNA levels relative to GADPH mRNA. Sixty-six colon cancer patients were enrolled between February 2002 and December 2003. The protocol excluded patients with history of cardiac disease or surgery < 4 weeks from the enrollment and were followed for recurrence for a median 30 months. A central statistician performed multivariate unconditional logistics regression analysis. Results: Among the patients without recurrence, 93% had a CD133 mRNA level < 4.79, whereas 7% had a CD133 mRNA value ≥ 4.79 (p = 0.029). Among patients with a CD133 mRNA value ≥ 4.79, 85% had experienced recurrence compared to 15% of the patient who had no recurrence (p = 0.03). Elevated CD133 mRNA levels at a cut-off point ≥ 4.79 versus < 4.79 were associated with an odd ratio of 22.6 for recurrence (95% CI, 1.7–291.2; p = 0.02); in comparison, the odds ratio for recurrence was 17.2 (95% CI, 1.8–164; p = 0.01) for stage IV patients versus stage I-III patients. No other predictive variables for recurrence were identified including age, race, sex, tumor differentiation, smoking, and diabetes etc. We also observed an trend of association with elevated carcinoma embryonic antigen (CEA) levels (p = 0.03, one sided) and a decreased survival (p = 0.035, one sided) with elevated CD133 mRNA level at a cutoff point ≥ 4.79. Conclusions: Elevated CD133 mRNA levels at a cutoff ≥ 4.79 in PBMC predict colon cancer recurrence independent of stage IV disease. The current assay has certain advantages over flow cytometry for wider clinical application. CD133+ cells measured by CD133 mRNA may contain both CEP and cancer stem cells, leading to increased risks of recurrence.

No significant financial relationships to disclose.
Validation of genomic markers that predict distant recurrence risk via FISH assays in women with early stage breast carcinoma
Authors: Williams T. M. , Budd G. T. , Gunter M. , Hines R. , Masood S. , Pawloski P. , Schwartzberg L. , Wei F. , Tubbs R. R.
Published: March 2020

10506

Background: Biomarkers offer the potential to better predict recurrence risk in early stage invasive breast cancer, especially if adaptable to common assays such as fluorescent in situ hybridization (FISH). We studied the ability of tumor copy numbers (CN) of 3 genes, BIRC5, CYP24, and PDCD6IP, to predict distant recurrence in women with breast cancer. Methods: We conducted a blinded, multi-site study of 350 women with lymph node negative, estrogen/progesterone receptor positive (ER/PR+), invasive ductal carcinomas with archived paraffin-embedded biopsy specimens available. Eligible women received local surgical and radiation treatment only (93) (LTO) or local treatment and tamoxifen therapy only (257), and had distant metastases or no evidence of distant recurrence with at least 5 years follow-up (FU). Tumors were subjected to FISH with DNA probes for the 3 genes to assess CN. A prognostic index (PI) was calculated for each patient based on the 3 genes’ CN. A predetermined threshold (3.0) was used to categorize PI's as low or high. Data were assessed by Fisher's exact analysis and by categorical and continuous Cox modeling. Results: The study included 350 women with Stage I (288) and II (62) disease. FU averaged 7.3 years. Distant recurrence occurred in 32 women (9.1%) overall and in 5.2% of women with Stage I disease. In a multivariate Cox analysis including continuous PI, age, tamoxifen treatment, grade, and tumor size, PI remained a significant predictor of recurrence for Stage I patients: OR=1.56, p=0.019, and Stage I/LTO patients: OR=6.02, p=0.00007. Using the PI as a categorical classifier, the high/low recurrence rates were significantly different: OR=2.24, p= 0.045. Similar results were seen in Stage I patients: OR=3.53, p=0.021 with recurrence rates of 3.5% and 11.5% in the low and high risk groups, respectively, and for the Stage I/LTO patients: OR=5.33, p=0.041. Conclusions: FISH analysis of 3 genes allows metastasis risk prediction in women with early stage ER/PR+ cancers. This may be particularly useful for Stage I cancers traditionally considered low risk. The markers are prognostic in that they predict metastasis in patients receiving only local therapy.

No significant financial relationships to disclose.
Real-time optical biopsy and analysis of breast cancer using clinical optical coherence tomography
Authors: Boppart S. A. , Zysk A. M. , Nguyen F. T. , Chaney E. J. , Bellafiore F. J. , Kotynek J. G. , Johnson P. A. , Rowland K. M.
Published: March 2020

10508

Background: Advances in high-resolution, real-time, optical imaging have enabled optical coherence tomography (OCT) for non-excisional optical biopsies of breast tissue. OCT is the optical analogue to ultrasound imaging, with resolution approaching that of histology. In breast tissue, regions of tumor, tumor margins, abnormal ducts, and foci of tumor cells can be identified based on increased scattering and morphological appearance. We have developed a portable clinical OCT system along with image criteria for identifying breast cancer in real-time during needle-biopsy and surgical-biopsy procedures. Methods: Over 4,000 depth-resolved OCT axial scans were extracted from over 50 cross-sectional OCT images from 9 ex vivo specimens of ductal carcinoma in situ (DCIS) of the human breast. OCT image data was acquired in real-time within 6 hours of surgical resection using a state-of-the-art OCT system with micron resolution. Imaged sites were marked for registration with hematoxylin and eosin-stained histology. Axial scan data was analyzed using frequency-domain analysis techniques to classify regions as tumor, stroma, or adipose tissue. OCT images of tissue types were compared with histological observations. Results: Real-time OCT images of microscopic breast cancer morphology showed strong correlations with corresponding histology, including regions of tumor, tumor margins, ducts, and adipose tissue. Computational frequency-domain analysis of depth-resolved axial scan data classified tissue types as tumor, stroma, and adipose with 91% sensitivity and 87% specificity. Conclusions: Optical biopsy of breast cancer with OCT is feasible for imaging at resolutions approaching histology. Frequency- domain analysis of axial scan data can be used to classify breast tissue types with a sensitivity and specificity that are comparable to or surpasses that of conventional mammography and ultrasound imaging of human DCIS. Clinical OCT imaging has the potential for real-time guidance and diagnostics in needle- or surgical-biopsy of breast cancer.

No significant financial relationships to disclose.
Breast cancer and DNA epair gene SNPs in a family cancer registry population
Authors: Langer L. R. , Papp J. , Sinsheimer J. S. , Kwan L. , Seldon J. , Reed E. F. , Dandekar S. , Korin Y. , Zhang Z. F. , Ganz P. A.
Published: March 2020

10514

Background: Alterations in the DNA double-strand break repair (DSBR) pathway are associated with cancer risk. Mutations in the genes BRCA1/2 disrupt DNA DSBR. Variations in breast cancer penetrance among BRCA1/2 mutation carriers, and familial patterns among women without known BRCA1/2 mutations may be related to polymorphisms of genes in the DNA-DSBR pathway. Methods: Using a case-control study design with individuals in the UCLA Family Cancer Registry (FCR), we examined the independent effects of 100 SNPs in 19 DNA-DSBR genes. SNPs were assayed using the Applied Biosystems SNPlex™ assay. Results: 630 consecutive females from 508 families in the UCLA FCR selected for familial risk of breast cancer were included in the study. Table 1 describes select subject characteristics. Preliminary association analysis of the Caucasian subset using a nonparametric permutation method, which controls for Ashkenazi Jewish heritage and dependencies among relatives, suggests that polymorphisms within RAD21 (p=0.0044, p=0.0005), XRCC2 (p = 0.0069), XRCC4 (p =0.0511), and BRIP1 (p =0.0107) may be associated with a change in risk of breast cancer. Using only unrelated Caucasian subjects in a logistic regression analysis with covariates such as age, BMI, and Ashkenazi Jewish heritage, the effects of these polymorphisms remain significant, with 32% to 74% change in the odds of breast cancer. Conclusions: We have identified five potential SNPs in genes in the DNA-DSBR pathway that appear to be associated with a change in risk of breast cancer. This hypothesis generating study lends support to a role for polymorphisms of the DNA-repair pathway in breast carcinogenesis. Assessment of gene-environment and gene-gene interactions will help to elucidate carcinogenic mechanisms. Further validation in similar populations is warranted. (Funded by the Breast Cancer Research Foundation and NIH/NCI CA87949 R25 Career Development Program.)

[Table: see text]

No significant financial relationships to disclose.
Efficacy of oral vinorelbine (NVBo), capecitabine (X) and trastuzumab (H) triple combination (NVBoXH) in HER2-positive metastatic breast cancer (MBC): First results of an international phase II trial
Authors: Chan A. , Ganju V. , Becquart D. , Conte P. , Petruzelka L. , Aubert D. , Villanova G. , Tubiana-Mathieu N.
Published: March 2020

1052

Background: Chemotherapy (CT) plus H is the standard first-line treatment for HER2-positive MBC. H plus vinorelbine is an active and well-tolerated regimen in this setting. The all-oral combination of NVBo and X also appears active and well-tolerated in MBC. We report efficacy and safety results from the first 34 patients (pts) included in an international trial evaluating NVBoXH in HER2-positive MBC. Methods: In this multicenter trial, main eligibility criteria included: HER2-positive disease (IHC 3+ or FISH+), documented measurable MBC previously untreated by CT, relapse 6 months after completing neoadjuvant or adjuvant CT, Karnofsky PS = 70, age =18 years. Pts received 3-weekly cycles of NVBo 60 mg/m2 (cycle 1) escalating to 80 mg/m2 (from cycle 2) days 1 and 8; × 1,000 mg/m2 bid (750 if = 65 years) days 1–14; H 4 mg/kg day 1 as a loading dose then 2 mg/kg i.v. weekly starting on day 8. Treatment was continued until progression or unacceptable toxicity. Primary endpoint is overall response rate. Results: Baseline characteristics: median age 54 years (20% = 65); prior (neo)adjuvant CT 21 pts (62%); type of CT: anthracycline 52%, anthracycline + taxane 29%, CMF 14%, taxane 5%; visceral involvement 29 pts (85%), >2 metastatic sites 13 pts (38%). Treatment administered: median 8 cycles, median relative dose intensity: NVBo 77%, X 81%, H 95%; NVBo dose escalation to 80 mg/m2 in 91% of pts. Safety (n=34, G3/4 NCI CTC v2 adverse events): neutropenia 22 pts (65%), diarrhea 4 pts (12%), febrile neutropenia 3 pts (9%), vomiting 3 pts (9%), hand-foot syndrome 3 pts (9%), asthenia 3 pts (9%), infection without neutropenia 2 pts (6%), LVEF decline 2 pts (6%), stomatitis 1 pt (3%), nausea 1 pt (3%), constipation 1 pt (3%). Efficacy (n=31 evaluable pts): objective response rate (RECIST) 71% (95% CI [52–86]), CR 13%, PR 58%, SD 23%, PD 6%, disease control (CR+PR+ SD for =6 months) 84%. Progression-free survival, overall survival and duration of response data are not yet mature. Conclusions: This is the first trial, in pts with HER2-positive MBC, to show high efficacy with first-line NVBoXH therapy. This regimen can be safely administered in this pt population.

No significant financial relationships to disclose.
Cancer penetrance of Lynch syndrome for MSH2 A636P mutation carriers
Authors: Moreno V. , Rennert G. , Gruber S. B.
Published: March 2020

10528

Background: Mutations in mismatch repair genes are responsible for Lynch syndrome. Estimating the penetrance of cancer related to MSH2 A636P, a founder mutation identified in Ashkenazi Jewish population, has clinical implications. Methods: The mutation was genotyped in all subjects of the MECC study, a population-based case-control study carried out in North Israel during 1998–2004 that included 2,112 cases of pathology-confirmed colorectal cancer (CRC) and 2,060 population controls. Approximately 50% of the subjects were of Ashkenazi Jewish origin. Family history of cancer (among first and second degree relatives) was obtained by personal interview. Penetrance of MSH2 A636P was estimated from relatives using a kin-cohort approach by the marginal maximum likelihood method, estimating cumulative risk among carriers and noncarriers. Results: Thirteen MSH2 A636P carriers were identified, all among CRC cases. Their relatives formed a cohort of 138 subjects contributing 8,802 person years (py); 14 of 138 had CRC (173 per 100,000) and 5 endometrial cancer (112 per 100,000). The cohort of relatives of noncarriers summed 46,257 subjects contributing 2.8M py; 582 had CRC (20 per 100,000) and 142 endometrial cancer (EC)(10 per 100,000). For carriers, the cumulative risk to age 70 of CRC was 0.44 (0.19–0.90) and that of EC was 0.29 (0–0.84). The cumulative risk of any cancer related with Lynch syndrome was 0.66 (0.47–0.93). These estimates of penetrance were not substantially modified if the cohorts were restricted to first degree relatives, to Ashkenazi Jews, or when relatives of controls were excluded. Compared to noncarriers, the hazard ratios were 28.7 (2.8–112) for CRC, 9.1 (0–181) for EC and 19 (6.4–50) for Lynch syndrome cancers. Conclusions: The MSH2 A636P missense mutation is highly penetrant, with a cumulative risk of cancers related to Lynch syndrome that is similar to other truncating mutations in mismatch repair genes. These results have implications for the tailored management of patients with this Ashkenazi founder mutation.

No significant financial relationships to disclose.
Correlation among [18-F] FDG-PET/CT, tumor marker CA 27.29, and circulating tumor cells in metastatic breast cancer
Authors: Saad A. A. , Rikhye S. , Kanate A. , Sehbai A. , Marano G. , Hobbs G. , Abraham J.
Published: March 2020

10533

Background: Both tumor marker CA 27.29 and combined [18-F]-fluorodeoxyglucose-positron emission tomography/computed tomography scan (PET/CT) are used to follow up response to treatment and disease progression in patients with metastatic breast cancer (MBC). Recently, circulating tumor cell testing (CTC) has been used in this context. It is not known if one of the three tests can be a surrogate for the other 2 tests. Methods: We analyzed the database of 35 patients with MBC. There were 173 time points (at least 6 weeks apart), when at least 2 of these tests were done. CA 27.29 test (chemiluminescent immunoassay by Bayer Advia Centaur) was either high or normal (< 38.6 U/ml). Circulating tumor cells cell test (Cell Search by Quest Diagnostics, Nichols Institute, Chantilly, VA) was either high or normal (0 cells detected). Results: PET/CT scan results were compared to CA 27.29 at 163 time points. There was statistically significant correlation between both groups (P value: 0.02), however, sensitivity of CA 27.29 to detect metastatic disease seen in PET/CT scan was 59%. The positive predictive value (PPV) of CA 27.29 was 90%, while the negative predictive value (NPV) was only 24%. PET/CT scan results were compared to CTC at 100 events, where there was statistically significant correlation between both groups (P value: 0.0002), however, sensitivity of CTC to detect metastatic disease shown in PET/CT scan was 55%. The positive predictive value of CTC was 98% while the negative predictive value was only 33%. CTC test was more specific (94% Vs 67%) than CA 27.29 to rule out metastatic disease that is seen in PET/CT scan. CA 27.29 results were also compared to CTC at 93 events, where there was statistically significant correlation between both groups (P value: 0.0002). However, only 64 % of those with high CA 27.29 had abnormal CTC. Conclusion: Our data shows correlation among PET/CT scan, CA 27.29, and CTC. However, both CA 27.29 and CTC had poor sensitivity and negative predictive value to detect metastatic disease seen in PET/CT scan. Normal CA 27.29 test or CTC has to be interpreted cautiously in patients with MBC.

No significant financial relationships to disclose.