bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis and initial evaluation of patients with gastrointestinal stromal tumor (GIST): An observational study of 1,226 patients.
Authors: Trent Jonathan C. , von Mehren Margaret , Pisters Peter W. T. , Picus Joel , Keir Christopher Hunt , Magley Andrea , Blanke C. D.
Published: March 2020

10088

Background: The GIST registry (reGISTry) is an observational database designed to determine diagnostic method and evaluation of GIST patients outside of clinical trials. We previously described differences in treatment of patients in community versus academic centers (Pisters, Ann Oncol 2011;22:2523-9). Herein we present distinct differences in the diagnosis and initial evaluation of patients with GIST. Methods: The analysis cutoff date was May 2010. Patient demographics, presenting symptoms, diagnostic methodology, and KIT and PDFGRA mutations were described. For localized tumors, size and mitotic index (MI) were collected. Results: 1226 patients were included in this analysis. Initial diagnosis was most commonly made by surgeons (54.6%) and gastroenterologists (15.7%). Primary management decisions were made at time of diagnosis by medical oncologists (53%) and surgeons (53%) (sum >100% due to ≥1 responses/site). 84% were symptomatic at diagnosis, while 16% were diagnosed incidentally. Diagnostic procedure was performed during surgery (75%) and/or by endoscopy (22%) or interventional radiology (11%) using percutaneous core biopsy or fine needle aspirate. Initial diagnostic imaging was by CT scan (76%), endoscopy (25%), ultrasound (12%), or a combination. Most primary GISTs were located in the stomach (55%) or small intestine (28%). At diagnosis, localized and metastatic disease was seen in 83% and 17% of patients, respectively, with metastases mainly in the liver (62%) and/or peritoneum (36%). KIT immunostaining was performed in 93% of patients, with 98% positive. Mutation analysis was carried out in 8% of cases (57% KIT exon 11 and 12% exon 9 mutations). Of localized primary tumors, 52% were >5 cm in size and 23% had >5 mitoses per 50 high-power fields. Conclusions: We found that initial diagnosis is made by several different modalities. The majority of GIST patients are managed by medical and surgical oncologists. Most patients with localized tumor were at intermediate risk of recurrence and would be considered for adjuvant imatinib therapy.
Single-dimension CT measurements with RECIST 1.1 to evaluate liver metastases in GIST patients on imatinib.
Authors: Schiavon Gaia , Ruggiero Alessandro , Sleijfer Stefan , Bekers Dave J. , van der Holt Bronno , Kloth Jacqueline S.L. , Krestin Gabriel P. , Schoffski Patrick , Verweij Jaap , Mathijssen Ron H.J.
Published: March 2020

10091

Background: Tumor response assessment to therapy is crucial in oncology, both in daily practice and research.We analyzed the morphology of liver metastases (LM) in gastrointestinal stromal tumors (GIST). Aims were to 1) determine whether uni-dimensional measurements of tumor lesions (according to RECIST 1.1) are accurate reflections of their volumes and 2) estimate eventual bias in volume change calculations, as introduced by using only the longest diameter. Methods: 78 GIST patients with LM were evaluated at baseline (n=139 lesions), 3 (n=129), 6 (n=128), and 12 months (n=108) after imatinib therapy. LM were segmented semi-automatically on standard CT scans. All measurements at baseline were obtained by 2 independent investigators and agreement between observers was assessed with Bland-Altman plots. Values for segmented volume (Vs; mL), maximum transaxial diameter (MTD; mm), and elongation value (EV, defined as 1 - [width/length], where EV of 1 = fully ellipsoidal and 0 = fully spherical) were reported for each lesion at several time-points. A calculated volume (Vc) of each LM was also generated using the MTD, with the hypothesis that metastases were fully spherical. Results: At baseline, 44% (61/139) of the LM was spherical and 56% (78/139) was ellipsoidal. Their EV ranged from 0.08 to 0.94 (mean, 0.53±0.17). During treatment, overall 42% of the lesions kept their morphology (spherical or ellipsoidal) and the other half changed from spherical to ellipsoidal or vice versa. At baseline, there was strong inter-observer agreement in the determination of Vs, with mean inter-observer variability of 1.5% (95% CI, -14.5% to 17.5%). The difference between Vs and Vc was highly significant (P<0.0001). Vc overestimates the actual volume of 35% (95% CI, -26% to 95%). Conclusions: LM are not always spherical and can change their morphology during imatinib therapy. Therefore, a lesion's single largest trans-axial dimension, as used in RECIST 1.1, is not an accurate surrogate of its actual volume. Further studies are warranted to fully understand the clinical impact of these findings and to assess whether we should apply different criteria for response assessment to therapies in solid tumors.
A phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense (dd) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC).
Authors: Tolaney Sara M. , Duda Dan G. , Boucher Yves , Goel Shom , Martin John , Ancukiewicz Marek , Potler Hannah , Incio Jaoa , Ligibel Jennifer A. , Isakoff Steven J. , Fukumura Dai , Winer Eric P. , Krop Ian E. , Jain Rakesh K.
Published: March 2020

1026

Background: Two recent preop studies evaluating bev showed conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive markers and their relationship to the pharmacodynamic effects of bev would facilitate the identification of BCs most likely to benefit from bev. To accomplish these goals, we conducted a unique preop trial with a run-in of single agent bev followed by ddACT with bev in two cohorts, one with HR+HER2– BC, and a smaller triple negative (TN) cohort. Methods: Pts with HR+, HER2– or TN BC were eligible if their tumor (T) was ≥1.5 cm and high grade, or had axillary LN involvement; or if T≥2.5cm and was low/intermediate grade. Treatment consisted of a single dose of bev 10 mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, followed by T 175 mg/m2 x1. Research core biopsies and interstitial fluid pressure (IFP) were assessed pre- and post- bev alone. Pathologic response was confirmed centrally and Miller-Payne (MP) was assessed. Results: 84 pts with HR+ and 20 pts with TN breast cancer were enrolled. Amongst HR+ pts, 74 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. Amongst TN pts, 18 pts had tissue centrally reviewed and 8 (44%) had a pCR. Grade was found to predict MP response in both HR+ and TN pts (p=0.001). Several biomarkers were evaluated as predictors of response to bev. Baseline sVEGFR1 correlated with MP response to treatment among TN pts (p=0.015). Single-agent bev reduced the mean vascular density by 18.5% (p=0.049) in HR+ patients and the mean IFP in the overall cohort and HR+ patients by 20 (p=0.020) and 24.5% (p=0.001), respectively. The reductions in IFP correlated with higher levels of sVEGFR2 (p=0.003). The IFP decreased > 50% in 24/65 pts and did not change in others. Gene expression profiling by PAM50 is underway. Conclusions: The addition of bev to preop chemotherapy is well tolerated. Tumor grade appears to predict MP response in HR+ and TN tumors, and sVEGFR1 may be a predictor of MP response to bev in TN tumors. Further work for biomarker predictors of response to bev is ongoing.
Utilization of post-lumpectomy radiation therapy in women 70 years of age or older: A report from the National Cancer Data Base.
Authors: Yao Katharine , Czechura Tomasz , Huo Dezheng , Winchester David Porter , Edge Stephen B. , Winchester David J.
Published: March 2020

1033

Background: The Cancer and Leukemia Group B (CALGB) 9343 trial published in 2004 showed no overall survival benefit from radiation in patients >70 years old with estrogen receptor (ER) positive, pT1 tumors with the use of tamoxifen. We tested the hypothesis that the use of radiotherapy decreased in this group of patients following publication of the trial, utilizing the National Cancer Data Base. Methods: 34,853 breast cancer patients 70 years or older with pT1N0/NX, ER positive tumors who underwent a lumpectomy between 2004 and 2007 were studied. Chi-square tests and logistic regression models were used to determine trends and factors related to the use of radiation. Results: The use of radiation decreased from 70.6% in 2004 to 66.4% in 2005, 66.6% in 2006, and 67.2% in 2007 (p<0.001). The use of standard external beam radiation decreased from 58.8% in 2004 to 45.8% in 2007 while the use of accelerated partial breast radiation using brachytherapy (APBI) increased from 4.5% to 10.0%, IMRT radiation from 3.1% to 5.3%, and 3D conformal radiation from 3.7% to 5.7% (p<0.001). Patients between the ages of 86+ years old were less likely to undergo radiation than patients 70-75 years old (OR=0.12, 95% CI: 0.11-0.13). Asian Pacific Islanders were more likely to undergo radiation than whites (OR=1.39, 95% CI: 1.13-1.70). In community cancer programs, 67% patients received radiation, compared to 69.1% in comprehensive community programs and 65.5% in academic programs (p<0.001). The use of radiation varied by facility location; 73.5% of facilities located in the Midwest radiated these patients as opposed to 62.6% in the South. In patients who had no nodes examined, 37% underwent radiation as opposed to 74% who did have nodes examined (p<0.001). Likewise, 79.4% of patients who received hormone therapy underwent radiation as opposed to 54.6% of patients who did not receive hormonal therapy (p<0.001). Conclusions: The use of radiation therapy decreased only slightly and remained high in women with ER+ stage I breast cancer over the age of 70, despite findings from the CALGB 9343 study. However, there was a large shift in radiation modality over the study period in the older patients.
A phase II study of foretinib in triple-negative, recurrent/metastatic breast cancer: NCIC CTG trial IND.197 (NCT01147484).
Authors: Rayson Daniel , Lupichuk Sasha M. , Chia Stephen K. L. , Potvin Kylea R. , Dent Susan , Tsao Ming Sound , Prady Catherine , Ellard Susan , Salim Muhammad , Allo Ghassan , Ludkovski Olga , Goodwin Rachel Anne , Wainman Nancy , Walsh Wendy , Farmer Pat , Eisenhauer Elizabeth A.
Published: March 2020

1036

Background: Met, a receptor tyrosine kinase, is preferentially expressed in basal-like compared to luminal breast cancer. In murine models, overexpression of the oncogenic Met receptor transgene induces tumors with human basal gene expression characteristics supporting Met inhibition as a treatment strategy for triple negative (TN) breast cancer. Foretinib is an oral multi-kinase inhibitor of Met, RON, AXL, TIE-2 and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Methods: Patients (pts) with TN breast cancer and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. Tumor samples were centrally reviewed to confirm ER/PR/HER2 status and for correlative studies including Met, PTEN and EGFR expression. Stage 1 accrual required 23 response-evaluable Met unselected patients with accrual continuing if >/= 1 response or < 17 early progressions (PD <= 8 weeks on study) were observed. Results: Accrual is 29 pts to date; 24 are eligible, 22 evaluable for toxicity and 15 for response. Median age is 56 y (43-81), ECOG PS 0-1 in 23/24. Grade 3 laboratory adverse events were: lymphopenia (9%), elevations in ALT (5%), GGT (5%) and INR (5%). Treatment-related non-hematologic toxicities included (all/grade 3-4) fatigue (64%/5%), nausea (55%/5%), diarrhea (41%/5%), hypertension (32%/14%), vomiting (27%/0%), anorexia (23%/5%) and rash (14%/0%). Three SAEs possibly related to foretinib included; asymptomatic pulmonary embolism, reversible CHF and pleural effusion with QTc prolongation. One PR (7%), 8 early PD (53%) and 6 SD (40%) have been observed to date with median SD duration of 5.4 months (range 2.7-5.5). Preliminary correlative results (IHC): 5/8 (62.5%) evaluable Met positive cases had SD and 4/5 (80%) Met negative cases had PD as best response. Met IHC was negative in the pt with PR. Conclusions: Foretinib shows preliminary evidence of activity and tolerability in metastatic, TN breast cancer. Stage 2 of accrual will include 15 pts with pre-treatment biopsies of metastases and circulating tumor cell collection.
Epigenetic aspects of triple-negative in patients with breast cancer.
Authors: Martínez-Galan Joaquina , Rios Sandra , Delgado Juan Ramon , Torres-Torres Blanca , Lopez-Peñalver Jesus , Núñez M. Isabel
Published: March 2020

1041

Background: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. However, the reproducibility of differential DNA methylation discoveries for cancer and the relationship between DNA methylation and aberrant gene expression have not been systematically analysed. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. Methods: By using Real Time QMSPCR SYBR green we analyzed DNA methylation in regulatory regions of 107 pts with breast cancer and analyzed association with prognostics factor in triple negative breast cancer and methylation promoter ESR1, APC, E-Cadherin, Rar B and 14-3-3 sigma. Results: We identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. Of the cases, 37pts (40%) were Luminal A (LA), 32pts (33%) Luminal B (LB), 14pts (15%) Triple-negative (TN), and 9pts (10%) HER2+. DNA hypermethylation was highly inversely correlated with the down-regulation of gene expression. Methylation of this panel of promoter was found more frequently in triple negative and HER2 phenotype. ESR1 was preferably associated with TN(80%) and HER2+(60%) subtype. With a median follow up of 6 years, we found worse overall survival (OS) with more frequent ESR1 methylation gene(p>0.05), Luminal A;ESR1 Methylation OS at 5 years 81% vs 93% when was ESR1 Unmethylation. Luminal B;ESR1 Methylation 86% SG at 5 years vs 92% in Unmethylation ESR1. Triple negative;ESR1 Methylation SG at 5 years 75% vs 80% in unmethylation ESR1. HER2;ESR1 Methylation SG at 5 years was 66.7% vs 75% in unmethylation ESR1. Conclusions: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.
Preclinical evaluation of PARP inhibition in breast cancer: Comparative effectiveness of olaparib and iniparib.
Authors: Cotter Maura B. , Pierce Aisling , McGowan Patricia M. , Flanagan Louise , Quinn Cecily , Evoy Denis , Crown John , McDermott Enda , Duffy Michael J.
Published: March 2020

1042

Background: The main function of PARP1 is repair of single-strand DNA. Phase I/II clinical trials have shown that the PARP inhibitor, olaparib has efficacy in BRCA1/2-related breast cancer. Due to the similarities between BRCA1/2-associated and triple negative breast cancer (TNBC), we hypothesise that TNBC may also be sensitive to PARP inhibition. In order to assess this we addressed the effects of 2 PARP/PARP-like inhibitors, on a panel of breast cancer cell lines. Methods: PARP1 was measured by immunohistochemistry in 101 TNBC and 116 non-TN cancers. Comparative growth inhibitory capacity of olaparib and iniparib was evaluated using cell viability (MTT) and colony formation assays in 12 breast cancer cell lines (TN=7, non-TN=5). Results: Using immunohistochemistry, PARP1 staining was predominantly nuclear with some cytoplasmic staining. High staining intensity for PARP1 was found more frequently in ER-negative (p = 0.001), in high grade (p = 0.013) and in Ki67-positive ( p = 0.003) samples. Potentially important was the finding that high PARP1 staining intensity was detected more frequently in TN than non-TN samples (p = 0.0001). IC50 concentrations across 12 cell lines ranged from 3.7-31 µM for olaparib and 13-70 µM for iniparib. No difference in sensitivity was observed between the TN and non-TN cell lines (by MTT). Olaparib also reduced the ability of cells to form colonies with IC50 values ranging from <0.01-2.5 µM. Addition of the CDKI inhibitor CDK1i (Calbiochem) to olaparib resulted in formation of significantly fewer colonies compared with either inhibitor alone, in a cell line dependent manner. Conclusions: Our results suggest that although PARP1 is expressed in the majority of breast cancer, significantly higher staining intensity was found in TN than non-TN samples. Furthermore, our work suggests that olaparib is a more potent inhibitor of the in vitro growth of breast cancer cells than iniparib. Combined inhibition of PARP1 with olaparib and CDK1 with CDK1i may be a way forward for the treatment of TNBC. Acknowledgement: The authors thank SFI (SRC award, 08/SRC/B1410 MTCI) for funding this work.
Neoadjuvant weekly nab-paclitaxel (wA), carboplatin (Cb) plus bevacizumab (B) with or without dose-dense doxorubicin-cyclophosphamide (ddAC) plus B in ER+/HER2-negative (HR+) and triple-negative (TN) breast cancer (BrCa): A BrUOG study.
Authors: Sinclair Natalie Faye , Abu-Khalaf Maysa M. , Rizack Tina , Rosati Kayla , Chung Gina , Legare Robert Duffy , DiGiovanna Michael , Fenton Mary Anne , Bossuyt Veerle , Strenger Rochelle , Sakr Bachir Joseph , Lannin Donald R. , Gass Jennifer S. , Harris Lyndsay , Sikov William M. ,   Brown University Oncology Group (BrUOG)
Published: March 2020

1045

Background: High risk BrCa patients (pts) often receive weekly paclitaxel (wP) as well as ddAC. Switching to wA(Abraxane) or adding B or Cb may enhance its efficacy, especially in TN pts. Methods: Pts with clinical stage IIA-IIIC BrCa received wA 100 mg/m2, Cb AUC 6 + B 15 mg/kg q3wks x 12 wks only (cohort 1/Yale) or followed by ddAC + B x 4 (cohort 2/Brown). Endpoints: pathologic complete response (pCR) - absence of invasive BrCa in breast + axillary nodes, residual cancer burden (RCB), clinical CR/partial response (cCR/cPR), and toxicity. Correlative studies are being performed on biopsies obtained at baseline and after run-in doses of wA or B only. Post-op pts resume B for 34 wks; other systemic therapy, including ddAC in cohort 1, is at MD discretion. Results: 55 of 60 pts (median age 47, range 25-68; 31 HR+/29 TN) are evaluable for response (see table below). Median # doses wA 11,Cb 4, ddAC 4. Dose reductions: wA 25% for neutropenia (ANC), Cb 15% for thrombocytopenia (tcp). B 7% held for hypertension. Grade 3-4 toxicities (>5%): ANC 85%, tcp 35%, anemia 25%. Serious adverse events during wA: 3 nausea/dehydration (N/D), 3 infection w/o neutropenic fever (FN), 2 GI bleed; during ddAC: 6 (21%) FN despite G-CSF, 3 N/D. Conclusions: The combination of wA, q3wk Cb + B was well tolerated, with cCR+cPR 84%. However, overall pCR was only 11% (27% in TN) after 12 wks of this regimen (cohort 1). Subsequent preop ddAC raised overall pCR to 54%, and 81% in TN, demonstrating that longer treatment duration or inclusion of anthracycline-based therapy improves responses. Results for cohort 2 compare favorably with those from I-SPY, GeparQuinto and NSABP B-40; the addition of Cb and/or B in TN is being evaluated in CALGB 40603. [Table: see text]
Patterns in circulating microRNA in black (B) versus white (W) patients with triple-negative (TN) breast cancer (BC).
Authors: Shapira Iuliana , Lee Annette , Oswald Michaela , Weiselberg Lora Rose , Ballard David , Taioli Emanuela , Cheng Kit , Mekan Sabeen Fatima , Barginear Myra F. , Keogh Mary , Mason Cathleen , Budman Daniel R.
Published: March 2020

1046

Background: Breast cancer is by far more common in W than in B women. Black women have more aggressive disease that occurs almost a decade earlier, it is usually triple negative and has a lower survival. Objectives to determine 1) if plasma miRNA expression differs between B and W women, and 2) if variation in miRs may explain the observed survival difference in TNBC in W compared to B women. Methods: We determined miRNA profiles in plasma collected before removal of breast tumors in three groups of W and B women: 1) normal controls (N), 2) TN and 2) ER/PR positive BC. Expression miRNA profiling of 754 miRNAs on the ABI Open Array detected 101miRNAs in plasma. We compared miRNA expression in cancer patients and race-matched controls. A moderated t-statistic through the R/Bioconductor 'limma' was used to compare the mean response between subject factors of interest. Results with a p<0.05 were considered statistically significant. Characteristics: 32 patients were included in this analysis (mean age 50 years; range 31-68), 10 had stage III TNBC (5 B & 5 W); 10 had stage III ER/PR+BC (5 B, 5 W); and 12 were controls (6 B, 6 W) Results: W TNBC patients overexpressed (15 fold higher than normal) 20 miRs in plasma (let-7d, let7g, miR-103, -10a, 15a, -9, -99b, -181a, -18a, -502, -187, -365 and others), these miRs were not found in any of the B patients. Six microRNAs (such as miR-34a, -127 and others) were 15 fold higher than normal controls in B cancer patients, these miRs were not detected in W patients with TNBC. Four miRs in B and 8 miRs in W were not previously reported in association with breast cancer suggesting that they may be connected to the host response. Conclusions: The striking difference in the patterns of plasma miRNA expression between B and W patients may provide the key to the large difference in outcome between these groups when receiving similar treatments, the worse prognosis group may carry the miRs that promote metastasis. The seed-soil hypothesis may explain the better prognosis in W patients. W women may carry those miRNAs that support an “exaggerated” response to systemic treatment, while the B may have the miRs that favour metastasis.
Gene expression-based predictors of chemotherapy response in basal-like breast cancer.
Authors: Prat Aleix , Lluch Ana , Albanell Joan , Fang Cheng , Chacon Lopez-Muniz Jose Ignacio , Parker Joel S , Calvo Lourdes , Plazaola Arrate , Arcusa Lanza Angels , Seguí-Palmer Miguel Angel , Burgues Octavio , Vicioso Luis , Sanchez-Simon Raquel , Bermejo Begoña , Ribelles Nuria , Melendez Asensio Barbara , Caballero Rosalia , Carrasco Eva Maria , Perou Charles M. , Alba E. ,   Spanish Breast Cancer Research Group GEICAM
Published: March 2020

10500

Background: The Basal-like subtype is generally associated with high chemo-sensitivity, but not all tumors respond and/or benefit to the same extend. In this study, we sought to identify gene expression predictors of neoadjuvant chemotherapy sensitivity in Basal-like breast cancer. Methods: Expression of 542 genes was measured using the Nanostring nCounter platform from 69 FFPE pre-treated samples of the GEICAM/2006-03 phase II trial, which were treated with epirrubicin/cyclophosphamide followed by docetaxel+/-carboplatin. Research-based PAM50 and Claudin-low predictors were also evaluated. The association between response (Miller-Payne criteria) and gene/signature expression was assessed by multivariable ordinal logistic regression. Significant findings were evaluated in 109 independent triple-negative and Basal-like tumors treated with anthracycline/taxane-based chemotherapy (Hatzis et al.). Finally, interaction tests were performed to identify genes/signatures associated with carboplatin response. Results: In GEICAM/2006-03, 61/69 (88%) tumors were identified as Basal-like by PAM50. High correlation to the Basal-like centroid, or high expression of proliferation-related genes (i.e. FANCA), were found to be significantly associated with high chemo-sensitivity, whereas high expression of genes associated with mesenchymal/stem cell biological processes (i.e. SNAI1 and IL6) and/or luminal differentiation (i.e. MUC1 and FOXA1) were significantly associated with chemo-resistance; similar findings were observed in Hatzis et al. Finally, high expression of genes associated with proliferation/DNA-repair (i.e. ATR) and tight junctions (i.e. CLDN3/4/7) were found associated with carboplatin response, whereas expression of the Claudin-low signature was found associated with carboplatin resistance. Conclusions: High expression of Basal-like and/or proliferation-related genes and low expression of luminal/mesenchymal/stem cell-like biological processes were consistently identified as predictive of chemotherapy response. Our data suggests that gene expression profiling might help shed light into the biological and clinical heterogeneity of Basal-like breast cancer.
Circulating tumor cell counts (CTC) as prognostic of overall survival (OS) in SWOG S0421-docetaxel with or without atrasentan for metastatic castration resistant prostate cancer (mCRPC).
Authors: Vogelzang Nicholas J. , Ely Benjamin , Fink Louis M. , Goldkorn Amir , Tangen Catherine M. , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Carducci Michael Anthony , Monk J. P. , Datar Ram H , Garzotto Mark , Mack Philip C. , Lara Primo , Higano Celestia S. , Hussain Maha , Quinn David I. , Cote Richard J , Thompson Ian Murchie
Published: March 2020

10503

Background: CTC are promising biomarkers in mCRPC but have not been prospectively validated for docetaxel treatment (Rx). Using CellSearch technology (J&J), we enumerated CTC in this Phase 3 trial & assessed prognostic value for OS. The aim of this correlative study nested within 0421 was to compare CTC via CellSearch technology to newer microfilter technologies (Cote & Goldkorn PIs RO1 CA141077). Comparative data analysis is ongoing. Methods: CTC were drawn at baseline (d1) & pre-cycle 2 (d21) of Rx & shipped overnight to a central site for enumeration (CTC/7.5 ml). Cox regression evaluated the association between OS and (i) baseline CTC counts & (ii) CTC dynamics (d1 to d21) in pts with good (<5) vs. poor (>=5) baseline CTC counts. Receiver operator characteristic (ROC) analysis and Characteristics & Regression Trees (CART) were used to explore further prognostic CTC cutpoints for 2-yr survival. Results: Of 263 patients (pts) consented, 238 were evaluable at d1 & 232 at d21. At d1 median CTC was 5 (range 0-5916) & d1 CTC < vs. >= 5 was associated with baseline PSA (mean 99 vs. 320 ng/ml, p=0.004) and worse bone pain (36% vs. 51%, p=0.03). There was a significant difference in OS for d1 CTC < vs. >=5, with a hazard ratio (HR) of 2.92 (95% CI 1.92-4.43, p<0.001) after adjustment for PSA & other factors. In pts with low d1 CTC (< 5), an increase in CTC was associated with shorter OS, HR 4.04 (95%CI 1.56-10.44, p=0.004); in pts with high d1 CTC (>=5), a >=2-fold decrease in CTC was associated with longer OS, HR 0.45 (95%CI 0.24-0.84, p=0.012); adjusting for risk factors. D1 CTC and 2-year survival had ROC AUC of 0.781. CART analysis identified prognostic subgroups based on CTC of 0, 1-5, 6-53, and >53: (HR 0.36, 0.77,1.3 and 2.8). Conclusions: In this phase 3 trial, d1 CTC was prognostic of OS after risk factor adjustment. CTC dynamics from d1 to d21 were also prognostic of OS. These data are an exploratory subset analysis of the overall study. Yet, they comprise the largest docetaxel-based prospective cohort to date, which validates a 5 CTC prognostic threshold for OS & identifies new potential prognostic subgroups that may extend the clinical utility of CTC enumeration in mCRPC.
PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations.
Authors: Janku Filip , Broaddus Russell , Bakkar Rania , Hong David S. , Stepanek Vanda M.T. , Naing Aung , Falchook Gerald Steven , Fu Siqing , Wheler Jennifer J. , Piha-Paul Sarina Anne , Moulder Stacy L. , Luthra Rajyalakshmi , Tsimberidou Apostolia Maria , Kurzrock Razelle
Published: March 2020

10510

Background: Loss of PTEN function increases PI3K/mTOR signaling. Preclinical data suggest that PTEN aberrations can predict sensitivity to drugs targeting the PI3K/mTOR pathway. Methods: Tumors from 461 patients with diverse cancers referred to the Clinical Center for Targeted Therapy were tested for cytoplasmic immunohistochemical expression of PTEN using the following scoring system: negative (no staining); positive (intact staining); reduced staining, with stroma serving as an internal positive control. Whenever possible, tumors were also tested for mutations in the MAPK pathway (KRAS, NRAS, and BRAF). We analyzed outcomes of patients treated with PI3K /mTOR with respect to their PTEN status. Results: Of 461 patients, 47 (10%) had negative PTEN expression, 168 (36.5%) had positive PTEN expression, and 246 (53.5%) had reduced PTEN. In tumor types with >10 patients tested, negative PTEN was most frequent in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary (3/24, 13%), and prostate cancers (2/19, 11%). Of 206 patients tested for MAPK (KRAS, NRAS, and BRAF) pathway mutations, patients with either negative or reduced PTEN had more MAPK mutations than patients with positive PTEN expression (72/144, 50% vs. 20/62, 32%, p=0.02). A total of 153 (33%) patients received therapies with PI3K /mTOR inhibitors and 17 (11%, 95% CI 0.07-0.17) achieved a partial response (PR). Proportions of PRs were 2/13 (15%) for PTEN negative, 3/50 (6%) for PTEN positive, and 12/90 (13%) for reduced PTEN. There was no significant difference in PR rate amongst patients with positive PTEN expression compared to patients with negative or reduced PTEN (3/50, 6% vs. 14/103, 14%; p=0.27). Conclusions: Complete loss of PTEN expression was found in 10% of patients. Positive PTEN expression was found in 36.5% of patients. PTEN status did not predict response to PI3K/mTOR inhibitors, perhaps because patients with negative and reduced PTEN expression had a higher incidence of simultaneous MAPK (KRAS, NRAS, BRAF) mutations.
Dynamic contrast-enhanced MRI versus 18F-misonidazol-PET/CT to predict pathologic response in bevacizumab-based neoadjuvant therapy in breast cancer.
Authors: Garcia-Foncillas Jesus , Martinez Purificación , Lahuerta Ainhara , Llombart Cussac Antonio , Garcia Gonzalez Maria , Gomez Rosa Maria Sanchez , Alvarez Isabel , Anton Antonio , Illarramendi Jose J. , De Juan Ana , Calvo Elena Galve , Plazaola Arrate , Morales Serafin , Hernando Blanca , Lao Juan , Boni Valentina , Puertolas Teresa , Sherer Stefan , Palacios Gemma , Lopez-Vega Jose Manuel
Published: March 2020

10512

Background: To investigate the role of DCE-MRI versus 18F-Misonidazole (FMISO) positron emission tomography (PET/CT) in the prediction of pathological response to bevacizumab-based neodajuvant therapy. Methods: 73 chemotherapy naïve, stage II and III breast cancer (BC) patients (pts) were enrolled in a phase II, single-arm, multicenter, open-label and prospective clinical trial. Pts received single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting of 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5), followed by surgery. Tumor proliferation, hypoxia and perfusion were evaluated respectively using 18F-Fluorothymidine (FLT) and 18F-Misonidazole (FMISO) positron emission tomography (PET/CT) and dynamic contrast enhancement magnetic resonance (DCE-MR). Serial imaging studies were performed in parallel at several time points including baseline (BL) and 14-21 days after bevacizumab alone (C1). Results: After only one administration of bev, tumor proliferation and perfusion assessed using FLT-PET and DCE-MRI significantly decrease (-26% and -46%, p<0.001) but these changes were not found to be associated with final response. Most important, changes in tumor hypoxia induced by bevacizumab was significantly associated with pathological response (p= 0.004) and was an independent predictor of response in multivariate analysis (RR=0.95, IC 95% 0.92-0.99, p=0.02). Decrease in FMISO uptake >10% yielded a ROC curve area of 0.7 (95% CI: 0.56 - 0.85) with high specificity (94%). Conclusions: Our findings suggest a significant value of early changes in tumor hypoxia assessed by FMISO-PET as a biomarker of pathological response in bevacizumab-based neoadjuvant therapy in breast cancer.
Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker females with pulmonary adenocarcinoma.
Authors: Chen Xiaoxia , Ren Shengxiang , Kuang Peng , Su ChunXia , Li Jiayu , Li Xuefei , Hu Qiong , Zhou Caicun
Published: March 2020

10527

Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement was found not only predict the efficacy of targeted drugs, but also associate with the efficacy of chemotherapy drugs in non-small cell lung cancer (NSCLC) patients. We investigated the relationship of EGFR mutation status or ALK rearrangement and DNA repair or synthesis genes, such as excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a potential explanation for these observations. Methods: In this surgical series, 104 resected lung adenocarcinomas from nonsmoker females were analyzed concurrently for the EGFR mutation, ALK rearrangement status and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR mutation detection was performed by the method of ADx-ARMS, ALK rearrangement was detected by PCR and the mRNA expression of different genes were tested using the method of real-time PCR. Results: 73 (70.2%) patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. The ERCC1 mRNA level in patients with EGFR mutation was 3.44±1.94×10-3 , which is significantly lower than in the patients with ALK positive and both negative(4.60±1.95×10-3 and 4.95±2.33×10-3 respectively, P=0.010). While the TS mRNA levels were significantly lower in the patients with EGFR mutation(1.15±1.38×10-3 VS 2.69±3.97×10-3, P=0.006) or ALK positive (1.21±0.78×10-3VS 2.69±3.97×10-3, P=0.020) than in patients with both negative. Conclusions: NSCLC specimens harboring activating EGFR mutations are more likely to express low ERCC1 and TS mRNA levels, while NSCLC patients with ALK rearrangement are more likely to express low TS mRNA levels, which could be helpful to select a proper chemotherapy regimen for NSCLC patients with known EGFR mutation or ALK fusion status.
New microRNA-based diagnostic test for lung cancer classification.
Authors: Aharonov Ranit , Lithwick Yanai Gila , Benjamin Hila , Sanden Mats Olot , Bibbo Marluce , Thurm Craig , Horowitz Laurie , Huang Yajue , Feinmesser Meora , Barshack Iris , Hou Steve j , Edmonston Tina B , Ashkenazi Karin ,   Rosetta Genomics Inc.
Published: March 2020

10528

Background: Lung cancer is the leading cause of cancer deaths in the US. Treatment options are determined by tumor subtyping, for which there is lack of standardized, objective, and highly accurate techniques. In 20%-30% of cases significant limitations of tumor quantity and quality prevent full classification of the tumor using traditional diagnostic methods. Using microRNA microarray data generated from over a hundred formalin-fixed, paraffin-embedded (FFPE) primary lung cancer samples, we have identified microRNA expression profiles that differ significantly for the main lung cancer types. Based on these findings, we have developed and validated a microRNA-based qRT-PCR assay that differentiates primary lung cancers into four types: squamous cell carcinoma, non-squamous non-small cell lung cancer, carcinoid and small cell carcinoma. Methods: Over 700 primary tumor samples from different histological types of lung cancer were collected. Samples included FFPE blocks from resection or biopsies and cell blocks from cytology specimens including fine needle aspiration, bronchial brushing and bronchial washing. High-quality RNA was extracted from the samples using proprietary protocols. Expression levels of potential microRNA biomarkers were profiled using microarrays followed by a sensitive and specific qRT-PCR platform. An assay for lung tumors classification using 8 microRNAs on qRT-PCR was developed based on data from 261 samples. This assay was validated on an independent blinded set of 451 cytological and pathological samples. Results: Using the expression levels of 8 microRNAs measured in qRT-PCR, accurate classification of the primary lung tumors into the four main cancer types is obtained. The microRNA-based assay reached an accuracy of 94%. Moreover, cytological samples composed over 50% of the validation set and reached an accuracy of 95%. Conclusions: We present here a new microRNA-based assay for the classification of the four main types of lung cancer based only on the expression of 8 microRNAs. This assay displays very high levels of accuracy for both pathological and cytological samples. The assay comprises a standardized, well-tested and objective tool which can assist physicians in the diagnosis of lung cancer.
Promoter methylation of MGMT in paired primary and recurrent glioblastomas.
Authors: Bie Li , Qiu Ji Qing , McClelland Michael , Ju Yan
Published: March 2020

10543

Background: Epigenetic sliencing of MGMT gene promoter in primary glioblastomas (GBM) of pts subsequently treated with temozolomide (TMZ) is associated with prolonged survival. Further, several studies have observed a change in MGMT silencing in paired primary and recurrent GBM. However, the relationship between this “MGMT switch” and patients outcome is largely unknown. Methods: The study involved primary and recurrent tumor tissue samples from 53 GBM pts diagnosed and treated within the First Hospital of Jilin University from Jan 2003 to Nov 2010. After surgical treatment, all pts were subjected to radiotherapy with concomitant administration of TMZ (75 mg/m2/d), followed by 5 cycles of adjuvant TMZ given at 4-weeks intervals. Pts that experienced recurrent tumors received TMZ at a dose of 200 mg/m2/5 days for 4 weeks. 53 pts underwent 58 further operations after recurrence (5 pts received a third surgery). MGMT promoter methylation levels were determined using qMSP. The relationship between “MGMT switch” and clinical outcome was investigated. Results: Fifty three (M/F=33/20; median age: 49.2±3.6, range: 19.5-72.3 ys) underwent a first operation for GBM. qMSP analysis revealed MGMT promoter methylation in 19 pts (35.8%, group A, OS 31.5 ms); no methylation in 34 pts (64.2%, group B, OS 7.9 ms). In the recurrent tumors, MGMT promoter methylation was detected in 25 pts (47.2%); and no methylation in 28 pts (52.8%). Comparison of individual pairs of primary and recurrent GBMs revealed a changed methylation status in 10 (18.9%), including eight changed from unmethylated to methylated tumors (15.1%, group C, OS 29.4 ms), two changed from methylated to unmethylated tumors (3.8%, group D, OS 10.5 ms). Median overall survival was 12.1 ms. MGMT promoter methylation was significantly associated with a favorable clinical outcome (group A vs group B, p=0.0027). The outcome of pts were not significant different between A and C (p>0.01). Conclusions: The methylation status of the MGMT promoter was altered in 10 (18.9%) of 53 recurrent GBM after chemoradiotherapy. Eight pts changed from unmethylated to methylated who have a median overall survival similar to methylated pts. The pts changed from methylated to unmethylated who have poor outcome.
Correlation between miRNA (miR) and gene expression profiles (GEP) and response to neoadjuvant chemotherapy (NT) in patients with locally advanced and inflammatory breast cancer (BC).
Authors: Li Sierra Mi , Wu Xiwei , Frankel Paul Henry , Gao Harry , Sun Guihua , De Snoo Femke , Rossi John , Wang Emily , Roepman Paul , Yen Yun , Peeters Justine , Stork Lisette , Somlo George
Published: March 2020

10545

Background: GEP may predict for pathologic complete response (pCR). Correlation between miRs, GEP, and pCR may reveal novel targets. Methods: Patients (pts) with HER2- BC were randomized to receive docetaxel, doxorubicin, cyclophosphamide (TAC, arm A) or A and C given every 2 weeks x 4, followed by carboplatin and nab-paclitaxel (arm B). Pts with HER2+ BC received NT per arm B, with trastuzumab added (arm C). Core biopsies were snap-frozen prior to NT, and RNA extracted for gene array analysis (Agilent 44K microarray) and deep sequence miRNA analysis (Solexa/Illumina platform). HER2 testing by IHC [3+] or FISH and/or gene array was carried out (Blueprint). MiRs were measured in 72 of 119 enrolled pts. Of 882 miRNAs reported by Solexa sequencing, 487 were assessed (observed at raw counts > 10 in at least 3 pts). TargetScan was used to obtain miRNA targets and negative correlation between miR and mRNA expression was applied. Results: In 44 HER2- cases, we found 17 miRs differentially expressed between pts who achieved pCR vs. pts who did not (< pCR), 13 with predicted targets by TargetScan (TS). We found 28 canonical pathways (including Embryonic Cell, EGF signaling, Estrogen-dependent signaling) affected by the identified miRs, and inclusive of 74 target mRNAs identified (Agilent) and correlating with pCR. The top overexpressed miRs are 31 [gene targets: FZD4]; 18a [IGF1, ALDH5A1]; 19a [PIK3R, IGF1]) and 3 lowest expressors are miR-190b [MMP1]; 29c [FOS, WNT5B]; 342-3p [BMP7]. Among the 28 HER2+ cases there were 14 miRNAs differentially expressed between BCs with pCR vs <pCR, and 8 had predicted targets from TS. We found 10 canonical pathways (including p53, HER-2, PTEN) affected by miRs, which included 44 target mRNAs (Agilent) correlating with pCR. The most overexpressed miRs are miR-708 [gene target: RRM2B; 193a-p5 [BMPR1B, RPRM] ; 92b [CCNE2, DKK2]. The lowest expressors are: miR-30a [FZD1, SMAD1, TP63]; miR-450-5p [FOXO1, WINT5A, ERBB2]; miR-497 [PIK3R1, FGFR1, FOXO1]. Conclusions: Combined assessment of miRNA and gene expression patterns is feasible, and may yield information leading to individualized and improved NT.
Topoisomerase II alpha gene status, HER2, and microtubule-associated protein tau as predictors of pathologic complete response after neoadjuvant chemotherapy.
Authors: Barnadas Agust , Tibau Martorell Ariadna , Lopez Vilaro Laura , Escuin Daniel , Alonso M Carmen , Ojeda Belen , Ramon y Cajal Teresa , Fuentes M Josefa , Perez Garcia Jose Ignacio , Garcia Valdecasas Barbara , Clotet Montserrat , Torrubia M Sofia , Gich Ignasi , Lerma Enrique
Published: March 2020

10555

Background: There is growing evidence that topoisomerase II-alpha (TOPOIIα) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER2 has been described as a marker of both anthracycline and taxane sensitivity.The goal of our study was to examine the predictive and prognostic value of TOPOIIα, MAPT and HER2 expression in breast cancer patients (pts) who received neoadjuvant chemotherapy (NAC) based on anthracycline-taxane regimens. We analyzed the relationship between these biomarkers and pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Methods: Between November 1993-2009, 140 pts (mean age 52 years) with locally advanced breast cancer (T1-4, N0-3, M0) were retrospectively studied. The study contained 2 groups: group A included 85 pts who received NAC with an anthracycline-taxane regimen and group B included the last 55 pts who received NAC with only an anthracycline-based regimen. HER2 was tested by immunohistochemistry (IH) or FISH, TOPOIIα by CISH and MAPT by IH. Expression of these proteins was evaluated in core needle breast biopsy. Results: Overall, 12 pts (8.5%) had a pCR. TOPOIIα was amplified in 6 (4%) of the tumors. Among pts without amplification, 6 (4%) had deletion of the TOPOIIα, and 10 (7%) polysomia of chromosome 17. TOPOIIα gene aberrations (amplification, deletion, polysomia), which was present in 22 (25%) of the tumors, was a strong predictive factor for pCR (p=0.018) but showed no direct association with prognostic outcome in multivariate analysis. HER2 amplification, which was present in 16% (21) of the tumors, show no direct association with pCR, DFS or OS. Finally, differences by treatment arm or pCR in low versus high MAPT expression groups were not observed, indicating that MAPT is not a useful predictive marker for taxane-based chemotherapy. In multivariate analysis high MAPT expression was associated with longer DFS (p=0.002). Conclusions: TOPOIIα gene aberrations but not HER2 are highly predictive of pCR for anthracycline-based regimen. MAPT is not associated with response to taxanes but has a prognostic value.
Exosomal-miRNA profiles as diagnostic biomarkers in cervical cancer.
Authors: Nishi Hirotaka , Nagamitsu Yuzo , Sasaki Toru , Takaesu Yotaro , Terauchi Fumitoshi , Isaka Keiichi
Published: March 2020

10557

Background: MicroRNA (miRNA) expression is altered in cancer cells and associated with the development and progression of various types of cancer. miRNA could serve as diagnostic or prognostic biomarker for cancer patients. Our study was designed to analyze circulating exosomal-miRNA in patients with cervical cancer. Methods: Total RNA was extracted from serum in healthy women and patients with cervical intraepithelial neoplasia (CIN) and cervical cancer. We first explored miRNA expression profiles using miRCURY LNA microRNA Array (Exiqon) in each six malignant and healthy serum samples. miRNAs with significant differences in expression were validated in larger sample sets by a quantitative real-time RT-PCR using TaqMan gene expression assays (Applied Biosystems). Results: Six of 1223 miRNAs compared in serum samples from cervical cancer and normal control were found to have a >3.0-fold change with a P value <0.01 using miRCURY LNA microRNA Array. In a validation set (n=101), expression of 3 of the 6 miRNAs, miR-483-5p, miR-1246 and miR-1275, was significantly different between the cervical cancer (n=40) and control (n=20) samples. We also found that the median levels of these miRNAs were significantly higher in patients with cervical cancer (n=40) than those in CIN (n=41). Circulating miRNAs were not correlated with clinical-pathological parameters except for miR-1246. Compared to patients with squamous cell carcinoma, the miR-1246 level was significantly higher in those with adenocarcinoma. Whereas, receiver-operator characteristic (ROC) curve analyses suggest that these serum miRNAs may be useful markers for discriminating patients with cervical cancer from healthy controls. Conclusions: Expression of circulating miR-483-5p, miR-1246 and miR-1275 is significantly higher in the blood of cervical cancer patients compared to controls and may potentially serve as a useful biomarker for cervical cancer diagnosis. Especially, miR-1246 may be a candidate for early detection of cervical adenocarcinoma. Larger-scaled studies are warranted to fully explore the role of circulating exosomal-miRNAs in cervical cancer.