bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a novel small molecule yk-4-279 on the "undruggable" target EWS-FLI1.
Authors: Toretsky Jeffrey , Gamble S. Ellen , Monroe Philip J. , Hong S. Peter , Summer Stephen J. , Uren Aykut , Hong Sung-Hyeok
Published: March 2020

10042

Background: Chimeric transcription factors are ideal anti-cancer targets since they are only present in tumor cells, however they are often considered ‘undruggable’ proteins. The EWS-FLI1 fusion protein of Ewings sarcoma (ES) has been validated as an anticancer target both alone and as a partner of RNA Helicase A (RHA). Our prior work identified (S)-YK-4-279 as an enantiospecific inhibitor of EWS-FLI1 by blocking the interaction with RHA leading to apoptosis. Methods: Pharmacokinetic (PK) models of YK-4-279 for both IP and IV administration were developed in SD rats and BL6 mice using drug concentrations determined by a validated LC-MS/MS assay. Xenograft ES mice validated PK models with apoptosis measured by TUNEL. A novel nude rat ES orthotopic xenograft was created give (S)-YK-4-279 by continuous IV infusion. Results: SD rat and BL6 mouse PK modeling demonstrated an elimination half-life t1/2 of 30 minutes following IV administration; SCID/bg mice demonstrated 50% faster clearance. A survival curve showed maximal killing of ES cells between 1 and 3 microM YK-4-279 over a 40-hour time course. Clonogenic replating assays demonstrated 3 microM exposure for 72 hours would reduce replating efficiency of ES cells to less than 0.01%. SCID/bg ES xenografts treated with IP YK-4-279 BID for 6 doses showed a 25-35% enantiospecific tumor regression with an average 3.5-fold increase in apoptosis. A nude rat xenograft, with continuous infusion (S)-YK-4-279 maintained an average level of 4.9 microM in plasma for 26 days. The ES1 xenograft tumor responded in 4 of 5 animals, with complete regression in 2 of 5, without toxicity. Conclusions: A combination of PK modeling and cell culture studies confirmed that (S)-YK-4-279 is required to be present at low microM levels for optimal tumor response. These levels were achieved in a novel rat xenograft of ES in order to demonstrate an important proof of efficacy. These PK-driven xenograft therapy studies are useful for development of PK models to compare YK-4-279 levels with functional activity. Targeting ‘undruggable’ protein-protein interactions with small molecules is novel and the ES model shows that continuous IV infusion may be required for optimal clinical translation.
Are adult and pediatric neuroblastoma clinically different entities?
Authors: Conter Henry Jacob , Gopalakrishnan Vancheswaran , Ravi Vinod , Ater Joann , Patel Shreyaskumar , Araujo Dejka M.
Published: March 2020

10049

Background: It is unknown if the presentation, treatment, and outcomes differ between adults and pediatric patients with neuroblastoma. Methods: Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2-17), who were treated for neuroblastoma at the University of Texas M.D. Anderson Cancer Center from 1994 to September 2012, were reviewed. International Neuroblastoma Risk Group (INRG) variables were abstracted. These include age, stage, tumor histology, and molecular and cytogenetic characteristics. The primary outcome of interest was overall survival (OS). Results: Median age of pediatric patients was 5 years (range 3-16) and 47 years (range 18-82) for adult patients. Beyond age and stage, other components of the INRG classification were not available for any adult patient. Cytogenetic and molecular studies were performed in 32 (26%) of pediatric patients. Adults with L1 disease experienced an actuarial OS of 94%, 90%, and 69% at years 3, 5, and 10, respectively. The cohort who presented with L2 disease had an estimated OS of 83% at 3 year, 73% at 5 years, and 41% at 10 years. Adults with M disease experienced an actuarial OS of 68%, 33%, and 13% at years 1, 2 and 5, respectively. In the adult cohort, the INRG stage was prognostic in univariate analysis (p<0.001). For all stage-matched risk categories, adults did not have a statistically different prognosis than children (L1-p=0.40, L2-p=0.54, M-p=0.73). Conclusions: Adult and pediatric patients with neuroblastoma achieve similar survival outcomes, with good prognosis for early-stage patients. Future work should focus on developing predictive markers for determining which patients benefit from more aggressive therapy. [Table: see text]
Clinical prognostic factors in pediatric Ewing sarcoma.
Authors: Abou Ali Bilal , Nader Ralph , Muwakkit Samar , Abboud Miguel , El Solh Hassan M.B. , Saab Raya Hamad
Published: March 2020

10052

Background: Treatment of Ewing sarcoma necessitates coordinated multi-disciplinary care that includes chemotherapy, surgery, and/or radiation. In developed countries, patients with localized disease have an overall survival of 70-80%, compared to 20-30% for those with metastases. The outcome of children with Ewing sarcoma in less developed countries has not been adequately described. We analyzed prognostic factors for Ewing sarcoma patients treated at a single institution in Lebanon, a developing country with available multidisciplinary treatment modalities. Methods: We reviewed characteristics and outcome of 42 pediatric patients treated at a multidisciplinary cancer center in Lebanon, between January 1999 and October 2012. Kaplan Meier curves were generated to estimate survival. Results: Median age at presentation was 10 years (range 1-18), and median follow-up was 41 months (range 8-110). Commonly affected primary sites included the extremity (36%, n=15), chest wall (19%, n=8), and pelvis (14%, n=6). Tumor size was ≥ 8cm in twenty (47.6%) patients. Thirty-two patients (76%) had localized disease, and ten (24%) had metastatic disease. All patients received 14 cycles of chemotherapy, with VDC alternating with IE. Local control was surgery alone (29%, n=12), radiotherapy alone (33%, n=14), or combination (38%, n=16). For patients with localized disease, the 5-year OS and DFS rates were 68% and 55% respectively, while for metastatic disease they were 28% and 25%. Tumor recurrence was local in 8 patients, distant in 8, and combined in 2. Factors associated with improved outcome included localized disease, extremity site, surgery, and timely local control. In multivariate analysis, timing of local control and metastatic disease were prognostically significant determinants of outcome. Conclusions: Treatment of childhood Ewing sarcoma in a multidisciplinary cancer center in Lebanon results in similar survival to that in developed countries when similar protocols are applied. Strong prognostic factors included stage (localized vs. metastatic), and timing of local control. Patients who had a local control time delay of more than 3 weeks fared worse, strongly suggesting that delays in local control should be actively minimized in Ewing sarcoma.
The Children’s Oncology Group and QuadW Foundation osteosarcoma banking experience.
Authors: Glover Jason Michael , Gorlick Richard Greg , Khanna Chand , Barkauskas Donald A.
Published: March 2020

10053

Background: Survival rates of osteosarcoma patients have remained stagnant over the last twenty years. Predictive biomarkers of response to treatment and likelihood of recurrence are yet to be developed. In order to develop new therapeutics and better risk-stratified regimens, a greater understanding of osteosarcoma biology is needed. The Children’s Oncology Group (COG) addressed this need by banking more than 10,000 tumor and tissue samples from over 1500 patients with osteosarcoma, but many samples lacked clinically relevant data. Methods: 1105 eligible patients enrolled on the COG osteosarcoma biology study P9851. Of those, 510 patients were not enrolled on a concurrent therapeutic trial, which limited the clinical annotation of those samples. 589 patients have enrolled on the successor study AOST06B1. The lack of clinical annotation of the P9851 specimens limited their value, and the lack of statistical support slowed the analysis of several biology studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) in 2008 to link clinically annotated patient data to the samples and to provide statistical support. Results: In 2008, only 5.3% of samples from the 510 P9851 patients not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses. As a result, 18 biology studies in osteosarcoma are completed, with 11 published in peer-reviewed journals. Samples were provided to the TARGET program (for gene expression arrays, copy number analysis, and sequencing data); the resulting data will be available to the scientific community for in silico studies. Conclusions: The efforts of the CSBAO have led to a substantial increase in the value of a large osteosarcoma biospecimen repository by clinically annotating the specimens and providing statistical resources for analyses of planned and completed studies. These samples with annotated patient information are available by request to the research community for basic and translational science projects to improve the biological understanding of, and the treatment of patients with osteosarcoma. Clinical trial information: NCT00899275.
Prognostic impact and detection of minimal residual disease (MRD) in neuroblastoma patients.
Authors: Druy Alexander , Tsaur Grigory , Popov Alexander , Verzhbitskaya Tatiana , Shorikov Egor , Saveliev Leonid , Fechina Larisa
Published: March 2020

10055

Background: Bone marrow (BM) involvement and MRD detection in neuroblastoma (NB) seems to be useful tool for patients’ prognosis, stratification and risk-adapted treatment. Real-time PCR (RQ-PCR) of tumor-specific gene transcripts and flow cytometry (FC) are commonly applied for this purpose. Aim. RQ-PCR MRD marker definition, its qualitative concordance with FC and prognostic impact in NB patients. Methods: We analyzed 331 BM samples from 57 NB patients and 26 ‘normal’ BM samples from 20 patients without malignancies for PHOX2B, TH, ELAVL4 and GD2 genes expression. BM samples were defined as positive either in case of positivity for PHOX2B or in case of NB cells presence in BM. 326 BM samples from 52 NB patients were analyzed by RQ-PCR and FC together. Results: PHOX2B and TH were not detecting in normal BM samples. Out of 224 negative BM samples TH was identified in 5 only, while ELAVL4 and GD2 expression was detected in the majority of normal and negative BM samples: 20 and 15 from 26 normal; 209 and 197 out of 224 negative samples correspondingly. TH, ELAVL4 and GD2 expression in positive BM samples was significantly higher comparing to negative and normal BM samples.Threshold levels of each gene expression were established by ROC-analysis and subsequently applied for overall correct prediction (OCP) calculation. OCP for PHOX2B and TH achieved 0.994 and 0.952, while OCP for ELAVL4 and GD2 were significantly lower: 0.828 and 0.767 respectively. Analytical sensitivity of RQ-PCR for PHOX2B achieved 1E-06, while sensitivity of FC ranged from 1E-03 to 1E-05. In 193(59.2%) out of 326 evaluated samples BM was negative by both methods. 38(11.7%) samples were negative by FC but positive by RQ-PCR for PHOX2B expression. 31(9.5%) samples were positive by FC but negative by RQ-PCR. 64(19.6%) samples were positive by both techniques. Thus qualitative concordance between RQ-PCR and FC achieved 78.8%. Conclusions: Patients with detectable PHOX2B expression have lower event-free survival comparing to patients with PHOX2B negative BM: 0.30±0.10 and 0.77±0.27 respectively, p=0.002 and overall survival is 0.51±0.11 and 0.79±0.07 correspondingly, p=0.083. Median of follow up in our NB patients series is 42 months, ranged from 1 to 156.
Birth and maternal characteristics, and childhood cancer in the United States: An ecological study.
Authors: Pereira Guilherme Abreu , Rodriguez-Galindo Carlos , Frazier A. Lindsay , Boffetta Paolo , Ribeiro Karina Braga
Published: March 2020

10061

Background: Childhood cancer is rare, yet it represents a major cause of mortality in this age group. Its etiology is largely unknown. The aim of this study was to identify associations between pre- and perinatal characteristics and cancer development in children below age 5. Methods: We developed an ecological study correlating birth information and childhood cancer incidence in 0-4 year old at the State level. The following variables were analyzed: birth weight (BW), preterm birth, maternal age, plurality, maternal smoking, chronic hypertension (CH), diabetes mellitus (DM), pregnancy associated hypertension (PH) and eclampsia. Birth characteristics were obtained from Centers for Disease Control and Prevention (CDC) database (1995-2009), and childhood cancer incidence data from the National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology and End Results (SEER) program (1999-2009). Spearman correlation coefficients were calculated with SAS 9.2 (Cary, NC). Bonferroni correction was applied for multiple comparisons, ie, only results with p£0.01 were considered significant. Results: Acute lymphoid leukemia (ALL) (r=0.47, p <0.001), astrocytoma (AST) (r=0.59, p <0.001), neuroblastoma (NB) (r=0.48, p <0.001) and rhabdomyosarcoma (RMS) (r=0.51, p=0.003) were positively correlated with high BW (>4000g). ALL (r=0.46, p <0.001) was also positively correlated with advanced maternal age (40+ years). Moreover, a positive correlation was found between plurality and NB (r=0.50, p <0.001). Regarding maternal conditions, the following positive correlations were identified: DM with AST (r=0.40, p=0.009), NB (r=0.38, p=0.01) and WT (r=0.38, p=0.01). Conclusions: Well established correlations were replicated and new associations were suggested (e.g., AST and DM). In spite of the limitation of an ecological approach, this study provided new hypotheses to be explored in further analytical studies based on individual data.
Depression and anxiety (DA) in children within one year of a cancer diagnosis.
Authors: Leavey Patrick , Germann Julie N , Leonard David , Stuenzi Thomas , LeVieux Jane , Stewart Sunita
Published: March 2020

10064

Background: While 10% of children were treated with anti-depressants within 1 year of a cancer diagnosis in a previous study, neither the prevalence nor time course of DA were studied. The American Association of Pediatrics advocates for the use of screening for DA, yet data are lacking regarding timing, frequency, or predictive success of screening in children concurrently receiving therapy for cancer. Methods: We evaluated 87 prospectively diagnosed children at a single institution for DA at 5 time points during the first year of a cancer diagnosis. 55 children completed all screening, 70 missed at most one visit. Starting within 1 month of cancer diagnosis, patients completed the Childhood Depression Inventory (CDI) and the Speilberger State/Trait Anxiety Inventory (STAI) and again at 3, 6, 9, and 12 months. Those patients who scored ≥ 11 on the CDI or ≥ one standard deviation above the mean for age on the STAI were referred for psychiatric consultation the same day. Results: Overall 33 patients (39%) indicated symptoms suggestive of either depression or anxiety during their first year of cancer therapy; n=29 (35%) depression, n=17 (20%) state and n=10 (12%) trait anxiety. Fifty-six consultations resulted in 33 psychiatry diagnoses confirmed in 21 patients (23 depression, 3 anxiety and 7 other). Half of the patients received a diagnosis of DA at least twice over the course of the study, suggesting persistent, significant symptoms. Conclusions: We conclude that screening for DA is effective in children with cancer and that prevalence for symptoms is high. The highest risk for symptoms of DA is within 1 month of diagnosis but during the 1st year of therapy children continue to suffer symptoms of DA highlighting the importance of continued screening. [Table: see text]
Neo-tAnGo science: A translational study of PAM 50 sub-typing in sequential fresh tissue samples during neoadjuvant chemotherapy.
Authors: Earl Helena Margaret , Chin Suet-Feung , Dunning Mark , Iddawela Mahesh , Rueda Oscar , Russell Roslin , Jones Linda , Vallier A-L , Hughes-Davies Luke , Abraham Jean , Chan Steve , Skene Anthony , Benstead Kim , Gallagher Christopher J. , Murray Nicholas , Ritchie Diana , Dunn Janet A. , Hiller Louise , Provenzano Elena , Caldas Carlos ,   Neo-tAnGo Investigators
Published: March 2020

1015

Background: Neo-tAnGo was an NCRI UK neoadjuvant breast cancer study testing the addition of gemcitabine to anthracycline and taxane-based treatment and also the sequencing of chemotherapy. In a translational substudy, sequential fresh tissue was analysed for PAM 50 subgroups. Methods: Neo-tAnGo recruited 831 patients. 162 patients were consented for Neo-tAnGo Science, for 3 additional fresh tissue samples to be taken at diagnosis (diag), mid-chemotherapy (CT) and end-CT. Standard methodology was used for PAM 50 subtyping. Results: Fresh tissue samples at diag were received from 123 patients (pts). 45 pts (37%) had 2 additional samples provided (at mid- and end-CT). 57 pts (46%) had 1 additional sample provided (34 at mid-CT, 23 at end-CT). PAM 50 subtyping at diag was as follows: 31 (25%) BASAL; 30 (24%) HER2; 39 (32%) LUM B; 13 (11%) LUM A; 10 (8%) NORMAL-like. Pathological complete response rates (pCR: no disease in breast or axillary nodes, n = 121 pts) differed between PAM 50 subtype at diag (p = 0.04): BASAL 11/31 (35%); HER2 8/30 (27%); LUM B 3/37 (8%); LUM A 1/13 (8%); NORMAL-like 3/10 (30%). Of the 94 pts who were not PAM50 NORMAL-like at diag and had 2+ samples, 42 (45%) ‘shifted to NORMAL-like’. This was associated with slightly higher pCR rates (24% vs 15% who didn’t ‘shift to NORMAL-like’, p = 0.44) and borderline significantly higher rates of pCR or minimal residual disease (MRD: <10% residual scattered tumour cells) (48% vs. 27% who didn’t ‘shift to NORMAL-like’, p = 0.06). In the 102 pts with 2+ samples, 58 pts (57%) showed a shift to a better prognosis PAM 50 subtype after CT (Group (Gp) 1), 37 (36%) showed no change (Gp 2) and 7 (7%) a shift to a worse prognosis subtype (Gp 3). pCR rates were 26% Gp1, 14% Gp2 and 0% Gp3 (p = 0.05). pCR/MRD rates were 48% Gp1, 22% Gp2 and 0% Gp3 (p = 0.001). Conclusions: PAM 50 subtype at diagnosis correlates with pCR to neoadjuvant chemotherapy. Shift to a better prognosis PAM 50 group during neoadjuvant chemotherapy was demonstrated in 57% of pts and was significantly correlated with higher pCR and pCR/MRD rates. Clinical trial information: 78234870.
Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer.
Authors: Somlo George , Frankel Paul Henry , Luu Thehang H. , Ma Cynthia , Arun Banu , Garcia Agustin , Cigler Tessa , Fleming Gini F. , Harvey Harold A. , Sparano Joseph A. , Nanda Rita , Chew Helen K. , Moynihan Timothy Jerome , Vahdat Linda T. , Goetz Matthew P. , Hurria Arti , Mortimer Joanne E. , Gandara David R. , Chen Alice P. , Weitzel Jeffrey N.
Published: March 2020

1024

Background: The combination of platinum agents and PARP inhibitors may benefit patients (pts) with BRCA-associated metastatic breast cancer (MBC). We report on the response and clinical benefit rates when combining the PARP inhibitor veliparib (V) and carboplatin (carb) in a phase I trial. Methods: BRCA carriers with MBC were eligible. Carb starting at an AUC of 6 was given IV in 21-day cycles (C) and V was given orally twice daily (BID) at dose levels (L) L1 through L5. Results: Twenty-eight pts (26 eligible) carrying BRCA1 (12) or BRCA2 (15), or both (1) mutations were accrued between June 2010 and June 2012. The median age (32-66) was 45 years. The number (#) of prior chemotherapy regimens given for MBC was 1 (0-5); 70% of BCs were ER+, and 7% were HER2+. The schema, dose limiting toxicities (DLT) during C 1, median # of Cs on trial, and maximum tolerated dose (MTD) are shown. There were 3 (12%) complete and 9 (35%) partial responses (PR). Unconfirmed PR or stable MBC (median duration: 8 months [6-10+]) were seen in 7 pts (27%); the clinical benefit rate was74%. The median progression-free survival (PFS) is 7.8 months (95% CI 7.3-9.5). The pt with Fallopian tube cancer had a CR. DLTs with C 1 were seen in 2/6 evaluable pts at L1 (1 pt w/grade 3 hyponatremia and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to de-escalation of carb. At L2, 1 pt had grade 4 PLT. At L5, 1 pt had grade 4 PLT, and 2 pts grade 3 PLT (1 pt also experienced grade 4 granulocytopenia [ANC]), defining the MTD at carb AUC 5 and V 150 mg BID (L4). Dose delays and/or dose adjustments due to grade ≥ 2 toxicities for ANC or PLT were seen during the first 3 Cs at L1 (100%), L2 (50 %), L3 (67%), L4 (83 %), and at L5 (67%). Conclusions: The combination of carb and V is active, and is associated with substantial clinical benefit rate and managable hematologic toxicities in BRCA carriers with MBC. Further definition of the role of V is warranted. [Table: see text]
NEOZOTAC: Efficacy results from a phase III randomized trial with neoadjuvant chemotherapy (TAC) with or without zoledronic acid for patients with HER2-negative large resectable or stage II or III breast cancer (BC)—A Dutch Breast Cancer Trialists’ Group (BOOG) study.
Authors: Charehbili Ayoub , van de Ven Saskia , Liefers Gerrit-Jan , Smit Vincent T. H. B. M. , Putter Hein , Heijns Joan Barbara , van Warmerdam Laurens , Kessels Lonneke , Dercksen Wouter , Pepels Manon J. , Maartense Eduard , Van Laarhoven Hanneke W. M. , Vriens Birgit , Wasser Martin N. , Hamdy Neveen A.T. , Meershoek – Klein Kranenbarg Elma , van Leeuwen-Stok Elise , Van De Velde Cornelis J. H. , Kroep Judith R. , Nortier J. W. R.
Published: March 2020

1028

Background: The role of bisphosphonates when added to the neoadjuvant treatment of BC in enhancing the efficacy of therapy is still unknown. Methods: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, Adriamycin and cyclophosphamide i.v.) CT followed by G-CSF on day 2 with or without ZA 4 mg i.v. ,q 3 weeks in patients (pts) with stage II/III, measurable, HER2-negative BC and absence of prior bisphosphonate usage. The primary endpoint is the pathologic complete response (pCR) rate in the resection specimen and positive lymph nodes. 228 pts are needed to show an improvement of the pCR rates from 17% to 34% in the experimental arm using a 5% significance level based on the two-sided Fisher’s exact test with a power of 80%. Randomization was done by using the Pocock’s minimisation technique stratified by cT, cN and estrogen receptor status. pCR rate was analyzed using the Cochran-Mantel-Haenszel test, adjusting for the stratification factors. Analysis was based on intent-to-treat. An unplanned subgroup analysis of postmenopausal women (PMW; FSH >20 and estradiol <110) and baseline vitamin D levels was performed. Results: From July 2010 to April 2012, 250 patients from 25 participating sites were randomized. Pathologic response data of 228 patients are currently available. pCR rate did not differ between the two study arms (17% vs 16%, p = 0.81). However, a trend in benefit in favor of ZA was observed in PMW (18% vs 11%, OR 1.90, 95% C.I. 0.52 – 6.88). Patients with severe vitamin D insufficiency (<25 nmol/L) seemed to respond worse to CT numerically (6% vs. 18%). At ASCO pCR and clinical response data of all patients will be reported. Conclusions: Previously, we have shown that adding ZA to neoadjuvant CT is safe with good compliance.In this study, treatment with ZA did not result in a pCR benefit in the total study population. However our findings suggest that addition of ZA to neoadjuvant CT might be effective for enhancing response in PMW with BC. Clinical trial information: NCT01099436.
The persistence of disseminated tumor cells after systemic therapy and their influence on prognosis in early breast cancer patients.
Authors: Hartkopf Andreas D. , Wallwiener Markus , Gruber Ines , Neubauer Hans , Hahn Markus , Wallwiener Diethelm , Taran Florin-Andrei , Fehm Tanja N.
Published: March 2020

1030

Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM) of early breast cancer (EBC) patients before the administration of systemic therapy is associated with poor outcome. The aim of this study was to evaluate the impact of DTC on overall survival (OS) and disease free survival (DFS) in a large cohort of EBC patients after the administration of systemic therapy. Methods: EBC patients receiving systemic therapy (endocrine therapy and/or chemotherapy +/- HER2-directed treatment) either prior to surgery (neoadjuvant systemic therapy, NST) or after surgery (adjuvant systemic therapy, AST) at Tuebingen University Hospital, Germany between 01/2003 and 06/2012 were available for this analysis. BM aspirates were collected during surgery / one year after surgery in patients receiving NST / AST. DTC were identified by immunocytochemistry (pancytokeratin antibody A45/B3) and cytomorphology. Survival was analyzed using univariate (log-rank test) and multivariate analysis (cox regression). Results: DTC were detected in 201 of 608 (35%) patients. 175 of 419 (42%) patients treated with NST and 35 of 189 (19%) patients treated with AST were DTC-positive. Chemotherapy / endocrine therapy was administered prior to BM aspiration in 399 (96%) / 19 (5%) of the patients receiving NST and in 99 (52%) / 158 (84%) of the patients receiving AST. On univariate analysis, the detection of DTC was a significant predictor of poor DFS (HR: 2.27, 95% CI: 1.48 – 3.48, p<0.001) and poor OS (HR: 1.89, 95% CI: 1.19 – 3.00, p=0.007). On multivariate analysis (considering all clinicopathological factors and the DTC-status), independent factors for DFS were DTC-status (negative vs. positive), grading (G2-3 vs. G3), nodal-status (negative vs. positive), and the ER-status (negative vs. positive). Independent factors for OS were grading, PR-status (negative vs. positive) and nodal-status. Conclusions: The persistence of DTC in the BM of EBC patients after systemic treatment is a strong and independent marker of poor prognosis. Determination of the DTC-status is thus promising to monitor the effect of systemic therapy and to identify patients that are in need of additional adjuvant therapy.
The effect of obesity on prognosis in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathologic subtypes.
Authors: Pollán Marina , Pajares Bella , Martin Miguel , Mackey John Robert , Lluch Ana , Gavila Joaquin , Vogel Charles L. , Ruiz Borrego Manuel , Calvo Lourdes , Pienkowski Tadeusz , Rodriguez-Lescure Alvaro , Seguí Miquel Angel , Tredan Olivier , Anton Antonio , Ramos Vazquez Manuel , Camara M Carmen , Rodriguez-Martin Cesar , Carrasco Eva Maria , Alba Emilio ,   Spanish Breast Cancer Research Group (GEICAM)
Published: March 2020

1031

Background: According to observational studies, obesity is an unfavourable prognostic factor in breast cancer (BC), regardless of menopausal status and treatment received. Information collected in clinical trials should confirm this effect and serves to test its homogeneity by pathologic subtype. Methods: We retrospectively analysed 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, 9805, 2003–02, and BCIRG 001) evaluating adjuvant anthracyclines and taxanes. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences by BC subtypes (ER/PR-positive/HER2-negative, HER2-positive, triple-negative). Cox models were fitted for each end-point, adjusted by potential confounders. Results: Analyses adjusting for age, tumor size, nodal status, menopausal status, surgery, grade, hormone receptor and HER2 status, chemotherapy regimen, and undertreatment showed that obese patients (BMI 30.0–34.9) had similar prognoses to that of patients with a BMI<25 (reference group) in terms of recurrence (HR 1.08 [95% CI 0.9–1.3]; p=0.41), BCM (HR 1.02 [0.81–1.29]; p=0.85), and OM (HR 0.97 [0.78–1.19]; p=0.747). Patients with severe obesity (BMI≥35) had a significantly increased risk of recurrence (HR 1.26 [1.00–1.59]; p=0.05), BCM (HR 1.32 [1.00–1.74]; p=0.05), and OM (HR 1.35 [1.06–1.71]; p=0.02) compared to our reference group (Table). The prognostic effect of severe obesity did not vary by subtype. Conclusions: Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with a BMI<25. The magnitude of the harmful effect of BMI was similar across subtypes. [Table: see text]
Increased expression of folate receptor-α (FRA) in triple-negative breast cancer: A potential therapeutic target.
Authors: Crozier Jennifer A. , Necela Brian M. , Thompson E Aubrey , Geiger Xochiquetzal , Moreno-Aspitia Alvaro , McCullough Ann E. , Pockaj Barbara A. , Cunliffe Heather , Sun Zhifu , Kalari Krishna R. , Kachergus Jennifer M. , O'Shannessy Daniel J. , Maltzman Julia D. , Ballman Karla V. , Andorfer Cathy A. , Perez Edith A.
Published: March 2020

1037

Background: Folate receptor alpha (FRA the product of the FOLR1 gene) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense expression of FRA in breast tumors and poor prognosis, yet little is known about FOLR1/FRA expression across clinically relevant breast cancer subtypes. Methods: 131 breast cancer tumors including 4 benign, 33 ER+, 26 HER2+, and 68 triple negative (TN) were constructed into tissue microarrays (TMAs). FRA expression was analyzed by immunohistochemistry (IHC) using a high affinity FRA antibody. Tumor membrane staining intensity was scored by a pathologist as negative (0), weak (1+), moderate (2+) and strong (3+). The percent of cells within each tissue core stained at each intensity was recorded to calculate an H-score. The H-score is a weighted score that captured both the proportion of positive staining and intensity for each tumor. H-score values can range from zero (no membrane staining) to a maximum of 300 (100% membrane staining at 3+). H-scores for each patient sample were averaged over 3 TMA cores. The mean H-scores for each tumor subtype and the percentage of 3+ staining in >30% of tumor cells were compared by a Mann-Whitney test. The distribution of FOLR1 mRNA was completed using a TCGA RNA-seq dataset from 691 breast tumors classified as ER+, HER2+ and TN. FOLR1 levels of TN versus ER+ and HER2+ were compared by a Mann-Whitney test. Results: The mean H-score for the benign tumors was 0, ER+ (13.31), HER2+ (39.36), TN (119.02). The median H-score for the benign tumors was 0, ER+ (0), HER2+ (7.5), TN (127.5). The TN tumors mean and median H scores were significantly higher than benign, ER+ or HER2+ (p<0.001). The largest percentage of 3+ staining in >30% of tumor cells was observed in TN tumors (36.7%) and lowest in ER+ tumors (0%) (p<0.001). TN tumors had significantly higher levels of FOLR1 mRNA compared to ER+ and HER2+ subtypes (p<0.0001). Conclusions: Our data indicate that expression of FRA is highly prevalent in TN tumors and is supported by FOLR1 mRNA levels. Anti-FRA therapy may represent an important therapeutic intervention in TNBC who to this point have no active targeted treatment options.
A phase III, open-label, randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes: Subgroup analyses.
Authors: Kaufman Peter Andrew , Cortes Javier , Awada Ahmad , Yelle Louise , Perez Edith A. , Wanders Jantien , Olivo Martin S. , He Yi , Dutcus Corina , Twelves Christopher
Published: March 2020

1049^

Background: This phase III study, comparing eribulin versus capecitabine, showed a non-significant trend for superior overall survival (OS; hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.77, 1.00]; p = 0.056) but not progression-free survival (PFS; HR 1.08 [95% CI 0.93, 1.25]; p = 0.31). Pre-specified exploratory subgroup analyses previously presented showed that patients with triple-negative, ER-negative or HER2-negative disease may have a greater benefit in OS with eribulin compared with capecitabine. Here we present further pre-specified exploratory analyses of OS and PFS. Methods: Patients (eribulin n=554; capecitabine n=548) with locally advanced or MBC had received ≤3 prior chemotherapy regimens (≤2 for advanced disease), including an anthracycline and a taxane. Patients were randomized (stratified for geographic region and HER2 status) 1:1 to 21-day cycles of eribulin mesylate 1.4 mg/m2 i.v. on days 1 and 8 or capecitabine 1.25 g/m2BID orally on days 1-14. Further pre-specified exploratory subgroups included: age; receptor status; number and setting of prior chemotherapy regimen(s); sites of disease; number of organs involved; and time to progression after last chemotherapy. Results: From analyses for OS, patients with only non-visceral disease (HR 0.51; 95% CI 0.33, 0.80), with >2 organs involved (HR 0.75; 95% CI 0.62, 0.90), who had progressed >6 months after last chemotherapy (HR 0.70; 95% CI 0.52, 0.95), or who had received an anthracycline and/or a taxane in the metastatic setting (HR 0.84; 95% CI 0.72, 0.98), appeared to benefit more from treatment with eribulin compared with capecitabine. For OS, in no subgroup was a trend favoring capecitabine seen. Data for other pre-specified subgroups for both OS and PFS will be presented. Conclusions: In addition to patients with triple-, ER-, or HER2-negative disease, further pre-specified exploratory analyses suggest that other patient subgroups may particularly benefit from treatment with eribulin; further studies are warranted to address these hypotheses. Clinical trial information: NCT00337103.
Phase III trial of nilotinib versus imatinib as first-line targeted therapy of advanced gastrointestinal stromal tumors (GIST).
Authors: Blay Jean-Yves , Shen Lin , Kang Yoon-Koo , Rutkowski Piotr , Qin Shukui , Nosov Dmitry , Novick Steven C. , Taningco Lilia , Mo Shuyuan , Reichardt Peter , Demetri George D.
Published: March 2020

10501^

Background: Nilotinib (N) is a Bcr-Abl, KIT, and PDGFR tyrosine kinase inhibitor. This Phase III trial compared N and imatinib (I) as first-line therapy of advanced GIST. Accrual was stopped when a futility boundary was crossed at interim analysis (IA). This final analysis of the core study examined the effect of mutation on outcomes. Methods: Patients (pts) with unresectable and/or metastatic GIST who had no prior antineoplastic therapy or had recurrence ≥6 months (mos) after adjuvant I were randomized 1:1 to open-label N 400 mg bid or I 400 mg qd (400 mg bid for KIT exon 9 mutants). The primary endpoint was progression-free survival (PFS) per adjudicated central review. Enrollment targeted 736 pts to observe 375 events, yielding 90% power to detect a hazard ratio (HR) of 0.71 (median, 28 [N] and 20 [I] mos) with two-sided 5% type I error. Prior to IA, crossover was allowed only for pts with progressive disease (PD); after IA, pts on N with or without PD were offered I. Results: At IA, the PFS HR for N vs I of >1.111 suggested a low probability of N superiority to I. Final analysis was performed in 644 pts; both PFS and OS favored I. In subgroup analysis of 401 pts who had mutational data, there was a large PFS difference favoring I in KIT exon 9 mutants, but similar PFS in KIT exon 11 mutants (Table). Based on immature data, OS favored I in all mutants. Conclusions: The IA showed N could not be superior to I for PFS in the overall population as first-line targeted therapy for pts with advanced GIST. PFS of N and I differed according to molecular subtypes, with PFSfavoring Iin KIT exon 9 mutants but roughly similar in exon 11 mutants. Clinical trial information: NCT00785785. [Table: see text]
Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS).
Authors: Chawla Sant P. , Blay Jean-Yves , Italiano Antoine , Gutierrez Martin , Le Cesne Axel , Gomez-Roca Carlos Alberto , Gouw Launce G. , von Mehren Margaret , Wagner Andrew , Maki Robert G. , Higgins Brian , Middleton Steven , Nichols Gwen L. , Geho David , Blotner Steven , Zhi Jianguo , Chen Lin Chi
Published: March 2020

10514

Background: Preclinical data demonstrate p53-dependent MIC-1 activation by both D and the MDM2 inhibitor RG7112. This study evaluated the tolerability of combining D with RG7112 in ASTS patients (pts) and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the combination. Methods: A phase 1b 3+3 dose escalation study was designed. Pts with ASTS in whom D was considered appropriate were eligible. D was administered IV at either 50 mg/m2 or 60 mg/m2on day 1 with RG7112 administered orally 500 or 1000 mg QD for 3 or 5 days (d1-3 or d1-5) in 28-d treatment cycles. Safety, PK and PD, including serum MIC-1 (an indicator of p53 activation), were assessed. Results: As of January 15, 2013, enrollment was complete with 23 pts with ASTS accrued; safety data for cycle 1 was available for preliminary review in 20 pts. Growth factor support was mandated following the first dosing group (D 60 mg/m2and RG7112 500 mg x 5d) due to febrile neutropenia or grade 4 neutropenia. Of the 20 pts for which cycle 1 safety data is available, 13 pts reported neutropenia (12 grade 3/4); 5 reported grade 3/4 febrile neutropenia (3 following mandatory GCSF prophylaxis); 12 pts developed thrombocytopenia (9 grade 3/4). PK parameters of the combination therapy are similar to single agent values and did not demonstrate evidence of drug-drug interactions. Serum MIC-1 rapidly increased to levels greater than for either agent alone. Best response to date is stable disease in 8/16 pts who have had interim evaluations. Conclusions: Combination therapy with D and RG7112 resulted in a high rate of grade 3/4 neutropenia (60%) or thrombocytopenia (45%). PK analysis does not suggest this is due to changes in the metabolism of either drug. This combination demonstrates apparent potentiation of p53 activation demonstrated by increased MIC-1 levels greater than additive effects of the single agents. Biomarker analyses, safety, PK, and MIC-1 data will be presented. Clinical trial information: NCT01605526. [Table: see text]
Gastrointestinal stromal tumor associated with neurofibromatosis type I.
Authors: Nishida Toshirou , Takahashi Tsuyoshi , Kaneda Mari , Ako Maiko , Omori Takeshi , Masuzawa Toru , Serada Satoshi , Naka Tetsuji , Tsujimoto Masahiko , Hirota Seiichi
Published: March 2020

10539

Background: Most gastrointestinal stromal tumors (GIST) have either KIT or PDGFRA mutations. Neurofibromatosis type 1 pts caused by mutations in the NF1 gene have increased risk of GIST development, which may have no mutation in both genes. In this study, we analyzed clinical and pathological features of NF-1 associated GISTs. Methods: Study 1: We have screened 95 adults NF1 pts (age 31-66, 35 male and 60 female) by enhanced MDCT between 2003 and 2012. Study 2: We collected 1,184 sporadic GISTs from community hospitals in Japan between 2001 and 2010 retrospectively, and found 24 primary NF1-GISTs (1.7% of sporadic) and 2 recurrent NF1-GISTs, of whom clinicopathological features were analyzed. Results: Study1: By MDCT screening, we have found histologically confirmed 6 GISTs (4 males and 2 female; 6/1,000 NF1-persons/year) in the small intestine. Median age of NF1-GIST was 45, and five pts had multiple tumors, ICC hyperplasia in the normal intestine and no mutation in the KIT and PDGFRA genes. Study 2: Median age of 26 NF1-GIST (12 male and 14 female) was 58. 25 GISTs were located in the small bowel and one in the stomach. 17 pts had multiple GISTs and 9 pts single lesion. Pathologically, KIT was positive for all NF1-GISTs. 24 pts had spindle cell tumors and 2 had mixed or epithelioid. No mutation was found in the KIT and PDGFRA genes of 11 pts examined. Median values of mitosis (0/50HPF) and Ki67 (0.5%) were lower than those of sporadic GIST (3/50HPF and 2.5%). With media follow-up of 3.6 years, 8 pts had recurrences and 4 pts died of the disease. By western blotting, KIT was faintly phosphorylated but its downstream kinases including MEK, p44/22, AKT, mTOR, p38 and STAT3, were activated. Six pts received imatinib and had no response and, subsequently, 5 pts received sunitinib with 4 PD and 1 short-term SD. Conclusions: NF1-associated GIST is a rare entity of GIST and has distinctive features from conventional sporadic GISTs. KIT-targeted TKI appeared to be ineffective to recurrent and advanced NF1-GISTs.
Preclinical studies with neratinib in triple-negative breast cancer.
Authors: Mullooly Maeve , O'Brien Neil A. , Conklin Dylan , Finn Richard S. , Slamon Dennis J. , Crown John , O'Donovan Norma , McGowan Patricia M. , Duffy Michael J.
Published: March 2020

1054

Background: Currently, one of the most urgent problems in breast cancer therapeutics is the validation of targeted therapy for triple-negative breast cancer (TNBC). Neratinib is an irreversible small molecule inhibitor that targets the kinase activity of EGFR, HER2 and HER4. As one of these targets, EGFR, is expressed at high levels in a subset of TNBC, we hypothesised that neratinib is a potential treatment for at least some patients with TNBC. Methods: The antiproliferative effects of neratinib were investigated in a panel of 35 breast cancer cells lines including 9 luminal, 12 HER2-positive and 14 triple-negative (TN). Baseline levels of total HER proteins were determined using flow cytometry. Results: IC50 values for neratinib across the panel of breast cancer cell lines ranged from < 0.001 - 1.9 µM. HER2-positive cell lines were significantly more sensitive to neratinib than HER2-negative cells (p = 0.008, Student’s t-test). For the 14 TN cell lines, IC50 values ranged from 0.03 – 1.9 µM. TN cell lines defined as basal-type A were significantly more sensitive to neratinib than those designated basal-type B (p = 0.02, Student’s t-test). Treatment with neratinib resulted in a reduction in HER-family signalling as detected by decreased Akt and ERK phosphorylation. Consistent with the finding that basal type A TN cells were more sensitive to neratinib than type B, significantly higher levels of EGFR expression were found in the A subtype compared to the B subtype (p = 0.02, Student’s t-test). To determine a possible predictive marker of response for neratinib, levels of all 4 HER proteins were related to response in the basal A subgroup. Baseline levels of HER3 expression were found to correlate significantly with response to neratinib (p = 0.02, r = -0.875, n = 7, Spearman), i.e., cell lines with the highest levels of HER3 expression had the lowest IC50values within this cohort. Conclusions: Our results suggest that neratinib is a potential novel therapeutic option for patients with basal A type triple negative breast cancer. HER3 may act as a predictive marker of response for this subgroup of patients. Acknowledgements: The authors thank SFI for funding MTCI (SRC award, 08/SRC/B1410 to MTCI) and an SFI Short Term Travel Fellowship to MM, for funding this work.
Genome study of PDGFRA D842V mutant GIST using next generation sequencing approach.
Authors: Pantaleo Maria A. , Astolfi Annalisa , Urbini Milena , Indio Valentina , Nannini Margherita , Saponara Maristella , Lolli Cristian , Pallotti Maria Caterina , Mandrioli Anna , Gatto Lidia , Biasco Guido
Published: March 2020

10540

Background: Mutations of the receptors KIT and PDGFRA in GIST are the oncogenetic events of disease as well as the targets of molecular therapies. Within the PDGFRA mutations, the D842V mutation in exon 18 confers in vitro and in vivo resistance to imatinib. Next generation sequencing techniques may completely dissect all the possible somatic mutations and genomic rearrangements in order to identify novel therapeutic targets in this patients population. Methods: Five patients with gastric GIST were analyased (3 M, 2 F; mean age 65,5 years, range 51-77). The tumor dimension ranged between 3 and 15 cm, MI < 2 and 8 /50 HPF. No metastases were present in all cases. The KIT and PDGFRA anlysis showed a D842V mutation in exon 18 of PDGFRA in all cases. Whole transcriptome sequencing was performed with Illumina HiScanSQ platform with a paired-end strategy (75x2). After performing quality controls, the short reads were mapped with Tophat-Botie pipeline against the human reference genome (HG19). The variations, such as Single nucleotide variants (SNVs) and InDels, were called by SNVMix2 (a software suited for SNVs discovery in tumor samples) implementing an accurate filtering procedures developed in our laboratory. Two predictors of mutations effect at protein level (SNPs&GO and Provean) were employed in order to prioritize the emerging variation. Results: An average of 206 coding non-synonymous variants were highlighted in the five GIST samples, of which ~ 30% were predicted as deleterious with at least one predictor. In addition to PDGFRA D842V mutation, in all five patients were found mutations on different receptor tyrosine kinases, such as FGFR4 and DDR2. Moreover three out of five patients harboured mutations on members of the MDR/TAP subfamily that are involved in multidrug resistance, in particular on ABCB1, ABCB4 and on ABCB6 genes. Other mutations were found on the hedgehog and MAPK signaling pathway and on SNF/SWI chromatin remodeling complex. Conclusions: New molecular events have been identified in PDGFRA D842V mutant GIST. These data should be validated in larger series and the role of these mutations as therapeutic targets should be further investigated.
Long-term responders and survivors on pazopanib for soft tissue sarcomas (STS): Subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072.
Authors: Kasper Bernd , Litière Saskia , Marreaud Sandrine , Sleijfer Stefan , Verweij Jaap , Bauer Sebastian , Kerst Jan M. , Van Der Graaf Winette T.A.
Published: March 2020

10553

Background: Pazopanib has recently received approval in US, EU & Japan for use in certain STS subtypes. We conducted a retrospective analysis on pooled data from two EORTC clinical trials on pazopanib in STS in order to characterize long term responders and survivors. Methods: Patients selected for analysis were treated with pazopanib in phase II study 62043 (n = 142) and phase III study 62072 (PALETTE) (n = 246). Combined median progression-free survival (PFS) was 4.0 months; median overall survival (OS) was 11.3 months. 34 % of patients had a PFS ≥ 6 months (n = 133) and were defined as long term responders; 33 % of patients survived ≥ 18 months (n = 128), defined as long term survivors. Following patient characteristics were studied: gender, age, performance status, tumor localization, histology, grading, treatment exposure and dose modifications, severity of adverse events and post protocol therapy. Results: Clinical cut-off dates for this analysis resulted in a pooled database with a median follow-up of 2.3 years. Patient characteristics were compared between four subgroups based on short / long term PFS and OS, respectively. 79 patients were both long term responders and long term survivors. The descriptive analysis confirmed the importance of known prognostic factors such as age, performance status and grading, but did not add additional characteristics translating into long term response or survival. We identified 12 patients remaining on pazopanib for more than two years: 9 aged younger than 55 years, 9 females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. Only two of those patients achieved a partial response; the remaining 10 experienced stable disease as best overall response. Median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. Four patients were still on pazopanib at the end of the studies with a median PFS of 2.3 years and a median OS of 2.8 years. Conclusions: 34 % and 33 % of STS patients given pazopanib in these studies have a long PFS and / or OS respectively. 3.1 % of patients demonstrate a clinical benefit even beyond 2 years.