bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of local control strategies in patients with localized Ewing sarcoma of bone: A report from the Children’s Oncology Group.
Authors: DuBois Steven G. , Krailo Mark D. , Gebhardt Mark C. , Donaldson Sarah S. , Marcus Karen Chayt , Dormans John P. , Shamberger Robert C. , Sailer Scott Lee , Nicholas Richard W. , Healey John H. , Tarbell Nancy , Devidas Meenakshi , Meyer James S. , Granowetter Linda , Womer Richard , Bernstein Mark L. , Marina Neyssa , Grier Holcombe E.
Published: March 2020

9537

Background: Patients (pts) with Ewing sarcoma (EWS) require local control, either with surgery alone (S), radiation alone (R), or a combination of surgery + radiation (S+R). Optimal choice of local control for disease control remains unclear. Our primary aim was to determine the mode of local control associated with the highest event-free survival (EFS). Methods: Pts with localized EWS of bone treated on INT0091, INT0154, or AEWS0031 phase III trials were included if they had complete local control data, did not have cranial tumors, received local control starting 2-6 months after enrollment, and were randomized to receive standard dose 5-drug chemotherapy every 3 weeks. We used propensity scores to control for differences in age, tumor site, and year of diagnosis between local control groups. We constructed Cox models controlling for local control propensity scores to assess the impact of local control type on EFS and overall survival (OS) from the start of local control. Results: 465 pts were included. Pts selected for S were treated more recently (p < 0.001), more likely to have appendicular tumors (p < 0.001), and younger (p = 0.02). Pts treated with R, compared to S, had higher unadjusted risk of any event (HR 1.70; 95% CI 1.18 - 2.44; p = 0.004) or death (HR 1.84; 95% CI 1.18 – 2.85; p = 0.006). Pts treated with S+R, compared to S, had higher unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p = 0.02). After adjusting for propensity scores, there was a trend of higher risk of any event for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p = 0.10) compared to S, though this was not statistically significant. No other differences in adjusted risk of event or death between local control groups were statistically significant. We confirmed these results with standard Cox models using age, tumor site, and year of diagnosis as covariates. Conclusions: In this large group of uniformly treated pts, investigator choice of local control approach was not significantly related to EFS. These data support current practice of surgical resection when feasible, while validating radiotherapy as a reasonable alternative in selected pts.
Phase I trial of temsirolimus (TEM), irinotecan (IRN), and temozolomide (TMZ) in children with refractory solid tumors: A Children's Oncology Group study.
Authors: Bagatell Rochelle , Norris Robin Elizabeth , Ingle Ashish M , Ahern Charlotte H , Saggio Jennifer , Little Anthony , Weigel Brenda , Blaney Susan
Published: March 2020

9540

Background: Inhibitors of mTOR have demonstrated activity in preclinical pediatric solid tumor models. A phase I trial to define the dose limiting toxicities (DLTs) associated with the mTOR inhibitor TEM in combination with IRN and TMZ was conducted in patients (pts) with refractory solid tumors. Methods: Escalating doses of TEM were administered intravenously on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50 mg/m2/dose) was administered orally on d1-5. TMZ (100 mg/m2/dose) was administered orally on d1-5. When the maximum planned dose of TEM was reached (35 mg/m2/dose), IRN was escalated stepwise from 50 to 90 mg/m2/dose. Pts were enrolled on 6 dose levels using the rolling-six design. Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma (4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other (8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered. Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose level 3 (TEM 25 mg/m2, IRN 50 mg/m2, TMZ 100 mg/m2); both pts were on chronic corticosteroids. The protocol was amended to preclude chronic systemic steroid use and modify hyperlipidemia management. Dose-limiting hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT (elevated GGT) was observed in 1 pt treated with TEM 35 mg/m2, IRN 65 mg/m2, TMZ 100 mg/m2. DLT has not been observed in 4 of the first 6 pts treated at the highest planned dose level (TEM 35 mg/m2, IRN 90 mg/m2, TMZ 100 mg/m2). Additional ≥Grade 3 regimen-related toxicities occurring in >1 evaluable pt include neutropenia (12), lymphopenia (10), leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5), hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases (2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1 pt had a confirmed partial response and 4 have remained on protocol therapy for ≥1 year. Conclusions: The combination of TEM (35 mg/m2/dose) d 1 and 8, IRN (90 mg/m2/dose) d 1-5, and TMZ (100 mg/m2/dose) d 1-5 of a 21-d cycle appears to be well tolerated in children with refractory solid tumors.
Trends in body mass index (BMI) during and after treatment for standard risk (SR) acute lymphoblastic leukemia (ALL): A report from the Children’s Oncology Group (COG).
Authors: Lindemulder Susan Joy , Stork Linda C. , Bostrom Bruce C. , Lu Xiaomin , Devidas Meenakshi , Neglia Joseph Philip , Kadan-Lottick Nina
Published: March 2020

9546

Background: Obesity is a potential complication in children treated for ALL. Limited data exist regarding timing of BMI changes and risk in long-term survivors of ALL treated without cranial radiation (CRT). This study describes temporal trends in BMI during and after therapy for SR-ALL and identifies associated factors. Methods: We conducted a retrospective cohort study of children with SR-ALL enrolled on two sequential clinical trials between 1993 and 2000 and on the COG ALTE02C2 follow-up study. Therapy included prednisone or dexamethasone during induction, the same steroid in maintenance phases, and no CRT. Standing height and weight was ascertained at diagnosis (dx), start of consolidation, start of maintenance, start of the last cycle of maintenance, and at least one year off therapy. Age and gender-specific BMI percentiles (BMI%) were calculated using 2000 CDC growth charts for patients 2-20 years. Results: The 269 subjects were a median of 3.5 years at dx, 46.7% female, 82.3% white, and a median of 9.1 years since dx at the last timepoint. The BMI% was associated with elapsed time since dx: BMI% increased between dx and consolidation (50.9%-68.3%, p < 0.0001), remained stably elevated until the end of maintenance, and then decreased somewhat from the end of maintenance to the last timepoint (74.1%-70.6%, p = 0.03). After therapy, 18.1% of survivors were overweight (BMI% 85-95) and 20.9% were obese (BMI% ≥ 95). By unadjusted linear regression, higher dx BMI% was positively associated with BMI% post-therapy (p < 0.0001). There was an interaction with steroid and dx BMI% such that the association between dx BMI% and post therapy BMI% was significantly greater for the dexamethasone group than the prednisone group (p = 0.01). There was no association with age at dx, gender, or race. Conclusions: In this retrospective study of SR-ALL survivors treated without CRT, we found that BMI% increased significantly in the month after dx and remained substantially elevated even several years after the end of therapy. Dx BMI% was highly associated with off-therapy BMI%, particularly in patients who had received dexamethasone rather than prednisone.
Pharmacokinetics (PK) of bendamustine in pediatric patients with relapsed/refractory acute leukemia.
Authors: Darwish Mona , Megason Gail C. , Bond Mary , Hellriegel Edward , Robertson Philmore , Clementi Regina , Phillips Luann , Grasela Thaddeus , Fraser Christopher
Published: March 2020

9547

Background: The PK profile of bendamustine in adult patients is well characterized. The objective of this analysis was to describe the pediatric PK profile of bendamustine relative to the adult PK profile and correlate the systemic exposure of bendamustine to efficacy and safety parameters. Methods: Samples were obtained after a single dose from patients aged 1-19 years with relapsed/refractory acute leukemia who were enrolled in an open-label, nonrandomized study of bendamustine (90–120 mg/m2, infused over 60 minutes). Samples were obtained prior to bendamustine infusion and preselected time points through 24 hours after start of infusion on day 1. Population PK modeling was performed using plasma concentration data from these patients. PK data from adults were used for comparison. Results: Systemic exposure of pediatric patients to bendamustine was similar to that obtained previously in adult patients. Mean Cmax was 6806 ng/mL and mean AUC0-24 was 8240 ng*hr/mL in pediatric patients, compared with a mean Cmax of 5746 ng/mL and AUC0-24 of 7121 ng*hr/mL in adults. Similarity in exposure despite the large range of body surface area across the pediatric and adult populations confirms appropriateness of the body surface area–based dosing scheme. In pediatric patients, age, race, sex, or disease state had no statistically significant effect on systemic exposure to bendamustine. No changes in systemic exposure to bendamustine in the presence of a CYP1A2 inhibitor/inducer were observed. Differences in PK were not observed in pediatric patients with mild renal impairment as compared with patients with normal renal function. Exposure in 2 pediatric patients with moderate hepatic dysfunction appeared to be higher. No clear exposure-response relationship was observed. Infection was the only adverse event for which the probability of occurrence increased with increase in exposure to bendamustine. Conclusions: The PK profile of bendamustine in pediatric patients was similar to the known PK profile in adults, demonstrating that exposures reflective of the therapeutic range in adults were attained following administration of 120 mg/m2 to pediatric patients. Support: Teva Pharmaceutical Industries Ltd., Frazer, PA.
Diagnostic and treatment challenges of adolescent and young adult oncology patients.
Authors: Xu Yanqing , Cardoso Mauro , Palumbo Michael Ostaric , Ishibashi Olivia , Kavan Petr
Published: March 2020

9557

Background: Adolescent and young adult (AYA) cancer patients are faced with obstacles and challenges related to their diagnosis and treatment compared to children and older adults. The aim of this study was to explore the patient and health care system-related delays in the interval from cancer symptom onset to diagnosis and treatment as well as to identify the possible contributing factors to these delays in the AYA group. Methods: This study was based on a questionnaire conducted in 2010-2011 completed by patients diagnosed with a malignancy between the ages of 16 and 39 in addition to older patients diagnosed with a pediatric type malignancy. Four categories of delays: patient delay (time from patient symptom onset until first health care contact date), health care system delay (time from first health care contact until diagnosis date), treatment delay (time from diagnosis date until first treatment) and oncologist delay (time from first health care contact until first medical oncologist meeting) were calculated. Median delay (in days) with interquartile interval (IQI) was the main outcome measure. Median time for each category of delay was further analysed to explore how they vary with different patient characteristics. Results: We identified a median patient delay of 30 days (IQI 1-131), a median health care system delay of 53 days (IQI 1-213), a median treatment delay of 36 days (IQI 5-92) and a median oncologist delay of 77 days (IQI 30-281). Patient delay was affected by patient gender, age at diagnosis and type of first health care contact. Health care system delay was associated with patient marital status, financial situation and attitude of first health care professional. Treatment delay was related to type of cancer. Conclusions: The health care system delay (including oncologist delay) accounts for much of the delay from symptom onset to first treatment. Professional characteristics of frontline medical personnel as well as socioeconomic and biological characteristics of the patients may contribute to delay. Healthcare professionals and the general community as a whole need to be aware of the factors contributing to delay in diagnosis and treatment in the underserved patient population.
Mitigating smoothened inhibitor-induced growth plate closure with parathyroid hormone.
Authors: Timsit Yoav E , Gunson Diane E , Krucker Thomas , Markovits Judit E , Buonamici Silvia , Boral Anthony , Amakye Dereck Dokyi , Nelson Aaron L , Pognan Francois , Chibout Salah-Dine , Turner Nancy A ,   Novartis Institutes for BioMedical Research Inc.
Published: March 2020

9562

Background: The Hedgehog pathway plays an important role in regulating growth plate patency by activating PTH/PTHrP signaling, and loss of PTH/PTHrP signaling is an expected pharmacological effect of smoothened (Smo) inhibition. LDE225, a Smo inhibitor currently in phase I/II trials for the treatment of basal cell carcinoma (BCC) and medulloblastoma (MB), causes closure of the epiphyseal (growth) plate in rodents and dogs. As a therapeutic strategy to mitigate these effects, we investigated whether administration of human parathyroid hormone (PTH amino acids 1-34 or PTH1-34) could prevent premature growth plate closure caused by LDE225. Methods: Oral LDE225 was given once daily to rapidly growing male rats (starting at 4 or 6 weeks of age) in combination with hPTH1-34 administered subcutaneously as a continuous infusion (to mimic signaling by locally-produced PTHrP) or as once-daily injections. Femur and tibial growth plates were scanned by microCT and growth plate volumes were calculated. Growth plates were also assessed histologically. Results: Continuous delivery of hPTH1-34 provided the greatest effect for maintaining patent growth plates compared to once-daily subcutaneous injections. However, the dose of continuous hPTH1-34 giving the greatest protection was not well-tolerated beyond 1 week due to PTH-induced hyperparathyroidism, confirmed by clinical chemistry and histological assessment. Reduction in the dose of continuous hPTH1-34 improved tolerability, but provided less protection to the growth plate. Once-daily hPTH1-34 injection for two weeks was well-tolerated, with anabolic effects clearly observed by histology and microCT. The extent of closure in animals co-treated with LDE225 and once-daily hPTH1-34 injections was less compared to that caused by LDE225 treatment alone. Conclusions: As shown in this preclinical model, hPTH1-34 administration mitigates LDE225-induced growth plate closure. Although hPTH1-34 shows promise experimentally, current use is restricted in pediatric patients and further study will be needed before considering hPTH1-34 treatment concurrent with LDE225 therapy in children or adolescents.
Cell cycle and apoptosis regulatory protein (CARP)-1 expression in neuroblastoma.
Authors: Hanmod Santosh S. , Siegel Samantha , Hatfield James , Levi Edi , Zidan Marwan , Rabah Raja , Ravindranath Yaddanapudi , Rishi Arun K , Wang Zhihong Joanne
Published: March 2020

9578

Background: Neuroblastoma (NB) is the most common extra-cranial solid tumor in children. The prognosis for patients with high risk NB is still poor. Study of additional prognostic factors will enhance current understanding of the tumor biology and risk stratification. CARP-1 is a recently identified molecule mediating apoptosis signaling by agents like doxorubicin and etoposide. Since these agents are used in the front line treatment of NB, we tested whether CARP-1 expression could be another prognostic factor in NB. Methods: CARP-1 expression was examined by Western blot in a pair of NB cell lines, SK-N-SH and SK-N-SH Dox. We reviewed medical records of patients with NB at Children’s Hospital of Michigan from 2000-2009 and examined CARP-1 expression by immune-histochemistry in the archived, formalin fixed paraffin embedded NB tissues. CARP-1 expression was recorded as positive or negative. Correlation of CARP-1 expression and progression free survival (PFS) was calculated. Results: CARP-1 expression was detected in SK-N-SH but not SK-N-SH Dox, a doxorubicin-resistant derivative of SK-N-SH, suggesting that resistance to doxorubicin is associated with decreased level of CARP-1 expression in NB cells. Of the 30 cases studied, 53 % (16/30) expressed CARP-1. There was no significant difference in N-myc amplification status (13% vs.14%, p=0.3), or proportion of unfavorable Shimada histology (60% vs. 64%, p=0.5) between CARP-1 positive vs. negative groups. Twenty three percent (7/22) patients progressed or relapsed, including 2/16 (13%) in CARP-1 positive group vs. 5/14 (36%) in CARP-1 negative group (p=0.1). There was no significant difference in the PFS at 1 year (94% vs.79%, p=0.2) and 3 year (86% vs.71%, p=0.2) between CARP-1 positive vs. negative groups. Conclusions: CARP-1 expression was decreased in doxorubicin resistant NB cell line. CARP-1 expression was detected in approximately half (53%) of NB tumors. Patients with NB who expressed CARP-1 showed trend towards better 1- & 3-year PFS as compared to those who did not express CARP-1, however, the results are not statistically significant which could be due to the small sample size. Further study with a larger number of patients is warranted to clarify these findings.
Assessment of peripheral blood T regulatory cells (Tregs) in PNET/Ewing sarcoma: A prospective study.
Authors: Tvsvgk Tilak , Sharawat Surender Kumar , Gupta Ritu , Agarwala Sandeep , Khan Shah Alam , Rastogi Shishir , Vishnubhatla Sreenivas , Bakhshi Sameer
Published: March 2020

9580

Background: Tregs in bone marrow have been previously evaluated in PNET patients; however, data on peripheral blood ccirculating Tregs is lacking. The objective of our study was to determine baseline Treg frequency in PNET patients and correlate the same with patient characteristics and outcome. Methods: Samples of 5ml venous blood were obtained from 38 newly diagnosed PNET patients at diagnosis along with six healthy controls. Flow cytometric analysis was done for detecting Treg cells [CD4+CD25+FoxP3+]. Results: Thirty-eight patients with median age 17 years; male/female ratio of 5.5:1 had significantly higher baseline Tregs than healthy controls [9.17%±.3.08 vs 3.16±1.49%; p=<0.0001]. Eight patients (21.1%) had fever at baseline presentation. The disease was extra-skeletal in one and metastatic at baseline in 11 (28.9%) patients. Ten patients relapsed on standard protocol of therapy and seven died. The median Treg frequency was 8.84% (Range: 2.49-16.31). When the Tregs were categorized as high and low based on the median value, patients with fever had a significantly higher Tregs than those without fever [11.3%±.3.5% vs 8.6% ±. 2.7%; p=0.02]. No significant association of peripheral blood Treg cells frequency was noted with other factors like age, sex, metastatic disease, relapse or death. The EFS was 55% and OS 70% of the entire cohort at a median follow up of 14 months. There was no significant difference in the EFS or OS between the high and low Treg cell groups [EFS- 52% vs 64%; p=0.99 and OS-75% vs 70%; p=0.26]. Conclusions: This is the first study on circulating Tregs in PNET, and it shows that the peripheral blood Treg frequencies are higher in these patients as compared to healthy controls. Further, PNET patients with fever had significantly higher Treg frequency. However, Tregs did not differ with respect to metastatic disease at presentation, EFS or OS.
Trends in survival of childhood solid tumors diagnosed 1985-2008 in the Nordic countries.
Authors: Cvancarova Milada , Jonsson Olafur G. , Schroder Henrik , Perkkio Mikko , Gustafsson Goran , Wesenberg Finn ,   Nordic Society of Paedric Haematology and Oncology
Published: March 2020

9590

Background: Classification of childhood solid tumors differs greatly from tumors diagnosed in adults. Thus establishment of childhood cancer registries is essential to monitor changes and progress in cancer care. Methods: All individuals born in the Nordic countries are allocated a unique ID number and have access to comprehensive health care services. Further, it is required by law that all new cases of cancer are reported to cancer registries. This makes it possible to achieve almost complete registration of all cancer cases and their status together with information regarding the cancer tumour and its treatment. Status registrations were made partly from national population registries and partly from death registries only, as conditions differ between countries. Crude survival was modelled using the Kaplan-Meier method stratified by selected diagnostic groups, age groups and diagnostic period. The crude estimates were compared with log-rank tests. Results: In total, 12,343 children <15 yrs of age were diagnosed with cancer during 1986-2010 in the Nordic regions (Denmark, Finland, Iceland, Norway, Sweden) and classified according to Birch & Marsden classification. Data were collected at the NOPHO solid tumour registry located at the Cancer Registry of Norway. The overall incidence for the whole period was 11.2 per 100,000 children per year. The overall 5-year survival for all solid tumours reached 80.0 %, 95% CI [79.3 to 80.7] %. There was a significant increase in survival for those diagnosed after 1991, p < 0.001. Children diagnosed when older than 10 years reached higher 5-yrs survival than those diagnosed <5 yrs, 82.4% and 78.3%, respectively. The highest 5-yrs survival was seen for retinoblastoma (97.0%), germ.cell neoplasm (90.8%), renal tumours (88.3%) and lymphomas (88.2%). The lowest 5-yrs survival was observed for sympathetic nervous system (65.4%). The highest increase in survival was seen for non-Hodgkin lymphoma pts, 77.2% diagnosed 1986-1990 vs. 85.9% diagnosed 2001-05. Conclusions: There has been some improvement in survival in recent time periods, especially for some diagnoses. However, there were no changes in overall survival wrt sex and only very limited changes in overall survival by age groups.
Bleomycin-associated lung toxicity in childhood cancer survivors.
Authors: Zorzi Alexandra Patricia , Yang Connie L , Dell Sharon , Nathan Paul C.
Published: March 2020

9591

Background: Bleomycin has been established as a pulmonary toxin, but the risk for toxicity in survivors of childhood cancer is poorly characterized. Methods: We conducted a cross-sectional study of lung function in survivors of childhood Hodgkin lymphoma and germ cell tumor treated with bleomycin at our institution between 1997 and 2010. We assessed their most recent post-therapy pulmonary function test (PFT). Spirometry and lung volumes were categorized as normal, restrictive, obstructive or mixed. Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or abnormal. Results: 195 patients were treated with bleomycin. Ten died of non-pulmonary causes. Of 185 survivors, 143 (77%) had complete data available for analysis. Median cumulative bleomycin dose was 60U/m2 (IQR 30-60). Three patients (2%) had a history of acute bleomycin toxicity. PFTs were performed a median of 2.3 years (IQR 1.4-4.9) from completion of therapy. Spirometry was abnormal in 58 patients (41%); of whom 5 (9%) had respiratory symptoms. 42 (70%) had obstructive, 11 (18%) restrictive and 5 (9%) mixed ventilatory defects. Abnormalities were mild in 53 (91%), moderate in 3 (5%) and severe in 2 (4%). DLCO was abnormal in 27 patients, 26 (96%) of whom had mildly reduced DLCO and were asymptomatic. Univariate analysis did not demonstrate a significant association between gender, smoking, lung metastases, lung radiation, chemotherapy regimen, or autologous transplant and abnormal lung function. Disease relapse was associated with abnormal lung function (p=0.01). Smoking (p=0.04) and relapse (p=0.03) were associated with abnormal DLCO. The odds ratio of developing abnormal spirometry for each 1unit/m2 increase in bleomycin was 1.01 (95% CI 1.00-1.02, p=0.07). Conclusions: Childhood cancer survivors treated with bleomycin frequently have evidence of asymptomatic abnormalities on PFT. The current recommendation for pulmonary function testing in childhood cancer survivors appears justified.
CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC).
Authors: Rugo Hope S. , Barry William Thomas , Moreno-Aspitia Alvaro , Lyss Alan P. , Cirrincione Constance , Mayer Erica L. , Naughton Michael , Layman Rachel M. , Carey Lisa A. , Somer Robert A. , Perez Edith A. , Hudis Clifford , Winer Eric P.
Published: March 2020

CRA1002

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Regional screening network for characterization of the molecular epidemiology of non-small cell lung cancer (NSCLC) and implementation of personalized treatment.
Authors: Zander Thomas , Heukamp Lukas Carl , Bos Marc Christiaan Allardt , Fassunke Jana , Mattonet Christian , Merkelbach-Bruse Sabine , Ko Yon-Dschun , Schlesinger Andreas , Brockmann Michael , Serke Monika , Gerigk Ulrich , Hekmat Khosro , Engel-Riedel Walburga , Stoelben Erich , Reiser Marcel , Schulz Holger , Schmitz Stephan H. , Frank Konrad , Buettner Reinhard , Wolf Juergen
Published: March 2020

CRA10529

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Patterns of decision making about cancer clinical trial participation among the online cancer treatment community: A collaboration between SWOG and NexCura.
Authors: Unger Joseph M , Hershman Dawn L. , Burg Kenda , Moinpour Carol , Albain Kathy S. , Petersen Judith A. , Crowley John
Published: March 2020

CRA6009

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News
Discordance between Oncotype Dx and Saint Gallen criteria, Adjuvant!, NCCN 2011 guidelines, and initial physician treatment recommendation.
Authors: Pereira Allan Andresson Lima , Santini Fernando Costa , Shimada Andrea Kazumi , Nascimento Ellen Caroline , Katz Artur , Mano Max S.
Published: March 2020

e11014

Background: The Oncotype Dx recurrence score (RS) assay quantifies the risk of distant recurrence (rDR) and its use has increased despite the lack of prospective studies. Methods: This is a cross sectional retrospective study of consecutive patients (PTS) from our institution with histologically confirmed invasive breast cancer who underwent surgery with curative intent and in whom Oncotype was performed. The main objectives were to compare (1) the predicted rDR by RS and Adjuvant! (2) Risk allocation by RS and St Gallen Criteria, (3) chemotherapy indication according to RS results and NCCN guidelines and (4) to evaluate the impact of RS results on the recommendation of adjuvant chemotherapy (aCT). Results: Between October/2006-June/2011, 74 PTS were evaluated. Forty seven (63,5%) were EC IA and all had estrogen receptor positive; axillary lymph node involvement was seen in 19 PTS (13 micro and 6 macrometastasis). The rDR by RS was low in 50 PTS (67%), intermediate in 19 (26%) and high in 5 (7%). According to Saint Gallen, 7 (9%), 51 (69%) and 14 PTS (19%) were classified as low, intermediate and high risk, respectively. There was a statistical significant discordance between risk allocation according to RS and Saint Gallen (Kappa coefficient=-0.002; p=0.971). Among the 55 node-negative PTS, there was also a statistical significant discordance between the predicted average rDR, obtained from Oncotype, and Adjuvant! with median risk of 8,5% vs 15,7%, respectively (p = 0.00001 rank sum Mann Whitney test). The NCCN 2011 would have indicated aCT to 62 PTS. Among 55 classified as low and high risk by RS, the NCCN would have indicated aCT to 46 PTS. In other words, 89% (41) of PTS who would receive aCT by NCCN were classified as low risk by RS, with a statistically significant discordance (Kappa coefficient=0.035, p=0.328). Conclusions: Oncotype changed the medical management in 28 (55%) of 51 PTS in which the initial intention of the physician was known. Of these, 93% were spared aCT. We found no statistical significant concordance among the Saint Gallen, Adjuvant! or NCCN guidelines with Oncotype Dx. The rDR may be overestimated by clinicopathological-based classifications.
Impact of obesity in postmenopausal early breast cancer patients receiving frontline adjuvant aromatase inhibitors.
Authors: Sahin Ugur , Petekkaya Ibrahim , Arslan Cagatay , Sarici Saim Furkan , Solak Mustafa , Keskin Özge , Ozisik Yavuz Yasin , Altundag Kadri
Published: March 2020

e11020

Background: Aromatase inhibitors (AIs), anastrozole (ANA) and letrozole (LET), have been shown to be more effective than tamoxifen in the adjuvant treatment of postmenopausal hormone receptor positive breast cancer. However, data from preclinical studies and subgroup analyses of some major clinical trials suggest differring efficacy among AIs. Yet the best clinical choice is still not very clear. This retrospective study aims at comparing the results of treatment with either AI among different subgroups of patients, especially among the obese patients. Methods: Between 2006-2011, 335 women with stage I to IIIC hormone receptor positive postmenopausal breast cancer treated with either ANA or LET as adjuvant treatment were included. Body mass index (BMI), estrogen and progesterone receptor (ER and PR) and HER-2 status at the time of diagnosis were recorded. Patients were grouped as BMI ≤ 30 and BMI > 30. The Kaplan-Meier survival estimates were calculated. Subgroups were compared with the log rank test. A 5 % type-I error was used to infer statistical significance. Results: The percentage of patients receiving ANA or LET were 47.2% and 57.8%, respectively. Median age at diagnosis was 58 (42-84) and lower in the ANA group (p=0.04). Stage II to IIIC disease was present in 76.8 % and the distribution was similar between ANA and LET (p=0.84). Median time of follow-up was 29 months (6-124) and median duration of hormonotherapy was 29 months (3-68) and similar between two groups (p=0.52 and p=0.55, respectively). Of the patients 41.2 % had a BMI of > 30. There was no significant difference in overall (OS) and progression-free (PFS) survivals between ANA and LET (p=0.08 and p=0.94, respectively). However, among patients with a BMI of > 30 a statistically insignificant benefit in PFS was observed with LET (p=0.1). ER, PR and HER2 status had no significant impact on OS and PFS. Conclusions: In a median follow-up of 29 months letrozole and anastrozole yielded similar OS and PFS. However, among patients with a BMI of > 30, LET might bring about a PFS advantage. In selected obese patients LET might be a reasonable choice in this setting. Larger studies with long term follow-up are needed to reach an exact conclusion.
Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline and taxen-based chemotherapy.
Authors: Wang Jiayu , Xu Binghe , Li Qing , Yuan Peng , Ma Fei , Luo Yang , Fan Ying , Zhang Pin , Cai Ruigang
Published: March 2020

e11025

Background: To determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline and taxane-based chemotherapy. Methods: We studied the incidence and duration of amenorrhea induced by adjuvant chemotherapy(regimens: 6EC(Epirubicin and cyclophosphamide) or 4EC follow by 4Taxen) in 68 premenopausal patients with different age group. Reversible amenorrhea was defined as recovery of regular menses or premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy. Results: The incidence of chemotherapy-induced amenorrhea(CIA) at the end of chemotherapy was similar in the two groups: 81.3% in the 6EC arm and 86.3% in the 4EC/4T arm. The incidence of CIA was not significance higher in the middle age arm(older than 40 years old) than in the younger arm(40 or younger than 40 years old): 97.4% versus 86.7% (P=0.114). However, more reversible amenorrhea was observed in younger arm than in middle age arm (76.7% vs. 34.2%, P=0.001). The median duration of regular menses recovering was 9 months in the younger arm and 11 months in the median age arm. More persistent amenorrhea had been detected in the middle age arm than in younger arm: 63.2% vs.10%, P<0.001). Multivariate analysis showed that age (>40years) was independently associated with the incidences of CIA (P=0.048). Conclusions: Age was the strongest predictor of the incidence of amenorrhea during adjuvant chemotherapy. Our study suggests that most of CIA in younger patients induced by adjuvant chemotherapy were reversible amenorrhea. Therefore adjuvant aromatase inhibitors for early breast cancer patients with CIA should be cautiously administered.
Anti-estrogenic effect of TAS-108 in breast cancer cell lines.
Authors: Kim Hadong , Choi Young , Kim Tae-Hoon
Published: March 2020

e11029

Background: TAS-108 (TAS) is an antiestrogen that binds to both ERα and ERβ and inhibits both estrogen-dependent and independent tumors and TAM resistant tumors. Breast cancer cell lines (BCC) with different pheno- and genotypes are reasonably acceptable models of in vivo breast cancer cell behavior. Thus, we have investigated anti-estrogenic activity of TAS on BCC in the presence of diarylpropionitrile (DPN), a pure ERβ agonist to find ERβ role in TAS activity. Methods: Cultured cells of (1) MCF-7 and ZR-75 (luminal epithelial cells), (2) BT-474 and SK-BR-3 (weakly luminal epithelial cells), and (3) MDA-MB-231 and Hs578T (invasive, mesenchymal-like cells) were treated with: (1) increasing concentrations of DPN or E2, (2) 100nM of 4-hydroxytamoxifen (4-HT) or TAS, and (3) 100nM of DPN or E2 with increasing concentrations of either 4-HT or TAS. After 6 days, cell proliferation was analyzed. The mRNA levels of ERβ and ERα isoform were determined by RT-qPCR. ERα, PR, and Her-2 status was determined by IHC. Percent proliferation compared to the control was calculated and P <0.05 based on T-test was considered significant. Results: The most significant proliferation and growth inhibition was seen in MCF-7 BCC. In the presence of DPN, IC50 (50% inhibitory concentration) was 12.5nmol of TAS vs 33.1nmol of 4-HT. In the presence of E2, IC50 was 2.15 nmol of TAS vs 49.7nmol of 4-HT. Other BCC showed insignificant or variable proliferative and inhibitory response. Overall, DPN displayed high proliferation in most BCC. TAS exhibited higher growth inhibition than 4-HT. Conclusions: Variable responses of different BCC lines to ERα and ERβ agonists and antagonists may be instructive in modeling in vivo breast cancer response to these compounds. Overall, exposure to ERβ agonists showed a significant proliferation in ERα+, ERα- and ERβ+ cells. TAS activity was more pronounced and its anti-estrogen activity may involve ERβ in addition to ERα. [Table: see text]
Does total breastfeeding time influence the clinicopathologic characteristics and prognosis in breast cancer patients?
Authors: Yaman Sebnem , Aksoy Sercan , Sendur Mehmet Ali Nahit , Arik Zafer , Ozdemir Nuriye , Zengin Nurullah , Altundag Kadri
Published: March 2020

e11033

Background: Several studies suggest that total breastfeeding time reduces breast cancer risk although the underlying mechanism is unclear. However the total breast feeding is not well studied as a prognostic factor in patients with cancer. We aimed to investigate the possible prognostic role of total breastfeeding time (TBT) in breast cancer patients both on relation with tumor characteristics and also on prognosis. Methods: We retrospectively evaluated 1673 breast cancer patients who followed up between 2004 and 2010 in our clinic. The total breastfeeding time was obtained by summing the breastfeeding time for each child. The total breastfeeding time was categorized as: 1-The total breastfeeding time between 0-12 months; 2-Total breastfeeding time more than 12 months. Results: The median total breastfeeding time of this population was 12 months. 1011(60.4%) of these have total breastfeeding time between 0-12 months and 662 (%39.6) of them have total breastfeeding time more than 12 months. T, N, M stages were similar in both groups. Total breastfeeding time was not correlated with any of clinical parameters including lymphovascular invasion, extracapsulary invasion, estrogen receptor, progesterone receptor, HER2 2 status, perineural invasion. There was a positive correlation found between total breastfeeding time and BMI (r=1.24; P<0.001).TBT (≥12 months) has poor disease free survival (DSF) time (116 vs. 75 months; p=0.002) and 3-years overall survival rate (98% vs 95.2%; p=0.049). Conclusions: In our study; total breastfeeding time was not found to be correlated with any of the clinico-pathological parameters. However, disease free survival and overall survival were statistically shorter in patients whose total breastfeeding time was more than 12 months.
Age as a prognostic factor for recurrence in premenopausal breast cancer patients.
Authors: Perello Antonia , Clemente Gemma , Duran Jose , Colom Bartomeu , Garcias-Espana Carmen , Torrecabota Joan , Avella Antoni , Canet Ramon , Rifa Julio
Published: March 2020

e11036

Background: It remains controversial if young age at diagnosis is an independent prognostic factor for recurrence in breast cancer (BC) patients. Data regarding recurrence with long-term follow-up in premenopausal women are sparse. The aim of the study was to compare the outcome of young patients (<=39 years) with older premenopausal patients. Methods: We collected clinical and pathological data from an inception cohort of 241 premenopausal patients aged <=50 years at diagnosis with stage I-III BC between January 2000 and December 2005 in a single institution. Disease-free survival (DFS) event was defined as time from diagnosis to local or distant recurrence, contralateral invasive BC or death from any cause. Kaplan-Meier curves and Cox model were used to analyze the covariable predictors for recurrence. Results: Median age was 43 years (range: 24-50) and median follow-up was 100 months (range: 72-137). Seventy seven patients (32%) were <=39 and 164 (68%) >39 years of age at diagnosis. Five and 10-year disease-free survival rate was 61 % and 48% respectively for the younger group and 77% and 74% for the older group (p<0.001). In the univariate analysis the hazard ratio (HR) for recurrence in young patients was 2.16 (95%CI: 1.38-3.37) (p< 0.001) Adjusting for T stage (<=2 cm versus >2 cm), N (negative versus positive nodes), Grade (grade 1-2 versus grade 3) and Hormonal Receptor status (positive versus negative), age less than 40 remains and independent prognostic factor for recurrence with an adjusted HR of 2.42 (95%CI: 1.42-4.10) (p<0.001), and was the most important adverse independent predictor among the factors included in the model. Conclusions: BC patients younger than 40 years of age at diagnosis have worse prognosis than older premenopausal patients, and have an independent prognostic value for recurrence after adjusting for known prognostic factors.
Fulvestrant (F) plus sorafenib (S) as salvage therapy for hormone receptor positive (HR+) metastatic breast cancer (MBC) failing prior aromatase inhibitor (AI) treatment.
Authors: Lethert Kristine H. , Nauman Deirdre J. , Prado Yolanda , Seligman Mark , Karamlou Kasra , Ey Frederick S. , Chui Stephen Y.
Published: March 2020

e11042

Background: Upon MBC progression with AI treatment; F, an estrogen receptor (ER) antagonist, is often used. Furthermore, vascular endothelial growth factor (VEGF) remains a potential target in MBC. S is a multi-kinase inhibitor of VEGF, Raf, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. Prior studies of S show activity with chemotherapy and as a single agent. Combination therapy with an anti-estrogen and a VEGF inhibitor may be more effective than either agent alone. This pilot study combines F + S for HR+ MBC. Methods: Upon disease progression with an AI, 8 pts were treated with F. Concurrent S was administered starting day 1 until disease progression or unacceptable toxicity. Assessment of tumor status with computed tomography and/or bone scan was performed at baseline and every 2 cycles until disease progression. Results: Median age = 58; 75 % <65. ER and PR + = 6 pts; ER + and PR - = 2 pts. 6 pts were treated with adjuvant chemotherapy and endocrine therapy, with subsequent AI for MBC. 2 pts were metastatic at presentation and treated with prior AI. Median number of days on treatment = 220; median number of cycles = 7. 75% had grade 2/3 HFS; 50% required S dose modification. However, HFS and rash/desquamation were the only grade 3 toxicities (3 pts) with no additional grade 3/4 toxicities or dose modifications for other toxicities. Other grade 2 toxicities: neutropenia, myalgias, arthralgias, fatigue, pruritis. Only 1 pt discontinued the study at investigator’s decision for grade 3 HFS. There were no deaths on study. The remaining 7 pts continued F + S until disease progression with stable disease over a range of 2 to 22 cycles. Median time to progression was 7.3 months. Conclusions: Upon progression with an AI, treatment with F + S may provide advantage for some HR+ MBC pts beyond treatment with F alone. Future studies involving S in MBC should focus on identifying the population that will benefit the most in exchange for toxicities associated with S. [Table: see text]
Reasons for changing hormonal therapy of advanced breast cancer.
Authors: Petrakova Katarina , Petruzelka Lubos B. , Kandrnal Vit
Published: March 2020

e11047

Background: Blood levels of tumor markers are widely used to assess response/progression to breast cancer treatment and guide therapy change in the real world setting compared to clinical trials where treatment efficacy is assessed by imaging methods. Our aim was to describe management of ER+ advanced breast cancer and reasons for treatment change in postmenopausal patients (pt) with hormone sensitive advanced breast cancer in the Czech Republic. Methods: The study was a retrospective, multi-centre, observational study that collected data from postmenopausal pt with hormone sensitive advanced breast cancer that have been treated with minimum two hormonal agents according to approved SmPC. Data collection started in February 2011in 16 centres in the Czech republic. The target number of enrolled pt was 400. Standard descriptive statistical methods were used for data analysis. Confidence intervals are reported where applicable. Results: We present an interim analysis of the study based on 169 pt enrolled till 21st July 2011. 150 pt have evaluable data. Median age was 55 years. Median time from diagnosis of BC to metastatic dissemination is 44.0 months (mean time 62.5 months). BC was diagnosed in Stage I in 12.0%, Stage II 43.3%, Stage III 24.0% and Stage IV 20.7%. Rebiopsy was done in 27.0% of pt who developed metastases (M). 63,5% pt were diagnosed with bone M, 45,3% with lymph node and soft tissue M, 22,3% with lung M, only 9,5% with liver M. 65% pt were treated with hormonotherapy in the first line and 84,2% in the second line. The main reason for hormonotherapy change was the progression according to examination (63%), elevation of tumor markers (13%), progression of symptoms (8%) intolerance of the treatment (3%) and other reasons (13%). Conclusions: Pt treated in the first line with hormonotherapy in daily practice in the Czech Republic are mostly pt without organ M. Pt with organ M are treated first with chemotherapy. Increase of tumor markers is the reason for treatment change in 13% of pt, progression of symptoms in 8%.
Frequency of PIK3CA mutations in HER2+ surgically resected breast cancers in a Hispanic cohort.
Authors: Munive Carlos , Gallo Aly , Neciosup Silvia P. , Doimi Franco , Dyer Richard , Pinto Joseph , Lopez-Ilasaca Marco , Gomez Henry
Published: March 2020

e11066

Background: PI3K signaling pathway is responsible for balancing cell survival and apoptosis, and plays an important role in the pathogenesis and progression of human breast cancers. Alterations in this pathway could influence the response to targeted therapy. Our aim is to know the frequency of mutations in the PIK3CA gene in HER2+, operable breast tumors in an Andean population. Methods: We include a cohort of 59 patients with HER2+ surgically resected breast cancer that received adjuvant anti-HER2 targeted therapy at the Instituto Nacional de Enfermedades Neoplásicas. Genomic DNA was extracted from Paraffin embedded-formalin fixed tumor samples and mutational status of PIK3CA gene was using PCR-based DNA sequencing Results: At the current date, the median of follow-up in our cohort is 2.4 years and two recurrences have been registered. Four samples were not evaluable for molecular analysis. Mutation in PIK3CA gene was detected in 12 cases (20.3%). In cases where PIK3CA mutation was detected, eight cases (66.7%) had mutations in exon 9 (A1634C/E545A in 6 cases; G1624A/E542K in 1 case and G1633A/E545K in 1 case). Four cases (33.3%) had exon 20 mutated (A3140G/H1047R in all cases). There was not coexistence of mutations in both exons. One case of tumor recurrence had mutation in exon 9. Conclusions: We found similar rates of PIK3CA mutations as described previously to HER2+, breast tumors. A longest follow upwill show the prognostic value of PIK3CA status in our cohort treated with targeted anti-HER2 therapy. [Table: see text]