bluuebunny/crossref_metadata_2025 huggingface dataset:
Second non-ocular tumors among survivors of retinoblastoma treated with proton therapy.
Authors: Sethi Roshan V , Shih Helen Alice , Kim David , Yeap Beow Y. , Mouw Kent , Marcus Karen Chayt , Grabowski Eric , Yock Torunn I. , Tarbell Nancy , Mukai Shizuo , MacDonald Shannon M.
Published: March 2020

10018

Background: The leading cause of death for patients with hereditary retinoblastoma is second malignancy. Proton radiation allows for significant sparing of non-target tissue. We sought to determine the risk of second malignancy for the largest and oldest cohort of retinoblastoma patients treated with proton therapy. Methods: We performed a retrospective review of patients treated at the Massachusetts General Hospital (MGH) between 1986 and 2011. Results: Fifty-two patients were identified (see Table). Forty-four patients (85%) were hereditary survivors. Patients were followed for a median of 6.9 years from the start of radiation therapy (range, 11.3 months to 24.4 years). The median age at follow-up was 9.0 years (range, 31.3 months to 24.5 years). Fifteen patients had more than 10 years of follow-up from the start of radiation therapy, and 20 patients were more than 10 years old at last follow-up. With 417.2 person-years of follow-up, we identified one secondary malignancy, an osteosarcoma of the distal femur. The cumulative incidence of second tumor was 5% at 10 years. No radiation-associated malignancies were reported. Conclusions: Retinoblastoma is highly responsive to radiation. The central objection to the use of radiation—the risk of second malignancy—is founded on studies of patients treated with relatively non-conformal techniques. We present the first series of patients treated with the most conformal of current available modalities. While longer follow up is necessary, our preliminary data suggest that the risk of radiation-associated malignancy is minimal with proton therapy. [Table: see text]
The effect of surgery type on survival and recurrence in very young women with breast cancer.
Authors: Quan May Lynn , Paszat Lawrence Frank , Fernandes Kimberley , Sutradhar Rinku , McCready David R. , Rakovitch Eileen , Warner Ellen , Wright Frances Catriona , Hodgson Nicole , Brackstone Muriel , Baxter Nancy
Published: March 2020

1002

Background: Young age has been identified as an independent predictor of recurrence and mortality in women with breast cancer. The equivalence of breast conserving surgery (BCS) with mastectomy remains unclear in this population in an era of multimodal therapy. We sought to determine the effect of surgery type on the risk of recurrence and survival in a large, population based cohort of very young women. Methods: All women diagnosed with breast cancer aged ≤35 between 1994 and 2003 in Ontario were identified from the Ontario Cancer Registry, a population based registry of all incident invasive breast cancers in the province. A retrospective chart review was undertaken to identify patient, tumor and treatment variables, as well as locoregional, distant recurrences and death. Univariable and multivariable Cox proportional hazards regression models were fit to determine the effect of primary surgery type on overall survival while controlling for known confounders. To examine time to recurrence in a multivariable analysis, the proportional subdistribution hazards model (Fine and Gray) was used to account for death being a competing risk. Results: A total of 1,381 patients were identified; the median age was 33 (range 18 – 35), median follow up was 11 years. Primary surgical treatment was BCS in 793 (57%) patients of which 89% had adjuvant radiotherapy. Of the 588 (43%) having mastectomy, 53% underwent post mastectomy radiation. Overall, 38% of patients sustained a recurrence of any type and 31% had died. After controlling for tumor size, margin status, node status, grade, LVI, ER/PR, HER2 and treatment (chemotherapy, radiation, hormones) there was no difference in overall survival (HR 0.99, 95% CI 0.79,1.26) or recurrence (HR 0.96, 95% CI 0.73,1.26) among women treated with BCS or mastectomy. Predictors of recurrence were size ≥2 cm, ≥ 1 positive node, neoadjuvant chemotherapy, and lack of radiation. Predictors of death were similar and included high grade and presence of LVI. Conclusions: Very young women selected for BCS had similar outcomes to those selected for mastectomy after controlling for known prognostic factors for recurrence and death.
Pulmonary function after treatment for embryonal brain tumors on SJMB03 that included craniospinal irradiation.
Authors: Green Daniel M. , Merchant Thomas E. , Billups Catherine A , Stokes Dennis C , Broniscer Alberto , Srinivasan Ashok , Chintagumpala Murali M. , Hassall Timothy E , Bouffet Eric , Gururangan Sridharan , Kellie Stewart J , Ashley David M , Cohn Richard J , Fisher Michael J. , Gajjar Amar J.
Published: March 2020

10021

Background: Treatment of children with embryonal brain tumors (EBT) includes craniospinal irradiation. There are limited data regarding the effect of radiation therapy (RT) on pulmonary function. Methods: Protocol SJMB03 enrolled patients 3 to 21 years of age with EBT. Pulmonary function tests (PFTs) [forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) by spirometry, total lung capacity (TLC) by plethysmography and diffusing capacity of the lung for carbon monoxide (DLCO)] were obtained following completion of RT, prior to each of four courses of high-dose chemotherapy (cumulative cyclophosphamide dose, 16 g/m2), and 24 months after completion of treatment (ACT). Differences between PFTs obtained following the completion of RT and 24 months ACT were compared using exact Wilcoxon signed rank tests. Results: 303 eligible patients were enrolled between June 24, 2003 and March 1, 2010, 258 of whom had at least one PFT. Median age at diagnosis - 8.9 years (range, 3.1 to 20.4 years). Median spinal RT dose - 23.4 Gy (range, 23.4 to 50.4 Gy). Median cyclophosphamide dose was 16.24 g (range, 0 to 34.38 g). 24 months ACT, DLCO was < 75% predicted in 23% (27/115 evaluated), FEV1 was < 80% predicted in 21% (32/150 evaluated), FVC was < 80% predicted in 27% (46/168 evaluated) and TLC was < 80% predicted in 18% (24/135 evaluated) of patients. DLCO was significantly decreased 24 months ACT compared to the end of RT (median difference (MD) in % predicted, - 3.00%; p = 0.035). Race and cumulative cyclophosphamide dose were not significant predictors of DLCO. DLCO was significantly higher among males (p = 0.037) than females in a model that included time point, sex, RT dose group, RT dose*time interaction and age at diagnosis. The differences in FEV1 ((MD, - 1.00%), FVC (MD, 0.00%) and TLC (MD, -2.00%) were not statistically significant. Conclusions: Among patients with EBT treated with spinal RT, DLCO was significantly decreased 24 months after completion of treatment compared to immediately post-RT. TLC was decreased 24 months ACT, suggesting that a significant minority of patients have restrictive lung disease. Continued monitoring of this cohort to five years ACT is planned. Clinical trial information: NCT00085202.
A phase I study of ridaforolimus (MK-8669) in pediatric patients with advanced solid tumors.
Authors: Pearson Andrew DJ , Federico Sara Michele , Aerts Isabelle , Hargrave Darren R , DuBois Steven G. , Iannone Robert , Geschwindt Ryan , Wang Ruixue , Trippett Tanya M. , Geoerger Birgit
Published: March 2020

10027

Background: Deregulation of the PI3K/AKT/mTOR signaling pathway occurs in many poor prognosis childhood malignancies and inhibition of this pathway is a promising novel therapeutic strategy. Ridaforolimus (MK-8669) is a highly selective orally bioavailable small molecule inhibitor of mTOR. This multi-centre, phase I dose escalation study of orally administered Ridaforolimus was designed to evaluate the maximum tolerated dose (MTD), safety profile, pharmacokinetic profile (PK), antitumor activity and pharmacodynamic (PD) biomarkers (phosphorylated Akt [pAkt] in platelet-rich plasma). Methods: Patients (pts) from 6 to <18 years (yrs) with advanced solid tumors were enrolled. Dose escalation was by a modified Toxicity Probability Intervals method (mTPI, Ji Y, et al. Clin Trials 2007) targeting a 30% dose limiting toxicity (DLT) ratio. Pts received 28 day cycles of Ridaforolimus (MK-8669), orally, five days out of seven. Dosing started at 22 mg/m2, escalated to 28 and 33 mg/m2, with an expansion cohort treated at the maximum administered dose. Results: 19 pts, age 8-17 (median 13.5 years), were enrolled and 18 treated from 6 international sites. Diagnoses included ependymoma (5), osteosarcoma (3), Ewings sarcoma (3) and other histologies (7). Four pts received dose level (DL) 1; 3 DL 2 and 11 DL 3. Pts received between 1-12+ courses. There was only one DLT (DL 2: grade 3 elevated alanine transaminase [ALT]) and no other grade 3-4 treatment-related toxicities. Preliminary analysis shows the most frequent drug-related adverse events were manageable grade 1-2 stomatitis (70.6%) and fatigue (52%). Dose escalation stopped at DL3 (33 mg/m2, 150% of the adult recommended phase 2 dose [RP2D]). There were no objective responses by RECIST1.1. Two pts remain on study, with continuing stable disease (pineoblastoma [12 courses], diffuse intrinsic pontine glioma [6 courses]). PK and PD analyses will be presented. Conclusions: Ridaforolimus is a safe and well tolerated, orally bioavailable mTOR inhibitor. The RP2D for Ridaforolimus in children is 33 mg/m2. Prolonged disease stabilization was observed in two patients. PK/PD data will provide further data to support the RP2D. Further combination studies are warranted. Clinical trial information: NCT01431547.
Characterization of neuroblastic tumors as developmental cancers with survival determined by histology, age, and location.
Authors: Effinger Karen Elizabeth , Merrihew Lindsey Elizabeth , Fisher Paul Graham
Published: March 2020

10046

Background: Mortality associated with peripheral neuroblastic tumors (pNT), comprising neuroblastoma (NB) and ganglioneuroblastoma (GNB), varies with some tumors spontaneously regressing and others showing poor response to therapy, indicating different biologic mechanisms. We aimed to determine how epidemiologic constructs inform the underlying biology of pNT. Methods: Using the Surveillance Epidemiology and End Results (SEER 18) population-based registry, we identified 3,540 pNT (3,003 NB and 537 GNB) in patients from 1973-2009. Differences in histology (NB vs. GNB), gender, age (<18 months, 18 months-4 years, 5-14 years, or ≥15 years), race (white, black, or other), location of primary tumor (adrenal, abdominal, chest, head/neck, pelvic, or other), and stage (locoregional vs. metastatic) were evaluated with chi-squared tests using SAS 9.3. Kaplan Meier curves with log-rank tests as well as univariate and multivariate Cox proportional hazard regression methods were employed to determine the influence of these factors on survival. Results: NB occurred more frequently in infants (50%), arose in the adrenals (45%), and were metastatic at diagnosis (57%), while GNB more often affected children 18 months-4 years (48%, p <0.001), occurred in the chest (31%, p <0.001), and were locoregional (78%, p <0.001). The 5-year overall survival (OS) rate in NB was 59% compared to 80% in GNB (p <0.001). In NB, the 5-year OS rate was 81% in infants <18 months and 21-39% in the older groups (p <0.001); however, in GNB, the 5-year OS was 40% in subjects >15 years and 81-93% in the younger groups (p <0.001). In multivariate analysis of pNT, neuroblastoma, age >18 months, adrenal site of primary tumor, and metastatic disease were independent poor prognostic factors. Chest (HR 0.27 [0.21-0.35]), head/neck (HR 0.34 [0.20-0.52]), and pelvic (HR 0.35 [0.24-0.52]) tumors had the most improved survival compared to adrenal primaries. Conclusions: Although pNT are often evaluated together, NB and GNB represent two significantly distinct diseases. For each, survival is strongly determined by age, primary tumor location, and stage. These differences may stem from unique developmental mechanisms underlying tumorigenesis.
A phase I dose-escalation study of intratumoral herpes simplex virus-1 mutant HSV1716 in pediatric/young adult patients with refractory non-central nervous system solid tumors.
Authors: Cripe Timothy P. , Racadio John M , Conner Joe , Towbin Alexander , Brunner Marianne M , Stockman Beth A , Currier Mark , Geller James I.
Published: March 2020

10047

Background: HSV1716 is a mutant herpes simplex virus type 1 deleted in the RL1 gene which encodes the protein ICP34.5, a specific determinant of virulence. Mutants lacking the RL1 gene are capable of replication in actively dividing cells but not in terminally differentiated cells – a phenotype exploited to selectively kill tumor cells. Studies in adult patients with high grade glioma, melanoma and squamous cell carcinoma report that HSV1716 is safe when administered by intra-tumoral injection. This is the first study of HSV1716 in pediatric/young adult patients. Methods: The primary endpoint of the study is to assess safety of intratumoral HSV1716 in pediatric/young adult patients, and to determine any dose-limiting toxicities (DLT) at the doses given. Patients undergo long-term follow up in accordance with FDA guidelines for viral vectors. The secondary endpoints of the study are to measure: (i) antiviral immune response; (ii) systemic viremia and viral shedding and (iii) the antitumor activity of HSV1716 by radiological response within the confines of a Phase I study. Patients aged 7 to 30 with solid non-CNS tumors refractory to standard therapy (or for which no therapy exists) are eligible for the study provided the target lesion is accessible to image-guided injection. Eligible patients receive a single dose of HSV1716 (Virttu Biologics Limited) at either 105 or 2x106 plaque forming units (pfu) HSV1716 administered directly into the tumor via ultrasound or CT-guided injection by an interventional radiologist. Tumor response between baseline and day 28 is assessed by modified RECIST criteria. Patients showing at least stable disease may receive up to a 3 additional doses of HSV1716. Results: Recruitment of the first cohort of 3 patients has been completed without DLT or procedure related severe adverse events. In the second cohort, 2 patients have been treated without DLT or procedure related SAE. Conclusions: The trial is in progress and the study is open to recruitment. Clinical trial information: NCT00931931.
Multicenter phase I/II trial of topotecan (T) and ifosfamide (I) combination as second-line therapy for pediatric solid cancer: Phase II results.
Authors: Kawamoto Hiroshi , Oba Mari Saito , Hosono Ako , Ishida Yuji , Taga Takashi , Kosaka Yoshiyuki , Inagaki Jiro , Mugishima Hideo , Okamoto Yasuhiro , Ogawa Atsushi
Published: March 2020

10050

Background: Both of T and I are key drugs for recurrent pediatric solid malignancies but rarely used in combination. Results of the phase I portion of the combination of T and I chemotherapy (TI) which is dose-finding study by CRM method in ASCO 2010. We hereby report the results of efficacy and safety screening of TI conducted as a phase II portion. Methods: Recurrent pediatric solid malignancies with history of chemotherapy no more than 20 cycles (Cs) are eligible. Combination of I (1.2g/m2/day) and T (0.6 mg/m2/day) were administered day 1 through 5 up to six Cs. In the phase II portion, a Simon optimal two-stage design was adopted using treatment compliance with 4 Cs of TI as primary endpoint. Unacceptable compliance was set at 20% and promising one at 40%. If more than two patients (pts) among initial 13-15 pts successfully complete 4 Cs, patients’ enrollment is allowed to continue until a total of 33 pts in the phase II portion. Complete or Partial Response (CR+PR) was evaluated according to RECIST 1.0 criteria and toxicity, CTCAE v3.0. Results: 35 pts, median age 12 years (range 1-28) has been registered in both phase I and II between March 2008 and January 2013 in 8 centers: 7 neuroblastoma (NB), 8 rhabdomyosarcoma (RMS), 8 osteosarcoma (OS), 6 Ewing’s sarcoma (ES), 2 hepatoblastoma (HB), and 4 others. 13 pts out of total 34 pts (38%) completed 6 Cs. 13 pts out of 28 pts (36%, the phaseII portion) received more than 4 Cs without meeting stopping criteria of protocol treatment. This has reached the predefined efficient level. No Grade 4 non-hematological toxicity occurred. Grade 2-4 fatigue, anorexia, and nausea were 20% or less. Grade 3 or 4 neutropenia was frequent (105/127 Cs, 83%), though only 9 % (12 Cs) developed febrile neutropenia. 2 CR (HB, ES) and 2 PR (RMS, OS) were observed at best response among 22 pts with measurable disease, leading to an estimated OR rate of 18% (95%CI 5-40%). 14 patients had disease stabilization. One year progression-free survival rate and overall survival rate are 21% and 64%. Conclusions: TI achieved very good compliance and favorable toxicity as well as good tumor control rate. This combination is a new promising 2nd line therapy for pediatric solid malignancies. Clinical trial information: UMIN000001037.
Evaluation of the necessity of bilateral bone marrow aspirates and biopsies for the diagnosis of metastatic disease in pediatric patients with solid tumors.
Authors: Abrantes Fernanda L. , Vergamini Lucas B. , Rodriguez-Galindo Carlos , Hofmann Inga , London Wendy B. , Ribeiro Karina Braga , Frazier A. Lindsay , Sun Pengling
Published: March 2020

10054

Background: Standard practice for staging solid tumors has been to perform bilateral bone marrow aspirates (BMA) and biopsies (BMB). However, the diagnostic yield of performing all 4 tests has not been thoroughly evaluated. This study evaluated the concordance between test types (aspirate and biopsy) and sites (right and left) to evaluate whether one type or one side would be sufficient. Methods: All patients with solid tumors who underwent a diagnostic bilateral bone marrow biopsy and aspirate performed between 2006 and 2011 at Children’s Hospital Boston were identifed in a search of hematopathology records.. Kappa coeffcients were estimated. Results: A search of the hematopathology data records revealed a total of 112 patients who had had a diagnostic bilateral BMA and BMB including patients with neuroblastoma (n=70 ), Ewing’s Sarcoma (n=11), rhabdomyosarcoma (n=25), retinoblastoma (n=5), and undifferentiated sarcoma (n=1). 73% (n=82) of the patients were negative for all tests; 27% (n=30) had at least one positive test. The results between right and left and aspirate and biopsy were highly correlated.(Kappa statistics: BMA and BMB (0.85); BMA-left and BMB-left (0.82); BMA-right and BMB-right (0.84); BMA-left and BMA-right (0.77); BMB-left and BMB-right (0.95). All 4 tests were positive in 63%, 3 tests positive in 10%, 2 tests positive in 13% and one test positive in 13%. The distribution of positive results did not differ by disease. Among 11 patients with less than 4 positive tests, 10 would have been diagnosed correctly with bilateral aspirates; only one patient (neuroblastoma) had positive results on biopsy only. In this patient, neither aspirate had spicules and was therefore likely an inadequate specimen. Conclusions: Bone marrow biopsy may not be essential for accurate diagnosis of metastatic disease in pediatric solid tumor patients. Further confirmation of these findings in a larger sample is warranted.
Biomarkers of radiation exposure in children with neuroblastoma treated with 131I-mIBG.
Authors: Karski Erin E , Matthay Katherine K. , Allen M. Shelly , Coleman Matthew , Kohlgruber Ayona , Haas-Kogan Daphne A. , Olow Aleksandra E , DuBois Steven G.
Published: March 2020

10060

Background: Neuroblastoma (NB) is the most common solid extra-cranial tumor of childhood. 131I-mIBG is a targeted radiopharmaceutical for patients with advanced NB and is one of the most active agents in this treatment resistant population. To date, no clinically relevant biomarkers of response or toxicity have been reported in patients treated with 131I-mIBG. Methods: Patients with relapsed or refractory NB who received 131I-mIBG at UCSF were eligible to participate in this prospective correlative study. Blood samples were obtained at baseline and 72 hours after 131I-mIBG infusion. We quantified a panel of biomarkers shown to be effected in patients receiving other forms of radiation, including: serum amylase; plasma Flt-3 ligand; plasma monocyte colony stimulating factor (MCSF); and CDKN1A mRNA in mononuclear cells. Extent of modulation of each marker was evaluated using paired t-tests at hour 0 and 72. We assessed potential differential modulation between groups based on response (PR/CR vs SD/PD), toxicity (grade 3 non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia) or administration of combination therapy (131I-mIBG alone vs in combination with vincristine/irinotecan or vorinostat) using unpaired t-tests. Results: 26 patients (21 male; median age 7 years) participated and received a median 131I-mIBG dose of 18 mCi/kg. 16 patients received 131I-mIBG in combination. We observed robust modulation of amylase (median fold increase from baseline 3.1; p <0.0001), Flt-3 ligand (median fold increase from baseline 3.6; p=0.0005), and CDKN1A mRNA (median fold decrease from baseline 4.3, p=0.0002). No differences were noted in MCSF (p=0.80). Patients receiving combination 131I-mIBG had more robust modulation of Flt-3 ligand (mean difference 296 pg/mL; p=0.02) compared to single agent 131I-mIBG. No correlations with clinical response or toxicity were found. Conclusions: Amylase, Flt-3 ligand, and CDKN1A mRNA all show robust modulation after 131I-mIBG treatment. Patients receiving 131I-mIBG in combination demonstrated the largest changes in plasma Flt-3 ligand. In this initial analysis, no associations were found between response or toxicity and the proposed biomarkers.
Health practices and behaviors of childhood cancer survivors not attending a comprehensive survivor clinic.
Authors: Iyer Neel Subramanian , Mitchell Hannah-Rose , Gross Cary Philip , Ma Xiaomei , Kadan-Lottick Nina
Published: March 2020

10063

Background: Little is known regarding the health practices and behaviors of childhood cancer patients who have not received recommended survivorship care, a group that represents the majority of survivors. Methods: Using the Yale Tumor Registry, consisting of patients from Southern Connecticut, we identified patients who were diagnosed from 2000-2011 with an invasive cancer at age ≤18 years, are currently alive and cancer-free at least one year after therapy, live within 100 miles of Yale HEROS Childhood Cancer Survivor Clinic, never previously attended a survivor clinic, and consented to a research study to investigate survivor care. Participants completed postal or on-line surveys regarding health communication preferences, utilization of services, and behaviors. Results: The 68 participants had a mean age of 16.8 (range 6-27) years at evaluation and 6.7 years since diagnosis with 53% female and 50% currently >18 years. Overall, 100% had seen a primary care physician and 71% their pediatric oncologist in the past year. Forty-six percent had also seen a subspecialist with orthopedics (10%), dermatology (9%), endocrinology (6%), and OB/GYN (6%) as the most common specialties; 16% reported two or more subspecialists. Most (83%) had commercial insurance, while 17% had federal insurance. For communication preferences with their providers, willingness to communicate by cell phone, text messages, and email were 59%, 56%, and 87%, respectively. For health behaviors, only 16% of participants met CDC guidelines for fruit and 19.1% for vegetable intake. Among adults, 12% were active smokers. Only 6% of children and 33% of adults met age-specific CDC recommendations for moderate weekly physical activity. Conclusions: Survivors of childhood cancer were overall highly connected to primary care and other health services, despite not participating in survivorship care. However, inadequate diet and physical activity results suggest patients could benefit from behavioral interventions.
First results of prophylaxis for bacterial and fungal infections in pediatric patients with high-risk acute lymphocytic leukemia (ALL).
Authors: Beaugrand Annick , Oliveira Renato Guedes , Gorender Ethel , Melaragno Renato , Epelman Sidnei
Published: March 2020

10065

Background: Bacterial and invasive fungal infections remain a major contributor to treatment related morbidity and mortality in cancer patients. It has been published data of potential prevention; in immunocompromised hosts derive primarily from adult studies. However, children differ from adults in terms of the infections types as they develop or manifest, as well as their metabolism of treatment agents. From April 2010 to January 2011, 6 ALL patients received 35 intensive chemotherapy cycles during the first 6 months after diagnosis, 2 died due to infection. Methods: From April 2011 to January 2012, a prospective analysis in 8 high risk ALL patients ( BFM criteria) after 31 cycles of intensive chemotherapy were performed during the first 6 months of treatment followed by antibacterial and antifungal prophylaxis. Drugs are: ciprophloxacin 1000mg per day when weight highest than 30 kg and 500mg per day when lower weigh and fluconazole 100mg per day for the lower weigh and 150mg for the higher. All patient received granulocyte colony-stimulating factor after each cycles until complete neutrophils recovery. Results: In 20/31 cycles, hospitalization was needed, due to febrile neutropenia. Diarrhea, sepsis and renal failure were other reasons for hospitalization. Platelet transfusions and blood transfusions were performed in 12 and 9 hospitalization respectively. The majority of proven infections (n=7) were bacterial, Gram negative (Pseudomonas aeruginosa and Klebsiella spp), Gram positive, Candida (1 cycle). Hospitalization time was between 2 and 25 days (median time 10 days). In 4 cycles, intensive care unit was needed. No death occurred. Conclusions: Bacterial and fungal infections continue to be a leading cause of morbidity and mortality in children receiving intensive therapy. Pharmacologic prophylaxis can contribute to decrease mortality due to infection in this population.
Attitudes to the return of incidental and targeted genomic findings obtained in a high-risk pediatric cancer versus an inherited genetic condition research setting.
Authors: Fernandez Conrad Vincent , Jabado Nada , Boycott Kym , Malkin David , Bouffet Eric , O'Connell Colleen , Avard Denise , Knoppers Bartha , Sorensen Poul , Orr Andrew C , McMaster Christopher
Published: March 2020

10066

Background: The disclosure of clinically significant, validated incidental and target findings to participants in genomic research is often recommended. There have been no reports on whether attitudes of parents differ if these findings emerge from an acquired pediatric cancer versus an inherited genetic condition setting. Methods: Parents in 3 large-scale projects [Canadian Pediatric Cancer Genome Consortium (CPCGC), the Finding of Rare Genes Canada Consortium (FORGE) and the Orphan Diseases: identifying Genes and Novel Therapeutics to Enhance Treatment Project (IGNITE)] were surveyed using a mailed, validated 29-item questionnaire. Two reminders were sent. Analysis was by descriptive and Chi-square statistics. Results: Response rate: 64% (n=307/480). 40% were > 50 yrs age; more than half had a grade 12 education. 86 were parents of poor risk pediatric cancer patients and 221 were parents or individuals with rare inherited conditions. Most stated a very strong or strong right to genomic research results, irrespective if from the target condition (97%) or incidental (86%). 70% wish genetic counselling pre- and post-research testing; an additional 20% were uncertain what this entails. Almost all indicated that genomic research for childhood onset conditions should occur, regardless of whether therapy existed (99%) or not (91%). A few indicated that they would not want incidental results showing an untreatable fatal condition (17%). Most want results, even if these suggest susceptibility to multiple conditions (87%) or are of uncertain health impact (84%). Most felt a right to genomic research that showed a serious condition in siblings, whether treatable (94%) or not (89%). 74% strongly support that results discovered after death of the proband be shared with family. Conclusions: Parents of children in both cancer and inherited rare conditions genomic research do not differ in indicating a strong right and desire to receive research results, even if they are of uncertain impact, of childhood onset, or after death of the proband. Clear delineation of what will or will not be offered from genomic research should be established at the time of consent.
Next-generation sequencing to find predictors for chemotherapy response in triple-negative breast cancer (TNBC).
Authors: Lips Esther H. , Michaut Magali , Mulder Lennart , Besselink Nicolle , Hoogstraat Marlous L. , Koudijs Marco J. , Voest Emile E. , Bernards Rene , Wesseling Jelle , Wessels Lodewyk F. A. , Rodenhuis Sjoerd
Published: March 2020

1010

Background: In TNBC initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. Methods: To identify biomarkers of chemotherapy resistance and putative directed treatment targets, we performed next generation sequencing (NGS) of 2,000 genes implicated in oncogenesis. DNA from 31 pre-treatment biopsies and matched normal blood was sequenced. Biopsies were derived from patients scheduled to receive neoadjuvant chemotherapy with doxorubicin/cyclophosphamide. For the analysis, the tumors were divided in responders and non-responders, depending on whether or not a pathological complete remission (pCR) was achieved. Two definitions of pCR were employed: either the complete absence of infiltrating tumor cells in the breast (n=18) or a pCR of both the breast and lymph nodes (n=15). Tumors with partial or no responses were grouped in the non-responder category. Results: As a positive control, we verified that all patients with a known germline BRCA1 mutation (n=8) could be detected by the NGS analysis. In further analyses, we focused only on somatic mutations. Overall, the mutation rate was slightly higher in the non-responders (per tumor, average=12, range=[3-25]) than in the responders (average=8, range=[3-19]) (p=0.17). The analysis of individual genes did not reveal significant differences between responders and non-responders. However, pathway analysis showed that mutations in phosphatidylinositol signaling (e.g., PIK3CA, CALML5) were significantly more frequent in the non-responders, with mutations present in 10/13 non-responders and 2/18 responders (adjusted p=0.013). The chemokine and integrin signaling pathways also revealed a significantly higher mutation rate in the non-responders. Conclusions: Mutations in genes of the phosphatidylinositol pathway occur frequently in TNBCs that do not achieve a pCR on a neoadjuvant chemotherapy regimen consisting of doxorubicin and cyclophosphamide. After validation, alternative chemotherapy regimens and targeted agents should be investigated for these tumors.
Molecular identification of basal-like breast cancer through genomic analyses across five cancer types.
Authors: Prat Aleix , Adamo Barbara , Fan Cheng , Vidal Maria , Galvan Patricia , Felip Enriqueta , Del Campo Jose Maria , Tabernero Josep , Cortes Javier
Published: March 2020

1011

Background: Common molecular alterations in different types of cancer are being identified and these might be successfully targeted regardless of the tumor´s tissue of origin. To better understand the genomic relationships among different types of cancer, we explored global gene expression patterns across breast, lung, ovarian, brain and colorectal cancers. Methods: A unified set of 1,707 samples of 5 human cancer types (breast [n=547], lung [squamous and adenocarcinomas, n=249], ovarian [serous carcinoma, n=489], brain [glioblastoma multiforme, n=202] and colorectal [n=220]) from The Cancer Genome Atlas (TCGA) project was evaluated. All microarrays were performed at the University of North Carolina under the same protocol and platform. All samples provided in each publication of TCGA were used, except for lung adenocarcinomas where we used TCGA public data. Consensus clustering was used to identify molecular entities, and breast cancer intrinsic subtyping was performed using the PAM50 predictor. Results: A total of 6 distinct and robust molecular entities were identified representing tumors from breast luminal/HER2-enriched, breast Basal-like, lung, ovarian, brain and colorectal cancers. Strikingly, 55%, 26%, 16% of Basal-like breast cancers were found to be more similar to squamous cell lung carcinomas, lung adenocarcinomas and ovarian cancers, respectively, compared to breast luminal/HER2-enriched tumors. Breast cancer intrinsic subtyping identified a Basal-like profile in 55% of squamous cell lung cancers, 53% of ovarian cancers and 8% of lung adenocarcinomas. Finally, single genes and gene signatures tracking cancer-related biological processes such as proliferation, angiogenesis and immune activation were found highly expressed in different proportions across the 6 molecular entities. Conclusions: These data suggest that breast tumors of the Basal-like subtype have a distinct cell of origin compared to luminal/HER2-enriched tumors. Clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer, squamous cell lung carcinoma and serous ovarian cancer.
Correlation of intratumor gene expression heterogeneity with chemotherapy sensitivity in breast cancer.
Authors: Natowicz Rene , Jiang Tingting , Shi Weiwei , Qi Yuan , Delpech Yann , Symmans William Fraser , Pusztai Lajos
Published: March 2020

1013

Background: The goal of this study was to develop a method to quantify intratumor heterogeneity of cancers using gene expression data. We compared gene expression heterogeneity between different molecular subtypes of breast cancer and between basal like cancers with or without pathologic complete response (pCR) to neoadjuvant chemotherapy. Methods: Affymetrix U133A gene expression data of 335 stage I-III breast cancers were analyzed. Molecular class was assigned using the PAM50 predictor. All patients received neoadjuvant chemotherapy. We measured tumor heterogeneity by the Gini index (GI) calculated individually for each case over the expression of all probe sets and random subsets. The GI was used as a metric of inequality of gene expression distributions between cases. The higher the GI, the greater the inequality of the expression distribution. Results: Basal like cancers (n=138) had greater heterogeneity than luminal cancers (n=197) (mean GI values 24.51 vs 23.05, p<0.001) and luminal B (n=71) cancers had greater heterogeneity compared to Luminal A (n=126) cancers (24.49 vs 22.25, p<0.001). Among the basal-like cancers, those with pCR (n=44) had significantly higher heterogeneity compared to cancers with residual disease (RD, n=94) (26.10 vs 23.77, p<0.001). Significant differences in GI between cancer subtypes remained for as low 2500 randomly selected probe sets. Conclusions: Breast cancer subtypes differ in intratumor gene expression heterogeneity. Greater degree of heterogeneity correlate with greater chemotherapy sensitivity. Importantly, among basal-like cancers only the heterogeneity metric differed significantly between cases with pCR or RD but not individual genes expression values or gene signatures.
Radiation-induced increases in PARP1 activity to predict for long-term radiosensitization by PARP1 inhibition in preclinical breast cancer models.
Authors: Feng Felix Yi-Chung , Liu Meilan , Wilder-Romans Kari , Speers Corey , Jagsi Reshma , Pierce Lori J.
Published: March 2020

1025

Background: Sustained locoregional (LR) control of breast cancer (BCa) is a significant issue for patients with inflammatory disease or chest wall recurrences. Inhibition of poly(adenosine diphosphate-ribose) (PAR) polymerase 1 (PARP1), a DNA damage response protein, is a promising strategy for radiosensitization (RS). We investigated RS by PARP1 inhibition and aimed to identify early biomarkers (BMs) predictive of long-term treatment efficacy in preclinical BCa models. Methods: Clonogenic survival assays in 12 BCa and normal epithelial cell lines were used to determine the degree of RS conferred by the PARP1 inhibitor ABT-888 and to optimize the sequencing of therapy. Immunoblots, immunofluorescent staining, flow cytometery, and xenograft studies were used to evaluate for pre-/intra-treatment BMs predicting for subsequent response to therapy. Results: ABT-888 preferentially radiosensitized BCa (vs. normal) cells (enhancement ratios (EnhR) up to 2.3 across different subtypes). The highest EnhRs resulted from concurrent and adjuvant ABT-888. The degree of RS did not correlate with pretreatment markers of PARP1 activity (e.g., PAR levels), DNA damage/repair (e.g. gamma-H2AX & RAD51 foci), or cell cycle distribution. However, increases in PARP1 activity from pretreatment to 24 hours after RT, was associated with long-term clonogenic death after treatment with ABT-888 + radiation (RT) (Spearman's coefficient=0.8, p=0.002). The four cell lines significantly radiosensitized by PARP1 inhibition (EnhR>1.5) averaged a 2-fold increase in PAR levels following RT. Findings were also confirmed in SKBR3 and MDA-231 BCa xenograft models. Conclusions: Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT in BCa cell lines. Treatment-induced increase in PARP1 activity 24 hours after RT predicts for long-term radiosensitization by PARP1 inhibition and is a potential biomarker of response. These studies have led to a clinical trial, incorporating intratreatment BM analyses, of PARP inhibitors and RT in BCa patients currently open for accrual through the Translational Breast Cancer Research Consortium.
Randomized phase III study of adjuvant chemotherapy for node-positive early breast cancer (BC) patients (pts) comparing epirubicin plus cyclophosphamide followed by docetaxel (EC-T) versus epirubicin plus docetaxel followed by capecitabine (ET-X): Efficacy analysis of the GEICAM/2003-10 trial.
Authors: Bermejo Begoña , Ruiz Amparo , Ruiz Borrego Manuel , Ribelles Nuria , Rodriguez-Lescure Alvaro , Munoz-Mateu Montserrat , Gonzalez Sonia , Margeli Mireia , Barnadas Agust , Ramos Vazquez Manuel , del Barco Sonia , Calvo Lourdes , Mendiola Cesar , Crespo Carmen , Rodriguez Cesar Augusto , Martinez Eduardo , Casas Maria Isabel , Camara M Carmen , Carrasco Eva Maria , Martin Miguel ,   Spanish Breast Cancer Research Group (GEICAM)
Published: March 2020

1027

Background: X is an active drug in metastatic breast cancer. GEICAM/2003-10 is an adjuvant trial investigating the integration of capecitabine into an epirubicin and docetaxel containing regimen for node-positive early breast cancer pts. Methods: Pts aged 18-70, with T1-T3/N1-3 operable BC were eligible. HER2+ pts were initially allowed. In October 2005, after 803 pts were included in the trial, the study was amended to exclude them. Pts were stratified by site, menopausal status, number of axillary nodes (1-3, 4-9, >9) and hormonal receptor status and randomized to receive EC (90/600 mg/m2 x4) followed by T (100 mg/m2 x4) or ET (90/75 mg/m2 x4) followed by X (1,250 mg/m2 BID, d1–14, x 4) all every three weeks. The primary endpoint was DFS. The trial was designed to detect an absolute 5-y DFS increase of 7% (72% EC-T, 79% ET-X); a sample size of 1,184 evaluable pts (592 per arm) was required to detect this difference (a=0.05, β=80%). Assuming a drop-out rate of 17%, 1,382 pts were required. The first analysis of DFS was planned after 290 events. Results: Between February 2004 and February 2007, 1384 pts (EC-T 669, ET-X 715) were randomized. Patient characteristics were balanced between arms, median age was 51, 84% of pts were HR positive and 11% HER2 positive; 66, 25 and 9% had 1-3, 4-9 and > 9 nodes respectively. The median relative dose intensity was 99% for EC, 99% for T, 99% for ET and 94% for X. The most frequent grade 3-4 toxicities (>5% in either arm) with EC-T vs. ET-X were neutropenia (19% vs. 10%) with 7% febrile neutropenia in both arms, hand-foot syndrome (2% vs. 20%), fatigue (13% vs. 11%), diarrhea (3% vs. 11%), stomatitis (6% vs. 5%) and vomiting (5% vs. 5%). After a median follow-up of 6.6 years and 292 events, the proportion of patients disease free at 5 years is 86% and 82% with EC-T and ET-X (HR for relapse 1.314, 95% CI: 1.042 – 1.657); log-rank p-value=0.0208. Overall survival was not different between treatment arms (HR 1.113, 95% CI: 0.809 – 1.531); log rank p-value=0.511. Conclusions: DFS has been in favour of EC-T in pts with node-positive early BC. Clinical trial information: NCT00129935.
Analysis of recurrence risk by subtype in ≤1 cm breast tumors.
Authors: Colonna Sarah V. , Higgins Ashantice K. , Alvarez JoAnn , Saville Benjamin R. , Lawrence Julia , Abramson Vandana Gupta
Published: March 2020

1034

Background: Triple-negative breast cancers (TNBC) comprise 15% of breast cancers and lack ER, PR, and HER2 expression. TNBC is biologically aggressive with high rates of recurrence, but little is known about the prognosis of small (≤1cm) TNBCs compared to similarly sized breast cancers with other receptor profiles. The role of adjuvant chemotherapy for TNBC that is ≤1cm remains unclear. Methods: Electronic medical records of all women aged ≥ 18 years with ≤1 cm, node negative, invasive breast cancer from 1997-2007 diagnosed or treated at Vanderbilt or Wake Forest were reviewed. Tumor grade, receptor status, treatment details, and follow up and recurrence information were tabulated. Rates of local and distant recurrence among three different receptor subtype categories, ER+ or PR+, HER2 negative; ER-/PR-, HER2 negative; or any ER/PR, HER2 positive were compared using chi-square tests. Results: 437 women with ≤1cm breast tumors were identified. Women with TNBC not given chemotherapy were more likely to have distant recurrence at 9% compared to 2% for ER+ or PR+, HER2 negative and 4% for any ER/PR, HER2 positive. There were no recurrences among the 14 women with ≤1cm TNBC who received chemotherapy. Conclusions: Based on our two institution review, women with ≤1 cm TNBC are at an increased risk for distant recurrence compared to other subtypes when not treated with adjuvant chemotherapy. Further studies to determine the benefit of adjuvant chemotherapy in this population are needed. [Table: see text]
A multicenter phase I-II trial of weekly paclitaxel and carboplatin plus bevacizumab in women with triple-negative metastatic breast cancer.
Authors: Saloustros Emmanouil S. , Polyzos Aristidis , Christophyllakis Charalampos , Kentepozidis Nikolaos K. , Vamvakas Lampros , Kalbakis Kostas , Agelaki Sofia , Georgoulias Vassilis , Mavroudis Dimitrios
Published: March 2020

1045

Background: Triple-negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents. The combination of carboplatin and paclitaxel administered weekly is active and well tolerated. Bevacizumab when added to paclitaxel prolonged progression-free survival in metastatic breast cancer (MBC). We investigated the activity and toxicity of paclitaxel plus carboplatin and bevacizumab in triple-negative MBC. Methods: The study’s primary objective was to estimate the objective response rate [complete (CR) + partial remission (PR)] and toxicity of the combination in women with triple negative MBC who had no prior chemotherapy for metastatic disease. The study followed the Simon's two-stage optimal design with 16 patients initially evaluated for response and toxicity and then expanding to a total of 46 patients. The null hypothesis that the objective response rate is ≤40% could be rejected if the number of CR/PR was ≥23. Paclitaxel 90mg/m2and Carboplatin AUC 2 were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. Results: 45 women with triple negative MBC have been recruited thus far. Of them, 12 were premenopausal and 27 had prior (neo-)adjuvant chemotherapy. The median cycles administered were 5 (range 1-8). Of 38 evaluable patients we observed 7 CR, 22 PR’s for an objective response rate 76%. Seven patients achieved stable disease, while two had disease progression. Median duration of response was 8.1 months with median time to progression 9.2 months. Neutropenia grade 3 and 4 was experienced by 13 and 6 patients, respectively, with one toxic death due to febrile neutropenia. Other grade 3 toxicities included anemia/neurotoxicity (n=2), thrombocytopenia/diarrhea (n=1). Conclusions: Although still ongoingthe study has achieved the primary objective of demonstrating clinical activity for weekly carboplatin and paclitaxel in combination with bevacizumab in triple negative MBC. We believe that this triplet combination merits further evaluation in this patient population for whom there is no standard treatment. Clinical trial information: NCT00691379.
A randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer: Kanagawa Breast Oncology Croup (KBOG) 1101 study.
Authors: Ishikawa Takashi , Shimizu Daisuke , Tanabe Mikiko , S.Oba Mari , Sasaki Takeshi , Morita Satoshi , Kida Kumiko , Nawata Shuichi , Mogaki Masatoshi , Doi Takako , Tsugawa Koichiro , Ogata Haruki , Kosaka Yoshimasa , Sengoku Norihiko , Suzuki Yasuhiro , Suto Akihiko , Chishima Takashi , Ichikawa Yasushi , Endo Itaru , Tokuda Yutaka ,   KBOG Study Group
Published: March 2020

1047

Background: Taxane-based regimens have been widely used to treat breast cancer. Accordingly, it has become important to identify subgroups in which anthracyclines are indispensable. Thus, we initiated a randomized phase II neoadjuvant chemotherapy (NAC) study to compare taxane with and without anthracycline in hormone-negative subtypes. Methods: Eligibility criteria were hormone-negative, an age younger than 80 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m2) q3wks ×6 or FEC (500/100/500 mg/m2) q3wks ×3 followed by D (100 mg/m2) q3wks ×3. The primary endpoint was the rate of pathological complete response (pCR; Grade 3 and Quasi-pCR; Grade 3+2b). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (HER2, Ki-67, P-53, CK5/6, EGFR, and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: 97 out of 103 patients were successfully analyzed (47 for TC6 and 50 for FEC-D). Severe adverse events (Grade ≥2) were frequently observed in FEC-D-treated patients with statistical significance (poor appetite, nausea/vomiting: p<0.001; febrile neutropenia: p=0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with that of TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.; Quasi-pCR: 46.0 vs. 40.4%, n.s.). There was no significant difference of pCR rates in the HER2 and triple negative (TN) subtypes between each regimen. Among predictors, only positive markers CK5/6 and EGFR predicted the superiority of the FEC-D treatment (p=0.05). Conclusions: TC6 was safe and relatively active even in HER2 subtype patients. Therefore, the concurrent use of trastuzumab with TC could be a reasonable option for NAC in HER2 subtype patients. However, anthracyclines are required to treat basal-type TN cancer. Clinical trial information: UMIN000002215.