bluuebunny/crossref_metadata_2025 huggingface dataset:
Frailty among childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Hayek Samah , Gibson Todd M. , Leisenring Wendy , Guida Jennifer Lyn , Gramatges Maria Monica , Lupo Philip , Howell Rebecca M. , Oeffinger Kevin C. , Bhatia Smita , Edelstein Kim , Hudson Melissa M. , Robison Leslie L. , Nathan Paul C. , Yasui Yutaka , Krull Kevin R. , Armstrong Gregory T. , Ness Kirsten K.
Published: May 2019

10026

Background: Childhood cancer survivors are at increased risk for frailty, which is a loss of physiological capacity that is typically observed among older adults. Aims: Estimate the prevalence of frailty among survivors, and examine direct and indirect effects of treatment, lifestyle, and chronic disease factors on frailty. Methods: CCSS participants who were > 5-year survivors of childhood cancer, diagnosed between 1970-1999 at <21 years of age (n=10,899, 48% male), and siblings (n=2,097, 42% male) were included. Frailty was defined from self-reported data at mean ages of 37.6±9.4 and 42.9±9.8 years for survivors and siblings, respectively, as ≥3 of the following: low lean mass, exhaustion, low energy expenditure, slow walking, and weakness. Results: The prevalence of frailty among survivors was higher compared to siblings (5.8%, 95% CI: 5.4-6.3% vs. 1.9%, 95% CI 1.4-2.5%). Prevalence was highest in survivors of CNS tumors (9.5%, 5.2-13.8%), bone sarcomas (8.1%, 5.1-11.1%) and Hodgkin lymphoma (7.5%, 4.9-10.1%). In models adjusted for sex, age at assessment, and race/ethnicity, treatment exposures were associated with frailty (Table). After adjusting for the presence of chronic diseases and lifestyle factors, these associations were attenuated. Conclusions: The prevalence of frailty among survivors (6.0% at 38 years of age) was similar to the general population aged ≥65 years (9.0%). Radiation, platinum, amputation and thoracotomy increased risk for frailty. Findings suggest interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to preserve function in this population. [Table: see text]
A phase II trial testing interventions to shorten time to diagnosis and reduce abandonment of treatment of children with Burkitt lymphoma in Kenya.
Authors: Langat Sandra , Njuguna Festus , Mostert Saskia , Lotodo Therese , Kigen Nikol , Boaz Odwar , Kaspers Gert Jan , Moormann Ann , Vance Gail , Loehrer Patrick J. , Vik Terry
Published: May 2019

10032

Background: Burkitt Lymphoma (BL) is a common pediatric cancer in sub-Saharan Africa. Despite advances in care, prognosis is poor. The BL treatment protocol at our center in Kenya used since 2010, had a one-year survival of 29% (Martijn et al. BMJ Paed Open 2017). We hypothesized that financial burdens and delays in start of therapy impact outcomes. Methods: Our trial tested interventions aimed to: 1) Shorten time from presentation to start of treatment to improve survival; and 2) Support families during therapy to reduce abandonment. Initial eligibility included clinical suspicion of BL in a child 0-13 years of age. Patients with confirmed diagnosis of a mature B-cell lymphoma received support to complete therapy. Children with prior treatment of cancer were excluded. The trial was approved by human protection boards in Kenya and Indiana and consent was obtained prior to study entry. We enrolled 96 children with possible BL. Study personnel expedited routing of tissue samples to laboratories. Touch preps or smears were stained with Giemsa and reviewed by pathologists. Fresh tissue from all sources was used for flow cytometry. Tissue from core needle or incisional biopsies was processed for routine and immunohistochemical staining. Of 96 patients, 43 had BL confirmed by pathologic studies and were treated with combination chemotherapy given over 25 weeks. We paid families for transport costs for care, called after missed appointments, and provided direct monetary support (~$200 USD) for the 200 days children were on treatment. Results: Facilitating the biopsy shortened, by 3 days, the median time from admission to initiation of therapy for BL, because families did not need to raise funds for testing. Monetary support reduced abandonment of treatment by patients. Only 2 of 43 (5%) patients abandoned therapy, compared to abandonment by 22 of a cohort of 63 (35%) patients treated previously (p < 0.001). The combination of rapid diagnosis, early therapy, and financial support and communication with families improved event free survival of children with BL to 50% at 1 year (p = 0.045). Conclusions: Simple interventions to improve efficiency of diagnosis and reduce abandonment leads to improved outcomes for children with BL in Kenya.
Impact of low-income public insurance on survival for children and young adults with bone and soft tissue sarcomas.
Authors: Penumarthy Neela Lakshmi , Goldsby Robert , Penumarthy Lena
Published: May 2019

10037

Background: Racial and ethnic survival disparities have been described for many pediatric malignancies, but the impact of income has not been extensively explored. To assess whether socioeconomic status affects outcomes, we evaluated low-income public health insurance as a proxy. We analyzed how low-income public health insurance influences overall survival in children, adolescents, and young adults diagnosed with bone and soft tissue sarcomas. Methods: The University of California San Francisco Cancer Registry was used to identify patients age 0-39 diagnosed with bone or soft tissue sarcomas between 2000-2015. Low-income patients were defined as those with Medicaid, which is only available under state law to eligible low-income individuals or families, or those with no insurance. The comparison group included all other patients with private insurance, Medicare, or Tricare. Survival curves were computed using the Kaplan-Meier method and compared using log-rank tests and Cox models. Logistic regression was used to investigate the association of low-income public insurance and presence of metastatic disease at diagnosis. Results: A total of 1,106 patients were included in the analysis. 444 (40%) were considered low-income; of these, 428 (39%) had public insurance and 16 (1%) had no insurance. Low-income patients were more likely to both be racial/ethnic minorities and present with metastatic disease on multivariable analysis. Low-income patients had significantly worse 5-year OS (61% vs 71%, p = 0.0003). When stratified by localized, regional, or metastatic disease, low-income patients consistently had significantly worse 5-year OS (localized: 78% vs 84%, regional: 64% vs 73%, metastatic: 23% vs 30% respectively, p < 0.0001). Age and race/ethnicity did not significantly impact OS in this study population. Conclusions: Low-income patients with bone and soft tissue sarcomas had decreased overall survival. While these patients were more likely to have metastatic disease, disparities in survival were noted even within the localized and regional disease groups. The means by which insurance status impacts survival requires additional investigation, but may be through reduced access to care.
Evaluation of the multi-kinase inhibitor regorafenib in the Pediatric Preclinical Testing Consortium osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma in vivo models.
Authors: Harrison Douglas James , Gill Jonathan Benjamin , Roth Michael , Zhang Wendong , Teicher Beverly , Erickson Stephen W , Gatto Gregory , Kurmasheva Raushan , Houghton Peter , Smith Malcolm A. , Kolb E. Anders , Gorlick Richard Greg
Published: May 2019

10038

Background: Regorafenib is a multi-kinase inhibitor, developed by adding a fluorine atom to the phenyl ring of sorafenib. Regorafenib inhibits multiple kinases including BRAF, FGFR1, KIT, PDGFRB, RAF, RET, and VEGFR1-3, many at a higher potency than sorafenib. Prior studies within the Pediatric Preclinical Testing Consortium (PPTC) demonstrated sorafenib exhibited intermediate activity for tumor growth inhibition in more than 50% of the sarcoma models tested at a dose of 60mg/kg by oral gavage daily (5 days/wk for 6 consecutive weeks). The in vivo effects of regorafenib were studied in the PPTC osteosarcoma (OS), rhabdomyosarcoma (Rh) and Ewing (EW) sarcoma xenograft models. Methods: The in vivo anticancer effects of regorafenib were assessed in a panel of 6 osteosarcoma models (OS2, OS9, OS31, OS33, OS36, OS60), two rhabdomyosarcoma models (Rh30, Rh41), and one Ewing sarcoma model (EW5). Regorafenib was administered by oral gavage at a dose of 30 mg/kg/day given daily for 21 consecutive days. Time to event and tumor volume responses were defined and analyzed utilizing standard PPTC statistical methods. Results: Regorafenib induced significant improvements in event-free survival (EFS) compared to control in 100% (9/9) of sarcoma models tested. Most models showed pronounced slowing of tumor growth compared to control during the 21 days of regorafenib treatment, with tumor growth generally approximating control rates soon after completion of regorafenib treatment. Three out of 8 sarcoma models demonstrated EFS T/C values > 2 (1/6 OS, 2/2 Rh, 0/1 EW). Minimum relative tumor volumes ranged from 0.74 to 1.60, with no models meeting criteria for objective response. Conclusions: Regorafenib induced modest inhibition of tumor growth in the PPTC sarcoma models evaluated. The overall pattern of response to the multi-kinase inhibitor regorafenib against the PPTC sarcoma models appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models that is limited to the period of agent administration being the primary treatment effect.
Patient-reported outcomes (PROs) in adult survivors of childhood hematopoietic cell transplant (HCT): A report from the St. Jude lifetime cohort study.
Authors: Bhatt Neel S. , Yen Hsiu-Ju , Eissa Hesham M. , Huang Sujuan , Ehrhardt Matthew J. , Bhakta Nickhill , Ness Kirsten K. , Krull Kevin R. , Srivastava Deo Kumar , Robison Leslie L. , Hudson Melissa M. , Huang I-Chan
Published: May 2019

10049

Background: We examined PROs including symptom prevalence and quality of life (QOL) in adult survivors of childhood HCT compared to those treated with conventional therapy and non-cancer controls, and risk factors of impaired PROs. Methods: Physical and psychological symptoms and QOL were reported by 112 survivors of hematologic malignancies treated with HCT, 1106 treated with conventional therapy, and 242 non-cancer controls. PROs were self-reported using a survey, which included demographics, Brief Symptom Inventory and 36-Item Short Form Survey. Each participant completed a clinical physical health assessment and chronic health conditions (CHCs) were graded using a modified Common Terminology Criteria for Adverse Events. Multivariable logistic regression was conducted to estimate odds ratios (OR) and 95% confidence intervals (CI) for PROs using demographics and CHCs as predictors. Results: HCT and conventional therapy survivors’ mean age at survey and time since diagnosis were 28 and 29 years, and 19 and 20 years, respectively. The mean age at survey for non-cancer controls was 35 years. HCT survivors reported high prevalence of pain (64%), sensory (39%) and memory problems (29%), anxiety (29%), and depression (24%), which was not significantly different from survivors treated with conventional therapy. Compared to non-cancer controls, HCT survivors had more sensory (OR 3.2; 95% CI 1.5-6.8), motor (OR 4.3; 95% CI 1.2-15.4), and memory (OR 3.7; 95% CI 1.5-8.9) problems, and worse physical QOL (OR 5.4; 95% CI 1.6-18.6). Presence of PROs were associated with organ-specific CHCs (grade 3-4 vs. grade 0-2) not receipt of HCT: cardiac symptoms with cardiovascular CHCs (OR 3; 95% CI 1.8-4.9), pulmonary symptoms with pulmonary CHCs (OR 2.5; 95% CI 1.4-4.3), nausea with gastrointestinal CHCs (OR 2; 95% CI 1.2-3.1), and sensory (OR 1.9; 95% CI 1.2-3.1) and motor (OR 3.3; 95% CI 2-5.5) problems with neurological CHCs. Conclusions: Prevalence of symptoms and impaired QOL in HCT survivors is comparable to survivors treated with conventional therapy, but higher than non-cancer controls. PROs may have a role in facilitating identification of adverse events in survivors.
Long term morbidity and mortality among survivors of infant neuroblastoma: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Friedman Danielle Novetsky , Goodman Pamela J , Leisenring Wendy , Diller Lisa , Cohn Susan Lerner , Tonorezos Emily S. , Howell Rebecca M. , Smith Susan A , Wolden Suzanne L. , Nathan Paul C. , Neglia Joseph Philip , Ness Kirsten K. , Robison Leslie L. , Oeffinger Kevin C. , Armstrong Gregory T. , Sklar Charles A. , Henderson Tara O.
Published: May 2019

10051

Background: Infants with neuroblastoma typically have low-risk disease with excellent survival. Therapy has been de-intensified over time to minimize late effects, however the impact on survivors’ risk of late mortality, subsequent malignant neoplasms (SMN), and chronic health conditions (CHC) is unclear. Methods: We evaluated late mortality, SMNs and CHCs (graded according to CTCAE v4.03), overall and by diagnosis era, among 990 5-year neuroblastoma survivors diagnosed at < 1 year of age between 1970-1999. Cumulative mortality, standardized mortality ratios (SMR), and standardized incidence ratios (SIR) of SMNs were estimated using the National Death Index and SEER rates, respectively. Cox proportional hazards estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC, compared to 5,051 CCSS siblings. Results: Among survivors (48% female; median attained age: 24 years, range 6-46), there was increased treatment with surgery alone across the 1970s, 1980s and 1990s (21.5%, 35.3%, 41.1%, respectively), but decreased treatment with combination surgery + radiation (22.5%, 5.3%, 0.3%, respectively) and surgery + radiation + chemotherapy (28.7%, 14.7%, 9.3%, respectively). The 20-year cumulative mortality was 2.3% (95% CI, 1.4-3.8), primarily due to SMNs (SMRSMN= 10.0, 95% CI, 4.5-22.3). The 20-year cumulative incidence of SMN was 1.2% (95% CI, 0.3-3.2), 2.5% (95% CI, 1.3-4.4), and zero for those diagnosed in the 1970s, 1980s, and 1990s, respectively. SIR was highest for renal SMNs (SIR 12.5, 95% CI, 1.7-89.4). Compared to siblings, survivors were at increased risk for grade 1-5 CHC (HR 2.1, 95% CI, 1.9-2.3) with similar HR across eras (HR1970s= 1.9, 95% CI, 1.6-2.2; HR1980s= 2.2, 95% CI, 1.9-2.6; HR1990s= 2.0, 95% CI, 1.7-2.4). The HR of severe, disabling, life-threatening and fatal CHC (grades 3-5) decreased in more recent eras (HR1970s= 4.7, 95% CI, 3.4-6.6; HR1980s= 4.4, 95% CI, 3.2-6.2; HR1990s= 2.9, 95% CI, 2.0-4.3). Conclusions: Survivors of infant neuroblastoma remain at increased risk for late mortality, SMN, and CHCs many years after diagnosis. However, the risk of grade 3-5 CHCs has declined in more recent eras, likely reflecting de-intensification of therapy.
Cost-effectiveness of screening guidelines to prevent heart failure in childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Ehrhardt Matthew J. , Ward Zachary J. , Liu Qi , Chaudhry Aeysha , Nohria Anju , Border William L. , Robison Leslie L. , Armstrong Gregory T. , Yasui Yutaka , Hudson Melissa M. , Diller Lisa , Armenian Saro , Yeh Jennifer
Published: May 2019

10052

Background: Childhood cancer survivors treated with anthracyclines or chest radiation therapy (RT) are at risk for left ventricular dysfunction (LVD) and subsequent heart failure (HF). The International Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms for LVD, but evidence supporting its frequency and cost-effectiveness is limited. Methods: Using data from the CCSS, we developed a microsimulation model of the clinical course of LVD and HF to estimate long-term health and economic outcomes associated with screening for IGHG-defined risk groups (low [anthracycline 1-99 mg/m2 and/or RT < 15 Gy], moderate [100 to < 250 mg/m2 or 15 to < 35 Gy], high [≥ 250 mg/m2 or ≥ 35 Gy or (≥ 100 mg/m2 and ≥ 15 Gy)]). We compared 1, 2, and 5-year interval-based screening to no screening. Screening performance and pharmacological treatment effectiveness were based on published studies. Costs and quality of life weights were based on US averages and published studies. Outcomes included lifetime HF risk, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs < $100,000/QALY gained were considered cost-effective. Results: Among the IGHG risk groups, the lifetime HF risk in the absence of screening was 37% (high), 25% (moderate) and 17% (low). Screening every 2 or 5 years was cost-effective for the high-risk group, and every 5 years for the moderate-risk group. In contrast, routine screening may not be cost-effective for the low risk group, representing ~40% of those for whom screening is currently recommended. Conclusions: Our findings can inform screening guidelines and suggest that LVD/HF surveillance for low-risk survivors warrants careful consideration. [Table: see text]
Incidence and predictors of significant hearing loss requiring hearing assistive devices among childhood cancer survivors: A population-based study.
Authors: Gupta Sumit , Lau Cindy , Cooke Bonnie , Hall Stephen , Nathan Paul C. , Beyea Jason
Published: May 2019

10055

Background: Though hearing loss is a significant late effect among childhood cancer survivors, recent guidelines note insufficient evidence to quantify natural history or risk associated with specific exposures. We examined the long-term incidence and predictors of hearing loss requiring hearing amplification devices (HAD) using population-based healthcare data. Methods: In Ontario, Canada, HAD costs are subsidized by the provincial Assistive Devices Program (ADP). Ontario children age <18 years at cancer diagnosis between 1987-2016 were identified using a pediatric cancer registry and linked to ADP claims. The cumulative incidence of HAD use was compared between cases and matched controls. Patient, disease, and treatment predictors of HAD were examined. Results: We identified 11,842 cases and 59,210 matched controls. Cases were at higher risk of HAD [hazard ratio (HR) 12.8, 95% confidence interval (95CI) 9.8-16.7; p<0.001]. The cumulative incidence of HAD among survivors was 2.1% (95CI 1.7-2.5%) at 20-years and 6.4% (95CI 2.8-12.1%) at 30-years. 30-year incidence was highest in survivors of neuroblastoma (10.7%, 95CI 3.8-21.7%) and hepatoblastoma (16.2%, 95CI 8.6-26.0%). Predictors of HAD in multivariable analyses included age 0-4 years at diagnosis (vs. 5-9 years, HR 2.2, 95CI 1.4-3.3; p<0.001). Relative to no cisplatin exposure, patients receiving 1-200mg/m2 were not at greater risk, unlike those receiving higher cumulative doses (Table). Relative to no radiation, those receiving ≤32Gy were at no higher risk, unlike while those receiving >32Gy. Carboplatin exposure was not associated with HAD. Conclusions: Childhood cancer survivors are at elevated risk of requiring HAD which continues to rise between 20 and 30 years from diagnosis. Thresholds of cisplatin and radiation exposure exist above which risk substantially increases. Prolonged monitoring and trials of otoprotective agents are warranted in high-risk populations. [Table: see text]
Emergency department (ED) visits and hospitalizations in survivors of childhood cancer in the Childhood Cancer Survivor Study.
Authors: Arsenault Valerie , Qiu Weiyu , Liu Qi , Yeh Jennifer , Leisenring Wendy , Ness Kirsten K. , Armstrong Gregory T. , Henderson Tara O. , Walsh Alexandra Maria , Yabroff K Robin , Oeffinger Kevin C. , Hudson Melissa M. , Yasui Yutaka , Nathan Paul C.
Published: May 2019

10056

Background: Chronic health conditions are frequent among childhood cancer survivors and lead to increased health care resource utilization. We compared rates of ED visits and hospitalizations between survivors and siblings. Methods: Analyses included 10,762 ≥5-year survivors and 2,069 siblings who completed a questionnaire from 2014-2016. We calculated ED visits and non-obstetric hospitalizations in the last 12 months per 1,000 person-years (PY) and evaluated cause-specific hospitalization rates using ICD-10 categories. Multivariable Poisson regression models evaluated predictors of survivor visits. Results: Median age in survivors and siblings was 35.3 years (interquartile range [IQR] 29.0-43.1) and 42.9 years (IQR 35.6-50.2), respectively; time from cancer diagnosis was 27.8 years (IQR 21.7-34.1). 24.2% of survivors and 16.2% of siblings had ≥1 ED visit (p < 0.001); rates were 521/1,000 PY for survivors and 246/1,000 PY for siblings (age/sex-adjusted relative rate [RR] 2.0; 95% confidence interval [CI] 1.7 - 2.3). Factors associated with increased survivor ED visits were black race (RR 1.6, CI 1.2-2.0), being obese (RR 1.4, CI 1.2-1.7) or underweight (RR 1.9, CI 1.2-3.0), female sex (RR 1.3, CI 1.1-1.5), younger age (p = 0.02) or abdomen/pelvis (RR 1.2, CI 1.1-1.4) or brain irradiation (RR 1.2, CI 1.0-1.4). 13.3% of survivors and 8.3% of siblings had ≥1 hospitalization (p < 0.001); rates were 219/1,000 PY for survivors and 130/1,000 PY for siblings (RR 1.9; CI 1.3 - 2.9). Factors associated with increased survivor hospitalizations were female sex (RR 1.3, 1.1-1.5), younger age (p < 0.0001), being obese (RR 1.3, CI 1.0-1.6) or underweight (RR 1.5, 95% CI 1.1-2.2) or platinum chemotherapy exposure (RR 1.6, CI 1.3-2.0). The most common indications for hospitalization were diseases of the digestive (21.9/1,000 PY; CI 18.7 - 25.7) and circulatory (20.9/1,000 PY; CI 17.8 – 24.4) systems. Leukemia survivors had the highest ED visit and hospitalization rates. Conclusions: Childhood cancer survivors had a 2-fold increased likelihood of an ED visit or hospitalization compared with their siblings. This increases the economic burden on survivors and the health care system.
Progression of frailty in young adult survivors of childhood cancer: St. Jude Lifetime Cohort.
Authors: Ness Kirsten K. , Partin, MS Robyn , Howell Carrie R. , Krull Kevin R. , Brinkman Tara M. , Armstrong Gregory T. , Chemaitilly Wassim , Wilson Carmen Louise , Mulrooney Daniel A. , Gibson Todd M. , Lanctot Jennifer Q. , Johnson Ruth E , Krull Matthew R , Shelton Kyla C. , Srivastava Deo Kumar , Robison Leslie L. , Hudson Melissa M.
Published: May 2019

10057

Background: Childhood cancer survivors are at risk for premature aging; over 8% (ages18-60 years) meet Fried Frailty Criteria (≥3 of low lean muscle mass, muscle weakness, slow walking speed, exhaustion, low energy expenditure). Longitudinal changes and new onset frailty has not been studied. Methods: Childhood cancer survivors (N = 1501, 51.5% male, 14.9% black, median age at diagnosis 7 [0-22] years), were evaluated clinically to ascertain frailty at baseline (median age 30 [18-45] years) and five years later. Risk factors for incident frailty and impact of baseline frailty on mortality were evaluated in proportional hazard models. Results: Frailty increased from 6.0% (95% CI 4.1-8.9) to 11.7% (95% CI 6.7-12.2) overall, and for all diagnoses (Table). Risk factors for new onset frailty among those not frail at baseline were amputation (HR 5.1, 95% CI 1.1-14.4), anthracyclines (HR 1.2, 95% CI 1.1-1.4 per 100 mg/m2), and carboplatin (HR 1.3, 95% CI 1.1-1.5 per 2000 mg/m2). Severe, disabling or life threatening chronic conditions (HR 1.2, 95% CI 1.1-1.4 per organ system) and inactivity (HR 2.0, 95% CI 1.2-3.2) also predicted new onset frailty. Sixty-nine participants died from baseline to follow-up. Accounting for age, sex and chronic conditions, baseline frailty was associated with a 2.9 (95% CI 1.6-5.2) increased hazard of death. Conclusions: Prevalent frailty nearly doubled in five years and was associated with increased risk for death. Given that previous treatment exposures cannot be altered, interventions to remediate chronic disease and promote activity may impact function and longevity for childhood cancer survivors. [Table: see text]
Polygenic risk of subsequent thyroid cancer after childhood cancer: A report from St. Jude lifetime cohort (SJLIFE) and Childhood Cancer Survivor Study (CCSS).
Authors: Wang Zhaoming , Liu Qi , Wilson Carmen Louise , Sapkota Yadav , Gibson Todd M. , Morton Lindsay M. , Sampson Joshua N , Neglia Joseph Philip , Arnold Michael A. , Rusch Michael C , Mulder Heather , Easton John , Zhang Jinghui , Downing James , Bhatia Smita , Armstrong Gregory T. , Chemaitilly Wassim , Hudson Melissa M. , Robison Leslie L. , Yasui Yutaka
Published: May 2019

10060

Background: Subsequent thyroid cancer (STC) is among the most common malignancies in childhood cancer survivors, especially those with thyroid exposure to radiotherapy (RT). Identification of genetic risk factors may inform screening practices. Methods: Twelve SNPs were previously identified as thyroid cancer risk loci in the general population of European ancestry. A polygenic risk score (PRS) was calculated as a sum of risk alleles carried by a survivor, weighted by the natural logarithm of the published per-allele odds ratios (range: 1.2-1.8). With piecewise exponential models, associations of STC rates with PRS were assessed, both overall and stratified by neck RT exposure. Models were adjusted for sex, age at primary diagnosis, attained age, neck RT dose, epipodophyllotoxin therapy, and eigenvectors within survivors of European ancestry from SJLIFE with whole-genome sequencing data and CCSS with SNP data imputed to Haplotype Reference Consortium. Results: Among 2,324 SJLIFE survivors, 61 (43 with, 18 without neck RT) developed STC. The rate of STC was increased by 5.3-fold (95% confidence interval (CI), 2.2-12.6) and 3.1-fold (CI, 1.3-7.7) for survivors in the third and second PRS tertiles, respectively, compared to those in the first tertile, with corresponding cumulative incidence at age of 40 years of 5.3% (CI, 3.3-7.3%), 2.5% (CI, 1.1-3.9%), and 1.0% (CI, 0.005-2.0%), respectively. Stratified by neck RT, the corresponding rate increases were 7.6 (CI, 2.3-25.3) and 3.8 (CI, 1.1-13.4), respectively, among survivors exposed to neck RT; however, no association was observed among survivors without neck RT (only 18 STC cases). Replication was performed among 4,302 CCSS survivors, 100 (61 with, 39 without neck RT) developed STC. The rates of STC were increased by 2.3-fold (CI, 1.4-3.9) and 1.7-fold (CI, 1.0-2.9) for survivors in the third and the second PRS tertiles, compared to those in the first tertile. The similar significant associations were observed in survivors with and without neck RT ( Ptrend = 0.04 and 0.02, respectively). Conclusions: High PRS conferring STC risk can inform screening practices and help personalize and improve survivorship care.
Educational attainment in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Bashore Lisa , Merchant Zahra , Lupo Philip , King Allison A. , Hamby Tyler , Srivastava Deokumar , Howell Rebecca M. , Gibson Todd M. , Oeffinger Kevin C. , Armstrong Gregory T. , Bowman W. Paul , Krull Kevin R.
Published: May 2019

10063

Background: Diagnosis and treatment of childhood cancer place survivors at risk for lower educational attainment, the increased burden of chronic conditions on attainment has not been examined. Methods: Participants included 16724 survivors (48% female; mean diagnosis age 9.1 years, current age 36.2 years, time since diagnosis 26.6 years) and 4098 siblings (mean current age 39.3 years) Educational attainment was categorized as college graduation (yes/no) among survivors ≥ age 25 years. Chronic conditions occurring before age 25 years of age were graded using Common Terminology for Adverse Events 4.3. Modified Poisson regression models estimated relative risks (RR) and 95% confidence intervals (CI) of treatment exposures and chronic conditions on education attainment, adjusting for age at diagnosis and sex. Results: College graduation was reported by 8391 (51%) survivors and 2410 (59%) siblings. Survivors of all diagnoses were more likely to not graduate compared to siblings (all p’s < 0.05), with survivors of CNS tumor (RR1.36, CI 1.25-1.49), leukemia (RR 1.17, CI 1.07-1.28), and Hodgkin lymphoma (RR 1.17, CI 1.07-1.29) being at higher risk than survivors of neuroblastoma. Compared to survivors with no history of cranial radiation therapy (CRT), higher risk of not graduating college was seen in those who received 20-30Gy (RR 1.16, CI 1.09-1.25), 30-50Gy (RR 1.37, CI 1.26-1.49) and ≥50Gy (RR 1.35, CI 1.28-1.42). Among survivors not exposed to CRT, dexamethasone had a protective effect on college education (RR 0.88, CI 0.80-0.97) compared to no corticosteroid exposure. Male sex and older age (≥ 5 years) at diagnosis were associated with being more likely to not graduate college. survivors reporting any serious/life threatening chronic condition prior to age 25 years (grades 3-4) were more likely to not graduate college (RR 1.14, 95% CI 1.10-1.18) compared to no or mild/moderate conditions (grades < 3). Conclusions: Survivors reporting chronic conditions are less likely to complete a college education by age 25 years and may need additional early educational or vocational resources.
Performance of FACT-GOG-Ntx to assess chemotherapy-induced peripheral neuropathy (CIPN) in pediatric Hodgkin lymphoma (HL) patients.
Authors: Castellino Sharon M. , Rodday Angie Mae , Pei Qinglin , Bush Rizvan , Keller Frank G. , Henderson Tara O. , Kelly Kara M. , Cella David , Parsons Susan K.
Published: May 2019

10064

Background: CIPN is a common, but under-recognized complication of tubulin toxins, which are key to curative therapy for HL. In the absence of validated, self- or proxy-report measures for children, CIPN reporting has depended on clinical grading scales. The goal of this study was to assess the psychometric properties of the FACT-GOG-Ntx measure in a pediatric population. Methods: Youth (11+ yrs) and parents of all children (5-18 yrs) with newly diagnosed high risk HL, enrolled on AHOD1331 (NCT02166463), serially completed the FACT-GOG-Ntx, a validated measure of CIPN in adults. Cronbach’s alpha coefficient (reliability) and intra-class coefficients (ICC) were calculated. FACT-GOG-Ntx total scale and 4-item sensory subscale scores (Ntx4) at Cycle 5 (dose peak) and 6-8 weeks after last cycle (End Rx) were compared to mandatory clinical grading, using the Balis Scale with any neuropathy defined as > grade 1 on Balis. Results: 279 youth and 291 parents completed study measures. Cronbach’s alpha exceeded 0.80 for both raters. Inter-rater agreement was strong (ICC=0.89). Sixty (20%) patients had any neuropathy on Balis. Those with CIPN had significantly lower total and Ntx4 scores than those without at cycle 5 and End Rx and for both raters (p<0.05) (Table). Conclusions: This is the first application of the FACT-GOG-Ntx in a pediatric HL trial. We demonstrate that the measure was reliable for both raters and had strong intra-rater agreement. Validity was demonstrated by significantly lower FACT-GOG-Ntx scores among patients with evidence of CIPN on clinical exam. Comparisons between study arms will be evaluated after study accrual is completed. [Table: see text]
Molecular profiling of ER+ metastatic breast cancers to reveal association of genomic alterations with acquired resistance to CDK4/6 inhibitors.
Authors: Razavi Pedram , dos Anjos Carlos Henrique , Brown David N , Qing Li , Ping Christina , Herbert Joshua , Colon Jodecy , Liu Dazhi , Mao Maiya , Norton Larry , Scaltriti Maurizio , Solit David B. , Robson Mark E. , Reis-Filho Jorge S. , Jhaveri Komal L. , Chandarlapaty Sarat
Published: May 2019

1009

Background: Genomic profiling of ER+ metastatic breast cancer (MBC) has revealed highly prevalent genomic alterations (e.g. ESR1, NF1, ERBB2) associated with exposure to antiestrogen therapy and endocrine resistance. It is not known whether any such acquired genomic alterations are observed after exposure to now standard CDK4/6 inhibitors (CDK4/6i). Methods: To identify genomic alterations associated with acquired resistance to CDK4/6i + antiestrogen combinations, we prospectively performed tumor and matched normal sequencing on 1059 ER+ breast cancers from 845 MBC patients collected prior to (n = 838) or post-treatment with CDK4/6i (n = 221), including 110 pre- and post-treatment pairs. We performed gene enrichment analyses to identify the oncogenic mutations and copy number alterations that were more frequent in post-CDK4/6i samples compared to CDK4/6i-naïve samples and further compared these results to those of post-hormone alone therapy datasets. Results: The post-CDK4/6i samples were collected following exposure to CDK4/6i plus aromatase inhibitors (51%), plus fulvestrant (28%), or multiple/other (21%). Along with alterations previously associated with resistance to hormonal therapy alone, our analysis identified multiple genes to be specifically enriched in the post-CDK4/6i tumors. Among these, loss-of-function alterations in RB1 were significantly enriched in the post-CDK4/6i compared to CDK4/6i-naïve samples (7.9% vs. 2.7%, p-value = 1.5e-5). The majority of the RB1 mutations in the post-CDK4/6i tumors had loss of heterozygosity (LOH), while LOH was uncommon in the CDK4/6i-naive tumors. Additionally, multiple alterations in effectors of PI3K/AKT signaling (excluding PIK3CA), cell cycle (such as CDKN2A loss) and in Hippo signaling were more frequent in the post-CDK4/6i tumors. Conclusions: This large clinico-genomic analysis of the post- and pre-CDK4/6i MBCs reveals multiple genomic lesions to be enriched after exposure to CDK4/6i, highlighting therapy-related genomic evolution as a recurrent phenomenon and identifying unique genomic subsets that have strong potential to alter the benefit of subsequent lines of therapies.
A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC).
Authors: Anders Carey K. , Le Rhun Emilie , Bachelot Thomas Denis , Yardley Denise A. , Awada Ahmad , Conte Pier Franco , Kabos Peter , Bear Melissa , Yang Zhengyu , Chen Yanyun , Tolaney Sara M.
Published: May 2019

1017

Background: Abemaciclib is a selective CDK4 & 6 inhibitor approved to treat HR+, HER2- MBC pts on a continuous dosing schedule as monotherapy or in combination with endocrine therapy (ET). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma. Methods: JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ MBC, non-small cell lung cancer, or melanoma. Here, we report on HR+, HER2- MBC pts. Eligible pts had ≥1 new or not previously irradiated measurable BM ≥10mm or a progressive previously irradiated BM. Pts receiving ET at the time of enrollment were permitted to continue the same ET provided that extracranial (EC) disease was stable ≥3 months and the CNS progression occurred on the ET. Abemaciclib was orally administered 200mg BID. Primary endpoint was objective intracranial response rate (OIRR; [CR+PR]) based on Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, and safety. Results: 58 HR+, HER2- MBC pts were enrolled and 52 pts were evaluable. Pts had a median of 4 prior systemic therapies, 75% of pts had prior chemotherapies (0-6, median of 2), and 71% of pts had prior ET (0-4, median of 1), in the metastatic setting. 50% of pts had prior whole brain radiotherapy, 39% stereotactic radiosurgery, and 8% surgical resection of BM. Median time from radiation to study enrollment was 9.4 months. Out of the 52 evaluable patients, 3 pts had a confirmed intracranial response (6% OIRR), and 38% of pts showed a decrease in the sum of their intracranial target lesions. Intracranial clinical benefit rate (CR+PR+SD persisting for ≥ 6 months) was 25%. Median PFS was 4.4 months (95% CI, 2.6-5.5). Safety and tolerability were similar to previous reports for abemaciclib. Conclusions: Abemaciclib demonstrated intracranial clinical benefit in heavily pretreated HR+, HER2- MBC pts with BM in this study. Further evaluations are ongoing to identify ABC patients with BM who might benefit most from abemaciclib. Clinical trial information: NCT02308020.
In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial.
Authors: Lu Yen-Shen , Hurvitz Sara A. , Su Fei , He Wei , Tripathy Debu , Campos Gomez Saul , Jung Kyung Hae , Colleoni Marco , Wheatley-Price Paul , Kuemmel Sherko , Harbeck Nadia , Franke Fabio Andre , Im Seock-Ah , Chow Louis , Taran Tetiana , Rodriguez-Lorenc Karen , Babbar Naveen , Bardia Aditya
Published: May 2019

1018

Background: The Phase III MONALEESA-7 study (NCT02278120) is the first dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in premenopausal patients (pts) with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) ABC. The study demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended progression-free survival (PFS; hazard ratio [HR] 0.55; Tripathy D, et al. Lancet Oncol. 2018). Here we present a gene expression analysis of baseline tumor mRNA from MONALEESA-7. Methods: Premenopausal pts with HR+/HER2− ABC were treated with RIB or placebo (PBO) + GOS with either an NSAI (letrozole or anastrozole) or TAM. Baseline archival tumor samples from 360 of 672 intent-to-treat (ITT) pts were evaluated for gene expression (RIB n = 185; PBO n = 175) using a customized NanoString nCounter® GX 800-gene panel containing relevant breast cancer, CDK, and proliferation pathway–related genes. Pt subgroups were classified as having low or high mRNA expression using median expression as the cutoff. Results: PFS benefit in the biomarker-assessed group was similar to that in the ITT population. A trend toward a more pronounced PFS benefit with RIB was observed in pts with high vs low expression of CCND1 (HR 0.38 vs 0.67, respectively), IGF1R (HR 0.33 vs 0.77), and ERBB3 (HR 0.33 vs 0.76). The PFS benefit seen with RIB also trended to be greater in pts with low vs high expression of CCNE1 (HR 0.38 vs 0.65, respectively) and MYC (HR 0.37 vs 0.69). The PFS benefit with RIB was similar in pts with high vs low expression of FGFR1 (HR 0.45 vs 0.61, respectively), ESR1 (HR 0.57 vs 0.57), and tumor proliferation genes, such as MKI67 (HR 0.50 vs 0.51). Conclusions: This is the first gene expression analysis of a large set of premenopausal pts with ABC. The benefit with RIB was generally consistent across gene expression subgroups, although the magnitude varied in certain subsets. This analysis suggests that there may be unique resistance mechanisms to ET ± CDK4/6 inhibitors in premenopausal pts with ABC. Clinical trial information: NCT02278120.
Genomic landscape of de novo stage IV breast cancer.
Authors: Garrido-Castro Ana Christina , Spurr Liam , Hughes Melissa E , Li Yvonne Y. , Cherniack Andrew D. , Bychkovsky Brittany L. , Barroso-Sousa Romualdo , Di Lascio Simona , Files Janet , Kumari Priti , Cerami Ethan , Krop Ian E. , MacConaill Laura E , Lindeman Neal Ian , Rollins Barrett J , Johnson Bruce E. , Wagle Nikhil , Winer Eric P. , Dillon Deborah , Lin Nancy U.
Published: May 2019

1022

Background: Genomic profiling of primary and recurrent metastatic breast cancer (rMBC) has revealed potential resistance mechanisms to therapy. In contrast, de novo stage IV breast cancer (DNIV) represents an opportunity to elucidate metastatic drivers in the absence of treatment selection. Methods: Targeted NGS (Oncopanel, OP) using multiplexed copy number variation (CNV) and mutation (mut) detection across the full coding regions of 300 genes and selected intronic regions of 35 genes was performed on either primary or metastatic samples collected in patients (pts) with DNIV or rMBC. Mut/CNV in primary and metastatic tumors were compared per subtype between DNIV and rMBC using Fisher´s exact test (significant p<0.05). FDR were computed ( q<0.25). Results: Between 8/2013-9/2016, of 929 pts who underwent OP testing 212 presented with DNIV; 136 HR+/HER2- (64%); 35 HR+/HER2+ (17%); 25 TNBC (12%); 16 HR-/HER2+ (8%). In 168 (79%) pts, the primary was tested; 44 had a metastatic site tested. Comparison of primary HR+/HER2- tumors showed that DNIV pts were more likely to harbor mut in CDKN1B, SETD2 and PMS2 and less likely to have TP53 mut than rMBC (Table). Metastases in HR+/HER2- DNIV (n=29) had higher mut in CDH1, PTCH1 and CTNNB1 and fewer CCND1 amplification (amp) than rMBC (n=121), albeit these findings lost significance after FDR correction. DNIV primary TNBC (n=19) was significantly enriched for CIITA mut (26% vs. 0%; q=0.046) and MYB amp (21% vs. 0%, q=0.098) compared to rMBC (n=101). TP53 mut, amp in RAD21, MYC, MYB, PTK2 and EGFR, and deletions in CDKN2A/2B and MAP2K4 significantly predicted poorer overall survival in DNIV. Conclusions: DNIV primary and metastatic tumors have distinct genomic profiles compared to rMBC. Alterations in genes involved in epigenetic modulation ( KMT2D, SETD2) and epithelial-mesenchymal transition ( CDH1, PTCH1, CTNNB1) are more prevalent in HR+/HER2- DNIV. DNIV TNBC is enriched for CIITA mut, described to promote immune escape via reduced MHC class II expression. If validated, these findings may provide insight into mechanisms underlying metastatic potential. [Table: see text]
Immunotherapy predictive biomarkers in metastatic breast cancer (MBC).
Authors: Ross Jeffrey S. , Sokol Ethan , Albacker Lee A. , Frampton Garrett M. , Pavlick Dean , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Sivapiragasam Abirami , Miller Vincent A.
Published: May 2019

1023

Background: We queried whether comprehensive genomic profiling (CGP) of mBC subtypes could identify biomarkers that have been linked to responsiveness to immunotherapy (IO) treatments. Methods: DNA was extracted from 3,871mBC: 1,388 ER+/HER2-, 1,969 HER2 amplified (amp) and 643 TNBC. CGP was performed using a hybrid-capture assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci in 564 cases. PD-L1 was determined by IHC (Dako 22C3). Results: Patient ages were similar. Genomic alterations (GA)/tumor were similar ranging from 5.9 to 7.3. MTOR pathway targets were common; lowest in TNBC. CDH1 and ESR1 GA most frequent in ER+/HER2- cases. ERBB2 short variant (SV) mut were most frequent in ER+/HER2- and HER2 amp and not seen in TNBC. Other kinase targets were uncommon except for FGFR1 GA in ER+/HER2-. BRCA1/ 2 GA least frequent in HER2 amp. AR was amplified in 1% of all mBC. Markers of potential IO benefit: CD274 ( PD-L1) amp (1-3%), BRAF GA (1-4%), TMB of ≥10 mut/Mb (8-12%), TMB of ≥20 mut/Mb (2-3%), MSI-High (0.1-0.4%), PBRM1 GA (1%) and low (1-10%) or high (0-3%) PD-L1 staining. Potential markers of resistance: inactivating GA in STK11 (1-2%) and MDM2 amplification (3-6%). Examples of mBC patients responding to IO therapies will be presented. Conclusions: In addition to guiding targeted therapy selection, CGP shows potential to identify GA linked to response and resistance to IO in mBC. The demonstrations of clinical benefit of immunotherapy in mBC supports the need for the development of biomarkers used to guide the use of ICPI drugs for these patients. [Table: see text]
Trastuzumab emtansine (T-DM1) and ribociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 (CDK 4/6), for patients with metastatic HER2-positive breast cancer.
Authors: Spring Laura , Goel Shom , Sutherland Sara , Supko Jeffrey G. , Juric Dejan , Isakoff Steven J. , Mayer Erica L. , Moy Beverly , Tolaney Sara M. , Bardia Aditya
Published: May 2019

1028

Background: Current therapeutic efforts in the management of HER2+ MBC focus on targeting the HER receptor family, however co-inhibition of targets downstream of the HER2 pathway, such as cyclin D-CDK 4/6, could enhance therapeutic efficacy. We conducted a phase 1b study of the CDK4/6 inhibitor ribociclib and T-DM1 in patients (pts) with HER2+ MBC. The primary objective was to determine the recommended phase 2 dose (RP2D) of ribociclib plus T-DM1. Secondary objectives included safety, PK assessments, and efficacy. Methods: Pts with HER2+ MBC who previously received at least 1 taxane and trastuzumab-containing regimen in any setting were eligible. Pts with previous CDK4/6 inhibitor exposure, QTcF > 450msec, or unstable brain metastases were excluded. Ribociclib was given orally for 2 weeks of a 21-day cycle (days 8-21), with T-DM1 given at 3.6 mg/kg every 3 weeks on day 1. A standard 3+3 dose escalation design was used to evaluate various doses of ribociclib in combination with T-DM1 to determine the RP2D. Results: From 5/2016 – 10/2018, 10 pts (8/10 ER+) were enrolled with a median age of 53 (38-72) and median of 1 (0-2) prior therapies for MBC. During dose-escalation, pts received doses of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 1). No DLTs were observed. The most common treatment related grade 3 or higher AEs were neutropenia (50%), infection (20%), anemia (10%), and thrombocytopenia (10%). 4/10 pts had dose reductions due to toxicity. The average concentration of ribociclib at steady state was similar at each dose level, ranging from 273 to 413 ng/mL. Among 9 evaluable pts, the ORR was 33% (3/9) and the other 6 pts had stable disease. After a median follow-up time of 10.9 months, the median PFS was 12.5 months (95% CI [10.5. 20.9]). Biomarker results will be presented at the meeting. Conclusions: Co-targeting HER2 and CDK4/6 with the combination of ribociclib with T-DM1 was well tolerated with evidence of clinical activity. Based on PK analysis and dose reductions, 400 mg is the RP2D. Further evaluation is warranted for patients with HER2+ MBC. Clinical trial information: NCT02657343.
Alpelisib (ALP) with fulvestrant (FUL) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC): Primary or secondary resistance to prior endocrine therapy (ET) in the SOLAR-1 trial.
Authors: Juric Dejan , Loibl Sibylle , Andre Fabrice , Mingorance J. Ignacio Delgado , Forget Frederic , Levy Christelle , Masuda Norikazu , Campone Mario , Conte Pier Franco , Iwata Hiroji , Mayer Ingrid A. , Rugo Hope S. , Wilke Celine , Ridolfi Antonia , Lteif Agnes , Ciruelos Eva
Published: May 2019

1038

Background: A contributor to ETR, phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation can result from mutations to PIK3CA; ~40% of pts with HR+, HER2– ABC exhibit tumors with this mutation. Use of the oral α-specific PI3K inhibitor ALP + FUL significantly improved progression-free survival (PFS) in pts with a PIK3CA mutation (HR 0.65; 95% CI, 0.50-0.85; P<0.001) in SOLAR-1, which included both ET sensitive (ETS) and ETR pts (Table). ETS pts were later excluded by a protocol amendment. ETR was further defined as primary (1R) or secondary (2R) per ESMO criteria in both 1L and 2L pts. This subgroup analysis evaluated pts with a PIK3CA mutation based on tx line and endocrine status. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP 300 mg QD or PBO Q28d + FUL 500 mg Q28d + C1d15 in men and postmenopausal women with HR+, HER2– ABC whose disease progressed on/after an aromatase inhibitor. PFS was estimated by Kaplan-Meier method and median PFS (mPFS) presented by tx arm. A stratified Cox proportional hazards model estimated HR and 2-sided 95% CI. Results: Of 341 pts in the PIK3CA mutant cohort, 39 (11%) were ETS; 302 (89%) were ETR. mPFS in the ALP vs PBO arms was 22.1 vs 19.1 mo (HR 0.87; 95% CI, 0.35-2.17) for ETS pts and 9.4 vs 4.2 mo (HR 0.64; 95% CI, 0.48-0.84) for ETR pts. For ETR pts, mPFS for 1L (n=138) was 9.0 vs 4.7 mo (HR 0.69; 95% CI, 0.46-1.05) and for 2L (n=161) was 10.9 vs 3.7 mo (HR 0.61; 95% CI, 0.42-0.89). Conclusions: In SOLAR-1, mPFS was improved with ALP + FUL vs PBO + FUL across ETR pts in 1L and 2L. Representation of ETS pts was low in SOLAR-1, which included more ETR pts. Analysis of the PI3K pathway in ETS pts is warranted in future studies. Clinical trial information: NCT02437318. [Table: see text]