bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.