Long-term Cancer Survivors Research Articles

Treatment and treatment-related toxicity following subsequent breast cancer: A report from the Childhood Cancer Survivor Study (CCSS).

10051 Background: Long-term survivors of childhood cancer are at high risk for treatment-related breast cancer and have elevated mortality risk after a breast cancer diagnosis than the general population. There is no standard of care for women with treatment-related breast cancer, and treatment patterns and risk for toxicity are not known. Methods: Female survivors in CCSS diagnosed and treated for childhood cancer between 1970-1999 who developed a subsequent breast cancer (N = 344) were matched with females with sporadic breast cancer (multi-institution sampling; 1:1 matching ratio) on age at breast cancer diagnosis, breast cancer treatment decade, race/ethnicity, histology, and hormone receptor status. Conditional logistic regression evaluated univariate associations with treatments, toxicities, and synchronous breast cancer (≤12 months from diagnosis). Hazard ratios (HR) for metachronous disease risk ( > 12 months from diagnosis) were estimated using proportional hazard models with robust variance estimation. Results: Among survivors, the median time between the primary cancer and initial breast cancer diagnosis at median age 40 years (IQR 35-45) was 26 years (IQR 21-30). Two-thirds received chest radiation therapy (RT) and 44% were treated with anthracyclines for their childhood cancer. In the matched sample, breast cancer clinical features were similar between survivors vs. controls, but the odds of synchronous bilateral disease at diagnosis was 4.8-fold greater (95% CI 2.2-10.2) among survivors. Surgical interventions (99% vs. 98%, P = 0.22) and treatment with chemotherapy (46% vs. 45%, P = 0.43) were similar between groups. However, women with sporadic breast cancers were more likely to receive RT (OR 4.4, 95% CI 2.9-6.8) or anthracyclines (OR 2.4, 95% CI 1.5-3.8). Survivors were more likely to undergo mastectomy (OR 3.0, 95% CI 2.1-4.2) and experience surgical complications (OR 2.2, 95% CI 1.4-3.4), and had 1.4-fold greater odds (95% CI 1.01-1.98) of experiencing any treatment-related toxicity compared to controls. The 15-year cumulative incidence of developing a metachronous breast cancer was 20% (95% CI 13-25%) in survivors versus 9% (95% CI 5-13%) in controls (P < 0.001). Risk of metachronous disease remained higher among survivors (HR 2.4, 95% CI 1.5-4.0) after adjusting for breast cancer treatments (mastectomy, RT, and anthracyclines). Conclusions: Female survivors of childhood cancer who develop subsequent treatment-related breast cancer are more likely to develop synchronous and metachronous breast cancer compared to controls. Despite similar biologic characteristics, survivors are treated differently from females with sporadic breast cancer and are more likely to experience treatment-related toxicities. Further study of how treatment of subsequent breast cancers and corresponding toxicities impact prognosis and survival is needed.

Prevalence of EGFR and PDL1 testing in a population-based lung cancer surgical resection cohort from 2018-2022.

e20585 Background: Most long-term survivors of lung cancer had surgery for early stage disease, but long-term survival rates are about 50%. In 2020 and 2021 the ADAURA and IMpower010 trials established adjuvant Osimertinib and Atezolizumab therapy for stage IB-IIIA non-small cell lung cancer. Eligibility for these treatments depends on specific biomarkers. We evaluated biomarker testing patterns and prevalence in a population based surgical resection cohort. Methods: In the prospective observational Mid-South Quality of Surgical Resection cohort, we evaluated EGFR and PDL1 testing from 2018-2022, spanning time before (2018-2020) and after (2021-2022) FDA approval of adjuvant Osimertinib and Atezolizumab therapy. We estimated the prevalence of EGFR mutations and PDL1 expression ( > 0%) using the binomial distribution with exact 95% confidence intervals (CI). We compared demographic characteristics using Wilcoxon and Fishers Exact tests. Results: From 2018-2022, 1687 patients had surgical resection across 12 institutions (1045 from 2018-2020; 642 from 2021-2022). They were 21% black and 77% white, 49% male and 51% female, with a median age of 69 years. From 2018-2020 11% had EGFR testing, compared to 38% in 2021-2022 (p < 0.0001). There were no differences in testing by age (p = 0.79), sex (p = 0.99), race (p = 0.69), or insurance type (p = 0.45). In 132 ADAURA eligible individuals (stage IB-IIIA, non-squamous, R0, > 4cm tumor), EGFR was tested in 13% in 2018-2020 and 56% in 2021-2022 (p < 0.0001) with no differences by demographic factors (all p > 0.20). 15% (53 of 360) of EGFR tests were next-generation sequencing, increasing from 4% in 2018-2020 to 20% in 2021-2022 (p < 0.0001). The prevalence of EGFR mutations was 8.1% (95% CI: 5.5% to 11.4%) overall; 9% in males vs. 7% in females (p = 0.57); 12% in black persons vs. 7% in white persons (p = 0.40). From 2018-2020 8% of patients received PDL1 testing, compared to 20% in 2021-2022 (p < 0.0001). There were no differences in testing by age (p = 0.47), sex (p = 0.41), and race (p = 0.51), but a trend for insurance type (p = 0.07). In 791 Impower010 eligible patients (Stage IB-IIIA, R0), PDL1 was tested in 8% in 2018-2020 and 23% in 2021-2022 (p < 0.0001) with no significant differences by demographic factors (all p > 0.10). Among all 207 PDL1 tests, PDL1 was > 0% in 143, for a prevalence of 69% (95% CI: 62% to 75%). It was 69% in males, 70% in females (p = 0.88); 68% in black persons, 69% in white persons (p = 0.99). Testing differed significantly by institution for both EGFR and PDL1 testing (p < 0.001). When EGFR was not evaluated, PDL1 was evaluated 2% of the time but when EGFR was evaluated, PDL1 was evaluated 51% of the time. Conclusions: With the advent of biomarker-directed adjuvant therapy, EGFR and PDL1 testing are rising but testing levels are sub-optimal. Institutional factors influence testing.

Longitudinal associations between peripheral neuropathy and neurocognitive decline in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.

10054 Background: Survivors of pediatric cancer treated without CNS-directed therapy are at risk of neurocognitive impairment and peripheral neuropathies. Using the St. Jude Lifetime Cohort, we investigated longitudinal associations with neuropathy to inform contributors to long-term cancer-related neurocognitive decline. Methods: Survivors of pediatric cancer (N=899 mean age 32 [SD 12], 24[10] years from diagnosis) treated without CNS-directed therapy completed neurocognitive testing and medical assessments at two timepoints (T1, T2 4.4[2.3] years apart). Peripheral sensory and motor neuropathy subscales combined with functional tasks were severity graded using a modified CTCAE (no neuropathy = none or grade 1 at T1 and T2; new onset = new grade 2 or 3 at T2; persistent = grade 2 or 3 at T1 & T2). Linear regression models estimated change in neurocognitive Z-score associated with neuropathy groups, adjusted for diagnosis age, time between visits, sex, race/ethnicity, high-dose intravenous methotrexate & baseline neurocognitive Z-score. Results: New onset sensory (n=33, 3.6%) and motor (n=35, 3.9%) neuropathy was associated with a 0.33 standard deviation (SD) decline in visual-motor processing speed (Table). New onset motor neuropathy was associated with a 0.50 SD decline in sustained attention as well as significant declines in verbal recall, working memory, and cognitive flexibility (p’s<0.05). Persistent sensory neuropathy (n=25, 2.8%) was associated with large declines in focused attention and cognitive flexibility (p’s<0.05). Persistent motor neuropathy (n=18, 2.0%) was associated with a 0.50 SD decline in sustained attention, verbal recall, and working memory (p’s<0.05). Conclusions: Peripheral neuropathies are associated with future neurocognitive decline in adult survivors of pediatric cancer. Research is needed to understand shared mechanisms (e.g. pain, inflammation) to inform targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]

Carvedilol for prevention of heart failure in anthracycline-exposed survivors of childhood cancer: Results from COG ALTE1621.

10013 Background: Carvedilol improves cardiac function in patients with heart failure (HF), but remains untested as cardioprotective therapy in long-term childhood cancer survivors at risk for HF due to high-dose anthracycline exposure. We hypothesized that low-dose carvedilol would be safe and efficacious in reducing anthracycline-related heart failure risk in long-term survivors without evidence of HF. Methods: This was a randomized, double-blind, placebo-controlled phase 2B trial (NCT02717507) conducted at 28 sites. Eligibility included ≥250 mg/m2 cumulative anthracycline exposure by age 21 years (y), ≥2y from completion of cancer treatment, and preserved systolic function (ejection fraction [EF] ≥55% and/or fractional shortening [FS] ≥28%) at enrollment. Patients were randomized 1:1 to take low-dose carvedilol (12.5 mg/day) or placebo for 2y; dose up-titration started at 3.125 mg/day. The primary objective was to determine the impact of carvedilol on echocardiographic indices of HF risk: standardized left ventricular (LV) wall thickness/dimension ratio (LVWT/Dz; primary endpoint), LV end-systolic wall stress (ESWS), LV chamber diameters, systolic and diastolic function. These indices were obtained every 6 months and measured centrally in a blinded fashion. Common Terminology Criteria for Adverse Events (CTCAE v4.0) was used to assess toxicity. Cardiac event was defined as relative EF/FS decline < 20% from baseline or both < 55% [EF] and < 28% [FS]. Treatment effects were analyzed using the Generalized Estimating Equation for normally distributed data, assuming linear time-trend. Group differences were evaluated by treatment*time interaction. Results: Of 196 participants enrolled, 182 were eligible and randomized. Characteristics (median, range): age at enrollment, 24.7y (10.4-53.9); time from cancer diagnosis, 13.4y (2.9-43.6); anthracycline dose, 374 mg/m2 (250-1760); 19% had received chest-directed radiotherapy. There were no group differences in baseline participant demographics, cardiotoxic treatment exposure, or cardiac endpoints. LVWT/Dz was similar (+0.053, p = 0.15) between arms at 2y. However, treatment effects varied by time since diagnosis (p = 0.008) suggesting greater efficacy among longer-term survivors. Compared to placebo, carvedilol arm participants had significantly better LV end-diastolic diameter (-0.16 cm, p = 0.005) and LVESWS (-7.53, p = 0.027) at 2y. There were no CTCAE grade ≥3 events; all except 2 participants tolerated full dose escalation. Six out of eight cardiac events occurred on the placebo arm; longer-term follow-up of study participants is ongoing. Conclusions: In this randomized trial of long-term survivors of childhood cancer treated with high-dose anthracyclines, low-dose carvedilol was safe and effective in reducing established biomarkers of HF risk and could serve as a risk reduction strategy. Clinical trial information: NCT02717507 .

Financial hardship among siblings of long-term survivors of childhood cancer: A Childhood Cancer Survivor Study (CCSS) report.

10048 Background: Siblings of children with cancer may experience adverse household economic and psychosocial impacts during and after treatment. While many long-term survivors of childhood cancer experience financial hardship, financial outcomes of siblings in later adulthood are unknown. Methods: We surveyed randomly selected nearest age siblings of survivors (aged 18-64y) enrolled in the CCSS to estimate the prevalence of financial hardship, using 20 items adapted from validated national surveys grouped into 3 domains (material, psychological, behavioral). We calculated the prevalence of reporting any hardship within each domain. Multivariable logistic regression estimated associations between sibling sociodemographic characteristics and each domain of hardship. For individual financial hardship items with a matching item in the contemporaneous National Health Interview Survey (n = 21,271) or Behavioral Risk Factor Surveillance System (n = 259,901), we compared siblings with national survey respondents aged 18-64, calculating adjusted prevalence ratios to sample-weighted responses, adjusted for sex, race, ethnicity, household income, education, and marital status. Results: 1,008 siblings participated (of 1,590 approached; 63%) with median age of 46y (IQR 39–53y). Siblings were 57% female, 89% non-Hispanic White, 69% college-educated, and 74% married. The prevalence of reporting any material, psychological, and behavioral hardship among siblings was 34%, 28%, and 23%, respectively. Sibling factors associated with reporting material financial hardship included: female sex (OR 1.7, 95% CI 1.2–2.4), age (30–39y vs 21–29y: OR 2.61, 95% CI 1.1–6.5), household income ($50,000–$74,999 vs ≥$75,000: OR 2.3, 95% CI 1.4–3.6), lack of health insurance (OR 2.4, 95% CI 1.1–5.1), presence of severe/disabling chronic medical conditions (OR 1.7, 95% CI 1.1–2.8), out-of-pocket medical expenses ≥10% of income (vs < 10%: OR 4.9, 95% CI 1.9–12.3), and increased non-medical/non-home debt (for example, $25,000–$49,999 vs none: OR 5.2, 95% CI 3.2–8.6). Associations with psychological and behavioral hardship were similar. Compared with national survey respondents, siblings were more likely to report financial hardship on several individual items: difficulty paying medical bills (PR 1.2, 95% CI 1.0–1.4), worries about bills (PR 1.1, 95% CI 1.1–1.2), foregoing medical care (PR 1.3, 95% CI 1.0–1.6) and dental care (PR 1.4, 95% CI 1.2–1.6) due to cost, and worries about affording nutritious foods (PR 1.7, 95% CI 1.5–2.0). Conclusions: Adult siblings of childhood cancer survivors are more likely to experience multiple aspects of financial hardship than US adults in the general population, suggesting that childhood cancer may have life-long impact on siblings. Increased support for families across the trajectory of cancer treatment may help prevent or reduce financial hardship.

Associations between psychosocial and lifestyle factors and biological age acceleration among long-term survivors of childhood cancer: A prospective study from the St. Jude Lifetime Cohort.

10049 Background: Survivors of childhood cancers may be at risk for premature, or accelerated, biological age aging, which is associated with cancer treatment exposures. However, life course theory and a growing body of evidence suggest that psychosocial and lifestyle factors may also contribute. The objective of this study was to explore associations between psychosocial and lifestyle factors and biological age acceleration in the St. Jude Lifetime Cohort. Methods: In this cross-sectional study, we applied physiology-based methods (Klemera-Doubal method and Phenotypic Age) and DNA methylation-based epigenetic clocks (Horvath’s, Hannum’s, Levine’s PhenoAge, GrimAge, and DunedinPACE clocks) to compare biological age acceleration, estimated as the residual from regressing biological age on chronological age, among survivors (n = 4,117) and age- and sex-frequency-matched non-cancer community controls (n = 606). We compared psychosocial and lifestyle factors between survivors and controls using t-tests/Wilcoxan rank sums, and chi-square. Multivariable linear regression was used to assess associations of self-reported smoking, alcohol use, physical activity, overweight/obesity, and depressive symptoms with biological age acceleration in survivors, adjusted for age, race/ethnicity, sex, education, and cancer treatment. Results: Childhood cancer survivors at a mean chronological age of 35.1 years (SD 10.2) were biologically older than controls according to KDM-BA, Phenotypic Age, Hannum’s clock, Levine’s PhenoAge clock, and DunedinPACE, with biological age acceleration ranging from 1.7-4.7 years (p < 0.05.) A greater proportion of survivors reported elevated depressive symptoms (10.3% v. 8.7%), current smoking (17.8% v. 12.3%), < 150 minutes of physical activity (47.3% v. 38.2%), and were overweight/obese (66.0% v. 59.9%) compared to controls (p’s < 0.001). In survivors, < 150 minutes of physical activity (B’s (difference in biological age acceleration [years]) = 1.10-2.68), current (B’s = 1.18-5.96) and former smoking (B’s = 2.53-4.29) were consistently associated with higher biological age acceleration across measures (p’s < 0.05). Risky drinking and higher depressive symptoms were associated with higher biological age acceleration, but only for KDM (B = 1.26, p < 0.021) and DunedinPACE measures (B = 0.15, p < 0.001), respectively. Conclusions: Biological aging in childhood cancer survivors is associated with psychosocial and lifestyle factors. Interventions designed to optimize healthy behaviors and mitigate poor emotional health may have potential to prevent or remediate this phenotype in childhood cancer survivors.

P-94 Overview of clinicopathological and prognostic factors for long-term survivors of pancreatic cancer from a multicenter study of 532 patients

P-94 Overview of clinicopathological and prognostic factors for long-term survivors of pancreatic cancer from a multicenter study of 532 patients

Genetic study of type 2 diabetes risk in diverse populations of survivors of childhood cancer: A report from the St. Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS).

10029 Background: Type 2 diabetes (T2D) is an established late effect of cancer treatment among long-term survivors of childhood cancer. Genetic factors underpinning T2D in diverse populations of survivors have not been well studied. Methods: We conducted a multi-ancestry genome-wide association study (GWAS) for clinically ascertained T2D among survivors of European (EUR; N = 3,102 with 261 cases) and African (AFR; N = 574 with 43 cases) ancestry from SJLIFE. Replication analyses were performed between ancestries in SJLIFE and in EUR survivors in CCSS (N = 5,965; 270 self-reported cases). Two published T2D polygenic risk scores (PRSs) were assessed in survivors: a 338-variant multi-ancestry PRS (N~1.4 million; 49% non-EUR descent) and a ~6.9 million-variant EUR-only PRS (N~160K; DIAGRAM Consortium and UK Biobank Study). Treatment-related T2D risk effect modification was evaluated for abdominal irradiation and alkylating agents. Results: In SJLIFE AFR survivors, one novel locus with suggestive significance was identified (5p15.2: OR = 10.19, P = 5.1x10-7), replicating in both SJLIFE EUR (P = 0.011) and CCSS EUR survivors (P = 0.021). A EUR-specific genome-wide significant association at 8q11.21 ( SNTG1 intronic variant; OR = 1.99; P = 4.4x10-8) was replicated in CCSS (P = 8.1x10-3). Two other loci with suggestive associations (P < 5x10-6) in SJLIFE EUR survivors replicated in SJLIFE AFR survivors (P < 0.05), achieving genome-wide significance in multi-ancestry meta-analysis (2p25.3: OR = 2.05, P = 4.5x10-8; 19p12: OR = 2.43 P = 5.7x10-9). Each of the three novel trans-ancestral loci overlapped putative Polycomb-repressed regions, i.e., chromatin-based gene regulation elements, in pancreatic cells and displayed treatment-related effect heterogeneity across ancestry groups. Notably, AFR survivors with risk alleles experienced disproportionately greater T2D risk if treated with alkylating agents (2p25.3: OR = 3.95; 19p12: OR = 5.74; 5p15.2: OR = 17.81). Increases in the T2D odds per multi-ancestry PRS standard deviation were consistent in survivors across ancestries (SJLIFE EUR: OR = 1.84, P = 1.1x10-16; SJLIFE AFR: OR = 1.80, P = 2.8x10-3, CCSS EUR: OR = 1.60, P = 8.4x10-13). However, T2D risk association with the EUR-only PRS was absent in AFR survivors (OR = 0.97, P = 0.95). Conclusions: Multi-ancestry genetic analyses revealed three novel T2D risk alleles associated with disproportionately greater alkylating agent-related risk among African-ancestry survivors. Furthermore, an external multi-ancestry T2D PRS was associated with increased risk in diverse ancestry survivors, whereas a EUR-only PRS was not useful for African-ancestry survivors. This study supports precision diabetes surveillance and survivorship care for all childhood cancer survivors, including those in minority ancestry groups.

Impact of general anaesthesia on breast cancer survival: a 5-year follow up of a pragmatic, randomised, controlled trial, the CAN-study, comparing propofol and sevoflurane.

Anaesthesia may impact long-term cancer survival. In the Cancer and Anaesthesia study, we hypothesised that the hypnotic drug propofol will have an advantage of at least five percentage points in five-year survival over the inhalational anaesthetic sevoflurane for breast cancer surgery. From 2118 eligible breast cancer patients scheduled for primary curable, invasive breast cancer surgery, 1764 were recruited after ethical approval and individual informed consent to this open label, single-blind, randomised trial at four county- and three university hospitals in Sweden and one Chinese university hospital. Of surveyed patients, 354 were excluded, mainly due to refusal to participate. Patients were randomised by computer at the monitoring organisation to general anaesthesia maintenance with either intravenous propofol or inhaled sevoflurane in a 1:1 ratio in permuted blocks. Data related to anaesthesia, surgery, oncology, and demographics were registered. The primary endpoint was five-year overall survival. Data are presented as Kaplan-Meier survival curves and Hazard Ratios based on Cox univariable regression analyses by both intention-to-treat and per-protocol. EudraCT, 2013-002380-25 and ClinicalTrials.gov, NCT01975064. Of 1764 patients, included from December 3, 2013, to September 29, 2017, 1670 remained for analysis. The numbers who survived at least five years were 773/841 (91.9% (95% CI 90.1-93.8)) in the propofol group and 764/829 (92.2% (90.3-94.0)) in the sevoflurane group, (HR 1.03 (0.73-1.44); P=0.875); the corresponding results in the per-protocol-analysis were: 733/798 (91.9% (90.0-93.8)) and 653/710 (92.0% (90.0-94.0)) (HR=1.01 (0.71-1.44); P=0.955). Survival after a median follow-up of 76.7 months did not indicate any difference between the groups (HR 0.97, 0.72-1.29; P=0.829, log rank test). No difference in overall survival was found between general anaesthesia with propofol or sevoflurane for breast cancer surgery. Swedish Research Council; Uppsala-Örebro Regional Research Council; Västmanland Regional Research Fund; Västmanland Cancer Foundation; Stig and Ragna Gohrton Foundation; Birgit and Henry Knutsson Foundation.

0831 Sleep in Long-Term Childhood Cancer Survivors Compared to Siblings: A Report from the Childhood Cancer Survivor Study

Abstract Introduction Sleep problems following treatment for childhood cancer may persist into adulthood. Because some sleep problems increase with age, it is important to understand whether cancer elevates this risk and assess associations with co-morbidities that frequently develop in long-term childhood cancer survivors. The current study compares sleep in long-term survivors to sibling controls. Methods Childhood cancer survivors (≥5 years from diagnosis; n=12,340; 51.5% female; mean [SD] age=39.4 [9.6] years; years since diagnosis=30.9 [7.9]; age at diagnosis=8.5 [5.8]) and siblings (n=2395; 57.1% female; age=44.6 [10.5]) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Binary sleep behaviors (Total Score >5, Short Sleep Duration [< 6 hours], Frequent Snoring [>3 times/week], Frequent Sleep Medication Use [≥3 times/week]) were compared between survivors and siblings using a multivariable generalized estimating equation with Poisson error to account for intra-family correlations, adjusting for age, sex, race, and BMI. Poisson regression models evaluated treatment and chronic health conditions (CHCs) as predictors of PSQI Total Score among survivors with the same adjustment variables. Results Survivors were more likely to report Short Sleep Duration (12.0% vs 10.6%; adjusted prevalence ratio [aPR] 1.18, 95% confidence interval [CI] 1.04-1.34), elevated PSQI Total Score (45.1% vs 40.0%; aPR 1.17, 95%CI 1.11-1.23), Frequent Snoring (18.0% vs 17.4%; aPR 1.11, 95%CI 1.01-1.23), and Frequent Sleep Medication Use (13.2% vs 11.5%; aPR 1.28, 95% CI 1.14-1.45) compared to siblings. Among survivors, elevated PSQI Total Score was associated with female sex (aPR 1.29, 95%CI 1.21-1.37) and BMI (overweight: aPR 1.13, 95%CI 1.06-1.22; obese: aPR 1.32, 95%CI 1.23-1.42), while age at diagnosis and cancer treatment exposures (i.e., chemotherapy/radiation) were not significantly associated. Survivors with 2+ CHCs had increased prevalence of elevated PSQI Total Score (aPR 1.39, 95%CI 1.28-1.50) relative to survivors without CHCs. Conclusion Childhood cancer survivors exhibit elevated risk for poor sleep quality, short sleep, and snoring relative to siblings well into middle age. These sleep problems are driven by demographics and current chronic health conditions rather than prior treatment exposures. Elevated use of sleep-promoting medications suggests interest in managing sleep difficulties and an opportunity for future behavioral sleep intervention trials. Support (if any) NCI 5U24CA055727-26 (PI: Armstrong)

Future trends in incidence and long-term survival of metastatic cancer in the United States

BackgroundPrevious studies have demonstrated epidemiological trends in individual metastatic cancer subtypes; however, research forecasting long-term incidence trends and projected survivorship of metastatic cancers is lacking. We assess the burden of metastatic cancer to 2040 by (1) characterizing past, current, and forecasted incidence trends, and (2) estimating odds of long-term (5-year) survivorship.MethodsThis retrospective, serial cross-sectional, population-based study used registry data from the Surveillance, Epidemiology, and End Results (SEER 9) database. Average annual percentage change (AAPC) was calculated to describe cancer incidence trends from 1988 to 2018. Autoregressive integrating moving average (ARIMA) models were used to forecast the distribution of primary metastatic cancer and metastatic cancer to specific sites from 2019 to 2040 and JoinPoint models were fitted to estimate mean projected annual percentage change (APC).ResultsThe average annual percent change (AAPC) in incidence of metastatic cancer decreased by 0.80 per 100,000 individuals (1988–2018) and we forecast an APC decrease by 0.70 per 100,000 individuals (2018–2040). Analyses predict a decrease in metastases to liver (APC = −3.40, 95% CI [−3.50, −3.30]), lung (APC (2019–2030) = −1.90, 95% CI [−2.90, −1.00]); (2030–2040) = −3.70, 95% CI [−4.60, −2.80]), bone (APC = −4.00, 95% CI [−4.30, −3.70]), and brain (APC = −2.30, 95% CI [−2.60, −2.00]). By 2040, patients with metastatic cancer are predicted to have 46.7% greater odds of long-term survivorship, driven by increasing plurality of patients with more indolent forms of metastatic disease.ConclusionsBy 2040, the distribution of metastatic cancer patients is predicted to shift in predominance from invariably fatal to indolent cancers subtypes. Continued research on metastatic cancers is important to guide health policy and clinical intervention efforts, and direct allocations of healthcare resources.

Beyond the treatment: The role of race, sex, and education in health trajectories between cancer survivors and noncancer older adults

Introduction: The number of older, long-term cancer survivors is increasing. However, little is known about how cancer and aging affect the health trajectories of older adults differently. In addition, the impact of race, sex, and education on the processes of aging and the cancer experience needs further investigation. The current study aims to address this knowledge gap by combining two National Cancer Institute (NIC)-funded longitudinal studies conducted in Cleveland from 1998 to 2010.Materials and Methods: The unique cross-sequential design facilitates a comparison between the health changes in long-term (five years +) older cancer survivors (breast, prostate, and colorectal cancer) and demographically matched older adults without a history of cancer in the same geographic area within the same period. The study also captured comprehensive information on how socioeconomic status interacts with cancer and aging over time. General linear models were employed in the data analysis.Results: The findings showed that early cancer experience did not affect long-term cancer survivors' health status in later life. Conversely, comorbidities, being an African American, being female, and having education less than a college degree significantly decreased the health trajectory in later life for all older adults. Moreover, compared to other groups, older African American cancer survivors reported a dramatic decrease in self-reported health after controlling for other conditions.Discussion: Study findings can inform public policy and social services to offer comprehensive treatment plans and help individuals overcome their diseases and lead longer and healthier lives.

Benign and malignant pulmonary parenchymal findings on chest CT among adult survivors of childhood and young adult cancer with a history of chest radiotherapy.

Childhood and young adult cancer survivors exposed to chest radiotherapy are at increased risk of lung cancer. In other high-risk populations, lung cancer screening has been recommended. Data is lacking on prevalence of benign and malignant pulmonary parenchymal abnormalities in this population. We conducted a retrospective review of pulmonary parenchymal abnormalities in chest CTs performed more than 5 years post-cancer diagnosis in survivors of childhood, adolescent, and young adult cancer. We included survivors exposed to radiotherapy involving the lung field and followed at a high-risk survivorship clinic between November 2005 and May 2016. Treatment exposures and clinical outcomes were abstracted from medical records. Risk factors for chest CT-detected pulmonary nodule were assessed. Five hundred and ninety survivors were included in this analysis: median age at diagnosis, 17.1 years (range, 0.4-39.8); and median time since diagnosis, 22.3 years (range, 1-58.6). At least one chest CT more than 5 years post-diagnosis was performed in 338 survivors (57%). Among these, 193 (57.1%) survivors had at least one pulmonary nodule detected on a total of 1057 chest CTs, resulting in 305 CTs with 448 unique nodules. Follow-up was available for 435 of these nodules; 19 (4.3%) were malignant. Risk factors for first pulmonary nodule were older age at time of CT, CT performed more recently, and splenectomy. Benign pulmonary nodules are very common among long-term survivors of childhood and young adult cancer. High prevalence of benign pulmonary nodules in cancer survivors exposed to radiotherapy could inform future guidelines on lung cancer screening in this population.

Self-reported outcomes on oral health and oral health-related quality of life in long-term childhood cancer survivors—A DCCSS-LATER 2 Study

PurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health–related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and treatment characteristics of CCS have been collected in a cross-sectional study, part of the multidisciplinary DCCSS-LATER 2 Study. To assess self-reported oral health problems and dental problems, CCS filled out the ‘Toegepast-Natuurwetenschappelijk Onderzoek’ (TNO) oral health questionnaire. OHRQoL was assessed by the Dutch version of the Oral Health Impact Profile-14 (OHIP-14). Prevalences were compared with two comparison groups from the literature. Univariable and multivariable analyses were performed.ResultsA total of 249 CCS participated in our study. The OHIP-14 total score had a mean value of 1.94 (sd 4.39), with a median score of 0 (range 0–29). The oral problems ‘oral blisters/aphthae’ (25.9%) and ‘bad odor/halitosis’ (23.3%) were significantly more often reported in CCS than in comparison groups (12% and 12%, respectively). The OHIP-14 score was significantly correlated with the number of self-reported oral health problems (r = .333, p<0.0005) and dental problems (r = .392, p <0.0005). In multivariable analysis, CCS with a shorter time since diagnosis (10-19 years vs. ≥30 years) had a 1.47-fold higher risk of ≥1 oral health problem.ConclusionThough the perceived oral health is relatively good, oral complications following childhood cancer treatment are prevalent in CCS. This underlines that attention to impaired oral health and awareness on this topic is mandatory and regular visits to the dentist should be a part of long-term follow-up care.

Does participation in therapeutic exercise programs after finishing oncology treatment still ensure an adequate health status for long-term breast cancer survivors? A ≥ 5 years follow-up study.

The aims of this study were to evaluate whether the effects of two therapeutic exercise programs are sustained over time (≥ 5 years) in long-term breast cancer survivors (LTBCS). Second, to determine the influence of the current level of physical activity (PA) performed on cancer-related fatigue (CRF) that these patients may present ≥5 years later. A prospective observational study was conducted with a cohort of 80 LTBCS in Granada during 2018. Firstly, considering their participation in one of the programs, they were allocated into two groups: usual care and therapeutic exercise program, to assess CRF, pain and pressure pain sensitivity, muscle strength, functional capacity, and quality of life. Secondly, they were also classified into 3 groups according to current level of weekly PA performed: ≤ 3, 3.1-7.4, and ≥ 7.5 (MET-hour/week) respectively, to assess its impact over CRF. Although the positive effects of the programs are not sustained over time, a trend toward significance can be observed for a greater reduction in overall CRF levels, lower intensity of pain in the affected arm and cervical region, and greater functional capacity and quality of life in the group that underwent therapeutic exercise. Additionally, 66.25% of LTBCS are inactive ≥ 5 years after completion of the program and furthermore, such inactivity is accompanied by higher CRF levels (P .013 to .046). The positive effects of therapeutic exercise programs are not maintained over time for LTBCS. Additionally, more than half of these women (66.25%) are inactive ≥ 5 years after completion of the program, this inactivity being accompanied by higher levels of CRF.

Learning from long-term adolescent and young adult (AYA) cancer survivors regarding their age-specific care needs to improve current AYA care programs.

Despite growing (inter)national awareness and appreciation, age-specific care is still not always self-evident and accepted as standard of care for adolescent and young adult (AYA) cancer patients. It is unknown whether long-term AYA cancer survivors have missed age-specific care, and if so, which survivors missed it and regarding which topics. The Netherlands Cancer Registry (NCR) identified all long-term AYA cancer survivors (aged 18-39 years at initial cancer diagnosis, 5-20 years past diagnosis) in the Netherlands, who were invited to participate in a population-based, observational, cross-sectional questionnaire study (SURVAYA study), including questions on care needs. In total, 3.989 AYAs participated (35.3% response rate). One-third of them had a need for age-specific care (33.5%), 41.2% had no need and 25.3% did not know whether they had a need. Those who had a need for age-specific care were significantly more often female, higher educated, diagnosed at a younger age, and treated with chemotherapy, radiotherapy or hormone therapy. Most frequent topics were disease and treatment (29.7%), emotions (24.1%), friends (22.6%), family and children (15.6%), fertility and pregnancy (14.8%), work and reintegration (10.5%), care not tailored (13.8%), and overarching care and life (27.7%). Palliative care (0.0%), spirituality (0.2%), death (0.7%), complementary care (0.7%), and late effects (1.3%) were mentioned least. A substantial proportion of long-term AYA cancer survivors showed a need for age-specific care, varying by sociodemographic and clinical factors, on a wide variety of topics, which could be targeted to improve current AYA care services.

Identification of lncRNAs involved in response to ionizing radiation in fibroblasts of long-term survivors of childhood cancer and cancer-free controls.

Long non-coding ribonucleic acids (lncRNAs) are involved in the cellular damage response following exposure to ionizing radiation as applied in radiotherapy. However, the role of lncRNAs in radiation response concerning intrinsic susceptibility to late effects of radiation exposure has not been examined in general or in long-term survivors of childhood cancer with and without potentially radiotherapy-related second primary cancers, in particular. Primary skin fibroblasts (n=52 each) of long-term childhood cancer survivors with a first primary cancer only (N1), at least one second primary neoplasm (N2+), as well as tumor-free controls (N0) from the KiKme case-control study were matched by sex, age, and additionally by year of diagnosis and entity of the first primary cancer. Fibroblasts were exposed to 0.05 and 2 Gray (Gy) X-rays. Differentially expressed lncRNAs were identified with and without interaction terms for donor group and dose. Weighted co-expression networks of lncRNA and mRNA were constructed using WGCNA. Resulting gene sets (modules) were correlated to the radiation doses and analyzed for biological function. After irradiation with 0.05Gy, few lncRNAs were differentially expressed (N0: AC004801.4; N1: PCCA-DT, AF129075.3, LINC00691, AL158206.1; N2+: LINC02315). In reaction to 2 Gy, the number of differentially expressed lncRNAs was higher (N0: 152, N1: 169, N2+: 146). After 2 Gy, AL109976.1 and AL158206.1 were prominently upregulated in all donor groups. The co-expression analysis identified two modules containing lncRNAs that were associated with 2 Gy (module1: 102 mRNAs and 4 lncRNAs: AL158206.1, AL109976.1, AC092171.5, TYMSOS, associated with p53-mediated reaction to DNA damage; module2: 390 mRNAs, 7 lncRNAs: AC004943.2, AC012073.1, AC026401.3, AC092718.4, MIR31HG, STXBP5-AS1, TMPO-AS1, associated with cell cycle regulation). For the first time, we identified the lncRNAs AL158206.1 and AL109976.1 as involved in the radiation response in primary fibroblasts by differential expression analysis. The co-expression analysis revealed a role of these lncRNAs in the DNA damage response and cell cycle regulation post-IR. These transcripts may be targets in cancer therapy against radiosensitivity, as well as provide grounds for the identification of at-risk patients for immediate adverse reactions in healthy tissues. With this work we deliver a broad basis and new leads for the examination of lncRNAs in the radiation response.

Dual Biomarker Combining DNA Damage Repair Gene Mutations and PD-L1 Expression for Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) improve long-term survival in advanced non-small cell lung cancer (NSCLC) and require robust predictive biomarkers for the selection of responders. This study investigated the optimal implementation of DNA damage repair (DDR) gene mutations to predict response to ICIs in real-world NSCLC patients. We retrospectively reviewed 55 advanced NSCLC patients who had undergone targeted high-throughput sequencing and received ICIs. Patients with two or more DDR gene mutations were defined as DDR2 positive. The patients' median age was 68 (range=44-82) years, and 48 (87.3%) were men. Seventeen patients (30.9%) showed ≥50% high programmed death-ligand 1 (PD-L1) expression. Ten patients (18.2%) received an ICI-chemotherapy combination as first-line therapy, and 38 (69.1%) received ICI monotherapy as more than second-line therapy. Fourteen patients (25.5%) were DDR2-positive. The objective response rate of patients with DDR2-positive or PD-L1 ≥50% was 45.5%, and that of patients with DDR2-negative and PD-L1 <50% was 11.1% (p=0.007). In the PD-L1 low expression subgroup (<50%), patients with DDR2-positive had improved progression-free survival (PFS) and overall survival (OS) after ICIs compared to those with DDR2-negative (PFS: 5.8 vs. 1.9 months, p=0.026, OS: 14.4 vs. 7.2 months, p=0.078). DDR2-positive patients or those with PD-L1 ≥50% (24, 43.6%) had statistically significant improvement in PFS and OS after ICIs compared to DDR2-negative and those with PD-L1 <50% (PFS: 4.4 vs. 1.9 months, p=0.006, OS: 11.6 vs. 7.2 months, p=0.037). A dual biomarker combining DDR gene mutations and PD-L1 expression improves the prediction of response to ICIs in advanced NSCLC.

Quality of life in older French long-term lung cancer survivors: VICAN5 national survey

ObjectivesThis study aimed to describe quality of life (QoL) five years after diagnosis, in a representative sample of lung cancer (LC) survivors, to compare the QoL of survivors aged 70 years or older with that of younger ones, and to identify factors associated with poorer long-term QoL in both age groups. Materials and MethodsOur study sample consists of all individuals with a LC diagnosed between January 2010 and December 2011, who participated in the French national survey VICAN 5. ResultsA total of 371 participants had LC. At the time of the survey, 21.3% of the participants were 70 years or older. In this older age group, feeling self-conscious about appearance and suspected neuropathic pain were independently associated with physical QoL impairment and lower Post-Traumatic Growth Inventory score, and suspected neuropathic pain was associated with impaired mental QoL. In younger patients, impaired physical QoL was independently associated with male gender, metastatic cancer, suspected neuropathic pain, report of severe after-effects of LC and difficulty breathing at rest in the past 7 days, and impaired mental QoL was independently associated with male gender, impaired ECOG-PS, and anxiety. ConclusionFactors associated with an impaired QoL in LC survivors, varied according to patient age. In both populations, psychological support and adapted physical activity can be offered to improve mental QoL and physical symptomatology. For older survivors with neuropathic pain, analgesic therapies can be discussed to improve long-term QoL.

Psychosocial outcomes in long-term Dutch adult survivors of childhood cancer: The DCCSS-LATER 2 psycho-oncology study.

This study compares a comprehensive range of psychosocial outcomes of adult childhood cancer survivors (CCS) to general population-based references and identifies sociodemographic and medical risk factors. CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (diagnosed 1963-2001) part 2 (attained age ≥18 years, diagnosed <18 years, ≥5years since diagnosis) completed the Rosenberg Self-Esteem Scale, Hospital Anxiety and Depression Scale, Distress Thermometer, Self-Rating Scale for Post-Traumatic Stress Disorder, and the Short Form-36 (Health Related Quality of Life). CCS' scores were compared with references using analysis of variances and logistic regression analysis, controlling for age and sex (p<.05). Risk factors for worse psychosocial outcomes were assessed with regression analyses (p<.05). CCS, N=1797, mean age 35.4years, 49.0% female, all ≥15years since diagnosis, participated. Three percent reported posttraumatic stress disorder because of childhood cancer and 36.6% experienced clinical distress. CCS did not differ from references on self-esteem and anxiety but were less depressed (d=-.25), and scored poorer on all health-related quality of life scales, except for bodily pain (.01≤d≥-.36). Female sex, lower educational attainment, not being in a relationship, and being unemployed were negatively associated with almost all psychosocial outcomes. Except for a central nervous system tumor diagnosis, few medical characteristics were associated with psychosocial outcomes. CCS appear resilient regarding mental health but have slightly poorer health-related quality of life than references. Sociodemographic characteristics and central nervous system tumors were related to most psychosocial outcomes, but no clear pattern was observed for other medical factors. Future studies should address additional factors in explaining CCS' psychosocial functioning, such as coping, social support, and physical late effects.