Female Childhood Cancer Survivors Research Articles

A Mega-Analysis of Anti-Müllerian Hormone Levels in Female Childhood Cancer Survivors Based on Treatment Risk, Time since Treatment, and Pubertal Status

A Mega-Analysis of Anti-Müllerian Hormone Levels in Female Childhood Cancer Survivors Based on Treatment Risk, Time since Treatment, and Pubertal Status

Sex chromosomes and hormones independently influence healthy brain development but act similarly after cranial radiation

The course of normal development and response to pathology are strongly influenced by biological sex. For instance, female childhood cancer survivors who have undergone cranial radiation therapy (CRT) tend to display more pronounced cognitive deficits than their male counterparts. Sex effects can be the result of sex chromosome complement (XX vs. XY) and/or gonadal hormone influence. The contributions of each can be separated using the four-core genotype mouse model (FCG), where sex chromosome complement and gonadal sex are decoupled. While studies of FCG mice have evaluated brain differences in adulthood, it is still unclear how sex chromosome and sex hormone effects emerge through development in both healthy and pathological contexts. Our study utilizes longitudinal MRI with the FCG model to investigate sex effects in healthy development and after CRT in wildtype and immune-modified Ccl2-knockout mice. Our findings in normally developing mice reveal a relatively prominent chromosome effect prepubertally, compared to sex hormone effects which largely emerge later. Spatially, sex chromosome and hormone influences were independent of one another. After CRT in Ccl2-knockout mice, both male chromosomes and male hormones similarly improved brain outcomes but did so more separately than in combination. Our findings highlight the crucial role of sex chromosomes in early development and identify roles for sex chromosomes and hormones after CRT-induced inflammation, highlighting the influences of biological sex in both normal brain development and pathology.

Unmet Reproductive Health Care Information Needs of Female Young Adult Survivors of Childhood Cancer: Oncology Providers' Perspectives.

This study aimed to characterize unmet reproductive health needs of female young adult survivors of childhood cancer (YASCC), as understood by oncology providers (N = 10) caring for this patient population. Providers completed brief online questionnaires and a one-time semi-structured interview. Descriptive statistics characterized quantitative data, and rapid qualitative analysis identified themes in interview data. In survey data, providers rated fertility as a top concern among YASCC. Qualitative data identified specific under-addressed reproductive and sexual health information needs for patients and also for their providers. The results provide preliminary knowledge to inform the development of behavioral interventions to address patients' unmet needs.

Anti-Müllerian hormone and fertility in women after childhood cancer treatment: Association with current infertility risk classifications.

To identify childhood cancer survivors (CCSs) at risk of premature ovarian insufficiency (POI) and impaired fertility is important given its impact on quality of life. The aim of this study was to assess ovarian markers and fertility outcomes in adult female CCSs. We used the Swedish and the PanCareLIFE classifications for infertility risk grouping. 167 CCSs, at median age 34.6 years (19.3-57.8) with a median follow-up time of 25.4 years (11.6-41.3), and 164 healthy matched controls were included in this cross-sectional study. We assessed anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), ovarian volume (OV), and fertility outcomes. Based on gonadotoxic treatments given, CCSs were categorized into infertility risk groups. The median levels of AMH, AFC and OV were lower in CCSs (1.9 vs. 2.1 ng/ml, 12.0 vs. 13.0, 6.8 vs. 8.0 cm3) compared with controls, although statistically significant only for OV (p = 0.021). AMH levels in CCSs <40 years were lower for those classified as high-risk (p = 0.034) and very high-risk (p<0.001) for infertility, based on the Swedish risk classification. Similarly, AFC was reduced in the high-risk (p<0.001) and the very high-risk groups (p = 0.003). CCSs of all ages showed a trend towards impaired fertility, especially in the very high-risk group. POI was diagnosed in 22/167 CCSs, of whom 14 were in the high- and very high-risk groups. The results according to the PanCareLIFE classification were similar. Both the Swedish and the PanCareLIFE infertility risk classifications are reliable tools for identifying those at risk of reduced ovarian markers and fertility, as well as POI. We recommend fertility preservation counselling for patients receiving highly gonadotoxic treatments (i.e., Cyclophosphamide Equivalent Dose ≥6 g/m2, radiotherapy exposure to ovaries or stem cell transplantation) with follow-up at a young reproductive age due to the risk of a shortened reproductive window.

P-521 Inter-individual variation in gonadotoxicity in female childhood cancer survivors – a genome-wide association study: results from the PanCareLIFE study

Abstract Study question To identify new variants associated with alkylating agent (AA) induced gonadotoxicity among adult female childhood cancer survivors (CCS) using a genome-wide association study approach (GWAS). Summary answer Upon meta-analysis of two independent cohorts, the variant rs78861946 was associated with lower AMH levels in CCS, but not separately in the smaller replication cohort. What is known already Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Study design, size, duration A genome-wide association study (GWAS) approach was used to discover new variants associated with AA-induced gonadotoxicity among adult female CCS. The discovery cohort included adult female CCS from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, CNS, total body irradiation, or stem cell transplantation. Results were replicated in the USA-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years) and combined in a meta-analysis. Participants/materials, setting, methods Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in both the discovery and replication cohort. A GWAS was performed using a linear regression model adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study. Main results and the role of chance Three genome-wide significant (&amp;lt;5.0x10E-8 ) and 16 genome-wide suggestive (&amp;lt;5.0x10E-6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (&amp;gt;0.01 if not genome-wide significant), p-value (&amp;lt;5.0 × 10E−6 ), and biological relevance, 15 SNPs were selected for replication in the independent replication cohort of the St. Jude Lifetime Cohort. None of the SNPs were statistically significantly associated with AMH levels in this smaller cohort. A meta-analysis indicated thatrs78861946 was associated at borderline genome-wide statistical significance (reference/effect allele: C/T;EAF: 0.04, Beta (SE): −0.484 (0.091), p-value= 9.39 × 10E−8). While the sample size of both the discovery and replication cohorts are large for CCS cohorts, they are very small compared to GWASs in the general population. The limited power is likely one of the reasons the identified SNPs were not statistically significant in our replication cohort of SJLIFE. Limitations, reasons for caution While AMH is a valuable surrogate marker for ovarian reserve, it remains a proxy for ovarian reserve and low AMH levels may still coincide with fertility potential and pregnancy. Wider implications of the findings Identification of risk-contributing variants such as rs78861946 may prove useful to better identify patients who are specifically susceptible for alkylating agent-induced gonadal toxicity. Future polygenic risk scores may aid individualized counselling regarding the treatment-related risk of gonadotoxicity and fertility preservation options for female childhood cancer survivors. Trial registration number not applicable

Factors associated with fertility status assessment among female survivors of childhood cancer.

10072 Background: Female survivors of childhood cancer with prior gonadotoxic treatment are at risk for infertility. As such, fertility status assessment (FSA) with ovarian reserve assessment and antral follicle count in consultation with a fertility specialist may be indicated to evaluate options for biological parenthood. FSA is underutilized in this population. This study explored psychosocial, developmental, and clinical factors associated with FSA. Methods: Female survivors (aged 18-29 years, diagnosis &lt; 21 years, &gt; 1 year from treatment completion, prior gonadotoxic treatment) were recruited from four cancer centers in the U.S. Participants reported sociodemographics (race, sexual orientation, gender identity, relationship status), developmental milestones (living and financial independence, full-time employment), reproductive concerns (modified Reproductive Concerns Scale), knowledge of reproductive health, decisional factors, and history of FSA. Clinical characteristics (cancer diagnosis, treatment-related risk for infertility, hormonal testing, clinical encounter with pediatric reproductive health subspecialist [gynecology, endocrinology]) were abstracted from the medical record. Multivariate logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for factors associated with FSA. Results: Of 325 participants, N = 260 completed all survey items of interest. Participants were an average of 23.7±3.1 years, 74% non-Hispanic white, 79% heterosexual and cisgender, and 48% in a committed relationship. Compared with those without FSA (N = 164), participants who completed an FSA (N = 96) reported greater attainment of developmental milestones (OR 2.20, 95%CI: 1.10-3.85, p = .027), greater desire for reproductive information (OR 1.86, 95%CI: 1.2-2.77, p = .001), greater knowledge regarding fertility-related procedures (OR 4.12, 95%CI: 2.36-7.57, p &lt; .001) and fertility preservation (OR 1.76, 95%CI: 1.31-2.44, p &lt; .001), having made an informed decision to pursue FSA (OR 1.82, 95%CI: 1.30-2.59, p = .001), clinical encounter with pediatric reproductive subspecialist (OR 3.37, 95%CI: 1.1-10.9, p = .032), and less knowledge regarding family building options (OR 0.47, 95%CI 0.27-0.79, p = .006). Diagnosis, infertility risk, and hormonal evaluation were not associated with FSA completion. Conclusions: Among emerging adult survivors, psychosocial factors associated with FSA completion include developmental milestones and knowledge of reproductive health. Clinical encounters with pediatric reproductive subspecialists may provide an opportunity for survivors to learn about and receive referrals to a fertility clinic. Psychoeducation is warranted to support survivors’ pursuit of FSA. Integration and consideration of survivor development and knowledge in these clinical encounters should potentiate optimal uptake of FSA.

Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors – a genome-wide association study: results from PanCareLIFE

ObjectiveWe aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DesignGenome-wide association study. SubjectsA discovery cohort of adult female childhood cancer survivors, from the pan‐European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA‐based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). ExposureFemale childhood cancer survivors are at risk of therapy‐related gonadal impairment. Alkylating agents are well‐established risk factors, and the inter‐individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. InterventionNo intervention was performed. Main Outcome MeasureAnti‐Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta‐analysis. ResultsThree genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10−6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): −0.484 (0.091), p‐value= 9.39×10−8). ConclusionThis study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

Risk Factors for Treatment-Related Amenorrhea in Female Survivors of Childhood and Adolescent Cancer: 10-Year Experiences at Oncofertility Clinic in Korean Tertiary Center.

Purpose: This study investigates the impact of gonadotoxic cancer treatment on treatment-related amenorrhea (TRA) and hormonal status in pediatric and adolescent females who underwent fertility preservation (FP) consultation. Methods: A retrospective review was conducted on 143 females under 21 with cancer referred to the FP clinic at Seoul National University Hospital between 2011 and 2022. We analyzed variables, including age, menarche status, cancer type, and treatment. Subsequently, subjects were evaluated to identify clinical factors affecting TRA at 1-year intervals following the completion of treatment. Upon cancer diagnosis, all patients received FP counseling and underwent semiannual evaluations for menstrual resumption and hormonal status. Results: The median age at diagnosis was 15; menarche was reported in 76.9%. Bone sarcoma (16.1%) and acute lymphoblastic leukemia (14.7%) were predominant. Most consultations (74.8%) occurred pretreatment. After FP consultations, 9.8% of patients underwent oocyte cryopreservation, and 99.3% used gonadotropin-releasing hormone agonists during systemic chemotherapy. One year after treatment completion, TRA was shown in 29.4% of this cohort. Cyclophosphamide-equivalent dose >4000 mg/m2 (adjusted odds ratio [aOR], 2.279; 95% confidence interval [CI]; 1.018-5.105, p = 0.045) and pelvic irradiation (aOR, 16.271; 95% CI, 1.545-171.408; p = 0.020) were independent clinical factors predicting TRA. Conclusion: The study delineates the clinical factors affecting TRA in pediatric and adolescent cancer survivors, revealing the significant impact of specific treatment. The data highlight the critical role of personalized oncofertility consultations in this demographic, offering valuable insights for designing targeted FP strategies at tertiary centers.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort

Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. Canadian Institutes of Health Research, US National Cancer Institute.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m−2: 1.24, 95% confidence interval (CI): 1.18–1.31), with more than twofold increased risk for survivors treated with ≥200 mg m−2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200–299 mg m−2, HR: 2.33 for 300–399 mg m−2 and HR: 2.78 for ≥400 mg m−2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59–6.63). For patients treated with or without chest irradiation, HRs per 100 mg m−2 of doxorubicin were 1.11 (95% CI: 1.02–1.21) and 1.26 (95% CI: 1.17–1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m−2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Quality of life after pediatric cancer: comparison of long-term childhood cancer survivors’ quality of life with a representative general population sample and associations with physical health and risk indicators

BackgroundThis study aimed to compare the quality of life (QoL) reported by childhood cancer survivors (CCS) drawn from a cohort of the German Childhood Cancer Registry with a representative general population sample and, within CCS, to test associations between QoL and health behavior, health risk factors, and physical illness.MethodsCCS (N = 633, age at diagnosis M = 6.34 (SD = 4.38), age at medical assessment M = 34.92 (SD = 5.70)) and a general population sample (age-aligned; N = 975) filled out the EORTC QLQ-C30. Comparisons were performed using General linear models (GLMs) (fixed effects: sex/gender, group (CCS vs. general population); covariates: age, education level). CCS underwent an extensive medical assessment (mean time from diagnosis to assessment was 28.07 (SD = 3.21) years) including an objective diagnosis of health risk factors and physical illnesses (e.g., diabetes and cardiovascular disease). Within CCS, we tested associations between QoL and sociodemographic characteristics, health behavior, health risk factors, and physical illness.ResultsCCS, especially female CCS, reported both worse functional QoL and higher symptom burden than the general population. Among CCS, better total QoL was related to younger age, higher level of education, being married, and engaging in active sports. Both health risk factors (dyslipidemia and physical inactivity) and manifest physical illnesses (cardiovascular disease) were associated with lower total QoL.ConclusionsIn all domains, long-term CCS reported worse QoL than the comparison sample. The negative associations with risk factors and physical illnesses indicate an urgent need for long-term surveillance and health promotion.

O-083 Ovarian reserve, Reproductive function and Pregnancy outcomes among Female survivors of childhood Hodgkin lymphoma: results from the DCOG LATER-VEVO Later study

Abstract Study question What is the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes? Summary answer Impaired markers of ovarian reserve in childhood HL survivors substantiate risk of a reduced fertile life span. Pregnancy outcomes seem reassuring at a young age. What is known already Childhood Hodgkin Lymphoma (HL) is nowadays highly curable with survival rates over 90%. Chemotherapy and radiation are associated with late adverse effects including risk of reduced ovarian function and -reserve. Study design, size, duration This study was embedded within the DCOG LATER-VEVO study, a nationwide, multicenter, retrospective cohort study performed between 2004 and 2014, in which the reproductive ability of 1106 female childhood cancer survivors was studied and compared to 798 controls (siblings and females from the general population). Participants/materials, setting, methods The current analysis included all female childhood HL survivors, treated between 1963 and 2002, and controls who provided written informed consent to participate in the LATER-VEVO study. Data collection consisted of a questionnaire and timed clinical measurements (blood sample and transvaginal ultrasound). Serum anti-Mullerian hormone (AMH), FSH, inhibin B, the antral follicle count (AFC) and self-reported (first) pregnancy rates and -outcomes were evaluated in linear and logistic regression models . Main results and the role of chance 84 HL survivors and 798 controls were included, aged 29.6 (IQR 19.8-36.6) and 32.7 (IQR 19.7-49.6) years old at time of assessment. Median age at HL diagnosis was 13.4 years (IQR 6.4-16.4), with median time since diagnosis of 16.5 (IQR 8.4;36.6) years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (&amp;lt;p10) 10.1 [95%CI 4.9;20.6]; low AFC (&amp;lt;p10) 4.6 [95%CI 2.1;9.9]; elevated FSH (&amp;gt;10IU/l) 15.3 [95%CI 5.7;41.1], low Inhibin B (&amp;lt;20ng/l) 3.6 [ 95%CI 1.7;7.7], all p &amp;lt; 0.001, 45 survivors and 413 controls). Pregnancy and live birth rates were comparable between survivors and controls (±80% live birth, ±20% miscarriage). However survivors were significantly younger of age at first pregnancy (27.0 years vs 29.0 yrs, P = 0.04, 42 survivors and 389 controls). Time to first pregnancy seemed to be increased in survivors (adjusted odds-ratio for time to pregnancy &amp;gt;12 months was 2.5 [95% CI 1.1;5.6] in survivors, p = 0.031). No significant differences in birth weight or gestational age were observed. Gonadotoxicity was specifically present after treatment with procarbazine and higher CED-score. No clear effect of age at diagnosis was observed. Limitations, reasons for caution The studied cohort comprised a relatively young population. Risk of premature ovarian insufficiency could not be assessed and a considerable number of women indicated they considered themselves too young to aim to achieve pregnancy. Heterogeneity in received treatment and sample size issues complicated the extent of the analyses. Wider implications of the findings HL survivors appear to have an impaired ovarian reserve, however chance to achieve pregnancy seems reassuring at a young age. Additional studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic. Trial registration number NTR2922

Examining decisional needs and contextual factors influencing fertility status assessment among young female survivors of childhood cancer: A sequential mixed methods study protocol.

Female cancer survivors who received gonadotoxic cancer treatment are at risk for profound diminished ovarian reserve and/or primary ovarian insufficiency with resulting infertility, which can be associated with distress and decreased quality of life.. Despite prioritizing future parenthood, many survivors are unsure of the impact of their treatment on their future fertility, and little is known about the perceived reproductive health needs and factors associated with receipt of a fertility status assessment (FSA). There is a lack of developmentally appropriate reproductive health decisional support interventions available for emerging adult cancer survivors. This study will explore the perceived reproductive health needs of emerging adult female survivors of childhood cancer and to identify decisional and contextual factors that influence pursuit of FSA using an explanatory sequential quantitative to qualitative mixed methods design. This study will enroll 325 female survivors (aged 18 to 29 years and >1-year post treatment; diagnosed with cancer < age 21 years) from four cancer centers in the United States. Sociodemographic and developmental factors, reproductive knowledge and values, decisional needs, and receipt of an FSA will be assessed through a web-based survey. Informed by survey findings, a subset of participants will be recruited for qualitative interviews to explore decisional factors associated with uptake of an FSA. Clinical data will be abstracted from the medical records. Multivariable logistic regression models will be developed to identify factors associated with FSA and qualitative descriptive analysis will be used to develop themes from the interviews. Quantitative and qualitative findings will be merged using a joint display to develop integrated study conclusions and direct future interventional research.

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 ( &gt; 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 &lt; 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.

Premature ovarian insufficiency and chance of pregnancy after childhood cancer: A population-based study (the Fex-Can study).

Endocrine complications are a common late effect after childhood cancer. Our study assessed the prevalence and predictors of premature ovarian insufficiency (POI) and prospects of pregnancy in young female survivors. This nationwide study combined registry and survey data for female childhood cancer survivors aged 19 to 40 years, identified through the National Quality Registry for Childhood Cancer in Sweden. Of 1989 approached young women, 1333 (67%) participated by completing a survey. Median age at diagnosis 1981 to 2017 was 6 (range 0-17) and at study 28 (19-40) years. There were two indicators of POI, induced puberty reported in 5.3% and estrogen replacement therapy (ERT) in 9.3% at assessment. In separate logistic regression analyses (P < .001), induced puberty and ERT were significantly predicted by hematopoietic stem cell transplantation (HSCT), abdominal irradiation, central nervous system irradiation and chemotherapy. ERT was also associated with older age at diagnosis. Of the 626 women (48% of responders) who had tried to become pregnant, 25% had undergone fertility investigations and 72% reported having a biological child. Treatment with HSCT was associated with 5.4 times the odds of needing fertility investigations (P < .001). Having a biological child was associated with non-HSCT treatment, but also with ever having had a partner and older age at the time of study (all P < .001). In conclusion, the majority of those female childhood cancer survivors who had tried to conceive were able to successfully give birth. However, a small identifiable group of female survivors are at risk of subfertility and early menopause.

Experiences of Female Childhood Cancer Patients and Survivors Regarding Information and Counselling on Gonadotoxicity Risk and Fertility Preservation at Diagnosis: A Systematic Review

Childhood cancer patients and their families are increasingly offered oncofertility care including information regarding their risk of gonadal damage by paediatric oncologists, fertility counselling by fertility specialists and fertility preservation options. However, experiences regarding oncofertility care are underreported. We aimed to summarize the available evidence of experiences of female childhood cancer patients and survivors regarding oncofertility care. Manuscripts were systematically identified using the PubMed and Embase database. From, respectively, 1256 and 3857 manuscripts, 7 articles were included and assessed, including risk of bias assessment. Outcome measures included data describing experiences of female childhood cancer patients and survivors, regarding fertility information, counselling and/or preservation. Female patients and survivors are variably satisfied with fertility information, report challenges in communication with healthcare professionals and prefer to receive general information at diagnosis and detailed fertility information later. Regrets after fertility counselling are underreported, but are associated with refusing fertility preservation. Lastly, regardless of counselling, female patients and survivors report fertility concerns about their future children's health and effect on relationships. Currently, the satisfaction with oncofertility care varies and female patients or survivors report regrets and concerns regardless of receiving fertility information or counselling. These results may help to improve the content of fertility information, communication skills of healthcare professionals and timing of counselling.

Gonadal Function in Female Adolescent and Young Adult Survivors of Childhood Cancer.

Childhood cancer survivors (CCSs) are at risk for premature ovarian insufficiency (POI). The aim of this study is to evaluate ovarian function and associated health outcomes in female adolescent and young adult survivors of childhood cancer. Sixty-nine female CCSs were enrolled. Medical records of CCSs were retrospectively reviewed. The subjects were categorized into three groups according to follicular stimulating hormone (FSH) levels (cutoff, 12, 40 IU/L). Anti-müllerian hormone (AMH) level less than 1 ng/mL was considered low AMH level. Of 69 subjects, 14 (20.3%) had POI and 14 (20.3%) had FSH levels between 12 and 40 IU/L. Forty-one of 69 (59.4%) had normal FSH levels. Pelvic irradiation and stem cell transplantation (SCT) were more frequently performed in subjects with POI (p=0.001 and p < 0.001). AMH levels were remarkably low when FSH levels were over 12 IU/L (p < 0.001). In multivariate analysis, cyclophosphamide equivalent dose and SCT were significant treatment factors for developing low AMH levels (p=0.005 and p=0.002, respectively). Total, low-density lipoprotein cholesterol and triglyceride were significantly different in three groups according to FSH levels (p=0.047, p=0.030, and p=0.045). Z-score of femur neck bone mineral density was significantly reduced when FSH levels were increased (p=0.011). Gonadal dysfunction is common in CCSs. Gonadal function was associated with a few treatment factors known to increase the risk of POI. Regular monitoring of gonadal function is needed for better health outcomes.

Pregnancy outcomes among female childhood, adolescent, and young adult cancer survivors assessed using internet-based nationwide questionnaire surveys in Japan

Objective Female cancer survivors planning to become pregnant are concerned about the impact of cancer treatment on their ability to maintain normal pregnancy and the negative impact on their offspring. However, studies on the pregnancy outcomes of cancer survivors in Japan are limited. Therefore, this study aimed to investigate the pregnancy outcomes of female cancer survivors by comparing them with women without a history of malignant tumors in Japan. Methods This cross-sectional study included 3308 subjects, based on an internet-based questionnaire (self-reported) survey conducted in Japan. Differences in pregnancy outcomes, including multiple pregnancies, stillbirth, preterm birth (PTB), and infant birthweight, between cancer survivors and subjects without a history of malignant tumors, were evaluated using a generalized linear mixed-effects model with adjustment for possible confounding factors. Results Of 3308 subjects included in this study, 629 (19.0%) were cancer survivors, among whom cervical (40.4%), breast (19.1%), and thyroid (7.0%) malignancies were most frequent. 71 (2.2%) and 53 (1.6%) participants had a history of multiple pregnancies and stillbirth, respectively; 385 (11.8%), 179 (5.5%), and 137 (4.2%) participants, respectively, had histories of PTB at less than 37, 34, and 32 weeks of gestation. Further, 302 (10.7%), 326 (11.6%), and 330 (11.7%) participants delivered to low birthweight (LBW), small-for-gestational-age (SGA), and large-for-gestational-age (LGA) infants, respectively. Subjects with a history of cervical or breast cancers had significantly higher odds of PTB at <37 weeks of gestation (adjusted odds ratios [ORs], 1.87 [95% CI: 1.25–2.81] and 2.61 [95% CI: 1.77–3.86], respectively), preterm LBW infants (adjusted ORs, 2.70 [95% CI: 1.39–5.24] and 2.76 [95% CI: 1.03–7.38], respectively), and LGA infants (1.98 [95% CI: 1.36–2.89] and 1.99 [95% CI: 1.14–3.49], respectively), compared to those without a history of a malignant tumor. Subjects with a history of thyroid cancer had significantly higher odds of stillbirth (adjusted OR, 5.11 [95% CI: 1.11–23.5]). Conclusion Cancer survivors had a higher risk of adverse pregnancy outcomes than those without a history of malignant tumors in Japan. Healthcare providers should consider the high likelihood of adverse pregnancy outcomes during preconception counseling for cancer survivors.

Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors

Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved. To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk. Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020. Radiation and chemotherapy dose changes over time. Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age. Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence. Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.

Temporal changes in the probability of live birth among female survivors of childhood cancer: a population-based adult life after childhood cancer in Scandinavia (ALiCCS) study in five Nordic countries

Temporal changes in the probability of live birth among female survivors of childhood cancer: a population-based adult life after childhood cancer in Scandinavia (ALiCCS) study in five Nordic countries