Female Childhood Cancer Survivors Research Articles

Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE).

The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population. Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression. The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3). Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors.

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol

BackgroundImproved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation.Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment as the primary outcome in CCS.MethodsAs part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort.DiscussionThis international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.

Fertility Among Female Survivors of Childhood, Adolescent, and Young Adult Cancer: Protocol for Two Pan-European Studies (PanCareLIFE).

BackgroundDespite a significant number of studies on female fertility following childhood, adolescent, and young adult (CAYA) cancer, studies establishing precise (dose-related) estimates of treatment-related risks are still scarce. Previous studies have been underpowered, did not include detailed treatment information, or were based on self-report only without any hormonal assessments. More precise assessments of who is at risk for sub- or infertility are needed.ObjectiveThe objective of our study is to describe the design and methods of 2 studies on female fertility (a cohort study and a nested case-control study) among female survivors of CAYA cancer performed within the European PanCareLIFE project.MethodsFor the cohort study, which aims to evaluate the overall risk of fertility impairment, as well as the risk for specific subgroups of female CAYA cancer survivors, 13 institutions from 9 countries provide data on fertility impairment. Survivors are defined as being fertility impaired if they meet at least one of 8 different criteria based on self-reported and hormonal data. For the nested case-control study, which aims to identify specific treatment-related risk factors associated with fertility impairment in addition to possible dose-response relationships, cases (fertility impaired survivors) are selected from the cohort study and matched to controls (survivors without fertility impairment) on a 1:2 basis.ResultsOf the 10,964 survivors invited for the cohort study, data are available from 6619 survivors, either questionnaire-based only (n=4979), hormonal-based only (n=72), or both (n=1568). For the nested case-control study, a total of 450 cases and 882 controls are identified.ConclusionsResults of both PanCareLIFE fertility studies will provide detailed insight into the risk of fertility impairment following CAYA cancer and diagnostic- or treatment-related factors associated with an increased risk. This will help clinicians to adequately counsel both girls and young women, who are about to start anticancer treatment, as well as adult female CAYA cancer survivors, concerning future parenthood and to timely refer them for fertility preservation. Ultimately, we aim to empower patients and survivors and improve their quality of life.Registered Report IdentifierRR1-10.2196/10824

Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve.

Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.

Spotlight on … adolescent gynaecology

Adolescents present with a variety of symptoms to the gynaecology clinic. A common gynaecological condition is heavy menstrual bleeding and usually this will be managed in primary care. However, patients who do not respond to first-line management or who have co-morbidities will be referred to the gynaecologist. Other common presentations are dysmenorrhea, menstrual irregularities primary and secondary amenorrhoea. Many of these symptoms are common during puberty and adolescence and usually are amenable to expectant management or simple therapies. Nevertheless, as they are common they also run the risk of delayed diagnosis and treatment. Delayed diagnosis of endometriosis in adolescence illustrates this problem. Research articles, review articles and guidelines serve to increase awareness and emphasise the need to keep a degree of suspicion regarding different pathologies, for timely diagnosis and treatment. The 2017 National Institute for Health and Care Excellence (NICE) guidance on the diagnosis and management of endometriosis (http://www.nice.org.uk/guidance/ng73) emphasises the need to suspect endometriosis in women (including young women aged 17 years and under) presenting with one or more of the following signs or symptoms: chronic pelvic pain; period-related pain (dysmenorrhoea) affecting daily activities and quality of life; deep pain during or after sexual intercourse; period-related or cyclical gastrointestinal symptoms, in particular, painful bowel movements; and period-related or cyclical urinary symptoms. Different causes of menstrual obstruction should also be borne in mind in evaluating pain. The Obstetrician and Gynaecologist (TOG) has attempted to maintain the presence of adolescent gynaecology in its contents. Two articles published in the last 2 years were centred on adolescent gynaecology and are highlighted below. A section of an article on polycystic ovary syndrome (PCOS) featured adolescents specifically and has therefore been included in this ‘Spotlight’. Genital outflow tract anomalies, management of menstrual disturbances, contraception in the under 16s have featured between 2011 and 2013 and updates on these topics are due. In the July 2017 issue of TOG, Dr Katherine Gilmore and colleagues aimed to increase awareness of child sexual exploitation and safeguarding among obstetricians and gynaecologists (TOG 2017;19:205–10). A helpful ‘spotting the signs’ pro forma was presented. Questions that would facilitate exploration of possibility of sexual abuse include whether someone is in a relationship, whether the relationship going well, and how she feels about herself. Several risk factors that should alert clinicians are enumerated in tables which are easy to read and act as memory aids. Emily Gelson and colleagues wrote about the assessment and care of female survivors of childhood cancer in the October edition of 2016 (TOG 2016;18:315–22). With increased survival in childhood cancers, there are increasing consequences such as premature ovarian insufficiency (POI). The authors have highlighted that in survivors who continue to have menstrual cycles, an assessment of ovarian reserve should be made because of the risk of POI. The authors presented evidence that anti-müllerian hormone (AMH) is a good marker of ovarian reserve and can be used to identify those at risk of POI. The care of survivors who go through menopause include counselling and hormone replacement therapy. Options for fertility and fertility preservation are also discussed in the paper. An update on PCOS by Professor Adam Balen was published in January 2017 (TOG 2017;19:119–29). The article included a section on the condition in adolescence. The problems of applying the Rotterdam criteria in adolescence were discussed. Many symptoms of PCOS, such as irregularity of menstrual cycles and acne, are common in adolescence. A pragmatic approach of treating symptoms, excluding other pathology and following up for evolution of symptoms with time are recommended. Paediatric and adolescent gynaecology is a vital component of obstetrics and gynaecology. However, this subspecialty has not been proportionately represented in TOG content. Updates on the management of heavy menstrual bleeding in adolescents and children, pelvic pain, primary amenorrhoea and ovarian cysts would be welcome. An online collection of all TOG articles on adolescent gynaecology is available at onlinetog.org.

Reproductive Function and Outcomes in Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Review.

Some survivors of childhood, adolescent, and young adult cancer are at increased risk of gonadal dysfunction and adverse pregnancy outcomes. We reviewed currently available literature that evaluated reproductive function and pregnancy outcomes of female cancer survivors diagnosed before the age of 25 years. High-dose alkylating agent chemotherapy and abdominal/pelvic radiotherapy adversely affect gonadal function in a dose-related fashion, with older age at exposure conferring greater risk as a result of the age-related decline in ovarian reserve. Gonadal injury clinically manifests as ovarian hormone insufficiency (delayed or arrested puberty, premature ovarian insufficiency, or premature menopause) and infertility. The effect of molecular-targeted agents on ovarian function has not been established. For female cancer survivors who maintain fertility, overall pregnancy (relative risk, 0.67 to 0.81) and live birth rates (hazard ratio, 0.79 to 0.82) are lower than those in the general public. Pregnancy in cancer survivors also may be associated with risks to both the mother and the fetus related to miscarriage; preterm birth; and, rarely, cardiomyopathy. Women at risk for these complications require preconception assessment and counseling from both obstetricians and oncology providers. The risk for inherited genetic disease in offspring conceived after cancer treatment exposure is not increased. The optimization of reproductive outcomes and minimization of risks of pregnancy complications in survivors requires informed, risk-based assessment and monitoring.

Fecundity and Quality of Life of Women Treated for Solid Childhood Tumors Between 1948 and 1992 in France.

To describe fecundity in female survivors of childhood cancer and consider the correlation with quality of life (QOL). Of 1744 women treated for childhood cancer before the age of 15 years at one of eight French cancer treatment centers between 1948 and 1992, 1187 who were alive in 2005 were sent a self-administered questionnaire, including questions about health status, QOL (MOS SF-36), and fecundity. A standardized fecundity ratio (SFR) was calculated (SFR: observed/expected number of children) for each individual based on a national reference. Of the 972 individuals (82%) who responded, 53% had at least 1 child. The overall SFR, 0.65, was dependent upon the initial diagnosis, more decreased in Central Nervous System tumors (0.24; p < 10-3) than in Germ cell (0.46; p = 0.03) or Sympathetic Nervous System tumors (0.79; p = 0.02). The average QOL motor score was 72.5 ± 19.5, and the average mental score was 61.4 ± 16.7. After adjusting for age, pathology, and self-reported sequelae in the questionnaires, it was determined that SF-36 mental (p = 0.002) and motor (p < 0.0002) scores correlated positively with fecundity, and SF-36 scores correlated negatively with locomotor late effects (p < 0.0001), growth insufficiency (p = 0.002), and psychological disorders (p < 0.001). Gonadal insufficiency was correlated with neither motor nor mental scores. Women treated for childhood cancer demonstrated impaired fecundity that correlated with poor QOL, as registered by the SF-36. Patients should be warned of the risk of impaired fecundity early during the follow-up. If possible, preservation of fertility should be prioritized at initiation of therapy.

Reproductive health of female childhood cancer survivors.

Current treatment schemes of childhood cancer are usually effective enough to enable successful management of the disease. With the high rates of survival, another problem arises because patients often suffer much later from side effects of the toxic therapy. A common complication caused by cancer treatment is impairment of the female reproductive system including dysfunction of the hypothalamus and hypophysis, the killing of gonadal cells, and uterine injury. This may lead to altered pubertal timing, gonadotropin insufficiency or deficiency, acute ovarian failure, premature ovarian insufficiency, sexual dysfunction, and complicated pregnancy. The severity of these side effects depends a lot on the patient's age at treatment and the particularities of their chemo- and/or radiotherapy regimens. While some types of cancer require aggressive treatment, and therefore negative side effects cannot be avoided, strategies which preserve the patient's reproductive potential are essential. Such strategies are more established in the treatment of adult women, however there are also promising opportunities in the treatment of pediatric oncology patients. Ovar-ian transposition is already widely applied before pelvic radiotherapy. Cryopreservation of ovarian tissue, cryopreservation and in vitro maturation of immature oocytes, or cryopreservation of mature oocytes when the patient's age is appropriate, have also shown to have promising results in pediatric patients. Concurrent combinations of several techniques can also be successful. Counselling of pediatric patients and their families is challenging, and the urgent commencement of anticancer therapies often discourages attempts to preserve the girl's reproductive system. Given that successful methods of fertility preserva-tion are already accessible, it is crucial not to leave this topic aside at the time of diagnosis.

Mortality following breast cancer in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

10511Background: Female childhood cancer survivors have a high risk of subsequent breast cancer (BC). Little is known about mortality following BC in this population. Methods: Risk of all-cause and...

Reproductive intentions and use of reproductive health care among female survivors of childhood cancer.

Do female childhood cancer survivors (CCSs) express a decreased desire to have children and do they use reproductive health care more often compared to women without a history of cancer? Overall, no difference was found in the desire to have children between CCSs and controls, whereas CCSs consult a fertility specialist more often, at a younger age, and sooner after their first attempt at conceiving. Female CCSs may face a shorter than anticipated reproductive window as a result of their cancer treatment. Little is known about their desire to have children and use of reproductive health care, especially in relation to their former cancer treatment. This study is part of the DCOG LATER-VEVO study, a nationwide retrospective cohort study on female fertility in Dutch CCSs. In total, 1749 CCSs and 1673 controls were invited for the study. Data collection took place between January 2008 and May 2014. Data on the desire to have children and use of reproductive health care were collected by questionnaire. The control group consisted of sisters from CCSs and females from the general population. In total, 1106 (63%) CCSs and 818 (49%) controls completed the questionnaire. Overall, no difference was found in the desire to have children between CCSs and controls (86% and 89%, respectively). However, survivors of a CNS tumour were less likely to desire children and CCSs without biological children at time of study were more likely to report that their desire to have children was unfulfilled because of medical reasons (9%), compared to controls (1%). In total, 12% of CCSs ever consulted a fertility specialist compared to 10% of controls (OR = 1.7, 95% CI: 1.3-2.4). Mean (SD) age at time of their first visit was 27.7 (4.4) years for CCSs and 29.9 (3.9) years for controls (P < 0.01). In total, 43% of CCSs consulted a fertility specialist within 12 months after they had started trying to achieve a pregnancy, compared to 27% of controls. Risk factors for consulting a fertility specialist included a previous diagnosis of renal tumour, leukaemia, lymphoma or a CNS tumour, and treatment with alkylating chemotherapy, gonadotoxic radiotherapy or both. In total, 70% of CCSs reported a female factor as cause of subfertility compared to 34% of controls (OR = 4.5, 95% CI: 2.3-8.7) and in this specific group, CCSs seemed more likely to use fertility treatment (OR = 2.9, 95% CI: 1.0-8.2). Because of the low number of CCSs who used fertility treatment, we were not able to look at specific diagnoses and treatment types associated with using fertility treatment. Nevertheless, we were able to identify diagnostic- and treatment-related risk factors for consulting a fertility specialist. Details regarding consultations with a fertility specialist and fertility treatment were based on self-report and may therefore be subject to recall bias. Decisions about parenthood affect all CCSs. It's important to evaluate reproductive intentions and function timely after cancer treatment, so CCSs can be adequately counselled regarding family planning and fertility treatment. This work was supported by the Dutch Cancer Society (Grant no. VU 2006-3622) and the Children Cancer Free Foundation (Project no. 20). NTR2922.

Psychosexual functioning in sexually active female survivors of childhood cancer.

136 Background: Childhood cancer survivors (CCS) may be at risk for low psychosexual function. We estimated the prevalence of low psychosexual function among female CCS, and evaluated associations with treatment exposures. Methods: 712 female CCS (mean age at assessment 31.2±7.71 years, at diagnosis 7.00±5.58 years; 31.3% acute lymphoblastic leukemia, 12.5% Hodgkin lymphoma) and 122 non-cancer controls enrolled in the St. Jude Lifetime Cohort Study completed a clinical assessment, reported sexual activity with or without a partner in the preceding month, and filled out the Sexual Functioning Questionnaire (SFQ) (25 items averaged to create overall and subscale scores ranging 0-5; lower is worse). CCS with SFQ scores &lt; 10th percentile of controls were classified as low function. Linear models, adjusted for age, were used to compare SFQ scores. Associations between CCS characteristics and psychosexual function were evaluated using logistic regression. Results: 19.9% of CCS had low psychosexual function with a lower mean overall SFQ score than controls (3.19 vs. 3.47, effect size 0.4; p &lt; 0.01). The most common impairments among CCS were performance problems (27.4%), orgasm (24.2%), satisfaction (17.6%), interest (17.2%), desire (15.4%), and arousal (12.5%). Survivors with low function reported poor quality of life in both physical (21.1% vs. 12.7%, p = 0.01) and mental health (36.5% vs. 18.2%, p &lt; 0.01) domains compared to those without. Untreated hypogonadism was associated with low function (OR 3.20, 95% CI 1.69-6.42) for the performance problems subscale. Compared to controls, CCS with germ cell tumors (OR 8.82, 95% CI 3.17-24.50), renal tumors (OR 4.49, 95% CI 1.89-10.67) and leukemia (OR 3.09, 95% CI 1.50-6.38) were at greatest risk for low function. Though 40.7% of CCS perceived a higher risk for low psychosexual function compared to other women their age, only 2.9% reported receiving an intervention. Conclusions: Low psychosexual function is prevalent among female CCS. CCS with low psychosexual function also report poorer quality of life and more psychological symptoms. Research is necessary to identify additional risk factors that characterize high-risk survivors who would benefit from targeted screening and intervention.

Pregnancy outcomes in female childhood cancer survivors: Nationwide survey in Japan.

The aim of this study was to investigate the outcomes of pregnancy in female childhood cancer survivors (CCS) in Japan, to encourage greater attention to the reproductive health of CCS. This was a retrospective nationwide questionnaire survey of delivery at ≥22 weeks of gestation in CCS at perinatal centers registered with the Japanese Perinatologists Association between 2010 and 2014. We evaluated the maternal characteristics, pregnancy and neonatal outcomes and the relationship between cancer treatment and these outcomes. The total number of CCS was 61, and the total number of deliveries was 71, corresponding to 0.019% of total deliveries. Regarding cancer, 46% of the patients had had leukemia. Epilepsy was seen in seven (11%). Mean gestational age at delivery was 37.9 weeks. The rate of preterm delivery was 24%. Mean birthweight was 2,718 g. There were three congenital anomalies (4.2%). The rate of preterm delivery was higher and mean birthweight lower in the women treated with radiotherapy than in those without radiotherapy (42% vs 16%, P = 0.025; 2,436 ± 737 g vs 2,827 ± 483 g, P = 0.010). The adjusted OR of radiotherapy for preterm deliveries was 3.53 (P = 0.049). Although the number of deliveries by CCS was low in Japan, the pregnancy outcomes were favorable. The important points for managing pregnancy in CCS were preterm delivery as an obstetric complication, especially in CCS who had been treated with radiotherapy, and epilepsy as a maternal complication, which may be related to previously received treatment.

Knowledge and perceptions of infertility in female cancer survivors and their parents

PurposeThe purpose of this study was to assess knowledge and perceptions of infertility, reproductive concerns, quality of life, and emotional burden of fertility concerns in adolescent female cancer survivors and their parents.MethodsA cross-sectional design was used to investigate reproductive knowledge and concerns among female childhood cancer survivors and their parents. The instruments administered at a single, routine visit were the 13-item knowledge instrument, Adolescent Fertility Values Clarification Tool (VCT), Impact of Event Scale (IES), and Pediatrics Quality of Life Assessment (PedsQL). The knowledge instrument was given to both patients and caregivers, while the PedsQL and VCT were given to only patients and IES only to caregivers.ResultsTwenty-six survivors and 23 parents completed evaluations. The mean age of survivors was 16. The mean knowledge instrument score for survivors was 9.5 (± 1.9) and 9.96 (± 1.7) for parents with a maximum possible score of 13. The VCT indicated almost all patients agreed or strongly agreed they would like more information on how their treatment may affect their fertility, with 84.6% identified wanting a baby in the future. The mean survivor PedsQL score was 67.7 (± 15.3). While parental IES scores as whole did not endorse symptoms of PTSD, 30% of our sample did fall within the range for PTSD.ConclusionAlthough this population of women has above average knowledge scores, they still demonstrated a desire for more information on reproduction after cancer therapy. While PedsQL scores fell within a normal range, survivors report infertility would cause negative emotions.Implication for cancer survivorsThis information can be used refine educational programs within survivorship clinics to improve knowledge of post-treatment reproductive health.

A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.

Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown. Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS). PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways. The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.

Fertility-related knowledge and reproductive goals in childhood cancer survivors: short communication.

Do young adult survivors of childhood cancer know their fertility status, in the context of their parenthood goals and screening for gonadal functioning? While 80% of survivors (who were without children) wanted children in the future, most did not know their fertility status, and screening for gonadal functioning was underutilized. Survivors of childhood cancer are at risk for infertility, but fertility counseling and assessment are underutilized. Separate studies indicated that survivors' fertility-related knowledge is poor and that they often wanted to have children. Yet, studies have not investigated the intersection of both issues, as well as potential distress if parenthood goals are not met. Young adult male and female survivors of childhood cancer (N = 149) completed cross-sectional surveys, and data for those without children (n = 105, 70.5%) are presented here. Participants were 20-40 years old (M = 26.5), diagnosed 5-33 years prior to study participation, and completed questionnaires online. Knowledge of fertility status, parenthood goals, and potential distress if survivors were unable to have children were assessed. Medical records were reviewed for hormone levels as indicators of screening for gonadal functioning. Most survivors (n = 81; 77.1%) did not know their fertility status, while over 80% (n = 89) wanted children (neither aspect varied by socio-demographic/cancer-specific factors). Two-thirds of survivors indicated they would be distressed if parenthood goals remained unfulfilled; especially female (versus male, t = 2.64; P = 0.01) or partnered (versus single, t = -3.45; P < 0.001) survivors. Forty survivors (38.1%) had documented assessments of gonadal functioning, of which 33 (82.5%) reported not knowing their fertility status. Relevant risk factors may have not been identified owing to limited sample size and missing treatment information. The underutilization of screening for gonadal functioning needs further exploration in other pediatric centers. Most adult childhood cancer survivors want to become parents, but do not know their fertility status, which could cause significant psychological distress. Healthcare providers should continuously address fertility among survivors, but more research is needed on how to implement routine fertility counseling and/or testing. This study was funded by the Research Institute at Nationwide Children's Hospital (V.L.) and Dutch Cancer Society (RUG2009-4442, M.A.T.). All authors have no conflict of interest to declare.

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts. Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.

Breast Cancer After Childhood, Adolescent, and Young Adult Cancer: It's Not Just About Chest Radiation.

Women who have been treated for a childhood, adolescent, or young adult cancer are at an increased risk for developing breast cancer at a young age, and breast cancer accounts for the most common subsequent malignant neoplasm among female childhood and adolescent cancer survivors. Risk of breast cancer in these survivors appears to be a multifaceted relationship between constitutional factors, exposures to radiation therapy (RT) and chemotherapy, and genetic predisposition. Given the significant morbidities and mortality associated with a breast cancer diagnosis, it is imperative that health care providers understand the risks, biology and genetics, recommended surveillance guidelines for early detection, and potential prevention strategies for women who have survived pediatric and young adult cancer.

Gonadal Function in Female Childhood Cancer Survivors

Gonadal Function in Female Childhood Cancer Survivors

Pregnancy and Labor Complications in Female Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study.

Background: Female survivors of childhood cancer treated with abdominal radiotherapy who manage to conceive are at risk of delivering premature and low-birthweight offspring, but little is known about whether abdominal radiotherapy may also be associated with additional complications during pregnancy and labor. We investigated the risk of developing pregnancy and labor complications among female survivors of childhood cancer in the British Childhood Cancer Survivor Study (BCCSS). Methods: Pregnancy and labor complications were identified by linking the BCCSS cohort (n = 17 980) to the Hospital Episode Statistics (HES) for England. Relative risks (RRs) of pregnancy and labor complications were calculated by site of radiotherapy treatment (none/abdominal/cranial/other) and other cancer-related factors using log-binomial regression. All statistical tests were two-sided. Results: A total of 2783 singleton pregnancies among 1712 female survivors of childhood cancer were identified in HES. Wilms tumor survivors treated with abdominal radiotherapy were at threefold risk of hypertension complicating pregnancy (relative risk = 3.29, 95% confidence interval [CI] = 2.29 to 4.71), while all survivors treated with abdominal radiotherapy were at risk of gestational diabetes mellitus (RR = 3.35, 95% CI = 1.41 to 7.93) and anemia complicating pregnancy (RR = 2.10, 95% CI = 1.27 to 3.46) compared with survivors treated without radiotherapy. Survivors treated without radiotherapy had similar risks of pregnancy and labor complications as the general population, except survivors were more likely to opt for an elective cesarean section (RR = 1.39, 95% CI = 1.16 to 1.70). Conclusions: Treatment with abdominal radiotherapy increases the risk of developing hypertension complicating pregnancy in Wilms tumor survivors, and diabetes mellitus and anemia complicating pregnancy in all survivors. These patients may require extra vigilance during pregnancy.

Physical and social characteristics and support needs of adult female childhood cancer survivors who underwent hormone replacement therapy.

Female childhood cancer survivors who develop gonadal dysfunction require female hormone replacement therapy (HRT) from puberty until menopause. However, the support provided in such cases has not been studied. We investigated the physical and social characteristics and support needs of adult female childhood cancer survivors who underwent HRT. Forty-nine adult female childhood cancer survivors completed self-administered questionnaires. We compared the clinical characteristics, health status, and social conditions between a group that underwent HRT and a group that did not, and we surveyed support needs of the group that underwent HRT. The median age of the subjects was 25.0years (range 20-41). Twenty subjects (40.8%) underwent HRT. A significantly high number of those who underwent HRT also underwent radiation therapy (p<0.01) and hematopoietic stem cell transplantation (p<0.001), and none of them had a history of pregnancy or childbirth (p<0.05). There were no significant differences in physical symptoms and social characteristics between the groups. Those who experienced anxiety regarding fertility required information about HRT, a platform to share their concerns, and psychological support and cooperation among healthcare providers. Although the subjects of this survey exhibited good social adjustment regardless of whether or not they underwent HRT, they were anxious about fertility. It is important to understand the concerns and anxieties unique to female childhood cancer survivors and to enhance psychological support in addition to providing educational support so that HRT can be administered.