BACKGROUND: Despite 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. OBJECTIVE: The 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. METHODS: For 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. RESULTS: Of 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. CONCLUSIONS: Results 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 IDENTIFIER: RR1-10.2196/10824.

• Publication type
• Journal Article MeSH

BACKGROUND: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. METHODS: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1-30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6-37.4). RESULTS: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): -0.706 (-1.11--0.298), p-value = 7 × 10-4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126-0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. CONCLUSIONS: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

• Publication type
• Journal Article MeSH

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

• MeSH
• Anti-Mullerian Hormone genetics   MeSH
• Child MeSH
• Adult MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Cohort Studies MeSH
• Humans MeSH
• Adolescent MeSH
• Ovarian Reserve * MeSH
• Ovary MeSH
• Protein Serine-Threonine Kinases MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

• MeSH
• Time Factors MeSH
• Adult MeSH
• Genes, BRCA1 * MeSH
• Genes, BRCA2 * MeSH
• Risk Assessment MeSH
• Incidence MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• Breast Neoplasms epidemiology   genetics   MeSH
• Ovarian Neoplasms epidemiology   genetics   MeSH
• Prospective Studies MeSH
• Family MeSH
• Neoplasms, Second Primary epidemiology   genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Age Factors MeSH
• Age Distribution MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Hodgkin Disease physiopathology   therapy   MeSH
• Publication type
• Collected Work MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• hematologie a transfuzní lékařství