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Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer.

ABSTRACT: OBJECTIVE:To study how genetics may play a role in determining risk of chemotherapy-related amenorrhea (CRA) in young women with breast cancer. DESIGN:Genome-wide association study. SETTING:Not applicable. PATIENT(S):Premenopausal women ?45 years of age enrolled in one of these three trials were included if they had at least one menstrual case report form after chemotherapy ended and if they were of European ancestry. Forms during and up to 3 months after receipt of GnRH agonist were excluded. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The association of single-nucleotide polymorphisms with post-chemotherapy menstruation adjusted for trial and arm, age, tamoxifen use, and nodal status. RESULT(S):The median age of the 1,168 women was 41 years (range 19-45). Among these, 457 (39%) never resumed menses after chemotherapy. Older age, tamoxifen use, and node-negative disease were associated with increased risk of CRA. Adjusting for these, rs147451859, in an intron of PPCDC (phosphopantothenoylcysteine decarboxylase), and rs17587029, located 5' upstream of RPS20P11 (ribosomal protein S20 pseudogene 11), were associated with post-chemotherapy menstruation. CONCLUSION(S):Genetic variation may contribute to risk of CRA. Better prediction of who will experience CRA may inform reproductive and treatment decision making in young women with cancer.

SUBMITTER: Ruddy KJ

PROVIDER: S-EPMC6765404 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer.

Ruddy Kathryn J KJ Schaid Daniel J DJ Partridge Ann H AH Larson Nicholas B NB Batzler Anthony A Häberle Lothar L Dittrich Ralf R Widschwendter Peter P Fink Visnja V Bauer Emanuel E Schwitulla Judith J Rübner Matthias M Ekici Arif B AB Aivazova-Fuchs Viktoria V Stewart Elizabeth A EA Beckmann Matthias W MW Ginsburg Elizabeth E Wang Liewei L Weinshilboum Richard M RM Couch Fergus J FJ Janni Wolfgang W Rack Brigitte B Vachon Celine C Fasching Peter A PA

Fertility and sterility 20190729 4

<h4>Objective</h4>To study how genetics may play a role in determining risk of chemotherapy-related amenorrhea (CRA) in young women with breast cancer.<h4>Design</h4>Genome-wide association study.<h4>Setting</h4>Not applicable.<h4>Patient(s)</h4>Premenopausal women ≤45 years of age enrolled in one of these three trials were included if they had at least one menstrual case report form after chemotherapy ended and if they were of European ancestry. Forms during and up to 3 months after receipt of ...[more]

PMID: 31371054

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Project description:BACKGROUND: Chemotherapy-induced amenorrhea (CIA) is common in young breast cancer patients. The incidence of CIA associated with regimens involving epirubicin and taxane was not well known. Furthermore, previous studies suggested leucopenia and amenorrhea may reflect inter-individual variations in pharmacokinetics. The purpose of this study was to investigate the association between leucopenia after first cycle of chemotherapy and CIA in young breast cancer patients receiving epirubicin and taxane based chemotherapy. Furthermore, the incidence of CIA was also assessed. METHODOLOGY AND PRINCIPAL FINDINGS: Between October 2008 and March 2010, 186 consecutive premenopausal patients, treated with epirubicin and taxane based chemotherapy, were recruited. Information about CIA was collected by telephone and out-patient clinic. Of these 186 patients, data from 165 patients were included and analyzed. Of all 165 patients, CIA occurred in 72 patients (43.64%). In multivariate analysis, age older than 40 y (OR: 16.10, 95% CI: 6.34-40.88, P<0.001) and previous childbearing (OR: 3.17, 95% CI: 1.06-9.47, P = 0.038) were significantly associated with probability of CIA. Compared to patients treated without taxane, patients treated with taxane-contained regimens did not have a significantly higher rate of CIA (P>0.05). The rate of CIA in leucopenia group (52.56%) was significantly higher than that in normal leukocyte group (34.62%) (P = 0.024). In patients treated with a FEC regimen (cyclophosphamide, epirubicin and 5-fluorouracil), the rate of CIA in leucopenia group (59.57%) was significantly higher than that in normal leukocyte group (36.84%) (P = 0.037). CONCLUSIONS: Age at diagnosis and previous childbearing were both found to significantly increase the risk of CIA, whereas additional taxane was not associated with increased rate of CIA. Importantly, leucopenia after first cycle of chemotherapy was associated with increased risk of CIA, which suggested that leucopenia may be an early predictor of chemotherapy-induced infertility.

Project description:Young women with breast cancer experience unique treatment and survivorship issues centering on treatment-related amenorrhea (TRA), including fertility preservation and management of ovarian function as endocrine therapy. The Young Women's Breast Cancer Study (YWS) is a multi-center, prospective cohort study of women diagnosed at age ≤40, enrolled from 2006 to 2016. Menstrual outcomes were self-reported on serial surveys. We evaluated factors associated with TRA using logistic regression. One year post-diagnosis, 286/789 (36.2%) experienced TRA, yet most resumed menses (2-year TRA: 120/699; 17.2%). Features associated with 1-year TRA included older age (OR≤30vs36-40 = 0.29 (0.17-0.48), OR31-35vs36-40 = 0.67 (0.46-0.94), p = 0.02); normal body mass index (BMI) (OR≥25vs18.5-24. =0.59 (0.41-0.83), p < 0.01); chemotherapy (ORchemo vs no chemo = 5.55 (3.60-8.82), p < 0.01); and tamoxifen (OR = 1.55 (1.11-2.16), p = 0.01). TRA rates were similar across most standard regimens (docetaxel/carboplatin/trastuzumab +/- pertuzumab: 55.6%; docetaxel/cyclophosphamide +/- trastuzumab/pertuzumab: 41.8%; doxorubicin/cyclophosphamide/paclitaxel +/- trastuzumab/pertuzumab: 44.1%; but numerically lower with AC alone (25%) or paclitaxel/trastuzumab (11.1%). Among young women with breast cancer, lower BMI appears to be an independent predictor of TRA. This finding has important implications for interpretation of prior studies, future research, and patient care in our increasingly obese population. Additionally, these data describe TRA associated with use of docetaxel/cyclophosphamide, which is increasingly being used in lieu of anthracycline-containing regimens. Collectively, these data can be used to inform use of fertility preservation strategies for women who need to undergo treatment as well as the potential need for ovarian suppression following modern chemotherapy for young women with estrogen-receptor-positive breast cancer.Clinical trial registration: www.clinicaltrials.gov, NCT01468246.

Project description:Most of the genetic variants identified from genome-wide association studies of breast cancer have not been validated in Asian women. No risk assessment model that incorporates both genetic and clinical predictors is currently available to predict breast cancer risk in this population.We analyzed 12 single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies mostly of women of European ancestry as being associated with the risk of breast cancer in 3039 case patients and 3082 control subjects who participated in the Shanghai Breast Cancer Study. All participants were interviewed in person to obtain information regarding known and suspected risk factors for breast cancer. The c statistic, a measure of discrimination ability with a value ranging from 0.5 (random classification) to 1.0 (perfect classification), was estimated to evaluate the contribution of genetic and established clinical predictors of breast cancer to a newly established risk assessment model for Chinese women. Clinical predictors included in the model were age at menarche, age at first live birth, waist-to-hip ratio, family history of breast cancer, and a previous diagnosis of benign breast disease. The utility of the models in risk stratification was evaluated by estimating the proportion of breast cancer patients in the general population that could be accounted for above a given risk threshold as predicted by the models. All statistical tests were two-sided.Eight SNPs (rs2046210, rs1219648, rs3817198, rs8051542, rs3803662, rs889312, rs10941679, and rs13281615), each of which reflected a genetically independent locus, were found to be associated with the risk of breast cancer. A dose-response association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the effect of these eight SNPs (odds ratio for women in the highest quintile of genetic risk score vs those in the lowest = 1.85, 95% confidence interval = 1.58 to 2.18, P(trend) = 2.5 x 10(-15)). The genetic risk score, the waist-to-hip ratio, and a previous diagnosis of benign breast disease were the top three predictors of the risk of breast cancer, each contributing statistically significantly (P < .001) to the full risk assessment model. The model, with a c statistic of 0.6295 after adjustment for overfitting, showed promise for stratifying women into different risk groups; women in the top 30% risk group accounted for nearly 50% of the breast cancers diagnosed in the general population.A risk assessment model that includes both genetic markers and clinical predictors may be useful to classify Asian women into relevant risk groups for cost-efficient screening and other prevention programs.

Dataset Information

Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer.

Publications

Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer.

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