Treatment-related Amenorrhea Research Articles

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.

Treatment-related amenorrhea in a modern, prospective cohort study of young women with breast cancer

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.

Abstract PD12-06: Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial

Abstract Background: Cytotoxic chemotherapy (CT) in combination with trastuzumab and pertuzumab (HP) is standard of care for patients (pts) diagnosed with HER2-positive early breast cancer (EBC). While highly effective, the toxicity associated with CT is challenging. In KRISTINE/TRIO-021, neoadjuvant T-DM1 was combined with pertuzumab (KP) and compared to standard TCHP. Pts. received six cycles of neoadjuvant treatment followed by adjuvant therapy (KP or HP). Pts. in the KP arm were allowed to receive standard adjuvant CT. Pathologic complete response (pCR) rate was significantly lower with KP versus TCHP and more pts. had disease progression prior to surgery with KP, resulting in a meaningfully lower event-free survival rate vs. the control (85.3% vs 94.2%). However, 3-year invasive disease-free survival was numerically similar in both arms. Neoadjuvant KP demonstrated less toxicity than standard CT, although treatment discontinuation was higher post-surgery. Association of KP and TCHP with treatment-related amenorrhea (TRA) in premenopausal EBC pts. has not been ascertained. Methods: All pts. with premenopausal status at study entry (those not meeting the menopause definition based on National Comprehensive Cancer Network Guidelines v3, 2012) and with menstrual period documented within 3 months of randomization, were independently evaluated for presence or absence of TRA by two reviewers. TRA, a prespecified exploratory endpoint of KRISTINE, was defined as cessation of menstruation for &amp;gt;12 months in the absence of treatment with ovarian suppression or other interventions that can induce amenorrhea. Pts. were followed from the time of study entry through the 3-year follow up period after surgery. For cases with inconsistent determination between the two reviewers, a third reviewer adjudicated. TRA rates were calculated per arm, hormone-receptor (HR) status, adjuvant CT and age group. Proportions were compared by estimating the odds ratio (OR) and the 95% confidence interval. Results: Of 444 pts. enrolled, 205 were excluded based on being post-menopausal per NCCN guidelines. Of 239 pts. remaining, 56 were excluded due to insufficient data. The median age of pts. included was 40 years (range: 22-53) for TCHP and 42.5 (range: 23-52) for KP. TRA was observed in 55% (50/91) of pts. treated with TCHP compared to 30% (28/92) treated with KP (OR=2.79; 95% CI 1.52-5.12). In pts. with HR-positive EBC, TRA occurred in 62% with TCHP vs 35% for KP (OR=2.998; 95% CI 1.44-6.25). In those with HR-negative EBC, TRA was observed in 42% with TCHP vs. 21% with KP (OR=2.77; 95% CI 0.88-8.72). In the KP arm, TRA was observed in 38% (8/21) of pts. treated with standard adjuvant CT vs. 28% (20/71) of those that did not (OR 1.57; 95% CI 0.57-4.36). For women age ≤ 40, the rate of TRA was 38% with TCHP vs. 17% with KP (OR=3.00; 95% CI 1.05-8.60). For those &amp;gt; 40 years, TRA was observed in 74% treated with TCHP vs. 39% of those with KP (OR=4.50; 95% CI 1.88-10.73). Conclusion: The rate of TRA with standard TCHP is nearly double that observed with KP, suggesting that targeted CT with an antibody-drug conjugate regimen is associated with less gonadal toxicity. Rates of TRA are higher in women over the age of 40 for each treatment arm however KP is associated with lower rate of TRA in each age group. Association of TRA with efficacy outcomes (pCR, iDFS) will be presented. Citation Format: Sara A Hurvitz, Rodrigo Fresco, Karen Afenjar, Daniil Stroyakovskiy, Chiun-Sheng Huang, Hans Wildiers, Kyung Hae Jung, Jean-François Boileau, Mario Campone, Miguel Martín, Vicente Valero, Joseph A. Sparano, W. Fraser Symmans, Peter A. Fasching, Alastair M. Thompson, Nadia Harbeck, Vanesa López-Valverde, Chunyan Song, Thomas Boulet, Eleonora Restuccia, Dennis J. Slamon. Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-06.

Abstract SP114: Body Image and Sexual Health

Abstract Attention to body image and sexual health after breast cancer are important components of treatment decisions, support through treatment and survivorship care. A high proportion of breast cancer survivors report dissatisfaction with their physical appearance. Body image issues are particularly common among women who undergo mastectomy with or without reconstructive surgery and those who experience weight gain, hair loss from chemotherapy, and other psychosocial issues. Scalp cooling, proactive counseling about potential effects of treatment on weight and physical activity, and psychosocial support through treatment may help to prevent some of these negative effects. Weight loss and subsequent weight maintenance are notoriously difficult to achieve through diet alone, and exercise plays an important role in energy balance through and after treatment. Sexual health is frequently a concern for breast cancer survivors as well, with up to 40% of women reporting issues with sexual interest and 60% with physical sexual function. Issues may arise in the short term following both surgery and chemotherapy, due to factors including lower perceived attractiveness and vaginal dryness. Endocrine therapy with tamoxifen, aromatase inhibitors, and treatment-related amenorrhea or ovarian suppression treatment in premenopausal women are associated with sexual dysfunction. However, a multi-prong approach has been shown to improve such problems. Providers should actively monitor for and manage the consequences of diagnosis and treatment on body image and sexual health in survivors, using psychosocial, behavioral, and pharmacologic tools as needed. Citation Format: A Partridge. Body Image and Sexual Health [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP114.

Body weight changes in young breast cancer survivors and associated predictors.

11574 Background: Weight gain after cancer diagnosis is common in cancer survivors and has been linked to increased treatment toxicity, poor quality of life, and increased risk of second cancers and overall mortality. Young breast cancer (BC) survivors may be especially susceptible to weight changes given the impact of treatments such as chemotherapy and hormonal therapy on menopausal status. Methods: We identified women with Stage 0-III breast cancer diagnosed at ≤40 years (y) between 2006-2016 from a multi-center prospective cohort study. Clinical data including self-reported pre-diagnosis and follow-up weights were obtained using baseline and follow-up patient surveys. Participants missing baseline weight, pregnant at diagnosis/within 1y of diagnosis or with BC recurrence within 1y were excluded; those pregnant or with BC recurrence between 1-3y from diagnosis were excluded from the 3y analysis. Menopausal status at baseline and treatment-related amenorrhea (TRA) in follow-up were defined by self-reported last menstrual period. Factors associated with weight gain (&gt;5%) were evaluated using univariate two-sided Fisher's exact test. Results: At baseline, 1y and 3y post diagnosis, 956, 899 and 687 women were eligible for analysis respectively. Median age at diagnosis was 37y (17 - 40), 65% received endocrine therapy and 74% chemotherapy. Premenopausal status was verified in 94% at baseline. Mean BMI at baseline was 24.4 (SD 5.3) kg/m2; 20% (187/956) were overweight and 12% (116/956) obese. At 1y and 3y, mean BMI increased modestly to 24.7 (SD 5.6) and 24.9 (SD 5.2), respectively with weight gain (&gt;5%) observed in 18% (164/899) and 13% (87/687) respectively. 37% (300/804) and 32% (196/615) of eligible premenopausal subjects experienced TRA at 1y and 3y, respectively. Receipt of chemotherapy, receipt of endocrine therapy and TRA were not associated with weight gain at any timepoint. Conclusions: In this large prospective cohort of young BC survivors, mean BMI increased only modestly over time. Self-reported weight gain was not associated with treatment and not exacerbated by TRA. Further analysis to understand the effects of physical activity and other predictors of weight gain in this population are ongoing.

Amenorrhea after lung cancer treatment.

More than 5,000 premenopausal women are diagnosed with lung cancer annually in the United States. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Premenopausal women diagnosed with lung cancer under age 50 were surveyed at diagnosis and annually thereafter about their menstrual status as a part of the Mayo Clinic Epidemiology and Genetics of Lung Cancer Research Program. Types of lung cancer-directed treatments were recorded, and frequencies of self-reported menopause at each survey were calculated. A cohort of 182 premenopausal women were included in this study, with average age at lung cancer diagnosis 43 years (SD 6). Among the 85 patients who received chemotherapy, 64% self-reported that they had become menopausal within a year of diagnosis. Platinum salts were universally included in these chemotherapy regimens, and the majority of these women also received taxanes within 1 year of diagnosis. Only 15% of the 94 patients who did not receive systemic therapy within 1 year of diagnosis experienced self-reported menopause. Three patients received targeted therapy alone, two of whom remained premenopausal at the final qualifying survey, completed a median of 3 years after diagnosis. Chemotherapy for lung cancer patients appears to increase risk of early loss of menses in survivors.

Amenorrhea and Menopause in Patients with Breast Cancer after Chemotherapy.

PurposeThe probability of ovarian failure after cytotoxic chemotherapy in patients with breast cancer has not been well established in Korea. This study aimed to assess the rate of ovarian failure in a large cohort of Korean premenopausal patients with breast cancer 12 months after chemotherapy.MethodsThis retrospective cohort study included premenopausal women (aged 20−44 years) with breast cancer who underwent chemotherapy after surgery. The rates of treatment-related amenorrhea (TRA) and chemotherapy-induced menopause (CIM) at 12 months after chemotherapy were analyzed.ResultsA total of 237 patients met the inclusion criteria. The rate of TRA was 61.6% and that of CIM was 13.1% at 12 months after chemotherapy. The rates of TRA and CIM were 28.0% and 4.0%, respectively, in women aged 25−34 years, and they gradually increased up to 75.9% (TRA) and 15.8% (CIM), respectively, in women aged 40−44 years. The frequency of CIM was significantly lower than that of TRA in both age groups. In multivariate analyses, only tamoxifen use was significantly associated with a decreased risk of CIM (p < 0.001). Age of 40 years or higher and the regimens of doxorubicin plus cyclophosphamide followed by docetaxel or paclitaxel were associated with increased risk of TRA (p = 0.001 and p = 0.002, respectively).ConclusionMarked discrepancy in the rates of CIM and TRA was observed in this study. Further, the age-specific frequency of CIM and TRA observed in this study is a reliable and practical estimate of the risks of CIM and TRA in the absence of gonadal protection.

Another step towards improving oncofertility counselling of young women with Hodgkin's lymphoma.

Another step towards improving oncofertility counselling of young women with Hodgkin's lymphoma.

Amenorrhea in lung cancer patients.

e20092 Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.

Treatment-related amenorrhea among young women one year following diagnosis of early-stage breast cancer.

9523 Background: Treatment-related amenorrhea (TRA) is common among premenopausal women treated for early-stage breast cancer and is associated with important reproductive, sexual, and metabolic si...

The effects of paclitaxel, dose density, and trastuzumab on treatment‐related amenorrhea in premenopausal women with breast cancer

Little information is available regarding the effects of new adjuvant treatment regimens on menstrual functioning in premenopausal women with early breast cancer. The authors conducted a retrospective review of data from premenopausal women who received treatment for early breast cancer to evaluate the rates of amenorrhea in follow-up. The women who were included received treatment with either doxorubicin and cyclophosphamide (AC) or combined AC and paclitaxel (T) (AC-T) given either every 3 weeks, or as a dose-dense (DD) regimen, or as AC followed by weekly T with trastuzumab or followed by trastuzumab (AC-T+trastuzumab). A multivariate logistic regression analysis was conducted to evaluate amenorrhea during follow-up. Of 431 patients who were eligible for analysis, the average age at diagnosis was 13 years (range, 25-55 years), 61% of women received AC only, and 39% received AC-T. Of the 39% who received AC-T, 49% of women received DD therapy, 14% received AC-T+trastuzumab, and 71% of all patients received tamoxifen (TAM). The median follow-up was 33 months (range, 6-114 months). After adjusting for age, weight, gravidity, parity, age at menarche, smoking, alcohol use, TAM use, type and regimen of chemotherapy, and use of trastuzumab, the likelihood of remaining amenorrheic was not statistically different in patients who received AC-T versus AC (odds ratio [OR], 1.59; 95% confidence interval [CI], 0.8-3.2), DD treatment versus treatment every 3 weeks (OR, 0.56; 95% CI, 0.25-1.3), or AC-T + trastuzumab (OR, 0.6; 95% CI, 0.22-1.61). Amenorrhea was associated significantly with TAM use and age at diagnosis. Recent advances in the adjuvant treatment of early breast cancer do not appear to have increased the risk of amenorrhea in premenopausal women.

Pregancy after bilateral dysgerminoma treated with conservative surgery and BEP chemotherapy

16039 Background: Pregnancy after treatment of germ cell tumours of ovary is common. However patients with bilateral dysgerminoma treated with unilateral oophorectomy, wedge biopsy of opposite ovary, and conservation of uterus face difficulty in conception. This study was conducted with the objective to evaluate the fertility status of ovarian dysgerminoma patients treated with conservative surgery and BEP chemotherapy. Methods: Patients of bilateral dysgerminoma who underwent conservative surgery and chemotherapy with cisplatin 20 mg / m2 and etoposide 100 mg / m2 day 1 to 5 and bleomycin 30 mg on day 1, 8 and 15 of three weekly cycles were eligible. A normal AFP and beta HCG at baseline was required. Post treatment CT scans of abdomen and pelvis were obtained. Patients were regularly followed on monthly basis. Pregnancy was allowed 2 years after completion of last cycle of chemotherapy. Results: From January 1998 to December 2003, 11 patients were enrolled. Medain age was 16 years (range 13–18). All patients had complete disappearance of disease after treatment. Treatment related amenorrhea did not last beyond one year. During a median follow up of 5 years, all patients conceived and a total of 14 pregnancies were completed successfully.Three patients required use of clomiphene citrate for ovulation induction. No patient was treated with gonadotrophins. Six patients underwent lower segment caesarean section for obstetric indications and seven delivered vaginally. All babies were healthy without the signs of birth abnormalities or retardation. Conclusions: With conservative surgery and BEP chemotherapy for treatment of bilateral dysgerminoma the fertility is retained with good pregnancy outcome, when conception occurs at least two years after the last dose of chemotherapy. No significant financial relationships to disclose.

Inadvertent Use of Aromatase Inhibitors in Patients with Breast Cancer with Residual Ovarian Function: Cases and Lessons

Aromatase inhibitors (AIs) are important adjunctive therapy for postmenopausal women with hormone receptor— positive, early-stage breast cancer. At the present time, AIs have no role for the management of breast cancer in premenopausal women. We report on several cases of the inadvertent use of AI therapy among women with residual ovarian function. A common experience in these cases was the onset of chemotherapy-related amenorrhea before initiation of AI therapy, which confounded assessment of true menopausal status. We believe clinicians should be aware of the potential ovarian reserve among women with treatment-related amenorrhea so as to avoid use of AI therapy in patients in whom there is uncertainty about menopausal status.

American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Status Report 2004

To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.

Fertility and the impact of systemic therapy on hormonal status following treatment for breast cancer.

Issues of long-term toxicity from treatment for breast cancer, including the induction of premature ovarian failure, appear to be of increasing importance for breast cancer survivors. The incidence of treatment-related amenorrhea is related to patient age and to the treatment regimen. Whereas the induction of ovarian failure may be advantageous with respect to breast cancer outcome, it is not clear that there is any advantage to permanent menopause over reversible hormonal manipulations. In addition, menopause may be associated with a variety of adverse health effects. Although nonhormonal therapies are available to manage many of the consequences of menopause, avoidance of chemotherapy-related ovarian toxicity may provide the best prospects for fertility after treatment. Pregnancy after breast cancer is a realistic consideration for some breast cancer survivors and is not clearly detrimental to either the mother or her offspring.

Treatment-related Amenorrhea and Hysterectomies in Female Cancer Survivors: Prevalence and Quality of Life Issues

Treatment-related Amenorrhea and Hysterectomies in Female Cancer Survivors: Prevalence and Quality of Life Issues