Treatment-related amenorrhea is a well-recognized consequence of chemotherapy in some premenopausal women (1). Amenorrhea is an imperfect surrogate for infertility and menopausal symptoms because it usually reflects at least temporary ovarian dysfunction. It has been associated with improved prognosis in hormone receptor–positive breast cancer (2–5). In a pivotal study published in the New England Journal of Medicine in 2010, Swain and colleagues reported that women with lymph node–positive breast cancer who experienced chemotherapy-related amenorrhea for six months or more had better disease-free survival and overall survival than those who did not across a variety of chemotherapy regimens, including doxorubicin and cyclophosphamide (AC) followed by docetaxel; concurrent AC and docetaxel; or concurrent doxorubicin and docetaxel (AT) (5). A subset analysis showed that this was true only in those with estrogen receptor (ER)–positive disease, who had a hazard ratio for death of 0.52 (P = .002) if they had experienced chemotherapy-related amenorrhea (6). Well-established predictive factors for premature amenorrhea include older age and higher dose of alkylating agents (2,7). Abusief and colleagues found that four cycles of doxorubicin and cyclophosphamide caused amenorrhea in less than 20% of women younger than age 40 years but in almost 70% of women age 40–49 years (8). Ganz and colleagues reported that 12 months after random assignment to three different chemotherapy regimens, amenorrhea was only present in 37.9% of those who received AT (without an alkylator) compared with 58.7%–69.8% of those who received AC sequentially or concurrent with docetaxel. Data regarding how much taxanes contribute to postchemotherapy amenorrhea are mixed and weak (8–10). In a 2016 systematic review that included eight studies that compared amenorrhea rates when anthracycline-based chemotherapy was or was not combined with a taxane, the odds ratio for amenorrhea was 1.45 (95% confidence interval [CI] = 0.94 to 2.23) with the addition of the taxane (10). Trastuzumab has not been well studied, but existing evidence suggests that it is likely not gonadotoxic (10,11). The risk of treatment-related amenorrhea with the administration of other human epidermal growth factor receptor 2 (HER2) targeted therapies, such as the monoclonal antibody pertuzumab and the tyrosine kinase inhibitor lapatinib, has not been previously described to our knowledge. Studying the gonadotoxicity of cancer-directed therapies is important to inform decisions about fertility preservation before therapy, and it also has the potential to help predict the likelihood of vasomotor symptoms, sexual dysfunction, and osteopenia (12–19). In this issue of the Journal, using data from ALTTO, a large phase III trial that randomized patients with HER2-positive breast cancer to adjuvant therapy with trastuzumab, lapatinib, trastuzumab followed by lapatinib, or trastuzumab concurrent with lapatinib, Dr. Lambertini and colleagues report that women in all four arms of the ALTTO trial experienced similar rates of amenorrhea (72%–75%) at 37 weeks after random assignment (20). This suggests that lapatinib is no more gonadotoxic than trastuzumab. Though all ALTTO patients were assigned to receive trastuzumab, lapatinib, or both, precluding a comparison with amenorrhea rates in patients who did not receive HER2-directed therapy, the absence of a difference between the arms supports the popular hypothesis that HER2-directed therapies do not damage the ovaries. Interestingly, amenorrhea rates were higher in patients who received docetaxel-carboplatin than those who received an anthracycline-based regimen (adjusted odds ratio = 2.24, 95% CI = 1.18 to 4.27) (20). This may be related to the gonadotoxicity of carboplatin (21,22). However, HER2-directed therapy began concurrent with docetaxel-carboplatin administration but after at least the anthracycline component of the anthracycline-based regimens. As a result, the amenorrhea assessment may have occurred sooner after completion of chemotherapy for those who received docetaxel-carboplatin than for most others, which may explain the higher rate of amenorrhea in patients who received docetaxel-carboplatin. A similar phenomenon may also have contributed to the higher rates of amenorrhea among women who received taxanes in addition to anthracycline-based chemotherapy when compared with women who received anthracyclines alone. Many of the former would have started HER2-directed therapy during the taxane, whereas those who received anthracyclines alone would have waited until after all chemotherapy finished to begin HER2-directed therapy, meaning that the median time between the end of chemotherapy and the amenorrhea assessment was longer for those who received anthracyclines alone. Menstrual recovery is quite common during the year after receipt of chemotherapy for breast cancer, such that an earlier assessment is likely to produce higher rates of amenorrhea. Later assessments are likely more accurate reflections of long-term ovarian function. Few women regain menses after two years (23–25). Repeated menstrual evaluations over time will be needed in the future to clarify how these regimens truly compare with regard to rates of treatment-related long-term amenorrhea. In addition to these findings regarding regimen-related likelihood of amenorrhea, this study (20) confirms that treatment-related amenorrhea is associated with an improved prognosis in women with hormone receptor–positive breast cancers (2,5). This is consistent with the findings of the Suppression of Ovarian Function Trial (SOFT) trial, published in 2015 and updated at the 2017 San Antonio Breast Cancer Symposium, in which the addition of ovarian function suppression (OFS) therapy to adjuvant tamoxifen improved disease-free survival in premenopausal women with hormone receptor–positive breast cancer (26,27). Patients with HER2-positive disease and, more broadly, recipients of chemotherapy seemed to benefit the most from OFS in SOFT. Combined with the SOFT results, the prognostic relevance of amenorrhea in ALTTO supports the use of OFS in premenopausal women whose menses continue during or return soon after chemotherapy for hormone receptor–positive, HER2-positive breast cancer. In summary, Lambertini and colleagues describe treatment-related amenorrhea after HER2-directed curative-intent chemotherapy for breast cancer. The authors report that lapatinib and dual HER2 blockade do not increase amenorrhea rates compared with trastuzumab alone. Furthermore, they identify that like OFS, treatment-related amenorrhea is associated with improved prognosis for premenopausal women with hormone receptor–positive, HER2 receptor–positive disease. Future research should assess the implications of menstrual patterns over a longer period after the completion of chemotherapy and should investigate whether or not pertuzumab is nongonadotoxic as well. Funding This publication was made possible by support for KJR from CTSA (Clinical and Translational Sciences Award) Grant Number KL2 TR002379 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH). Notes Affiliations of authors: Departments of Oncology (ECR, KR) and Internal Medicine (KCG), Mayo Clinic, Rochester, MN. The funder had no role in the writing of this editorial or the decision to submit it for publication. The contents of this editorial are solely the responsibility of the authors and do not necessarily represent the official view of NIH. The authors have no conflicts of interest to disclose. References 1 Lee SJ , Schover LR , Partridge AH et al. , American Society of Clinical Oncology recommendations on fertility preservation in cancer patients . J Clin Oncol. 2006 ; 24 18 : 2917 – 2931 . Google Scholar CrossRef Search ADS PubMed 2 Walshe JM , Denduluri N , Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer . J Clin Oncol. 2006 ; 24 36 : 5769 – 5779 . Google Scholar CrossRef Search ADS PubMed 3 Zhao J , Liu J , Chen K et al. , What lies behind chemotherapy-induced amenorrhea for breast cancer patients: A meta-analysis . 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Google Scholar CrossRef Search ADS PubMed 12 Howard-Anderson J , Ganz PA , Bower JE , Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review . J Natl Cancer Inst. 2012 ; 104 5 : 386 – 405 . Google Scholar CrossRef Search ADS PubMed 13 Cameron DA , Douglas S , Brown JE , Anderson RA. Bone mineral density loss during adjuvant chemotherapy in pre-menopausal women with early breast cancer: Is it dependent on oestrogen deficiency? Breast Cancer Res Treat. 2010 ; 123 3 : 805 – 814 . Google Scholar CrossRef Search ADS PubMed 14 Shapiro CL , Manola J , Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer . J Clin Oncol. 2001 ; 19 14 : 3306 – 3311 . Google Scholar CrossRef Search ADS PubMed 15 Saha P , Regan MM , Pagani O et al. , Treatment efficacy, adherence, and quality of life among women younger than 35 years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy trials . J Clin Oncol. 2017 ; 35 27 : 3113 – 3122 . Google Scholar CrossRef Search ADS PubMed 16 Ganz PA. Breast cancer, menopause, and long-term survivorship: Critical issues for the 21st century . Am J Med. 2005 ; 118 ( Suppl 12B ): 136 – 141 . Google Scholar CrossRef Search ADS PubMed 17 Ruddy KJ , Gelber SI , Tamimi RM et al. , Prospective study of fertility concerns and preservation strategies in young women with breast cancer . J Clin Oncol. 2014 ; 32 11 : 1151 – 1156 . Google Scholar CrossRef Search ADS PubMed 18 Ganz PA , Land SR , Geyer CE Jr et al. , Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial . 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Google Scholar PubMed 23 Jacobson MH , Mertens AC , Spencer JB , Manatunga AK , Howards PP. Menses resumption after cancer treatment-induced amenorrhea occurs early or not at all . Fertil Steril. 2016 ; 105 3 : 765 – 772, e4 . Google Scholar CrossRef Search ADS PubMed 24 Lambertini M , Boni L , Michelotti A et al. , Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: A randomized clinical trial . JAMA. 2015 ; 314 24 : 2632 – 2640 . Google Scholar CrossRef Search ADS PubMed 25 Moore HC , Unger JM , Albain KS. Ovarian protection during adjuvant chemotherapy . N Engl J Med. 2015 ; 372 23 : 2269 – 2270 . Google Scholar PubMed 26 Francis PA , Regan MM , Fleming GF. Adjuvant ovarian suppression in premenopausal breast cancer . N Engl J Med. 2015 ; 372 17 : 1673 . Google Scholar CrossRef Search ADS PubMed 27 Francis PA , Fleming GF , Pagani O. Update of the SOFT trial. SABCS Abstract #844 GS4-03. 2017 . https://www.abstracts2view.com/sabcs/view.php?nu=SABCS17L_844&terms=. Accessed April 1, 2018. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
JNCI: Journal of the National Cancer Institute – Oxford University Press
Published: Jun 5, 2018
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