What Can We Learn From Menstrual Patterns After Treatment for HER2-Positive Breast Cancer?
Mené sur 1 679 patientes atteintes d'un cancer du sein HER2+ de stade précoce diagnostiqué avant la ménopause (âge médian : 43 ans), cet essai de phase III évalue l'efficacité, du point de vue de la survie sans maladie et de la survie globale, d'un traitement adjuvant par lapatinib et/ou trastuzumab, et analyse l'effet de ce traitement sur une aménorrhée
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.(6).