Third-generation aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, have become important treatment options for hormone-responsive, postmenopausal breast cancer patients, the prerequisite for which must be menopause or complete suppression of ovarian function. However, there is no consensus in the industry on how to define menopausal status, creating great confusion and resulting in the misapplication of AIs, which not only severely affects the efficacy, but also a few patients have experienced serious events in which pregnancy has occurred. Recently, many academic journals and experts have conducted in-depth research on this issue, which has gradually unified the criteria for determining menopause and laid the necessary foundation for the rational clinical application of aromatase inhibitors. Liu Aihui, Department of Breast Medicine, Beijing Maternity Hospital The criteria for defining menopause in breast cancer patients have not been unified for a long time, and even in the ATAC trial, IES031 trial, MA-17 trial and other important clinical trials that have been completed in recent years, the criteria for menopause are quite different. Menopause criteria of the ATAC trial: (1) Bilateral oophorectomy. (2) Age ≥ 60 years. (3) If the age is between 45 and 59 years, with an intact uterus and at least 12 months of amenorrhea. (4) If the patient has been amenorrheic for less than 12 months (including amenorrhea due to hysterectomy, hormone replacement therapy, chemotherapy), FSH must be at menopausal levels. The criteria for menopause in the IES031 test are on the simpler side, age ≥ 55 years, amenorrhea for more than 2 years or amenorrhea for more than 1 year prior to diagnosis. The MA-17 trial was an extension trial after 5 years of adjuvant TAM treatment. The study’s criteria for menopause: (1) Age at least 50 years before starting 5 years of TAM. (2) Underwent bilateral oophorectomy despite being younger than 50 years of age at the start of TAM. (3) If younger than 50 years of age or pre-menopausal at the time of starting TAM, but developed menopause during adjuvant chemotherapy or adjuvant TAM. (4) At any age, but FSH and LH are at menopausal levels. From the above three important clinical trials on AIs, it can be seen that bilateral ovariectomy, age ≥ 60 years, age ≥ 55 years and amenorrhea for more than 1 year before diagnosis can be considered as menopause. For amenorrhea due to chemotherapy or endocrine therapy at age less than 55 years, although FSH and LH testing is recommended to define it, the frequency of testing, testing techniques, and whether estrogen is tested are not clearly stated. the recommendations of the 2006 NCCN guidelines for breast cancer regarding the criteria for menopause are clearly influenced by the criteria for menopause in the above trials and are generally consistent with the criteria studied in the above trials. Menopause can be defined by bilateral oophorectomy and age ≥60 years. If age <60 years, menopause can be defined only if natural amenorrhea is ≥12 months and FSH and estrogen levels are in the menopausal range. For treatment-related menopause determination, FSH and estrogen testing is also recommended, but again, the specific frequency of testing and testing techniques are not addressed. The recent JCO study by Smith, Royal Marsden Hospital Institute of Oncology, UK
IE et al. have brought to light the problems hidden by these unclear criteria for menopause, and have made the industry aware of the seriousness of the problem. The study investigated the use of AIs in 45 younger early-stage breast cancer patients aged ≥40 years with hormone receptor-positive, post-chemotherapy amenorrhea. The median age of this group was 47 (39-52) years, and 33 of the 45 patients had confirmed ovarian suppression by biochemical tests before starting AIs. The median duration of amenorrhea in these 12 patients was 12 months, and the median duration of AIs application before menstruation resumed was 6(3-18) months. In fact, unintended pregnancies resulting from the application of AIs were reported several years ago. In a group of 22 patients treated with letrozole, 4 cases of unintended pregnancy occurred. This shows that treatment-induced amenorrhea must be taken seriously, and there are indeed many unspecified questions about whether AIs can be applied in this group of patients, when they should be applied, and how to monitor follow-up. AIs were actually first developed as ovulation-inducing agents in premenopausal women, and by reducing peripheral estrogen levels, they weaken the feedback of estrogen to the hypothalamus and pituitary gland, leading to increased gonadotropin secretion and promoting restoration of ovarian function. In a small number of younger female patients, recovery of ovarian function may occur if the suppression of ovarian function due to chemotherapy is incomplete. In view of the above-mentioned problems during the application of AIs, the British Royal
Marsden Hospital Institute of Oncology experts, recommended guidelines on how to choose the application of AIs especially for breast cancer patients who are under 50 years old, who are still not amenorrheic before chemotherapy, and who have chemotherapy leading to amenorrhea. The guidelines suggest that for the above-mentioned group, (1) AIs should not be applied alone if they are younger than 40 years of age, and if they want to be applied they need to be combined with ovarian function depot at the same time; (2) for women older than 40 years of age, AIs should be applied with caution alone if monitoring is not available or accurate estradiol testing is not possible. In this group, it is best to start with triamcinolone acetonide and combine it with ovarian deactivation if desired; (3) in women over 40 years of age, if monitoring is not available or accurate estradiol testing is not possible, serum estradiol and gonadotropin levels should be monitored continuously from baseline and in a validated, accurate manner. If estradiol levels are >20 pmol/L and gonadotropins are normal, triamcinolone, or triamcinolone combined with ovarian deactivation, or AIs combined with ovarian deactivation are recommended. If estradiol levels are <10 pmol/L and gonadotropins are elevated, the choice of AIs is appropriate but requires serial monitoring for 6 months. For patients who switch to AIs after triamcinolone therapy, monitoring for 6 consecutive months is recommended. If estradiol levels fall and remain below 10 pmol/L, the patient can be considered to be entering a postmenopausal state and continuation of AIs is appropriate. If estradiol levels remain above 10 pmol/L, the AIs are not functional and a combination of ovarian function depot or a switch to triamcinolone should be considered. In addition, all patients with post-chemotherapy amenorrhea should be seen as soon as symptoms of bleeding or hot flashes that may be menstrual suddenly disappear during treatment with AIs. All patients during the monitoring period should use adequate contraception. The international academic community is also aware of the deficiencies in the definition of menopause during the application of AIs, and the 2007 edition of the NCCN guidelines for breast cancer has provided additional clarification on the definition of menopause compared with the 2006 edition, suggesting that serial monitoring of FSH and estrogen levels in treated amenorrheic patients should be strengthened to ensure the safe and rational application of AIs. In the practice of clinical application of AIs, we also deeply feel that there are deficiencies in the definition criteria regarding post-chemotherapy amenorrhea and have been seeking more scientific means of confirming menopause. Royal
Marsden Hospital Institute of Oncology’s expert recommended guidelines give timely advice on this area, and we think that the accumulation of more samples, more scientifically designed controlled studies, and the development of more effective and accurate laboratory tests should lead to scientific standards regarding therapeutic menopause.