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Treatment-related amenorrhea incidence consistent among anti-HER-2 regimens
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Treatment-related amenorrhea incidence appeared consistent among premenopausal women with hormone receptor-positive or HER-2-positive breast cancer regardless of the anti-HER-2 therapy they received, according to results of the phase 3 ALTTO trial.
Incidence of treatment-related amenorrhea also appeared associated with significant DFS and OS benefits.
“We believe that these findings are of great importance to better guide not only treatment decision-making (eg, whether to receive cytotoxic systemic therapy for a small estimated reduction in risk of recurrence) but also the need of fertility-preserving techniques prior to chemotherapy,” Matteo Lambertini, MD, of the department of medical oncology in the breast cancer translational research laboratory at Institut Jules Bordet in Belgium, told HemOnc Today. “In addition, these results would facilitate optimal counseling on the pros and [cons] of the different treatment options, including the possible indication for ovarian function suppression as part of adjuvant endocrine therapy.”
Chemotherapy and 1 year of trastuzumab (Herceptin, Genentech) therapy is standard treatment for most patients with HER-2-positive early breast cancer.
Prior studies have shown systemic anticancer therapies to be associated with gonadotoxicity among premenopausal women; and this can lead to treatment-related amenorrhea.
“The loss of ovarian function can have negative short- and long-term quality-of-life implications being associated with several side effects, including infertility,” Lambertini said. “Failure to address these concerns can influence patients’ choice and adherence toward the different treatment options.”
Guidelines have supported clinicians discussing risk for treatment-related amenorrhea during oncofertility counseling with all premenopausal women with breast cancer. Yet, the gonadotoxicity of anti-HER-2-targeted agents has remained unknown, and no studies have investigated prognostics of treatment-related amenorrhea among women with HER-2-positive early breast cancer.
Lambertini and colleagues randomly assigned 2,862 patients (median age, 43 years) evenly to one of four regimens: 1 year of trastuzumab alone; 1 year of lapatinib (Tykerb, Novartis) alone; 1 year of trastuzumab plus lapatinib; or 12 weeks of trastuzumab, followed a 6-week washout period and 34 weeks of lapatinib.
All patients had histologically confirmed, excised, invasive nonmetastatic HER-2-positive breast cancer, and either node-positive or node-negative disease with tumors 1 cm or greater.
Researchers randomly documented menopausal status for all patients at random assignment and at their week 37 visit.
Comparison of DFS in each of the three lapatinib groups separately with the trastuzumab monotherapy group served as the primary endpoint. OS served as a secondary endpoint.
Median follow-up was 6.9 years (interquartile range, 6.6–7).
Researchers reported treatment-related amenorrhea incidence of 72.6% in the trastuzumab monotherapy group, 74% in in the lapatinib monotherapy group, 72.1% among those who received trastuzumab followed by lapatinib, and 74.8% among those who received the trastuzumab-lapatinib combination. The differences were not statistically significant.
“The absence of higher treatment-related amenorrhea rate in the dual blockade arm as compared to single agent arms may suggest the gonadal safety of these agents,” Lambertini said. “This is crucial information to share with patients during oncofertility counseling.”
The association between treatment-related amenorrhea and survival outcomes differed based on hormone-receptor status (P for DFS = .007; P for OS = .003).
Among patients with hormone receptor–positive disease, those with treatment-related amenorrhea achieved longer DFS (adjusted HR = 0.58; 95% CI, 0.45-0.76) and OS (adjusted HR = 0.63; 95% CI, 0.4-0.99) than those who did not develop treatment-related amenorrhea.
Also among patients with hormone receptor-positive disease, the 6-year OS rate was 95.6% (95% CI, 94.3-96.6) for those who developed treatment-related amenorrhea and 92.2% (95% CI, 88.8-94.5) for those who did not (adjusted HR = 0.63; 95% CI, 0.4-0.99).
Researchers reported no difference in DFS or OS based among patients with hormone receptor-negative disease.
Multivariable analysis revealed four factors significantly associated with higher risk for treatment-related amenorrhea: older age at diagnosis (adjusted OR = 2.84; 95% CI, 1.93-4.17), addition of taxanes to anthracycline-based chemotherapy (adjusted OR = 1.92; 95% CI, 1.44-2.56), receipt of adjuvant endocrine therapy (adjusted OR = 2.84; 95% CI, 1.85-4.35), and administration of trastuzumab with docetaxel and carboplatin (adjusted OR = 2.24; 95% CI, 1.18-4.27).
Lambertini acknowledged the study’s definition of gonadotoxicity and timepoint of the evaluation as limitations.
“Specifically, for its definition, we had to rely only on menstrual function after treatment, [yet] menstrual function is not an optimal surrogate for assessing treatment-associated gonadal damage,” he said. “Menopausal status was evaluated at only one fixed timepoint after a median time from chemotherapy completion of 9.5 months (38 weeks). Recent guidelines suggest using a composite endpoint that includes both treatment-related amenorrhea as well as a postmenopausal hormonal profile, and assessing gonadotoxicity not earlier than 2 years after the end of treatment.”
Future research should be designed to provide more evidence on gonadotoxicity of newer and proposed anticancer treatments.
“This could [be] possible with the use of more sensitive biomarkers such as [anti-Müllerian hormone levels] to be evaluated during treatment and at least up to 2 years afterward,” Lambertini said. “In addition, considering that chemotherapy and dual anti-HER-2 blockade with trastuzumab plus pertuzumab (Perjeta, Genentech) has been recently approved for [patients with] high-risk HER-2-positive early breast cancer, studies addressing the gonadotoxicity of this combination should be considered a research priority.”
The findings from Lambertini and colleagues confirm prior study results that suggested treatment-related amenorrhea is associated with improved prognosis among women with hormone receptor-positive breast cancers, Elizabeth J. Cathcart-Rake, MD, medical oncologist at Mayo Clinic in Rochester, Minn., and colleagues wrote in an accompanying editorial.
“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 therapy to adjuvant tamoxifen improved disease-free survival in premenopausal women with hormone receptor–positive breast cancer,” Cathcart-Rake and colleagues wrote. “Combined with the SOFT results, the prognostic relevance of amenorrhea in ALTTO supports the use of ovarian function suppression in premenopausal women whose menses continue during or return soon after chemotherapy for hormone receptor–positive, HER2-positive breast cancer. ...
“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,” Cathcart and colleagues added. – by Melinda Stevens
For more information:
Matteo Lambertini, MD, can be reached at Institut Jules Bordet and Universite Libre de Bruxelles, Boulevard de Waterloo 121, 1000 Brussels, Belgium; email: matteo.lambertini85@gmail.com.
Disclosures: Lambertini reports a travel grant from Astellas and a consultant role with Teva unrelated to the study. Please see the full study for a list of all other authors’ relevant financial disclosures. The editorial authors report no relevant financial disclosures.
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