Prognostic impact of chemotherapy-induced amenorrhea on premenopausal breast cancer: a meta-analysis of the literature

Abstract

Objective: We conducted this meta-analysis of published data to assess the exact prognostic value of adjuvant chemotherapy-induced amenorrhea (CIA) as a prognostic factor for premenopausal breast cancer.

Methods: We searched for all relevant studies published before May 2014 in the PubMed, OVID, and EMBASE databases. Relative risks (RRs) were used to estimate the association between CIA and various survival outcomes, including disease-free survival (DFS) and overall survival (OS).

Results: This meta-analysis identified 13 eligible studies including 5,513 cases and 2,008 controls for DFS and 5 eligible studies including 2,331 cases and 776 controls for OS. Results demonstrated that CIA is associated with improved DFS (RR, 0.67; 95% CI, 0.61-0.74; P < 0.001) and OS (RR, 0.60; 95% CI, 0.50-0.72; P < 0.001). In subgroup analyses, CIA was found to affect DFS (RR, 0.73; 95% CI, 0.61-0.88; P = 0.001) in estrogen receptor (ER)-positive patients; however, similar results were not observed in ER-negative patients (for DFS: RR, 0.97; 95% CI, 0.66-1.41; P = 0.858). Participants with CIA achieved a significantly better prognosis than participants without CIA, irrespective of nodal status, chemotherapy regimen, endocrine therapy, or publication year.

Conclusions: This meta-analysis clarifies that CIA contributes to improved prognosis in premenopausal women with ER-positive breast cancer and is at least partially responsible for the benefits of adjuvant chemotherapy in these women, which induce chemical castration.

FIG. 1

Forest plot of relative risks (RRs) for the association of chemotherapy-induced amenorrhea (CIA) with disease-free survival in women with breast cancer. The size of the box is proportional to the weight that each study contributed to the meta-analysis. Overall estimates and CIs are marked by diamonds. Symbols to the right of the solid line indicate lnRRs greater than 0, and symbols to the left of the solid line indicate lnRRs less than 0. All combined RRs were calculated using the fixed-effects model. CTX, cyclophosphamide; CMF, cyclophosphamide/methotrexate/fluorouracil; HR⁺, hormone receptor–positive; HR⁻, hormone receptor–negative; LBCSG, Ludwig Breast Cancer Study Group.

FIG. 2

Forest plot of relative risks (RRs) for disease-free survival in subgroup analyses of (A) lymph node with the fixed-effects model, (B) estrogen receptor with the fixed-effects model, (C) chemotherapy regimen with the fixed-effects model, (D) endocrine therapy with the fixed-effects and random-effects models, and (E) publication year with the fixed-effects and random-effects models. The size of the box is proportional to the weight that each study contributed to the meta-analysis. Overall estimates and CIs are marked by diamonds. Symbols to the right of the solid line indicate RRs greater than 1, and symbols to the left of the solid line indicate RRs less than 1. When P < 0.1 or I² was higher than 50%, heterogeneity was considered to exist. RRs were calculated with the DerSimonian-Laird method (D + L; random-effects method); otherwise, inverse-variance method (I-V; fixed-effects method) was applied. These two methods provided similar results. LN⁺, lymph node–positive; HR⁺, estrogen receptor–positive and/or progesterone receptor–positive; HR⁻, estrogen receptor–negative and/or progesterone receptor–negative; LBCSG, Ludwig Breast Cancer Study Group; CTX, cyclophosphamide; CMF, cyclophosphamide/methotrexate/fluorouracil; CIA, chemotherapy-induced amenorrhea; ER⁺, estrogen receptor–positive; ER⁻, estrogen receptor–negative.

FIG. 3

Forest plot of relative risks (RRs) for overall survival for the association of chemotherapy-induced amenorrhea (CIA) with breast cancer outcome. The size of the box is proportional to the weight that each study contributed to the meta-analysis. Overall estimates and CIs are marked by diamonds. Symbols to the right of the solid line indicate RRs greater than 1, and symbols to the left of the solid line indicate RRs less than 1.