Sage Journals: Discover world-class research

Abstract

Managing estrogen receptor-positive breast cancer in young women (<40 years) requires a multidisciplinary/personalized approach, covering both clinical and psychosocial aspects. Five years of tamoxifen has been the standard adjuvant endocrine therapy for many years. Recent data from the adjuvant randomized trials TEXT–SOFT show that the aromatase inhibitor exemestane plus ovarian suppression significantly reduces recurrences as compared with tamoxifen plus ovarian suppression. The ATLAS and aTToM trials represent the first evidence of a beneficial effect of extended endocrine therapy with tamoxifen in premenopausal women. Outside of a clinical trial, no data support neoadjuvant endocrine therapy in young women. In the metastatic setting, tamoxifen or aromatase inhibitors, both with ovarian suppression/ablation, should be the preferred choice, unless rapid tumor shrinkage is needed. No data are available with fulvestrant in young patients.

Keywords

advanced breast cancer early breast cancer endocrine therapy exemestane ovarian suppression premenopausal young women

The current definition of ‘young women’ as women under the age of 40 is arbitrary, as biology and the endocrine milieu are a continuum but this group of patients has specific issues such as fertility preservation, induction of treatment-related early menopause, that deserve a different approach and management from slightly older premenopausal and perimenopausal women.

Approximately 11,000 cases of invasive breast cancer (BC) were expected among young US women (<40 years) in 2013, which represent about 5% of all new diagnoses [1]. The same proportion is seen in European countries [2].

Whether young age is associated with unique cancer biology remains controversial. Several studies report an inverse correlation between estrogen receptor (ER) status and age. In a large cohort of Danish women (26,944) diagnosed with primary BC from 1989 to 2004, the proportion of ER⁺ patients increased with age (from 51.4% in patients <35 years to 67.6% in women 40–44 years) [3]. ER positivity by immunohistochemistry was also lower in 200 patients <45 years from five North American public data sets, as compared with their older counterparts (211 patients ≥65 years; positive vs negative; 71% vs 80%, respectively; p = 0.027) [4]. In a cohort of 399 women <40 years diagnosed at Dana-Farber/Harvard Cancer Center, 68% had ER⁺ disease [5]. In addition, Anders and colleagues initially reported an age-related expression of key BC-associated genes [4] but when they corrected for subtype and other significant clinicopathologic features (i.e., ER status and histologic grade) no gene differences were retained between age-defined groups (<45 years and ≥65 years) [6]. In a series of 873 patients aged <45 years from 20 publically available data sets, the proliferation gene signatures showed no significant interaction with age in ER⁺/HER2-tumors [7].

The choice of systemic treatment for invasive BC should not be based on patient's age but only on the biological characteristics of the tumor and patient's comorbidities [8].

Adjuvant endocrine therapy

The most effective adjuvant endocrine therapy (ET) for premenopausal women with ER⁺ BC is still a matter of debate.

Tamoxifen for at least 5 years is considered standard of care [8 –11]. The Early Breast Cancer Trialists' Collaborative Group metaanalyses repeatedly reported the benefits of adjuvant tamoxifen, in premenopausal and postmenopausal women with ER⁺ BC regardless of age, the use of chemotherapy and nodal status. In the 2011 overview [12], 5 years of tamoxifen compared with no ET were associated with a 15-year risk reduction of 39% in BC recurrence and of 30% in BC mortality. The sustained reduction in BC mortality well beyond year 10 is of particular interest in young women. Efficacy was evident also in disease only weakly ER⁺ positive and independent of progesterone receptor status. HER-2 overexpression has been associated with tamoxifen resistance [13]: data in younger women are limited, but in the presence of oophorectomy, the impact of adjuvant tamoxifen on outcome is comparable in patients with HER2-positive and HER2-negative tumors [14]. An association between CYP2D6 genotype and tamoxifen metabolism influencing antitumor activity was investigated in >20 published studies with highly inconsistent results [15]. At present, CYP2D6 pharmacogenetic-driven treatment decisions cannot be recommended outside clinical studies. Genetic polymorphisms in premenopausal women will be specifically investigated in Tamoxifen and Exemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) patients.

The duration of ET has not been adequately studied in young women: in the past, small trials did not suggest any benefit to extend tamoxifen beyond over five years [14,16]. Recent data from the ATLAS and aTTom studies showed that continuing tamoxifen to 10 years gives a further reduction in recurrence and mortality [17,18].

The ATLAS trial included 15.244 premenopausal and postmenopausal women [17] randomized to ten versus 5 years of adjuvant tamoxifen. With a median follow-up of 7.6 years, continuing tamoxifen reduced the risk of BC recurrence, compared with a 5-year treatment course (18% vs 21%; RR: 0.84; 95% CI: 0.76–0.94). A persistent and more significant effect was found after year 10 (RR: 0.90; 95% CI: 0.79–1.02 during years 5–9 and 0.70; 95% CI: 0.62–0.90 during subsequent years). There was a 29% reduction in the risk of BC mortality after year 10 (RR: 0.71; 95% CI: 0.58–0.88). The effect was independent of age (10% of patients were premenopausal at study entry) and nodal status (41% of patients were node-positive at diagnosis): despite being only a small subgroup, the proportional risk reduction was the same in premenopausal patients as compared with postmenopausal patients (RR: 0.81 and 0.85, respectively). The study group had an increased risk for pulmonary embolism (RR: 1.87; 95% CI: 1.13–3.07, p = 0.01), and endometrial cancer (RR: 1.74; 95% CI: 1.30–2.34; p = 0.0002) with lower risk in premenopausal women, but no increase in the incidence of stroke (RR: 1.06; 95% CI: 0.83–1.36), and a decrease in the incidence of ischemic heart disease (RR: 0.76; 95% CI: 0.60–0.95; p = 0.02). The aTTom trial was conducted on 7000 women, most with unknown ER status, randomized to 10 versus 5 years of adjuvant tamoxifen: the reported findings confirm the ATLAS reduction in recurrence and death from BC [18]. Extended tamoxifen therapy is therefore an option that should be considered in premenopausal women at high risk for late relapse (i.e., pathologically involved nodes, larger tumors, high tumor grade) taking into account quality-of-life (QoL) issues.

The NCIC-CTG MA.17/BIG 1–97 trial reported a significant benefit in postmenopausal women with ER⁺ tumors with 5 years of letrozole after 5 years of tamoxifen [19]. The benefit, in terms of disease-free survival (DFS), was higher (hazard ratio [HR]: 0.25; 95% CI: 0.12–0.51) in premenopausal women at diagnosis who became definitively postmenopausal at the time of randomization after 5 years of adjuvant tamoxifen [20].

Extended ET with an aromatase inhibitor (AI) after tamoxifen has never been evaluated in premenopausal BC survivors. AIs alone are contraindicated in premenopausal women because the suppression of peripheral aromatase results in reduced feedback to the hypothalamus and consequent ovarian stimulation [21]. A Phase II single-arm trial in women who remained premenopausal after at least 4.5 years of adjuvant tamoxifen evaluated 2 years of ovarian function suppression (either the gonadotropin-releasing-hormone agonist (GnRHa) leuprolide 7.5 mg monthly or 22.5 mg every 3 months, or bilateral salpingo-oophorectomy [BSO]) [22]. After six to 8 weeks on ovarian function suppression (OFS), participants began the AI letrozole 2.5 mg orally daily for 2 years. Due to unsufficient accrual over 3.5 years the study closed after only 16 patients enrolled. Four patients stopped treatment before 1 year, owing to toxicity; five completed 2 years of protocol-directed therapy; and seven remained on treatment as of study closure. Hot flashes, vaginal dryness and joint/muscle pain were common. This study's poor accrual may suggest young women may not be highly motivated to pursue extended ET and future studies of this strategy may be challenging. Despite the different toxicity profile of extended tamoxifen, it will be important to monitor what proportion of young women will choose to continue ET beyond 5 years and their motivations.

Considering the efficacy shown in postmenopausal women [23], adjuvant AIs in combination with OFS have been first investigated in premenopausal patients with early BC in the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial (Figure 1) which still shows, with a median follow-up of 94.4 months, that 3 years of adjuvant therapy with the AI anastrozole plus the GnRHa goserelin provide a comparable DFS (HR: 1.13; 95% CI: 0.88–1.45; p = 0.335), to that associated with tamoxifen plus goserelin [24]. The overall survival (OS) was not significantly worse with anastrozole than with tamoxifen (HR: 1.63; 95% CI: 1.05–1.45; p = 0.030) but after disease recurrence, women receiving tamoxifen were more likely to be switched to an AI than those in the anastrozole group (61% vs 41%, respectively) who were switched to second line, non-AIs, ET [24]. In overweight patients (BMI ≥25 kg/m²) treated with anastrozole the risks of recurrence and death were significantly higher (HR: 1.49; 95% CI: 0.93–2.38; p = 0.08 and HR: 3.03; 95% CI: 1.35–6.82; p = 0.004, respectively) than in patients treated with tamoxifen. The increased total body aromatization in the fat tissue may in fact negatively affect AIs efficacy, inducing incomplete suppression of estrogen production in peripheral body fat.

Figure 1.

Austrian Breast and Colorectal Cancer Study Group-12 trial design.

The TEXT and SOFT trials were designed (Figure 2) to evaluate 5 years of therapy with the AI exemestane plus the GnRHa triptorelin versus 5 years of tamoxifen plus triptorelin [26]. In addition, the SOFT trial evaluated 5 years of tamoxifen plus triptorelin versus tamoxifen alone in women who were suitable candidates for treatment with adjuvant tamoxifen.

Figure 2.

TEXT and SOFT design.

The planned primary combined analysis of TEXT and SOFT comparing adjuvant exemestane plus OFS with adjuvant tamoxifen plus OFS after a median follow-up of 68 months has shown a 5-year DFS of 91.1% among patients who received exemestane plus OFS and of 87.3% among those assigned to tamoxifen plus OFS (HR: 0.72; 95% CI: 0.60–0.85; p < 0.001), in other words a 28% relative reduction in the risk of disease recurrence, second invasive cancer or death. The difference in OS was not significant [27]. The analysis also showed a 34% relative reduction in the risk of BC recurrence. These results compare favorably with the results of randomized trials of adjuvant AIs versus tamoxifen in postmenopausal women [23].

The difference between the results of TEXT and SOFT and of ABCSG-12 trial may relate to greater statistical power in the combined analysis of TEXT and SOFT (three times the number of events of disease recurrence, second invasive cancer or death), to different treatment durations or to both. The shorter duration of the AI in the ABCSG-12 trial may have been insufficient, as compared with 3 years of tamoxifen, which is known to exert a carryover effect [12]. A difference in the AIs efficacy is unlikely, given the absence of a difference reported in postmenopausal women [28]. Of note, >90% of patients in both trials remained disease free without adjuvant chemotherapy, suggesting that combined adjuvant et al. one, in appropriately selected ER⁺ premenopausal women, can be effective. A word of caution should be raised in very young women, as only 10% of women were <35 years of age when randomized in the TEXT–SOFT trials [27].

The additional benefit of OFS/OA is still a matter of debate. The 2005 EBCTG overview demonstrated that OA (by surgery/irradiation) or OFS with a GnRHa significantly reduce the risk of both recurrence and BC mortality in women <50 years with ER⁺ or ER-unknown early BC [29]. A larger EBCTG metaanalysis looked only at trials with known ER status and GnRHas as method of OFS [30]. OFS proved to be beneficial whether used alone (recurrence risk reduction of 28%; p = 0.08), in addition to tamoxifen or chemotherapy (recurrence risk reduction of 13%; p = 0.02), and as an alternative to chemotherapy. The effects were greater in women <40 years in whom chemotherapy is less likely to induce permanent amenorrhea. The recently published results of the SOFT trial showed that, after a median follow-up of 67 months, the addition of OFS/OA to tamoxifen did not result in a significant benefit in terms of DFS in the overall study population (86.6% in the tamoxifen–OFS group vs 84.7% in the tamoxifen group; HR: 0.83; 95% CI: 0.66–1.04; p = 0.10). However, for women at higher risk of recurrence (i.e., <40 years at diagnosis, node positive, with tumors >2 cm and grade 3) who received adjuvant chemotherapy and remained premenopausal within 8 months after its completion, the addition of OFS was associated with an absolute improvement of 4.5% in the 5-year BC-free interval, benefit which increased to 11.2% in women <35 years at diagnosis (11.5% of the entire population) [31]. The optimal duration of GnRHas is also unknown, although most studies have utilized 2–3 years of monthly injections with 5 years of tamoxifen. Data comparing the efficacy of monthly and trimonthly formulations of GnRHa in women with BC are lacking. The effects of monthly goserelin and trimonthly leuprolide on estradiol levels did not differ significantly in a study comparing 79 early BC patients receiving GnRHa for at least 6 months [31] but further research in needed before trimonthly administration can be recommended in women <40 years of age.

OFS is not always successfully achieved with GnRHa as demonstrated in patients with advanced BC (ABC) by a pooled analysis of 193 premenopausal women treated with goserelin from 29 European trials (5% of patients) [32] and in 32 patients treated with anastrozole in combination with goserelin (1/3 of patients) [33]. Menses cessation does not guarantee complete estrogen suppression, estradiol assays are not standardized and their accuracy and interpretation can be problematic in presence of very low levels of estradiol [34]. Despite these limitations, estradiol levels should be checked on a regular basis (at least every 6 months), always in the same laboratory and preferably in a central reference laboratory.

The reversible OFS with GnRHa can be particularly attractive to younger women, especially to those who did not complete childbearing before diagnosis. Prophylactic BSO is known to significantly reduce the risk of both breast and ovarian cancer in mutation carriers, who are often identified at the time of BC diagnosis. BSO may therefore be considered when discussing adjuvant ET in this subgroup of young women [35].

Chemotherapy-induced amenorrhea (CIA), even if transient, is associated with improved treatment outcome: in addition to direct cytotoxicity, adjuvant chemotherapy has an indirect endocrine effect in ER⁺ BC through the induction of OFS. A recent metaanalysis in 15,916 premenopausal patients from 46 randomized trials showed a significant DFS advantage in ER⁺ patients (HR: 0.61; 95% CI: 0.52–0.72; p < 0.00001) [36]. The three-drug combination regimens of cyclophosphamide/anthracycline/taxanes caused the highest rate of chemotherapy-induced amenorrhea. The limited evidence available on the addition of trastuzumab to anthracyclines and/or taxanes seems not to increase the rate of permanent amenorrhea [37].

Neoadjuvant endocrine therapy

Neoadjuvant ET should not be proposed to young women outside clinical trials [8].

In the Phase III, randomized, double-blind, multicenter STAGE study, 204 patients were treated with 24 months' neoadjuvant therapy with the GnRHa goserelin plus anastrozole or tamoxifen. Anastrozole plus goserelin showed a significantly better overall response rate (ORR) than tamoxifen plus goserelin (70.4 vs 50.5%; 95% CI: 6.5–33.3; p = 0.004) [38], both among patients who had a baseline Ki-67 index ≥20% and among those who had a baseline Ki-67 index <20% [39]. The use of letrozole and a GnRHa as primary therapy was investigated in 32 premenopausal women with ER⁺ BC. The ORR was 50% (95% CI: 32–68%) and no patient progressed during treatment. Response was significantly associated with younger age (p < 0.05) and a longer duration of treatment (p < 0.05) [40]. These results compare favorably to the ORR achieved with neoadjuvant ET in postmenopausal women [41] and neoadjuvant chemotherapy in Luminal B patients [42] and this evidence is reinforced by the recent results with AIs plus OFS in the adjuvant setting [27] but definitive data are awaited before neoadjuvant ET can be routinely proposed to young women.

The activity of letrozole plus a GnRHa administered concurrently with preoperative chemotherapy (n = 119) was retrospectively compared with a nonrandomized unmatched control group of premenopausal women with locally advanced ER positive BC receiving preoperative chemotherapy, followed by tamoxifen and GnRHa after surgery (n = 95). The 5-year DFS was 78% vs 41% in the study and in the control group, respectively (adjusted HR: 0.46; 95% CI: 0.27–0.79; p = 0.0047) [43]. These retrospective data do not provide evidence-based indication to change clinical practice but suggest the role of chemoendocrine neoadjuvant therapy in this patients' population should be explored in randomized studies.

GnRHas have shown marked in vitro and in vivo antiproliferative activity in BC [44]. An International Breast Cancer Study Group (IBCSG) randomized Phase II trial (IBCSG 41–13 TREND) is evaluating the efficacy of the GnRHa degarelix versus triptorelin as neoadjuvant treatment in 50 premenopausal patients receiving letrozole.

Endocrine therapy in metastatic breast cancer

ET should be the preferred option for ER⁺ABC, unless there is evidence of endocrine resistance or need for rapid disease and/or symptom control [45,46].

In premenopausal women with ER⁺ABC, a variety of ETs have proven to be effective. A metaanalysis comparing GnRHa ± tamoxifen showed that the outcomes were significantly improved in patients who received the combination [47]. On the basis of these results, a GnRHa plus tamoxifen is currently recommended as the standard first-line therapy in ABC.

Based on the available evidence in postmenopausal women with recurrent BC [45], the role of AIs has also been studied in premenopausal women. In a prospective, single-arm, multicenter Phase II trial, 32 premenopausal patients were treated with goserelin and anastrozole achieving a clinic benefit rate of 71.9%, similar to that observed with AIs in postmenopausal women [48]. Other small Phase II studies confirm the efficacy of AIs as first- and second-line treatment in combination with a luteinizing hormone-releasing hormone (LH–RH) agonist [49 –52]. The combination of goserelin and letrozole proved to be effective and well tolerated also in 35 very young (<35 years) women as first-line therapy with a clinic benefit rate of 65.7% [53].

In a Phase II parallel group study, at median follow-up of 27.4 months, there was no statistical difference in the median time to progression (TTP) between premenopausal patients receiving letrozole plus goserelin and postmenopausal patients treated with letrozole alone (9.5 months [95% CI: 6.4–12.1 months] vs 8.9 months [95% CI: 6.4–13.3 months]) [54].

Considering the demonstrated improved efficacy of AIs and OFS in the adjuvant setting [27], this combination can be reasonably proposed as first-line therapy in selected premenopausal women with ER⁺ABC but the exact role of this option requires further investigation in randomized trials.

Based on the documented efficacy of the selective estrogen receptor downregulator fulvestrant in postmenopausal patients [55], studies have been conducted in premenopausal patients as well [56,57]. Bartsch et al. demonstrated a clinical benefit rate of 58% with fulvestrant plus goserelin in 26 patients pretreated with tamoxifen and AIs in combination with goserelin: the median TTP was 6 months (95% CI: 2.4–9.6 months) and the OS 32 months (95% CI: 14.28–49.72 months [58].

In ER⁺ABC, most studies addressing the combination of ET and chemotherapy showed an increased ORR or an increased TTP but no improvement in OS with no age-related differences [59]. Trials examining concurrent versus sequential treatment with ET and chemotherapy need therefore to be conducted [60].

Side effects of endocrine therapy

Side effects of ET in young women mimic menopausal symptoms, including hot flashes, sweats, weight gain and sexual dysfunction which may negatively impact QoL [61]. Hot flashes are the most common side effect of tamoxifen. Nonhormonal and nonpharmacological therapies such as phytotherapy or acupuncture can be effective to reduce the intensity of symptoms as well as low-dose antidepressants [62]. The US FDA recently approved paroxetine for the treatment of moderate-to-severe vasomotor symptoms [63]: despite the known interaction between this class of drugs and the CYP2D6-mediated tamoxifen metabolism, there is currently no contraindications to prescribe antidepressants to control vasomotor symptoms [15]. Tamoxifen has both estrogen agonist and antagonist properties with different side effect profile depending on the target organ: there is little uterine cancer risk or excess risk of fatal pulmonary embolism before the age of 45 years [12]. To date, no evidence-based recommendations for routine screening (i.e., transvaginal ultrasound or endometrial biopsy) in women assuming tamoxifen are available. However, abnormal bleeding should be promptly investigated and expert opinion recommendations suggest annual gynecologic examinations [11]. As opposed to menopausal women, there is some evidence that tamoxifen may decrease bone mineral density (BMD) in premenopausal women, although the exact mechanism remains unclear. BMD has therefore to be regularly checked in premenopausal women receiving ET for BC [64].

Weight gain is often reported by women treated with tamoxifen ± OFS. Randomized trials have not reported an excess in weight gain in patients treated with tamoxifen as compared with those who received placebo [65]. In prevention trials, weight gain did not differ between anastrozole, tamoxifen and placebo [66,67]. Weight gain ≥10% after BC diagnosis was associated with a nonsignificant increased risk of death (HR: 1.15; 95% CI: 0.98–1.35) but not of BC-specific mortality (HR: 1.03; 95% CI: 0.84–1.26) in 12,915 patients with BC (diagnosed between 1990 and 2006) from four population-based prospective cohort studies examining the role of physical activity, BMI, dietary factors and interventions and QoL in BC prognosis [68]. Several mechanisms have been postulated through which weight gain may influence survival, including enhanced conversion in fat tissue of androgens to estrogens and associated high levels of fasting insulin which may bind to insulin receptors that are overexpressed on most human BC cells [69]. As a consequence, prevention of weight gain appears to be a sound public health goal for BC survivors [70].

Tamoxifen may adversely affect cognition [71], although few specific investigations on this side effect have been conducted and none in young women. In the ZIPP trial (six cycles of CMF ±2 years of goserelin, goserelin plus tamoxifen or tamoxifen), no effect of treatment on the patients' self-evaluation of memory and concentration was shown [72]. Cognitive function is being prospectively investigated in patients participating in the SOFT trial.

Tamoxifen may also increase plasma estradiol concentrations by interfering with the normal negative pituitary feedback mechanisms: endogenous sex hormone levels were not correlated with outcome in a high-risk postmenopausal population prevention trial [73] but further studies may be required to explore the potential impact on the breast of increased serum estrogen levels in premenopausal BC patients treated with tamoxifen.

Treatment with GnRHa is associated with menopausal side effects such as hot flushes and vaginal dryness [74] and with more severe sexual dysfunction than tamoxifen alone. Vaginal dryness can be mitigated by the addition of tamoxifen [72].

Side effects of AIs when combined with a GnRHa are consistent with the known safety profiles for each of the agents administered [24,27]. The recently reported SOFT–TEXT data show musculoskeletal symptoms, fractures, vaginal dryness, decreased libido and dyspareunia as specific AI side effects. Of note, depression was reported in 50% of patients, with grade 3–4 in 4% of the patients [27]. Bisphosphonates, although not yet approved for this indication, can prevent cancer therapy-induced bone loss and improve BMD in premenopausal BC patients [75,76] and should be promptly introduced at first signs of significant bone loss. Regular exercise has also a positive impact on bone mineralization and stimulation of osteogenesis [77].

Fertility issues, feasibility and safety of pregnancy after the disease should be addressed early after diagnosis and patients should ideally be referred to a fertility specialist before starting therapy [78,79]. In women <35 years, adjuvant chemotherapy is less likely to induce permanent amenorrhea [80]. The two largest randomized trials (PROMISE and POEMS) both demonstrated an increased resumption of ovarian function in women receiving a GnRHa during adjuvant chemotherapy and suggest this approach should be discussed to prevent premature ovarian failure [81,82]. Pregnancy following BC does not seem to negatively influence DFS or OS in ER⁺ premenopausal patients [83,84]. Within the Breast International Group–North American Breast Cancer Group collaboration the IBCSG has just launched a trial (POSITIVE–IBCSG 48–14 NCT02308085 [85]) (Figure 3) to assess patients' safety and pregnancy outcomes of interrupting ET after having received at least 18 months but no longer than 30 months, to attempt conception.

Figure 3.

POSITIVE study design.

Patients should be informed of the possibility of getting pregnant while on tamoxifen, despite developing amenorrhea: the relatively high frequency of severe congenital abnormalities mandates a reliable nonhormonal contraception [86].

Younger age has been associated with lower rates of treatment adherence [87]. In a cohort of 288 French women diagnosed with BC <40 years, 29.7% (95% CI: 24.1–36.4%) had discontinued tamoxifen after 2 years; after 3 years the proportion increased to 39.5% (95% CI: 32.9–47.0%) [88]. In contrast, in the SOFT–TEXT trials, only 13.7% had stopped early all protocol assigned treatments (16.1% of the patients in the exemestane–OFS group and 11.2% of those in the tamoxifen–OFS group) and the overall QoL assessment did not favor either treatment [27]. These data suggest that motivated women, such those included in clinical trials, are willing to complete the full course of treatment and can be of particular interest when considering extended ET in young women and their impact on QoL.

Conclusion

The incidence of ER⁺ BC among younger women has increased in the past decade. Current available therapies in young women with ER⁺ early and ABC either modulate ER activity (tamoxifen) or decrease estrogen production (OFS/OA/AIs).

In early BC, recent data on the combination of AIs and OFS show that outcomes in young patients with ER⁺ disease, still considered at high risk due to age, are extraordinarily good, also in women who did not receive chemotherapy.

In advanced disease, ET has a major role in the long-term control of indolent disease and most of the time is associated with an acceptable toxicity profile.

Better tools to manage early menopause signs/symptoms (e.g., bone resorption, cognitive problems, fertility impairment and sexual disturbances) and careful monitoring of late toxicities (e.g., second cancers) need to be routinely implemented and specifically investigated.

The complex physical and psycho-social scenario of BC at young age mandates individualized and multidisciplinary approaches in order to maximize outcome while minimizing the impact of diagnosis and treatment in women with demanding personal, social and family commitments.

Future perspective

Further progress in the management of young women with BC cannot be achieved without a global commitment by healthcare professionals, researchers, patients, payers and regulators.

In early BC, several questions still need to be answered in order to maximize treatment individualization: the exact role and tailoring added value of OFS added to tamoxifen in the routine clinical management of young women with early BC, especially in those <35 years at diagnosis; the optimal duration of OFS; the optimal extended ET and duration in high-risk patients; and the value of sequential versus concomitant chemotherapy and OFS, particularly in those women for whom chemotherapy is indicated.

Executive summary

Adjuvant endocrine therapy

Five years of adjuvant tamoxifen is standard endocrine therapy (ET) for premenopausal women: the addition of OFS to tamoxifen should be considered in women who remain premenopausal after adjuvant chemotherapy, especially if <35 years at diagnosis.

The ATLAS and aTTom trial showed 10 years of tamoxifen reduce the risk for BC recurrence and mortality compared with 5-year treatment.

The NCIC-CTG MA.17/BIG 1–97 trial reported a significant advantage to extended adjuvant ET with 5 years of letrozole in premenopausal women with ER⁺ tumors at diagnosis who became definitively postmenopausal and who had received 5 years of tamoxifen.

Data from TEXT and SOFT showed that adjuvant exemestane plus OFS compared with adjuvant tamoxifen plus OFS improves disease-free survival, BC and distant recurrence-free interval.

Optimal duration of LH-RH agonists is unknown, although most studies have utilized 2–3 years of luteinizing hormone-releasing hormone agonists with 5 years of tamoxifen.

Chemotherapy-induced amenorrhea, even if transient, is associated with improved outcome.

Neoadjuvant endocrine therapy

Neoadjuvant ET should not be proposed to young women outside clinical trials.

Neoadjuvant ET with aromatase inhibitor (AI) and gonadotropin-releasing-hormone agonist showed to be effective and should be investigated in randomized trials.

Endocrine therapy in metastatic breast cancer

ET is the preferred option for ER⁺ disease, unless there is evidence of endocrine resistance or need for rapid disease and/or symptom control.

OFS + tamoxifen is the standard first-line therapy in ABC.

OFS + AIs showed comparable activity to AIs in menopausal women and require further investigation in randomized trials.

Further studies are needed with fulvestrant + OFS.

Trials examining concurrent versus sequential treatment with ET and chemotherapy need to be conducted.

Side effects

Side effects of tamoxifen and OFS/OA mimic menopausal symptoms, including hot flashes, sweats, weight gain, cognitive impairment and sexual dysfunction.

Side effects of AIs when combined with OFS include fractures, musculoskeletal symptoms, vaginal distress, decreased libido and dyspareunia.

Fertility preservation should be discussed early after diagnosis and patients should be referred to a fertility specialist before treatment start.

Pregnancy following BC does not seem to negatively influence disease outcome and should not be discouraged.

Neoadjuvant ET should be appropriately studied in young women with particular focus on translational end points of different endocrine pathways of proliferation in this patients' population.

In ABC, efforts should be made to extend to young women the efficacy data onselective estrogen receptor downregulators to widen their therapeutic armamentarium and to study endocrine resistance compounds (i.e., mTOR-PI3K-MEK-CDK inhibitors).

The number of long-term young survivors either cured after early BC or living with the disease, will increase in the next decades. Resources need to be invested to specifically address their needs (i.e., return to work, social coverage, family management) and to support their caregivers.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest; •• of considerable interest

DeSantis

Bryan

Jemal

. Breast cancer statistics, 2013. CA Cancer J. Clin. 64(1), 52–62 (2014).

Allemani

Minicozzi

Berrino

. Predictions of survival up to 10 years after diagnosis for European women with breast cancer in 2000–2002. Int. J. Cancer 132(10), 2404–2412 (2013).

Bentzon

Düring

Rasmussen

Mouridsen

Kroman

. Prognostic effect of estrogen receptor status across age in primary breast cancer. Int. J. Cancer 122(5), 1089–1094 (2008).

Anders

Hsu

Broadwater

. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J. Clin. Oncol. 26(20), 3324–3330 (2008).

Collins

Marotti

Gelber

. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res. Treat. 131(3), 1061–1066 (2012).

Anders

Fan

Parker

Carey

Blackwell

. Breast carcinomas arising at a young age: unique biology or a surrogate for aggressive intrinsic subtypes? J. Clin. Oncol. 29(1), e18–e20 (2011).

Azim

Jr Michiels

Bedard

. Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin. Cancer Res. 18(5), 1341–1351 (2012).

10.

Partridge

Pagani

Abulkhair

. First international consensus guidelines for breast cancer in young women (BCY1). Breast 23(3), 209–220 (2014).

11.

Specific guidelines for the management of young patients with early and advanced breast cancer.

12.

Goldhirsch

Winer

Coates

. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann. Oncol. 24(9), 2206–2223 (2013).

13.

Senkus

Kyriakides

Penault-Llorca

. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 24 (Suppl. 6), vi7–vi23 (2013).

14.

Gradishar

Anderson

Blair

. NCCN. Breast cancer version 3. 2014. J. Natl Compr. Canc. Netw. 12(4), 542–590 (2014).

15.

Davies

Godwin

Gray

. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378 (9793), 771–784 (2011).

16.

Osborne

Shou

Massarweh

Schiff

. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin. Cancer Res. 11(2 Pt 2), s865–s870 (2005).

17.

Fisher

Dignam

Bryant

. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J. Natl Cancer Inst. 93(9), 684–690 (2001).

18.

Berry

. CYP2D6 Genotype and Adjuvant Tamoxifen. Clin. Pharmacol. Ther. 96(2), 138–140 (2014).

19.

Stewart

Forrest

Everington

. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br. J. Cancer 74(2), 297–299 (1996).

20.

Davies

Pan

Godwin

. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381(9869), 805–816 (2013).

21.

First evidence of efficacy of extended adjuvant tamoxifen in young women with early breast cancer.

22.

Gray

Rea

Handley

. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J. Clin. Oncol. 31(Suppl.), Abstract 5 (2013).

23.

Jin

Zhao

. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J. Clin. Oncol. 30, 718–721 (2012).

24.

Higgins

Liedke

Goss

. Extended adjuvant endocrine therapy in hormone dependent breast cancer: the paradigm of the NCIC-CTG MA.17/BIG 1–97 trial. Crit. Rev. Oncol. Hematol. 86, 23–32 (2013).

25.

Dowsett

Folkerd

Doody

. The biology of steroid hormones and endocrine treatment of breast cancer. Breast 14, 452–457 (2005).

26.

Ruddy

DeSantis

Barry

. Extended therapy with letrozole and ovarian suppression in premenopausal patients with breast cancer after tamoxifen. Clin. Breast Cancer 14(6), 413–416 (2014).

27.

Dowsett

Cuzick

Ingle

. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J. Clin. Oncol. 28(3), 509–518 (2010).

28.

Gnant

Mlineritsch

Stoeger

. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann. Oncol. 26(2), 313–320 (2014).

29.

Gnant

Mlineritsch

Luschin-Ebengreuth

. Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. Presented at: The 2011 San Antonio Breast Cancer Symposium. San Antonio, Texas, USA, 6–10 December 2011 (Abstract S1–S2).

30.

Regan

Pagani

Fleming

. Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials. Breast 22(6), 1094–1100 (2013).

31.

Pagani

Regan

Francis

. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. New Engl. J. Med. 371(2), 107–118 (2014).

32.

First evidence of efficacy of adjuvant aromatase inhibitors and ovarian function suppression in young women with early breast cancer.

33.

Goss

Ingle

Pritchard

. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27 – a randomized controlled Phase III trial. J. Clin. Oncol. 31(11), 1398–1404 (2013).

34.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet 365 (9472), 1687–1717 (2005).

35.

Cuzick

Ambroisine

Davidson

. LHRH-agonists in Early Breast Cancer Overview group. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 369(9574), 1711–1723 (2007).

36.

Francis

Regan

Fleming

. Adjuvant ovarian suppression in premenopausal breast cancer. New Engl. J. Med. 372(5), 436–446.

37.

Pivotal evidence to better tailor endocrine therapy.

38.

Blamey

Jonat

Kaufmann

. Goserelin depot in the treatment of premenopausal advanced breast cancer. Eur. J. Cancer 28A(4–5), 810–814 (1992).

39.

Carlson

Theriault

Schurman

. Phase II trial of anastrozole plus goserelin in the treatment of hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women. J. Clin. Oncol. 28(25), 3917–3921 (2010).

40.

Dowsett

Folkerd

. Deficits in plasma oestradiol measurement in studies and management of breast cancer. Breast Cancer Res. 7(1), 1–4 (2005).

41.

Valachis

Nearchou

Lind

. Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis. Breast Cancer Res. Treat. 144(3), 443–455 (2014).

42.

Zhao

Liu

Chen

. What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. Breast Cancer Res. Treat. 145(1), 113–128 (2014).

43.

Abusief

Missmer

Ginsburg

Weeks

Partridge

. The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer 116 (4), 791–798 (2010).

44.

Masuda

Sagara

Kinoshita

. Neoadjuvantanastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised Phase 3 trial. Lancet Oncol. 13(4), 345–352 (2012).

45.

Iwata

Masuda

Sagara

. Analysis of Ki-67 expression with neoadjuvantanastrozole or tamoxifen in patients receiving goserelin for premenopausal breast cancer. Cancer 119(4), 704–713 (2013).

46.

Torrisi

Bagnardi

Pruneri

. Antitumor and biological effects of letrozole and GnRH analogue as primary therapy in premenopausal women with ER and PgR positive locally advanced operable breast cancer. Br. J. Cancer 97(6), 802–808 (2007).

47.

Charehbili

Fontein

Kroep

. Neoadjuvant hormonal therapy for endocrine sensitive breast cancer: a systematic review. Cancer Treat. Rev. 40(1), 86–92 (2014).

48.

Alba

Calvo

Albanell

. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006–2003 a multicenter, randomized, Phase-II study. Ann. Oncol. 23(12), 3069–3074 (2012).

49.

Torrisi

Bagnardi

Rotmensz

. Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer. Breast Cancer Res. Treat. 126(2), 431–441 (2011).

50.

Gründker

Föst

Fister

Nolte

Günthert

Emons

. Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo. Breast Cancer Res. 2(4), R49–R57 (2010).

51.

Cardoso

Costa

Norton

. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23(5), 489–502 (2014).

52.

Cardoso

Harbeck

Fallowfield

Kyriakides

Senkus

. ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 23(Suppl. 7), vii11–vii9 (2012).

53.

Michaud

Jones

Buzdar

. Combination endocrine therapy in the management of breast cancer. Oncologist 6(6), 538–546 (2001).

54.

Carlson

Theriault

Schurman

. Phase II trial of anastrozole plus goserelin in the treatment of hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women. J. Clin. Oncol. 28(25), 3917–3921 (2010).

55.

Zhu

. Role of goserelin in combination with endocrine therapy for the treatment of advanced breast cancer in premenopausal women positive for hormone receptor: a retrospective matched case–control study. Cancer Biother. Radiopharm. 28(10), 697–702 (2013).

56.

Cheung

Winterbottom

Owers

. Goserelin plus anastrozole as first-line endocrine threrapy for premenopausal women with oestrogen receptor (ER) positive advanced breast cancer (ABC). J. Clin. Oncol. 23, Abstract 731 (2005).

57.

Forward

Cheung

Jackson

. Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer. Br. J. Cancer 90(3), 590–594 (2004).

58.

Nishimura

Anan

Yamamoto

. Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH–RH analogue with tamoxifen: results of the JMTO BC08–01 Phase II trial. Oncol. Rep. 29 (5), 1707–1713 (2013).

59.

Liu

Cao

Wang

. Efficacy of combined therapy of goserelin and letrozole on very young women with advanced breast cancer as first-line endocrine therapy. Endocr. J. 60(6), 819–828 (2013).

60.

Park

Lee

. Phase II parallel group study showing comparable efficacy between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first-line hormone therapy. J. Clin. Oncol. 28 (16), 2705–2711 (2010).

61.

Croxtall

McKeage

. Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women. Drugs 71(3), 363–380 (2011).

62.

Robertson

Semiglazov

Nemsadze

. Effects of fulvestrant 250 mg in premenopausal women with oestrogen receptor-positive primary breast cancer. Eur. J. Cancer 43(1), 64–70 (2007).

63.

Young

Renshaw

Macaskill

. Effects of fulvestrant 750 mg in premenopausal women with oestrogen receptor-positive primary breast cancer. Eur. J. Cancer 44(3), 391–399 (2008).

64.

Bartsch

Bago-Horvath

Berghoff

. Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer. Eur. J. Cancer 48(13), 1932–1938 (2012).

65.

Pritchard

. Combining endocrine agents with chemotherapy: which patients and what sequence? Cancer 112(3 Suppl.), 718–722 (2008).

66.

Cardoso

Bedard

Winer

. International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J. Natl Cancer Inst. 101(17), 1174–1181 (2009).

67.

Perez

. Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer. Ann. Oncol. 18(Suppl. 8), viii26–viii35 (2007).

68.

Kligman

Younus

. Management of hot flashes in women with breast cancer. Curr. Oncol. 17(1), 81–86 (2010).

69.

Useful treatment algorithm for the most frequent side effect of endocrine therapy in young women with breast cancer.

70.

Orleans

Kim

. FDA approval of paroxetine for menopausal hot flushes. N. Engl. J. Med. 370(19), 1777–1779 (2014).

71.

Christinat

Di Lascio

Pagani

. Hormonal therapies in young breast cancer patients: when, what and for how long? J. Thorac. Dis. 5(Suppl. 1), S36–S46 (2013).

72.

Cuzick

Sestak

Baum

. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10 year analysis of the ATAC trial. Lancet Oncol. 11(12), 1135–1141 (2010).

73.

Sestak

Harvie

Howell

. Weight change associated with anastrozole and tamoxifen treatment in postmenopausal women with or at high risk of developing breast cancer. Breast Cancer Res. Treat. 134(2), 727–734 (2012).

74.

Cuzick

Forbes

Sestak

. Long-term results of tamoxifen prophylaxis for breast cancer – 96 month follow-up of the randomized IBIS-I trial. J. Natl Cancer Inst. 99(4), 272–282 (2007).

75.

Caan

Kwan

Shu

. Weight change and survival after breast cancer in the after breast cancer pooling project. Cancer Epidemiol. Biomark. Prev. 21(8), 1260–1271 (2012).

76.

Protani

Coory

Martin

. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res. Treat. 123(3), 627–635 (2010).

77.

Chlebowski

. Nutrition and physical activity influence on breast cancer incidence and outcome. Breast 22(Suppl. 2), S30–S37 (2013).

78.

Onami

Mortimer

Pal

. Cognitive changes associated with endocrine therapy for breast cancer. Maturitas 67(3), 209–214 (2010).

79.

Nystedt

Berglund

Bolund

. Side effects of adjuvant endocrine treatment in premenopausal breast cancer patients: a prospective randomized study. J. Clin. Oncol. 21(9), 1836–1844 (2003).

80.

Beattie

Costantino

Cummings

. Endogenous sex hormones, breast cancer risk, and tamoxifen response: an ancillary study in the NSABP Breast Cancer Prevention Trial (P-1). J. Natl Cancer Inst. 98(2), 110–115 (2006).

81.

Colleoni

Giobbie-Hurder

. Benefits and adverse effects of endocrine therapy. Ann. Oncol. 21(Suppl. 7), vii107–vii111 (2010).

82.

Aft

. Protection of bone in premenopausal women with breast cancer: focus on zoledronic acid. Int. J. Womens Health 4, 569–576 (2012).

83.

Hadji

Kauka

Ziller

. Effects of zoledronic acid on bone mineral density in premenopausal women receiving neoadjuvant or adjuvant therapies for HR+ breast cancer: the ProBONE II study. Osteoporos. Int. 25(4), 1369–1378 (2014).

84.

Hojan

Milecki

Molińska-Glura

. Effect of physical activity on bone strength and body composition in breast cancer premenopausal women during endocrine therapy. Eur. J. Phys. Rehabil. Med. 49(3), 331–339 (2013).

85.

Ruddy

Gelber

Tamimi

. Prospective study of fertility concerns and preservation strategies in young women with breast cancer. J. Clin. Oncol. 32(11), 1151–1156 (2014).

86.

Tomasi-Cont

Lambertini

Hulsbosch

Peccatori

Amant

. Strategies for fertility preservation in young early breast cancer patients. Breast 23(5), 503–510 (2014).

87.

Useful treatment algorithm for fertility management in young women treated for breast cancer.

88.

Christinat

Pagani

. Fertility after breast cancer. Maturitas 73(3), 191–196 (2012).

89.

Del Mastro

Boni

Michelotti

. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA 306(3), 269–276 (2011).

90.

Gerber

Ortmann

. Prevention of Early Menopause Study (POEMS): is it possible to preserve ovarian function by gonadotropin releasing hormone analogs (GnRHa)? Arch. Gynecol. Obstet. 290(6), 1051–1053 (2014).

91.

Azim

Jr Kroman

Paesmans

. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J. Clin. Oncol. 31(1), 73–79 (2013).

92.

Pagani

Azim

Jr . Pregnancy after breast cancer: myths and facts. Breast Care (Basel) 7(3), 210–214 (2012).

93.

ClinicalTrialsDatabase: NCT02308085 https://clinicaltrials.gov/ct2/show/NCT02308085

94.

Braems

Denys

De Wever

. Use of tamoxifen before and during pregnancy. Oncologist 16(11), 1547–1551 (2011).

95.

Cluze

Rey

Huiart

. Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time. Ann. Oncol. 23(4), 882–890 (2012).

96.

Huiart

Bouhnik

Rey

. Early discontinuation of tamoxifen intake in younger women with breast cancer: is it time to rethink the way it is prescribed? Eur. J. Cancer 48(13), 1939–1946 (2012).

97.

Specific perspective on adherence to adjuvant endocrine treatment in young women.

New Insights into Endocrine Therapy for Young Women with Breast Cancer

Abstract

Keywords

Adjuvant endocrine therapy

Neoadjuvant endocrine therapy

Endocrine therapy in metastatic breast cancer

Side effects of endocrine therapy

Conclusion

Future perspective

Financial & competing interests disclosure

References