Trial
Patient population characteristics
Study design
Median follow-up
DFS (HR, 95 % CI)
OS (HR, 95 % CI)
1,803 premenopausal women. No adjuvant chemotherapy
Median age 45
Stage I/II (75 % T1 tumors, 67 % N0).
Randomized, open-label, two-by-two factorial design
Goserelin + tamoxifen vs. goserelin + anastrazole +/− zoledronic acid for 3 years
62 months
HR 1.08, 95 % CI 0.81–1.44; p = 0.591
HR 1.75, 95 % CI 1.08–2.83; p = 0.02)
3,066 premenopausal women. 53.5 % received chemotherapy
Median age 40 chemotherapy arm, 46 no chemotherapy arm)
Stage I–III (59 % T1 tumors, 66 % N0)
Randomized, open-label 1:1:1 ratio
Tamoxifen vs. triptorelin + tamoxifen vs. triptorelin + exemestane for 5 years
68 months
Combined analysis Tamoxifen + triptorelin vs. exemestane + triptorelin:
HR 0.72, 95 % CI 0.60–0.86; p < 0.001)
tamoxifen + triptorelin vs. tamoxifen alone: HR 0.83, 95 % CI 0.66–1.04; p=0.10
HR 1.14, 95 % CI 0.86–1.51; p = 0.37). Data not mature
TEXT (IBCSG 25–02) [95]
2,672 premenopausal patients
39.6 % received adjuvant chemotherapy
Median age 45 chemotherapy arm, 43 no chemotherapy arm)
Stage I–III (66 % T1 tumors, 52 % N0)
Randomized, open-label 1:1 ratio
Triptorelin + tamoxifen vs. triptorelin + exemestane for 5 years
68 months
E-3193, INT-0142 [97]
345 premenopausal women. No adjuvant chemotherapy
Median age 45
Stage I–II (91% T1 tumors, 100 % N0)
Randomized, open-label 1:1 ratio
Tamoxifen vs. tamoxifen + ovarian ablation
For 5 years
Ovarian ablation included LHRH agonist (36 %), surgical (42 %), or RT (13 %) ovarian ablation
9.9 years
HR 1.17, 95 % CI 0.64–2.12; p = 0.62)
No difference in OS between study arms. HR 1.19, 95 % CI 0.52–2.70; p = 0.67)
HR 1.19, 95 % CI 0.52–2.70; p = 0.67
At present time, there is no role for aromatase inhibitors with or without ovarian ablation in patients who remain premenopausal after 5 years of tamoxifen. For patients who become menopausal during/after completion of adjuvant tamoxifen, a switching or extended adjuvant strategy may be considered. Ovarian ablation in combination with aromatase inhibitor may be considered as upfront adjuvant therapy in premenopausal patients in view of SOFT/TEXT combined analysis however, longer follow-up is needed at this point. Only INT0142 had long-term follow-up; however, the study is underpowered for survival analysis due to early closure as a result of poor accrual. Nevertheless, the sample size was achieved for patient-related outcomes with results indicating, as expected more menopausal symptoms and decline in sexual activity in the ovarian ablation arm [97]. Another concern is the worse outcome of the ovarian ablation + anastrazole arm compared to ovarian ablation + tamoxifen arm of the ABCSG-12 trial. Several hypotheses have been proposed to explain these results including short treatment duration (3 years) and also lack of HER2 status assessment. More recently, an unplanned analysis of the ABCSG-12 trial suggested that the poor outcome of the anastrazole arm is only restricted to overweight population, which constituted around 30 % of the study population [99]. These results raise questions regarding the use of aromatase inhibitors in overweight/obese premenopausal women. This becomes more complicated when compliance issues are also considered. Higher rates of musculoskeletal and gynecologic side effects with aromatase inhibitors may further compromise low compliance rates in this patient population. Conversely, potential incomplete ovarian suppression due to non-adherence with scheduled LHRH administration coupled with continued use of aromatase inhibitor therapy in a patient population considered at higher risk for recurrence also warrants careful consideration. Given these issues and taking into account the relative short follow-up in SOFT/TEXT, awaiting mature data from these two trials seems more cautious at this time.
2.4.3 Neoadjuvant Therapy
Data comparing the impact of neoadjuvant chemotherapy in younger compared to older patients are scarce. Evidence suggests that younger patients with TNBC seem to derive the more benefit from neoadjuvant chemotherapy with higher rates of pathologic complete response (pCR) reported in women <35 compared to older patients [100, 101]. However, a pooled neoadjuvant trial analysis did not find a difference in DFS according to age when patients achieved pCR to neoadjuvant chemotherapy. As such, age per se should not guide the use of neoadjuvant chemotherapy.
Similarly, limited data regarding the use of neoadjuvant hormonal therapy are available. Non-randomized studies and more recently a randomized double-blind Study of Tamoxifen or Arimidex, combined with Goserelin acetate, to compare Efficacy and safety (STAGE) trial have looked at ovarian ablation combined with an aromatase inhibitor in the neoadjuvant setting [102–104]. In STAGE, neoadjuvant goserelin combined with either tamoxifen or anastrazole for 24 weeks prior to definitive surgery was compared in premenopausal patients with T2N0M0 ER-positive breast cancer with the primary endpoint being best overall response (complete and partial response) assessed clinically [102]. Significantly higher clinical response rates (complete and partial) were seen with the aromatase inhibitor-LHRH combination (70 % vs. 50 %); however, no differences in pCR rates were noted between study arms. Interpretation of these findings and the applicability of neoadjuvant endocrine therapy in young patients in the absence of long-term outcome data are limited at this time.
2.4.4 Metastatic Breast Cancer
The choice of chemotherapy and HER2-targeted therapy is guided by the same principles irrespective of age [105]. There is also no evidence to suggest that combination cytotoxic chemotherapy in young patients with metastatic breast cancer offers survival or quality of life benefit over sequential monotherapy [106].
Options for endocrine therapy in metastatic breast cancer in premenopausal patients include single-agent tamoxifen and, unlike in the adjuvant setting, the combination of tamoxifen with an LHRH analog shown to offer survival advantage in this setting [107]. The combination of LHRH agonist with aromatase inhibitor has been evaluated in small studies either as first- or second-line therapy in the metastatic setting [108–114]. Very limited data are available on the use of fulvestrant and everolimus in premenopausal patients [115]. Therefore, they should not be currently considered: although there is no reason to think that they would not be as effective as in postmenopausal patients and is worthy of investigation in young patients.
2.5 Take-Home Messages
Management of young patients with breast cancer still poses challenge to clinicians with several questions unanswered at this time. Reconciling the divergent findings of neoadjuvant, adjuvant, and non-randomized studies in small node-negative HER2-positive or TNBC is needed to better understand the prognostic significance of younger age in these breast cancer subtypes. In ER-positive disease, better stratification of late relapse risk in young patients could help optimize the use of extended adjuvant hormonal therapy in this patient population. The role of ovarian ablation in the adjuvant setting in combination with tamoxifen or an aromatase inhibitor with or without prior adjuvant chemotherapy needs to be better defined and mature data from SOFT/TEXT should provide further insight into this matter. Exploiting the biology of ER-positive breast cancer in young patients to tailor adjuvant chemotherapy is also the subject of ongoing research. Evaluation of drugs such as everolimus with potential activity against deregulated molecular signaling associated with breast cancer in young patients may potentially lead to decreased indiscriminate cytotoxic chemotherapy use in this patient population. Correlating underlying tumor biology, treatment, and outcome in these studies will be important to design meaningful targeted therapy. The contribution of stromal signaling to carcinogenesis and tumor progression in young patients is increasingly being recognized and future research will also help determine the significance of stromal signaling and its influence of recurrence and outcome in younger patients.
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