Advances in medical oncology, including several approaches for adjuvant treatment, have improved the prognosis of premenopausal patients with BC; however, young women with metastatic deposits in axillary nodes show a 10-year survival rate as low as 57.9% (17
). Ovarian ablation, among the oldest described methods for treating advanced BC (18
), has been confirmed by meta-analyses to be effective in the adjuvant treatment of premenopausal patients (19
). With the development of new cytotoxic drugs, enthusiasm for the use of chemotherapy has grown. The Early Breast Cancer Trialists’ Collaborative Group showed a highly significant benefit from chemotherapy compared with no chemotherapy in the adjuvant treatment of BC, especially for women of <50 years of age (21
). However, due to the poor results obtained in certain sets of patients (17
), the improvement of our knowledge and the need for less toxic treatments, the value of hormonal therapy has continued to grow.
The importance of oestrogens in BC development has been highlighted by several studies. The Nurses’ Health Study II evaluated 18,521 premenopausal women and showed that the highest follicular total and free E2 levels were associated with significantly increased BC risks (22
). Young age has been reported as an independent predictor of worse survival in patients with BC; this correlation may be correlated with higher levels of circulating oestrogens (23
), which activate an angiogenic switch promoting further tumour progression (24
Therefore, our primary objective was to decrease circulating oestrogens. Through administration of an LH-RH analogue, this goal was rapidly reached and maintained for five years.
Two weeks after LH-RH analogue administration, chemotherapy was started. All patients were initially treated with anthracyclines and taxanes, as this combination has been shown to improve the PFS and OS of high-risk early BC patients, independent of tumour and patient characteristics (25
). Subsequently, concurrent chemotherapy and radiation therapy were delivered over eight weeks, which is reportedly associated with a lower risk of local recurrence (39% decrease) in node-positive patients (26
). The sequential administration of LH-RH analogue and chemotherapy was designed to compensate for tumour heterogeneity; oestrogen deprivation may induce apoptosis on slowly proliferating cell clones that are not sensitive to chemotherapy (27
), while chemotherapy may be active in cellular clones that are rapidly proliferating.
VEGF is an important prognostic factor for PFS and OS in primary node-positive and node-negative BC, and it may be useful in predicting hormone unresponsiveness of ER+
). In addition, it has been shown that 70% of patients with advanced BC have high serum VEGF (31
). High plasma VEGF has been associated with progressive advanced-stage disease, and in several studies VEGF level changes were correlated with treatment response (8
Another action of VEGF is the increase in vascular permeability that may augment tumour cell extravasation and metastasis formation. Moreover, VEGF may be responsible for the decreased immune competence observed in advanced cancer, through the reduced maturation of dendritic cells that are important antigen-presenting cells (32
). For this reason, prolonged exposure of the immune system to high levels of VEGF may decrease immune response and, thus, facilitate tumour growth. Moreover, VEGF upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells (33
T-Regs are also associated with prognosis and progression in invasive and noninvasive BC, and are an independent molecular marker for BC clinical outcome (10
). Furthermore, the numbers of T-Regs were higher in patients with invasive ductal carcinomas compared with invasive lobular cancers (35
). Additionally, a positive correlation has been shown between FOXP3 and VEGF expression (36
Both of our primary endpoints were met: Statistically significant decreases in levels of VEGF and T-Regs were observed at four years.
The five-year PFS and OS rates were 93.4 and 98%, respectively. Although our study was a non-randomised phase II study, the patient accrual was consecutive for five years, with no selection bias. Only high-risk patients were accrued; 31 patients with lower risk were screened but not entered into the study (data not shown). In contrast to other studies, our protocol planned the administration of LH-RH analogues from the beginning of therapy and concurrent with chemotherapy, XRT. The analogue was administered to all patients, and chemotherapy was tailored to each patient’s characteristics. The ZEBRA adjuvant trial enrolled premenopausal patients with node-positive BC, similar to our population in age distribution and ER status, and randomised patients to CMF or LH-RH analogue (37
). ZEBRA patients randomised to CMF who were amenorrhoic at 36 weeks showed a significant improvement in PFS compared with those who were not, demonstrating that the endocrine effect of chemotherapy may be due to oestrogen deprivation, which was achieved in all patients in our study. A recent analysis of the National Surgical Adjuvant Breast and Bowel Project Protocol B-30 trial has revealed that amenorrhoea after chemotherapy was correlated with a substantial survival advantage (38
). In addition, another just published study has shown that persistence of menstruation after cytotoxic chemotherapy was a poor prognostic factor for disease-free survival in premenopausal patients with early BC (39
In conclusion we have shown that E2 deprivation with an LH-RH analogue, followed by tailored chemotherapy, radiation therapy and hormonal therapy in ER+ tumours, decreased plasma VEGF and T-Regs in premenopausal high-risk ER+ and ER− BC patients.