Aromatase inhibitors reduce risk of breast cancer recurrence compared with tamoxifen in pre-menopause

18th February 2022

Aromatase inhibitors are better than tamoxifen at reducing the subsequent risk of breast cancer recurrence in premenopausal women

Using aromatase inhibitors reduces the risk of breast cancer recurrence in premenopausal women with ovarian suppression to a greater extent than tamoxifen. This was the key finding of a meta-analysis of individual patient data from randomised trials undertaken by a team from the Early Breast Cancer Trialists’ Collaborative Group, based in Oxford, UK.

An analysis of 20 trials with over 21,000 women in 2011 concluded that 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. Moreover, aromatase inhibitors such as anastrozole, exemestane or letrozole, which block the conversion of androgens into oestrogens, have been found to reduce recurrence rates of breast cancer by about 30% compared with tamoxifen in postmenopausal women.

However, whether this class of drugs can benefit premenopausal women with early-stage oestrogen receptor positive breast cancer and ovarian suppression is unclear.

For the present study, the team undertook a meta-analysis of individual patient data from randomised trials in which an aromatase inhibitor was compared with tamoxifen for between 3 and 5 years in premenopausal women and who were receiving ovarian suppression with goserelin, triptorelin or ablation.

Data were collected on patient’s baseline characteristics including age, use of chemotherapy, body mass index, tumour grade, involvement of lymph nodes etc. They set the primary outcome as recurrence of invasive breast cancer, breast cancer mortality, death but without cancer recurrence and all-cause mortality. In addition, they set pre-specified investigations for any recurrence, distant recurrence and mortality during years, 0 – 1, 2 – 4, 5 – 9 and greater than 10 years.

Aromatase inhibitors and breast cancer recurrence

The analysis included data from 7230 premenopausal women with oestrogen-receptor positive tumours.

Among these women, 888 (12.6%) experienced a breast cancer recurrence and 418 (5.9%) deaths occurred of which 54 were unrelated to breast cancer. When compared to women receiving tamoxifen, use of aromatase inhibitors led to a significant reduction in the rate of breast cancer recurrence (ratio ratio, RR = 0.79, 95% CI 0.69 – 0.90, p = 0.0005).

Interestingly, the main benefit from aromatase inhibitors on the risk of recurrence was only seen in year 0 – 4 of follow-up (RR = 0.68, 95% CI 0.55 – 0.85, p < 0.0001). Between years 5 – 9, there was no further benefit (RR = 0.98, 95% CI 0.73 – 1.33, p = 0.89).

The authors calculated the 5-year absolute risk of breast cancer recurrence to be 3.2% which was lower for aromatase inhibitors compared to tamoxifen (6.9% vs 10.1%). There was also a significant reduction in the risk of distant recurrence with aromatase inhibitors (RR = 0.83, p = 0.018) compared to tamoxifen but again this benefit was lost over time.

There was no difference in the risk of breast cancer mortality compared to tamoxifen (RR = 1.01, 95% CI 0.82 – 1.24, p = 0.94), death without recurrence (RR = 1.30, 95% CI 0.75 – 2.25, p = 0.34) and all-cause mortality (RR = 1.04, 95% CI 0.86 – 1.27, p = 0.68). Interestingly, women experienced a higher incidence of fractures with aromatase inhibitors (6.4% vs 5.1%).

The authors concluded that compared to tamoxifen, use of an aromatase inhibitor, reduced the absolute risk of breast cancer recurrence by 3% at 5 and 10 years. They also called for future studies to examine the effect of endocrine therapy and ovarian suppression on women’s quality of life alongside the reduced risk of breast cancer recurrence.

Citation
Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials Lancet Oncol 2022

Use of tamoxifen and tumour size best predictors of long-term survival in breast cancer

9th July 2021

An analysis of breast cancer trial data suggests that tumour size and use of tamoxifen are both associated with greater long-term survival.

Breast cancer is the most common cancer in women worldwide and in 2020, there were 2.2 million cases and nearly 685,000 deaths. Breast cancer is a heterogenous disease with various types and different sensitivities to treatment, e.g., oestrogen receptor (ER) positive, progesterone receptor (PR) positive and hormone receptor (HR) negative. Among those with ER positive tumours, treatment with adjunctive therapy such as tamoxifen for five years is recommended. Nevertheless, even after treatment with tamoxifen, breast cancer can return over the intervening years, metastasise and lead to death. The use of clinical breast cancer markers such as tumour size or grade can be used to provide estimates of survival for up to 10 years and both increased tumour size and grade are associated with a reduced short-term survival. However, what is far less clear, is whether any of these markers are associated with longer term survival.

Given that both ER-positive and ERBB2-negative (i.e., HER2) disease are associated with a continuous risk of recurrent disease after the primary diagnosis, a team from the Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden, sought to determine whether both clinically used markers and treatment with tamoxifen were associated with long-term survival in patients with breast cancer. The team turned to data from the Stockholm tamoxifen (STO-3) trial, which enrolled postmenopausal women with lymph-node negative breast cancer and tumours less than 30mm in diameter, between 1976 and 1990 and who were randomised to tamoxifen 40mg daily or no endocrine therapy. In 1983, women with no recurrence after 2 years on tamoxifen, were given the drug for a further 3 years. The team undertook an analysis of tissue samples that were available from patients in the study. The tumour grade (1 to 3) had been assessed in 2014 by a pathologist and tumour size was categorised as T1a/b if 10mm or less, T1c if 11–20mm and T2 if larger than 20mm. All patients had a unique national registration number and which was linked with a cancer registry, allowing the team to obtain long-term follow-up data after 25 years.

Findings
The sample contained 565 postmenopausal women with a mean age of 62 years. Just over half (52.2%) of tumours were graded as T1c and nearly a third (30%), T1a/b. Patients with T1a/b tumours had the best long-term survival (88%) compared to those with T1c tumours (76%) or T2 tumours (63%). Similarly, the highest level of survival (81%) occurred in those with grade 1 tumours compared with grade 3 tumours (65%). Using this data, the team estimated a 69% reduced risk of disease recurrence for those with T1a/b sized tumours (hazard ratio, HR = 0.31, 95% CI 0.17–55). In terms of treatment, those given tamoxifen with grade 1–2 tumours also experienced a significantly reduced risk of disease recurrence (HR = 0.24, 95% CI 0.07 – 0.82) compared with those who did receive the drug. However, use of tamoxifen also produced a significant survival benefit in those with T2 tumours (HR = 0.34).

The authors concluded that tumour size, followed by grade and use of tamoxifen were independently associated with long-term survival in breast cancer.

Citation
Dar H et al. Assessment of 25-Year Survival of Women with Oestrogen Receptor–Positive/ERBB2-Negative Breast Cancer Treated with and Without Tamoxifen Therapy. A Secondary Analysis of Data from the Stockholm Tamoxifen Randomised Clinical Trial. JAMA Netw Open 2021.