The role of adjuvant systemic therapy in patients with operable breast cancer

Tamoxifen

Until recently, 5 years of tamoxifen was the standard adjuvant ET for both pre- and postmenopausal women. The results of an overview of tamoxifen trials involving around 21 000 women carried out by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) have shown that tamoxifen given for 5 years reduces the risk of death by around one-third (relative risk [RR] = 0.71 ± 0.07). The proportional reduction is not significantly affected by age, nodal status or use of chemotherapy. The absolute benefit relates to the absolute risk. The reduction in the risk of recurrence is seen both during the 5 years of treatment (RR = 0.53 ± 0.03) and extends into years 5–9 (RR = 0.70 ± 0.06). The benefits were similar and highly significant in both ER-positive/progesterone receptor (PR)-positive and ER-positive/PR-negative disease. The reduction was greater in strongly positive ER disease (RR = 0.51 ± 0.07) than in weakly ER-positive disease (RR = 0.65 ± 0.07).

These benefits have to be viewed in the light of side-effects, including vasomotor symptoms, and a small but significantly increased risk of developing uterine cancer and thromboembolism. Combined, these two conditions are associated with a 10-year mortality of 0.2%.

In 2013 the results of two trials looking at durations of tamoxifen of longer than 5 years were published. The Adjuvant Tamoxifen: Longer against Shorter (ATLAS) trial included 12 894 women who had completed 5 years of adjuvant tamoxifen. Patients were randomised to either continue tamoxifen for an additional 5 years or to stop endocrine treatment. Women completing 10 years of treatment had a significant reduction in risk of breast cancer recurrence and reduced breast cancer mortality and overall mortality. Importantly, a reduction in both recurrence and mortality rate were evident following 10 years of treatment, rather than during years 5–9 (recurrence rate ratio [RR] 0.90 [95% CI (95% CI) 0.79–1.02] during years 5–9 and 0.75 [0.62–0.90] in later years; breast cancer mortality RR 0.97 [0.79–1.18] during years 5–9 and 0.71 [0.58–0.88] in later years). This demonstrates a benefit with an additional 5 years of treatment as well as a possible carryover effect from the tamoxifen.

A similarly designed UK study, Adjuvant Tamoxifen: To offer More? (ATTOM) included 6953 women with ER-positive or unknown ER status breast cancer who were disease free after 5 years of tamoxifen. They were randomised to complete a total of 10 years of tamoxifen or to stop after 5 years. As with the ATLAS study, a similar benefit was demonstrated with 10 years of tamoxifen. There was a reduced rate of breast cancer recurrence ( P = .003) in a time-dependent manner; RR was 0.99 during years 5–6, 0.84 in years 7–9 and 0.75 later. Breast cancer mortality was also reduced ( P = .05). The common toxicities associated with tamoxifen were hot flushes, vaginal discharge, an increased risk of venous thromboembolism and endometrial cancer, but the absolute risk for the latter was less than 1%.

Tamoxifen has been the mainstay of adjuvant ET for premenopausal women for many years ( Table 14.1 ). However, there has also been a longstanding debate as to the potential benefit of ovarian function suppression (OFS). OFS can be achieved by LHRH (luteinising hormone-releasing hormone) agonists (such as goserelin), bilateral oophorectomy or (rarely) bilateral ovarian irradiation.

In 2003, the International Breast Cancer Study Group (IBCSG) initiated two randomised trials, SOFT (Suppression of Ovarian Function) and TEXT. Eligible patients were premenopausal women with ER-positive breast cancer who had undergone complete surgical excision of primary breast cancer, chemotherapy and radiotherapy where indicated. The SOFT prospective trial randomly assigned 3066 premenopausal women to receive either 5 years of tamoxifen, tamoxifen plus ovarian suppression (OFS) or exemestane and OFS. The 8-year disease-free survival (DFS) rates were 78.9%, 83.2% and 85.9%, for tamoxifen alone, tamoxifen and OFS and exemestane plus OFS, respectively ( P = 0.009 for tamoxifen alone vs tamoxifen plus ovarian suppression). The group of women who derived the greatest benefit were those who were under the age of 35 (94% of whom received chemotherapy).

The Tamoxifen and Exemestane Trial (TEXT) was designed to compare exemestane with tamoxifen, both with OFS, in premenopausal women with early hormone receptor-positive breast cancer. A total of 2660 premenopausal women were randomly assigned to receive exemestane plus OFS or tamoxifen plus OFS. A joint analysis was performed including both patients treated with these combinations in TEXT and the two identical arms from the SOFT trial. This analysis included 4960 patients and demonstrated an improvement in 8-year DFS for the exemestane–OFS group compared with the tamoxifen–OFS group (86.8% vs 82.8%, P < 0.001). In the combined analysis of SOFT and TEXT, after 9 years median follow-up, there was no significant difference in overall survival (OS) rate between the two groups.

In summary, ovarian suppression in combination with tamoxifen or exemestane should be considered for premenopausal patients with early breast cancer at sufficient risk of recurrence. However, the side-effects and impact on quality of life of this treatment should not be underestimated. Grade 3 or higher adverse events were reported in 32.3% of the patients receiving exemestane–OFS and 31.0% of those assigned to tamoxifen–OFS. Frequently reported events included hot flushes, musculoskeletal symptoms and hypertension. Grade 3 or 4 depression was reported in 4.1–4.6% of the patients, with over 90% of participants reporting the symptom at some level. Osteoporosis (T score <-2.5%) was more common in the exemestane–OFS group than in those receiving tamoxifen–OFS, 14.8% and 7.2%, respectively. Thromboembolic events, hot flushes and urinary incontinence were reported more often by patients receiving tamoxifen–OFS. Endometrial cancers occurred in nine patients having tamoxifen–OFS compared to four patients receiving exemestane–OFS.

Aromatase inhibitors: first-line therapy

The aromatase inhibitors (AIs) anastrozole and letrozole have each been shown to improve DFS compared with tamoxifen when given as first-line adjuvant therapy for a planned 5 years in postmenopausal women with hormone receptor-positive early breast cancer ( Fig. 14.1 ).

AIs are the treatment of choice in postmenopausal women as first-line ET. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial was the first study to directly compare tamoxifen with an AI. A total of 9366 postmenopausal women with early invasive breast cancer were randomised to receive either anastrozole, tamoxifen or a combination of both drugs for a total of 5 years after completion of their surgery and chemotherapy, where required. The 100-month analysis of the ATAC trial showed improved DFS (hazard ratio [HR] 0.85, P = 0.003), time to recurrence (HR 0.76, P = .0001), contralateral breast cancer rate (HR 0.6, P = 0.004) and distant recurrence rate (HR 0.84, P = .022) ( Table 14.2 ). The absolute differences in time to recurrence increased over time: 2.8% at 5 years and 4.8% at 9 years. Recurrence rates were also significantly lower on anastrazole than tamoxifen and remained low after completion (HR 0.75 [0.61–0.94], P = .01). However, there were higher fracture rates in patients receiving anastrazole, with an incidence rate ratio of 1.55 ( P < .0001) but the difference resolved once treatment was completed. There was no OS benefit.

The BIG1-98 trial enrolled 8010 postmenopausal women with ER-positive breast cancer, who were randomised to receive letrozole or tamoxifen alone for 5 years or a combination of either tamoxifen for 2 years followed by letrozole for 3 years or letrozole for 2 years followed by tamoxifen for 3 years. With a median follow-up period of 8.7 years, letrozole proved to be superior to tamoxifen and there with similar results seen as for the long-term follow-up from ATAC: DFS (HR 0.82, 95% confidence interval [CI] 074–0.92) and OS (HR 0.79, CI 0.69–0.90). The results of these two trials are summarised in Table 14.2 .

The two non-steroidal AIs were directly compared in the FACE trial which compared adjuvant letrozole with adjuvant anastrazole in 4136 postmenopausal women with node-positive early-stage breast cancer. There were no statistically significant differences in DFS or OS between the two AIs, meaning that based on efficacy criteria either agent can be chosen as superior to tamoxifen.

Comparative toxicities of first-line aromatase inhibitors and tamoxifen

The ATAC and BIG1-98 trials have both shown that tamoxifen is associated with a small but significant increase in the incidence of hot flushes compared with anastrozole or letrozole (4.5–5% increase), vaginal bleeding (3.3–3.7% increase), vaginal discharge (8.6% increase), endometrial cancer (0.2–0.4% increase) and venous thromboembolism (1.4–2% increase). The ATAC trial has likewise shown a small but significant increase in ischaemic cerebral vascular disease (1.1% increase) with tamoxifen compared with anastrozole, but this has not been confirmed in the BIG1-98 trial compared to letrozole. In contrast, anastrozole and letrozole have been shown to be associated with a statistically significant increase in the incidence of musculoskeletal problems (6.5–8% increase) and fractures (1.7–2.2% increase). When the two AIs were directly compared in the FACE trial, there were no significant differences in adverse event profile.

Of note, tamoxifen is associated with a significant increase in gynaecological surgery compared with either of the AIs. In the ATAC trial 5.1% of women had hysterectomies compared with 1.3% on anastrozole. In the BIG1-98 trial 288 women (9.1%) have required endometrial biopsies compared with 77 (2.3%) with letrozole.

It is therefore important that all women should be appropriately counselled about the side-effect and risks of adjuvant ET prior to embarking on treatment, and during treatment depending on emerging side-effects.

Sequential therapy with aromatase inhibitors after tamoxifen

When adjuvant AI studies were first initiated, there was considerable interest in trials assessing the benefit of sequential adjuvant AIs given 2–3 years after tamoxifen. For example, in the Intergroup Exemestane double-blind Study (IES), 4274 patients who had already been on tamoxifen for around 2 years were randomised to continue tamoxifen or to switch to exemestane to complete 5 years of treatment. Updated results with a median follow-up of 91 months have shown a significant reduction in the risk of relapse and an improvement in OS (HR 0.86, 95% CI 0.75–0.99) with the switch. Three other sequential trials involving anastrozole have shown similar results.

These results suggested the superiority of sequential switching and the possibility emerged that this might be superior to first-line AI therapy. Two trials have addressed this issue directly. Two of the arms in BIG1-98 compared tamoxifen for 2 years followed by a switch to letrozole with letrozole alone for 5 years and found no significant benefit of the switch compared with letrozole up front (8-year DFS 85.9% vs 87.5%). However, letrozole monotherapy was superior to tamoxifen followed by letrozole, particularly in controlling distant recurrences in patients at higher risk of relapse. Nonetheless, switching to tamoxifen after an initial 2 years of letrozole would seem to be a reasonable option for patients who require letrozole cessation for any reason.

Extended adjuvant therapy with aromatase inhibitors: beyond 5 years

The risk of recurrence of early breast cancer continues for at least 10 years after diagnosis and is greater in patients with hormone receptor-positive cancers. In the EBCTCG overview analysis more than half of breast cancer recurrences occur after 5 years.

A seminal trial, NCIC-CTG MA.17/BIG1-97, assessed the efficacy of 5 years of letrozole after 5 years of adjuvant tamoxifen. At a median follow-up of 2.4 years, patients receiving letrozole had a significant 43% reduction in the risk of recurrence ( P = 0.00008) and a non-significant reduction in all-cause mortality. Consequently, the trial was unblinded and patients on placebo were allowed to cross over to letrozole. Intent-to-treat analysis at 64 months’ follow-up showed a persistent 32% improvement in DFS despite 66% of patients on tamoxifen crossing over to letrozole ^. Further analysis has confirmed that patients initially assigned to receive letrozole had significantly better DFS (HR 0.52), distant DFS (HR 0.51) and better OS (HR 0.61), compared to control patients. Of note, amongst patients who were deemed premenopausal when starting tamoxifen and who subsequently became postmenopausal during treatment, the reduction in DFS events was 75% (HR 0.26, P = 0.03). These data demonstrate that the strategy to switch ET should be discussed for all premenopausal patients who become postmenopausal during tamoxifen treatment following appropriate consideration of side-effects in the context of their risk profile.

In two subsequent trials, extended adjuvant anastrozole (ABCSG-6a) and extended adjuvant exemestane (NSABP B-33), both after 5 years of tamoxifen, showed that extended therapy with an AI reduces the risk of recurrence significantly. ^,

The MA17R clinical trial assessed the efficacy of extending adjuvant AI therapy to 10 years. This trial randomised over 1900 postmenopausal women with hormone receptor-positive disease to receive either an additional 5 years of letrozole therapy or placebo, following 5 years of an AI. This study followed MA17 and so a proportion of women (approximately 68%) had initial treatment with 5 years of tamoxifen and 5 years of letrozole, before randomisation for further AI or placebo. The study demonstrated a benefit for extended treatment with an AI with an improvement in 5-year DFS: HR 0.66 (95% CI, 0.48–0.91) and a reduction in the annual incidence rate of contralateral breast cancer: HR 0.42 (95% CI 0.22–0.81). There was no difference in OS after a median follow-up of 6.3 years. Whilst statistically significant, the absolute benefits of treatment were small, given the relatively low rate of recurrences in the study population. Although the incidence of toxicities was similar in both groups, patients receiving letrozole had a significantly lower bone mineral density, compared to patients on placebo, with a greater number of women diagnosed with new-onset osteoporosis. Among 133 patients who were taking letrozole and who had a fracture, 56% were taking bisphosphonates and 90% were taking calcium supplements. There was no clinically significant difference in the quality of life scores in either group but the women who elected to participate in the trial are likely to have tolerated the initial 5 years of AI treatment, so are a selected population.

Other trials are continuing to address the question of extended AI therapy, including NSABP B-42 (5 vs 10 years letrozole) and the ABCG-16 Secondary Adjuvant Long-term Study with Arimidex (SALSA) comparing a further 2 years versus a further 5 years of adjuvant treatment with anastrozole after an initial 5 years of adjuvant ET. The NSABP B-42 trial randomised 3699 patients to receive letrozole or placebo, who were disease-free after 5 years of either AI or tamoxifen–AI for 5 years. After a median follow-up period of 9.3 years, this study demonstrated an improvement in DFS for letrozole vs placebo (HR 0.84, 95% CI 0.74–0.96; P = 0.011). The absolute improvement in rate of distant recurrence was 1.8% in the group receiving letrozole. Despite the difference in DFS, breast cancer-free interval and disease recurrence, there was no significant difference in OS between the two groups.

Taking the results of MA17R and NSABP B42 together suggests that the decision for prolonged therapy with an AI will largely depend on a number of factors, including the patient’s tolerability, quality of life, changes in bone mineral density and an individual risk assessment of (late) recurrence.

Other AI issues

AIs are contraindicated in premenopausal women. Therefore, caution must be observed when used in younger women following chemotherapy-induced amenorrhoea. In an audit carried out at the Royal Marsden Hospital, 12 of 45 younger women (27%), median age 47, treated with an AI following chemotherapy-induced amenorrhoea developed clinical or biochemical return of ovarian function (including up to the age of 53 years). AIs should therefore be used with great caution in this group of women, and ideally, serum oestradiol should be monitored using a high sensitivity assay.

Vaginal dryness, atrophy and dyspareunia are significant issues in women on AIs. In a small study, six of seven women given vaginal oestradiol (Vagifem®) while on an AI developed a significant rise in serum oestradiol from less than 5 pmol/L to a mean of 72 pmol/L (maximum 219 pmol/L) at 2 weeks. Therefore vaginal oestrogen preparations should generally not be used in women on AIs unless serum oestradiol levels can be monitored with a high-sensitivity assay. An alternative for women with particularly difficult symptoms may be switching from an AI to tamoxifen (acknowledging a small compromise in efficacy) under which circumstances vaginal oestrogens can be safely used.

See Table 14.3 for a summary of recommendations for adjuvant ET.