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- Patients and Methods
- Disclosure Statement
The present study examined long-term efficacy outcomes in a subgroup of postmenopausal, estrogen receptor-positive Japanese breast cancer patients from the Pre-Operative “Arimidex” Compared with Tamoxifen trial, following pre-operative (3 months) and post-operative (5 years) adjuvant treatment with either anastrozole or tamoxifen. Patients with large, potentially operable, locally-advanced breast cancer were randomized to receive anastrozole (1 mg/day) plus tamoxifen placebo or tamoxifen (20 mg/day) plus anastrozole placebo pre-operatively. After surgery at 3 months, patients continued on the same study medication as adjuvant therapy for up to 5 years or until recurrence, intolerable toxicity or withdrawal of patient consent. Recurrence-free survival and overall survival were measured from the date of randomization to the date of recurrence or death, whichever occurred first. Patients were monitored for adverse events throughout the study period and up to 30 days following administration of the last study medication. During post-operative adjuvant therapy, 4/48 (8%) anastrozole and 25/49 (51%) tamoxifen patients experienced recurrence. There was a significant difference in recurrence-free survival between the two groups (hazard ratio 0.14; 95% confidence interval 0.05–0.41; P = 0.0003). There was a significant increase in overall survival with anastrozole (0.21; 0.05–0.96; P = 0.0436) and there were 2/48 (4%) and 10/49 (20%) deaths with anastrozole and tamoxifen, respectively. Most patients responding to pre-operative therapy remained recurrence-free. Sequential pre-operative/post-operative treatment with anastrozole resulted in lower recurrence and death rates, compared with tamoxifen. (Cancer Sci 2012; 103: 491–496)
Although several pre-operative trials comparing hormonal therapy with an aromatase inhibitor (AI) versus tamoxifen have reported the superior efficacy of AI in terms of primary tumor response, long-term follow-up outcomes from pre-operative and subsequent post-operative therapy have rarely been reported.(1–5) For instance, in the P024 neoadjuvant endocrine therapy trial, which compared 4 months’ pre-operative letrozole versus tamoxifen, patients were treated with post-operative tamoxifen only, regardless of the randomized pre-operative treatment received.(6) Thus, it was not possible to evaluate the impact of a pre-operative and subsequent post-operative AI over tamoxifen on prognosis.
The Pre-Operative Arimidex Compared with Tamoxifen (PROACT) trial was a randomized, double-blind, double-dummy, multicenter study, conducted in the USA (12 centers), in Europe and the rest of the world (44 centers) and in Japan (25 centers) that compared anastrozole versus tamoxifen as pre-operative (12 weeks’ treatment prior to primary surgery), in terms of objective response (OR), and subsequent post-operative (adjuvant) treatments in 451 postmenopausal women with large, operable, or potentially operable, locally-advanced, hormone receptor-positive (HR+) breast cancer. PROACT demonstrated that anastrozole was at least as effective as tamoxifen in the pre-operative phase, in terms of primary tumor response rate (40% vs 35% for the anastrozole and tamoxifen treatment groups, respectively), and more patients in the anastrozole group showed an improvement between feasible surgery at the baseline and actual surgery compared with those in the tamoxifen group. The effect of ethnicity on the response to treatment was also investigated and Japanese centers were included to provide a cohort of non-white patients. There were no specific treatment–ethnicity interactions, with respect to OR, between the Japanese patients and the rest of the population.(7) In the post-operative phase, PROACT was planned to continue for 5 years to investigate the long-term efficacy of anastrozole and tamoxifen in terms of recurrence-free survival (RFS: the time interval between randomization and disease recurrence or death, whichever occurred first) and overall survival (OS). However, when PROACT reached a median follow up of 3.8 years in the blinded phase, the study was unblinded and closed because the Arimidex, Tamoxifen, Alone and in Combination (ATAC) trial showed superior efficacy for anastrozole compared with tamoxifen in the post-operative adjuvant setting.(8) Furthermore, the combined analysis of data from two other prospective trials demonstrated the benefit of switching from adjuvant tamoxifen therapy to anastrozole after 2 years of treatment.(9)
In Japan, however, the PROACT study continued for a further 1.2 years, to meet regulatory commitments, stressing the importance of collecting data for anastrozole during post-operative adjuvant use in Japanese women with HR+ early breast cancer. At unblinding, the Japanese PROACT patients had the option to re-consent and receive either anastrozole or tamoxifen on an open-label basis, thus allowing them to complete a total of 5 years’ follow-up.
This analysis reports the long-term outcomes for this subgroup of Japanese patients from PROACT who received anastrozole or tamoxifen as pre-operative and subsequent post-operative adjuvant treatment.
- Top of page
- Patients and Methods
- Disclosure Statement
While the superiority of the AI (including anastrozole and letrozole) over tamoxifen is well established in the post-operative adjuvant setting, the efficacy of the AI over tamoxifen given as pre-operative and subsequent post-operative treatments has yet to be reported. We believe that this is the first randomized study to make such a comparison. At 5 years’ follow-up in Japanese patients, we found that in the anastrozole group, 92% of patients were free from recurrence and 96% of patients were still alive. In the tamoxifen group, 49% of patients were free from recurrence and 80% of patients were still alive after 5 years. Thus, patients treated with anastrozole had significantly lower risk of disease recurrence and death than those treated with tamoxifen.
Unexpectedly, the difference in RFS between anastrozole and tamoxifen was substantial, and a significant difference in OS was also observed. The reduction in RFS (HR 0.14, 95% CI 0.05–0.41; P = 0.0003) with anastrozole versus tamoxifen observed in this study was much greater than that in the ATAC trial at 5 years’ follow-up (HR 0.87, 95% CI 0.78–0.97; P = 0.01).(8) Furthermore, no significant difference in OS was reported in the ATAC trial between anastrozole and tamoxifen.(8) The latest analysis of ATAC data (at a 10-year median follow up) has confirmed a significant difference for anastrozole versus tamoxifen in RFS (HR 0.91, 95% CI 0.83–0.99; P = 0.04) in the overall population, but no significant differences in OS (HR 0.97, 95% CI 0.88–1.08; P = 0.6).(12)
The reason why the efficacy of anastrozole was so great in this long-term follow up for a cohort of Japanese patients from the PROACT trial is unclear. One potential suggestion is that a number of patients were not included in the adjuvant treatment phase who did not respond to neoadjuvant treatment (5/48 patients in the anastrozole group and 6/49 patients in the tamoxifen group). It is possible that this extra level of selection or censorship might, therefore, have led to a slightly higher OS and RFS rate compared with the ATAC trial. Another possible explanation lies in the difference in the proportion of patients with CYP2D6 genotypes of decreased or no activity between Asians (approximately 30%) and white people (approximately 10%),(13) because recently these genotypes have been shown to be associated with a poor response to tamoxifen,(14–16) although such an association remains to be established.(17)
In this study, twice as many tamoxifen patients received concomitant chemotherapy and more tamoxifen patients were ER+/PgR− or ER−/PgR+, compared with anastrozole patients. In general, concomitant chemotherapy would be expected to improve clinical response. In the main PROACT study, in both treatment arms, OR rates were numerically higher for patients who received both endocrine and chemotherapy compared with patients who received endocrine therapy alone, indicating that concomitant chemotherapy improves response.(7) Therefore, the greater use of concomitant chemotherapy in the tamoxifen arm of the Japanese cohort would be expected to improve response compared with the anastrozole arm, which, if anything, would underestimate the effect of anastrozole. These HR imbalances between the two groups could have had a bearing on the RFS and OS results. However, an adjusted Cox regression analysis was not performed due to the small patient population. Because the PROACT study design did not include a comparison of Japanese versus matched non-Japanese data, we must emphasize that the RFS and OS benefits with anastrozole observed in this post-hoc analysis might only apply to the subgroup of Japanese patients examined in this study.
Of the patients who responded to pre-operative treatment with anastrozole or tamoxifen, the majority remained recurrence-free; that is DFS appeared to be similar between the anastrozole (88%) and tamoxifen groups (79%). However, among patients who had stable disease in the pre-operative phase, DFS in the tamoxifen group (50%) was much worse than for the anastrozole group (100%). In the results of the National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27, pathological response, rather than clinical objective response to pre-operative chemotherapy, was significantly correlated with treatment outcome in terms of RFS and OS.(18,19) We have previously reported the results of a comparison of objective clinical responses versus histopathological tumor responses in the same cohort of Japanese patients from PROACT.(11) Although the objective clinical response rate (according to RECIST assessed by ultrasound) in the pre-operative phase was similar for anastrozole versus tamoxifen (40% and 33%, respectively; Table 2), the difference in the histopathological response rate (i.e. a degenerative change in one-third or more of constituent carcinoma cells, according to Pathological Response Criteria for Breast Cancer as defined by the Japanese Breast Cancer Society)(10) was numerically greater (35% vs 12%, respectively), although there was no pathological complete response in either treatment arm.(11) This difference in histopathological response between the two groups might reflect the effectiveness of the post-operative treatment. The superiority of the AI over tamoxifen in the pre-operative and post-operative settings has also been corroborated in previous studies comparing letrozole versus tamoxifen, in which letrozole has led to statistically significant improvements in overall response and breast-conserving surgery in the pre-operative setting(1,20) and fewer early relapses in the post-operative setting, although OS was not significantly different to tamoxifen.(21) In this study, the safety profiles of anastrozole and tamoxifen for a Japanese patient cohort were similar and consistent with those observed in previous studies.(5,8)
In conclusion, this long-term follow up of the PROACT study has shown that pre-operative and subsequent post-operative adjuvant therapy with anastrozole might lead to a lower recurrence and death rate compared to tamoxifen in a Japanese patient subgroup. Because this study started in 2000, it was not possible to further classify the participating patients into luminal type A or B categories, or to determine their human epidermal growth factor receptor 2 or Ki67 status. Nonetheless, the results from this trial suggest that sequential pre-operative and post-operative anastrozole treatment is a suitable treatment strategy for HR+ postmenopausal breast cancer patients, in particular those with relatively large tumors and lower-risk oncotype profiles. Further research involving a greater number of patients is needed to confirm our present observations, particularly in relation to any confounding factors such as concomitant chemotherapy.