Extended adjuvant therapy for early stage breast cancer: Are there markers for its use?
The debate surrounding the duration adjuvant endocrine therapy for early stage hormone receptor positive breast cancer has not ended. While many studies have shown that 10 year duration of endocrine therapy improves outcomes as compared with 5 years of therapy, many of these therapies have significant long term negative side effect profiles. Given the negative side effect profile of both tamoxifen and aromatase inhibitors, and the fact that extending treatment improves disease free survival (DFS) but not overall survival (OS) extending the length of treatment from 5 10 years for all patients with ER positive breast cancer may not ideal. In this context, the study by T Murata et al "Clinicopathological features of hormone receptor positive breast cancer patients with late recurrence" provides valuable prognostic information on hormone receptor positive breast cancer risk of recurrence as well as its timing. These authors investigated the clinical and pathologic features of hormone receptor positive breast cancer with late recurrences to determine which groups of patients were at highest risk of late recurrence. Their goal was to determine subgroups of patients who are at the highest risk of late recurrence and therefore would gain the most benefit from extending endocrine therapy. A secondary aim of this study was to determine if aromatase inhibitors were superior to tamoxifen and if they were associated with lower rates of late recurrence. This single center retrospective cohort study included 454 Japanese hormone receptor positive patients who were treated between January 1989 and December 2003. Hormone receptor positive was defined as positive ER and/or PR status by enzyme immunoassay or Allred score. Patients HER2 status was not included in this study. Patients with bilateral breast cancer, DCIS, or de novo breast cancer were excluded. Patients were followed every 6 months from diagnosis for 10 years. Patients were on a variety of endocrine therapies including tamoxifen, toremifene, anastrozole, letrozole, exemestane, and goserelin. In a multivariate analysis, the study determined that high nodal involvement >4) was significant risk factor for late recurrence (P .001) Univariate analysis showed younger age, larger tumor size, and premenopausal status were also associated with late recurrence, although these factors were not significant in multivariate analysis. Factors not associated with late recurrence included 1 3 positive lymph nodes at initial diagnosis, nuclear grade, lymphovascular invasion, proportion of patients receiving chemotherapy (4 cycles anthracycline and/or 4 cycles taxanes) proportion of patients of patients receiving radiotherapy, and type of surgery (lumpectomy vs mastectomy) The authors mention that in data which is not shown in this study, nuclear grade was, in fact, a predictor of early recurrence. In postmenopausal women in this cohort, treatment with aromatase inhibitors resulted in longer DFS than tamoxifen (10 year DFS: 97.6% vs 89.7% P .0955) but this result was not statistically significant. Several issues in this study decrease its overall relatability to clinical practice. First, this is a relatively small single center retrospective cohort study, and a larger multicenter cohort would give more statistically robust conclusion. Second, Japanese breast cancer patients have different baseline comorbidities as well as different socioeconomic factors in comparison with other patient cohorts which influences prognosis and recurrence rates, and notably, this study did not account for patients' baseline comorbidities using the Charlson Comorbidity Index (CCI) in their multivariate analysis for risk factors for late recurrence. High CCI is a known risk factor associated with worse overall survival. Tumor biology may also differ in patients from different racial backgrounds, decreasing the applicability of this trial worldwide. Another limitation of this study was the manner in which hormone status was defined and analyzed. Hormone receptor positive was defined as positive if tumors were either ERand/or PR positive. Previous data have shown there is a prognostic difference between ER positive/PR negative diseases vs ER negative/PR positive disease vs ER positive/PR negative disease. The study also did not include Ki 67 labeling index or grade of ER and PR positivity. Previous data have shown weakly positive ER positive patients have worse prognosis and therefore are higher risk patients. Additionally, HER2 status was not included in this study. Currently, ASCO guidelines recommend adjuvant tamoxifen for 10 years in preor perimenopausal patients with HER2 positive disease given the concern that these women are at greater risk of late recurrence. However, Yamashita et al previously reported that in ER positive patients under the age of 60, HER2 negative status is a predictor of late recurrence. Despite these limitations, it would be reasonable to consider extending length of endocrine therapy for ER positive women with 4 or greater lymph nodes involved at initial breast cancer diagnosis. Clinicians still need to have an in depth discussion on both the risks and benefits of extended endocrine therapy with each patient as part of shared decision making. In this study, factors not associated with late recurrence included 1 3 positive lymph nodes at initial diagnosis, nuclear grade, lymphovascular invasion, proportion of patients receiving chemotherapy (4 cycles anthracycline and/or 4 cycles taxanes) proportion of patients of patients receiving radiotherapy, and type of surgery (lumpectomy vs mastectomy) These Received: 6 March 2018 Accepted: 6 March 2018 DOI: 10.1111/tbj.13038
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