Hormone receptor low-positive (1–10%) cancers are rare, and the survival benefit of adjuvant endocrine therapy in these cancers is controversial. In this retrospective longitudinal follow-up study of 448 women with hormone receptor low-positive primary invasive breast cancer, the DFS and OS for women who received and did not receive adjuvant endocrine therapy were not significantly different in the propensity score-weighted log-rank test (P = 0.40, DFS; P = 0.45, OS) and Cox proportional regression analysis (HR, 0.8; P = 0.42 for DFS and HR, 1.3, P = 0.48 for OS). The survival benefit of adjuvant endocrine therapy was observed in the subgroup of women who did not receive adjuvant radiation therapy (HR, 0.5; P = 0.04 for DFS and HR, 0.4; P = 0.046 for OS). AJCC clinical stage III, positive BRCA1/2 genetic test, absence of pretreatment breast MRI, and not receiving adjuvant radiation therapy or chemotherapy were independent factors associated with worse DFS and/or OS in women with hormone receptor low-positive breast cancer.
Few studies have compared the survival outcomes of hormone receptor low-positive breast cancer with or without adjuvant endocrine therapy. A recent systematic review and meta-analysis of 6 studies consisting of 16,606 patients (ER < 1%, 4,176 patients; ER 1–9%, 834 patients; ER ≥ 10%, 11,596 patients) revealed that primary breast cancer patients with ER-low-positive (1–9%) expression had no survival benefit from endocrine therapy but manifested overall better prognosis than those with ER negative (< 1%) cancer [10]. Most previous studies have compared the survival outcomes of patients with hormone receptor low-positive breast cancer who received adjuvant endocrine therapy versus those with hormone receptor negative (< 1%) or high-positive (> 10%) cancers who received adjuvant endocrine therapy [4, 7, 9, 13–15]. The strength of our study is that we directly compared the survival outcomes of patients who did and did not receive adjuvant endocrine therapy and used propensity score weighting to balance the background characteristics between the two groups. Propensity score weighting is an effective way to reduce or eliminate systematic differences between observational and treatment groups to a comparable degree and allows a nonrandomized study to mimic a randomized controlled trial [23, 24].
The 2010 ASCO/CAP Guidelines Update is based on studies showing the potential benefits of endocrine therapy in patients with as little as 1% ER or PR expression [5]. Although this increases the chances of patients being treated with less toxic endocrine therapies, the side effects of anti-estrogen therapy cannot be ignored. The side effects of tamoxifen include vasomotor symptoms, gynecologic symptoms, sexual dysfunction, and increased rates of endometrial cancer, stroke, pulmonary embolism and deep vein thrombosis; aromatase inhibitors are associated with increased risk of osteopenia, osteoporosis, and fractures [25, 26]. According to our study results, it may be possible to selectively consider or omit adjuvant endocrine therapy in a specific subgroup of patients based on clinical and pathologic factors. For instance, adjuvant endocrine therapy may be considered in patients not planning to receive adjuvant radiation therapy and may be omitted in patients with low (≤ 14%) Ki-67 expression in breast cancer who are planning breast-conserving surgery and adjuvant radiation therapy, if our study results are validated in future prospective multi-institution studies. Analysis of molecular signatures in breast cancer with hormone receptor low-positive expression by IHC is another possible way to identify subgroups that may benefit from adjuvant endocrine therapy. Iwamoto et al [7] showed that a significant proportion of ER-low-positive tumors possess ER-negative molecular characteristics based on the quantitative estimation of ER mRNA and ER-related gene transcripts. In addition, as the landscape of adjuvant therapy is rapidly changing, research on new treatments for hormone receptor low-positive breast cancer is needed [27–29].
Our study has several limitations. First, it was a retrospective study performed at a single institution. Second, hormone receptor low-positive breast cancers were selected through a retrospective pathology review of IHC slides prior to June 2009, and there may be selection bias because cases without available pathology slides could not be reviewed. Third, although the patient cohorts in this analysis were well balanced in terms of measured confounders that could have influenced the treatment choice and patient outcome, unmeasured confounders still represent a source of bias. Lastly, adherence to adjuvant endocrine therapy and duration of administration were not considered, and whether adjuvant endocrine therapy was administered was based on the prescription in the medical records.
In conclusion, we found that adjuvant endocrine therapy was not associated with a survival benefit in our study cohort of women with hormone receptor low-positive primary invasive breast cancer. However, our study has shown the potential to select subgroups with a survival benefit from adjuvant endocrine therapy based on clinical and pathological factors. Prospective studies with a longer follow-up and larger sample sizes are needed to validate our findings and optimize treatment strategies in patients with hormone receptor low-positive breast cancer.