ER plays an important role in the signaling pathway for breast cancer carcinogenesis and disease expression.13 Hormonal therapy targeting ER including selective estrogen receptor modulators, aromatase inhibitors, ER down-regulators, and ovarian suppression has led to significant improvement in the clinical outcome of breast cancer treatment.7 ER+ tumors show excellent response to hormonal therapy, and therapeutic effect depends on the proportion of ER expression.14,15 In contrast, ER− tumors show no response to hormonal therapy; however, these tumors respond relatively better to chemotherapy compared to ER+ tumors.16 Therefore, it is critical to set an optimal cutoff point for ER positivity to properly select patients eligible for individualized treatment options.17
In 2010, the cutoff value for ER positivity was lowered to 1% from 10% by the ASCO/CAP guideline update.18 Although the currently accepted cutoff is 1%, multiple studies have since reported that ERlow tumors with ER expression less than 10% show characteristics closer to ER− tumors, including questionable response to hormonal therapy.10–12 The latest recommendation of the ASCO/CAP guideline to report these tumors separately as ER Low Positive reflects this concern. If ERlow breast cancer is indeed a distinct disease subtype closer to ER−, ERlow patients currently classified as ER+ will not only receive unnecessary hormonal treatment with potential side effects, but they might also fail to receive chemotherapy that is needed.17
Several studies have addressed the clinicopathological features of ERlow tumors. Compared to ERhigh, ERlow breast cancer is associated with younger age, advanced stage, larger tumor size, higher HER2 expression, and lower PR expression.19,20 When morphologically analyzed, ERlow tumors exhibit features previously described for basal-like and triple-negative tumors, including higher grade, higher proliferation index, sheet-like growth pattern, intratumoral lymphocytic inflammatory infiltrate, and necrosis.12 In our current study, we focused specifically on early stage breast cancer, a novel approach not presented in previous literature. ERlow tumors showed higher grade, positive HER2, negative PR, and higher proliferation index compared to ERhigh tumors, which was consistent with previous studies. Age at diagnosis showed no statistically significant difference between ERlow and ERhigh groups, and tumor size was smallest in the ERlow group compared to both ERhigh and ER− patients. Detailed morphological analysis was not performed in this study. Patients with ERhigh tumors were more likely to receive hormonal therapy compared to ERlow and ER− groups; in contrast, a significantly small proportion of ERhigh patients received chemotherapy in comparison to their ERlow or ER− counterparts. This result was in concordance with previous literature.17,19,20
Although limited data is available on the survival outcome of ERlow breast cancer, a few previous studies showed that ERlow patients exhibit significantly worse disease-free and overall survival rates compared to ERhigh patients, but similar to those who are ER−.11,21,22 In the current study, the ERlow group had a slight, but not statistically significant, survival benefit over the ER− group. At the same time, ERlow tumors showed worse prognosis compared to ERhigh tumors, yet also with no statistical significance. Recurrence rate showed a proportional decrease with ER expression level. In multivariate regression analysis, we failed to prove the effect of ER expression level on recurrence. This study was confined to DCIS and stage 1 IDC, and the overall recurrence rate was low. It is possible that the low proportion of recurrent cases hindered to show a clear difference between ER subgroups. Future prospective studies with larger cohorts might validate the difference in survival outcome between ERlow and ERhigh groups.
Most breast cancers exhibit either strong ER expression or its complete absence, and the number of patients in the ERlow subgroup is limited.23 Therefore, prospective data on the endocrine responsiveness of ERlow tumors is scarce.19 Yet many retrospective studies have suggested that primary breast cancer patients with low ER expression might not benefit significantly from hormonal therapy.17 Viale et al.21 compared disease-free and overall survival of ERlow and ER− groups and reported that hormonal therapy had no effect on survival outcomes. In HER2-negative stage II/III breast cancer, ERlow tumors showed limited benefit from hormonal therapy and better response to neoadjuvant chemotherapy.24 In our current study, we found that hormonal therapy had no effect on recurrence in ERlow patients; on the contrary, ERhigh patients showed clear endocrine responsiveness. This suggests that hormonal therapy might have limited apparent benefit in early stage ERlow breast cancer.
ER+ tumors have been subjected to multigene assays to identify more aggressive types that are expected to benefit from additional chemotherapy.12 Our study sheds light on the possibility that early stage ERlow breast cancer might be a high risk subtype and potential candidate for chemotherapy. It is suggested that treatment options for ER− tumors may be appropriate for some ERlow tumors; however, endocrine responsiveness of primary breast cancer patients with low ER expression needs to be further explored in prospective studies.20
This study has certain limitations. First, the study was limited by its retrospective design, and treatment options were not assigned in a randomized manner. Second, although the current study was performed on a large cohort, the sample size of the ERlow group was relatively small. It is known that majority of breast cancers show either completely absent or strongly positive ER staining, and tumors with low ER expression are rare. Future studies with larger study populations could possibly overcome this limitation and provide more information on ERlow tumors.
In conclusion, ERlow breast cancer shows distinct clinicopathological features compared to ERhigh and ER− types. ERlow tumors seem to have higher recurrence rates compared to ERhigh tumors, although future large scale prospective studies are necessary. Similar to patients with ER− tumors, those with ERlow tumors do not appear to benefit from hormonal therapy. Treatment options for ERlow breast cancer should be reconsidered, including omission of hormonal therapy and addition of adjuvant chemotherapy.