One of the main issues when using NET is the appropriate selection of patients. As is the case with endocrine adjuvant therapy (ET), NET should be considered for luminal-like tumors; however, although ET is recommended for tumors with even low ER levels,[10, 26] NET is normally used only with high ER expression tumors, since most trials have achieved better results in these cases.[28, 29] In our cohort, all 115 tumors had a diffuse ER expression, which could explain the high response rate we found. PR expression and/or Ki67 levels can also influence NET outcomes.[30] As a result, many authors recommend NET only for luminal A-like tumors, because initially low PR expression or high Ki67 levels (i.e. luminal B-like features) have been associated with a poorer response[29, 31]. However, we included in our study both luminal A- and luminal B-like tumors, and we did not find significant differences between them with regard to clinical-biological response or BCS rates, which could mean that NET may be a good approach even in those cases. HER2 overexpression or high histologic grade usually discourages the use of NET.[29, 31] Although a few studies (IMPACT, P024)[4, 6] included small subpopulations of HER2 positive, reporting over 50% of clinical response, we excluded ER+/HER2+ patients from our study. A higher histologic grade is considered a poor prognostic factor; consequently, many of these tumors are eligible for chemotherapy. Nevertheless, in our study we observed a decrease in Ki67 levels, as well as in size, in most of these G3 cases. Additionally, up to 80% of these tumors changed to an intermediate grade after four weeks of treatment, although some of them were classified again as G3 in the surgical sample. It is difficult to know why a few of these tumors initially modify their histologic grade and, later, go back to a higher grade, although sampling bias or a limited amount of tissue in the core biopsy could explain these findings. In any case, all these observations could imply that these types of tumor, in well-selected cases, may benefit from NET.
NET duration is usually established at 3 to 6 months, based on the regular duration of NCT, although the optimal period for this therapy has not yet been clearly determined. Several trials have been conducted to establish an optimal duration.[32–34] Most of them found that a prolongation of NET produced extra benefits, such as higher pCR rates or axillary downstaging,[35, 36] although good responses and BCS rates can be achieved with a NET duration of six months or less.[3] The mean duration in our cohort was five months, becoming longer as we got more comfortable with NET implementation, and at all times it was conditioned in light of the response, either a decrease in Ki67 proliferation rates or clinical-radiological changes.
As mentioned above, NET provides an opportunity for assessing the in vivo response of ER+ breast cancers. In our cohort, significant downgrading changes were observed with regard to Ki67 levels, size, histological grade, and PR expression. Ki67 is a nuclear antigen expressed in proliferating tissues and is considered a surrogate marker of cell proliferation. Reduction in Ki67 proliferation rate has been identified only a few days from the initiation of NET.[6, 19] We found a significant decline in Ki67 expression after four weeks, and this was usually maintained throughout treatment, although in a few cases its value increased. The changes that appear in the Ki67 proliferation rate with NET constitute a biomarker with prognostic and predictive power, much more precisely related to long-term results than baseline Ki67.[17, 19, 20, 25] As demonstrated in the POETIC trial, patients with initially low Ki67 levels, or low postaromatase inhibitor-induced Ki67 proliferation rates, probably do well enough with standard endocrine therapy, whereas those with high Ki67 scores might need further adjuvant treatments.[19] A Ki67 >10% after two to four weeks of endocrine therapy has been suggested as a cutoff for early identification of nonresponders with increased risk of relapse.[20] Like other authors in various trials,[37, 38] we consider a Ki67 >10% after four weeks to be an indicator of innate endocrine resistance and, therefore, a criterion for withdrawing NET. For most of the patients who did not lower their Ki67 proliferation rates, surgery was then indicated.
Most of the tumors in our cohort were T2. Maximum tumor diameter was reduced by 40%, which probably indicates a much larger volume decrease. This enabled BCS to be performed on over 85% of the patients, these being numbers that are hardly possible in average conditions [39] and slightly larger than other likely figures for BCS reported after NET,[40, 41] although they may be explained by a mean tumor size that was not excessively large. Downstaging in the axilla was not achieved, since all cN1 tumors were at least pN1 and some cN0 tumors were pN1 after NET. In our cohort, ultrasound FNR was close to 25%, which is consistent with rates published by other authors who find higher FNR in luminal tumors.[42–46] On the other hand, axillary downstaging with NET is rather uncommon, with nodal pCR rates ranging from 1.3%-3.0%, at least when it is applied over short periods (<6 months),[35, 36, 47] as happened with most of our patients. As pointed out by both Hammond and Rusz et al., these numbers could be increased with longer periods of NET.[37, 48] Axillary management after NET is not well defined in clinical guidelines. Most surgeons seem to apply the same criteria to NET as they do to NCT,[49] but the context of NCT (mainly because it is usually indicated for high-risk tumors) does not seem applicable to NET, since any low-burden disease left in the axilla may not significantly impact the prognosis.[50] Kantor et al. analyzed the type of axillary surgery and residual nodal disease burden after NET in over 6,500 patients, finding limited axillary disease (ypN1) in more than 90% of the cases. [50] In the study published by Weiss et al. including stage II-III ER+/HER2- patients, those receiving NET (2,138) were more likely to be managed with an SLNB than those treated with NCT.[51] Based on this, we consider that Z0011 criteria for avoiding axillary dissection can be safely applied to these patients, as they can to those who go through upfront surgery. Therefore, only a small percentage of patients in our cohort needed an axillary dissection, and an SLNB was feasible in most cases.
In luminal-like breast cancers, pCR is infrequent with both NET and NCT. In the meta-analysis published by Spring et al., pCR rates were <10% in both the NCT and the NET arms.[52] In any case, the absence of pCR does not impact survival as much as happens with triple negative or HER2+ tumors,[22] meaning that it is not an optimal indicator of outcomes after NET. No cases of pCR were reported in our cohort. The PEPI score constitutes a validated prognostic model[5] that could be analogous to pCR with an escalation of therapy for those patients with PEPI > 0 and a de-escalation (avoiding chemotherapy) for patients with PEPI-0 status. In our cohort, almost half of the patients presented a PEPI score of 0. We also found that a larger Ki67 decrease after four weeks of treatment was related to a lower PEPI score, meaning that Ki67 changes indicate a higher responsiveness to NET, with prognostic implications, and NET continuation should be discouraged when the Ki67 rate does not readily decline. One inconvenience of the PEPI score is that nodal involvement is a qualitative measurement, so a positive axilla always implies a score ≥ 3, regardless of whether one or more than three nodes are involved. Nevertheless, a rigid parallelism between a nodal involvement and chemotherapy should be avoided, as recently demonstrated in the Rxponder trial where most of the ER+/HER2- tumors in postmenopausal women with 1-3 nodes involved had a low recurrence score and, therefore, would not have benefited from chemotherapy.[53] Consequently, response to NET may be a helpful tool to guide adjuvant treatments. Interestingly, the findings of the Z1031 trial show that tumors that do not lower Ki67 after two to four weeks also fail to respond well to chemotherapy, indicating an intrinsic endocrine resistance, which makes it essential to consider alternative therapies.[20] Genomic profiling performed on diagnostic core biopsies can also provide useful information for predicting NET response or endocrine resistance, although larger prospective studies in this area are necessary in order to establish which group of genes can provide the maximum information, and therefore act as a reliable biomarker.[3] In our study, a poor response to NET, as well as other risk factors such as a large nodal involvement, were considered when indicating adjuvant chemotherapy, which was necessary in one fourth of our patients.
The value of our study is that it is based on a single-institution prospective cohort and the use, outside a clinical trial, of Ki67 reduction as a clinical tool for maintaining or withdrawing NET. The early decline in Ki67 levels is a sensitive biomarker of endocrine responsiveness, with very remarkable prognosis implications. This allows NET to be offered safely to a broader range of patients, including those with luminal-B features, provided that a reduction in the Ki67 proliferation rate is recorded. Nevertheless, we acknowledge that there are limitations in our study, because of the nonrandomization of patients as well as the short-term follow-up. Only mild adverse effects were reported, and no treatment abandonment occurred, which is consistent with data from other studies.[23]
In conclusion, results from our study indicate that NET can be considered a safe and effective alternative for postmenopausal women with ER+/HER2- breast cancer and that it increases the rates of BCS in both luminal A-like and luminal B-like tumors. Early changes in Ki67 proliferation rates become a feasible and reliable tool that provides crucial information about endocrine responsiveness and patient prognosis.