Clinical significance and prognostic value of receptor conversion in hormone receptor positive breast cancers after neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) has been generally accepted in patients with locally advanced breast cancer. Besides reducing tumor stage, NAC is a practical approach to individually test chemosensitivity preoperatively. And some patients who reached pathologic complete response (pCR) through NAC tend to have prefer prognosis compared with those who still have residual disease [1‐4]. Guarneri et al. [2] reported that 5-year disease-free survival rates were 87.1 vs. 61.1% and 10-year disease-free survival rates were 74.9 vs. 39.9% for patients with and without pCR, respectively.

Before treatment, core needle biopsy (CNB) is essential for diagnosis and biomarkers assessment. Hormone (estrogen and progesterone) receptors (HR) are important biomarkers in breast cancers and indication of adjuvant endocrinotherapy [5‐7]. However, patients with HR expression tumors benefit less from chemotherapy since they have lower pCR rates compared with patients with HR negative [8‐10]. Conversely, HR expression is a predictor of favorable prognosis in breast cancers partially because of adjuvant endocrinotherapy. In general, HR status has an unreplaceable predictive and prognostic value for breast cancer patients.

Immunohistochemistry (IHC) is a standard method to quantify HR expression mainly based on the fraction of stained tumor cells. Several studies have reported conversions of estrogen receptor (ER) and progesterone receptor (PR) status between CNB and surgical specimens after NAC [11‐13]. Conversions of receptor are also prevalent in patients that did not receive NAC, it is statistically more frequent in NAC patients [14]. However, the influences of these conversions on following treatment and prognosis in breast cancers are still unclear.

The objectives of this study were to assess the conversion frequency of ER and/or PR status in HR expression patients after NAC and to determine whether these conversions influence prognosis.

This study focused on ER and/or PR conversion after receiving NAC and its influences on the prognosis and adjuvant endocrinotherapy in breast cancer patients. Only HR positive tumors are recommended to receive adjuvant endocrinotherapy. There are no clear guidelines about adjuvant endocrinotherapy for those patients who had ER and/or PR conversion after NAC. Therefore, only HR-positive disease patients before NAC were enrolled to reduce the influence of adjuvant endocrinotherapy after surgery. In addition, patients with HR negative disease were more sensitive to chemotherapy [15, 16], and less patients had residual disease at breast after NAC to assess biomarkers.

In this retrospective study, we set positive ER and PR expression cutoff value as 1%. For 231 HR-positive disease before NAC, 55 (23.8%) had ER and/or PR conversion, 13 (5.6%) had ER conversion, and 45 (19.5%) had PR conversion. Hirata et al. [12] used 10% as the cutoff value for ER and PR expression. Of 214 HR positive disease in their study, 38 (17.8%) had ER conversion and 89 (41.6%) had PR conversion after NAC. Other studies which used a cutoff of 5% or Allred score (≥ 3) to define ER and PR positive staining also reported discordance of receptor expression after NAC [11, 17]. Except for sampling error of core needle biopsy before treatment, receiving NAC may be a main cause of this phenomenon [14]. Our analysis show that younger (≤ 50 years) patients were more likely to have conversion, due to an unknown underlying mechanism.

The influence of HR status changes to prognosis remained controversial. Hirata et al. [12] did not find a significant difference in DFS and OS between the HR-positive group and HR-conversion group. However, in their study, there were 18 (38.3%) of 47 patients who had HR negative tumor before NAC in the HR conversion group. Chen et al. [18] adjusted the influence of adjuvant endocrinotherapy in HR positive patients and found negative influence in DFS and OS for patients who had HR positive to negative change after NAC. Parinyanitikul et al. [19] used the 20% cutoff for absolute percent change for ER and PR expression and found that patients with any receptor change had better relapse-free survival (RFS) than patients with no receptor change. Those previous studies focused on the influence of HR status conversion or absolute percent change of ER or PR expression, but there were few studies focused on the influences of at least one of ER and PR status conversion in HR positive patients. After adjusting the influence of adjuvant endocrinotherapy, patients with receptor stable disease had significantly higher DFS than patients with any receptor conversion (P = 0.017). Our multivariable analysis also revealed that any receptor conversion status was associated with worse DFS (HR, 1.881; 95% CI, 1.058–3.342; P = 0.031). While 5-year OS estimates for patients without any receptor conversion was higher than the other patients (86.0 vs. 82.4%), the difference was not statistically significant in univariate analysis (P = 0.588). Moreover, we also analyzed survival differences for patients who did not receive endocrinotherapy between the two groups. For nine patients with any receptor conversion, the 5-year DFS and 5-year OS rates were 77.8 and 88.9%, respectively. And these rates were not only similar to patients with no receptor conversion (88.9 and 88.9%) but also similar to patients with any receptor conversion who received adjuvant endocrinotherapy (60.8 and 87.0%).

In this study, the proportion of HER2 positive-to-negative change was higher than negative-to-positive change (22.6 vs. 2.7%). However, it only reflected change pattern of tumors which were HR-positive before NAC. Niikura et al. [20] reported change pattern of HER2 status regardless of pre-NAC HR status, and they had similar results (21.4% for HER2 positive-to-negative change and 3.4% for HER2 negative-to-positive change) to ours. Though HER2 status may have conversion after receiving NAC, this phenomenon was not significant when compared with patients who did not receive NAC [14]. By the way, 52.4% of patients had low Ki-67 expression after NAC, and it was much more than the proportion (25.5%) before NAC (P < 0.01). Above 60% of breast cancer patients with non-pCR disease had reduction of Ki-67 expression after NAC [21, 22]. Some studies had also reported that patients with reduction of Ki-67 expression had more favorable prognosis after NAC [21, 22]. In our present data, we did not do further study on the influence of reduction of Ki-67 expression on prognosis.

Our study showed that conversion in ER and/or PR status after NAC should not be neglected for breast cancer patients. Patients with any conversion in ER or PR status was associated with poor DFS after adjusting for adjuvant endocrinotherapy. Biomarkers testing is recommended in patients with residual disease for receptor conversion. These patients may need more individualized therapy after surgery.