Negative Conversion of Progesterone Receptor Status after Primary Systemic Therapy Is Associated with Poor Clinical Outcome in Patients with Breast Cancer

Abstract

PurposeAlteration of biomarker status after primary systemic therapy (PST) is occasionally found in breast cancer. This study was conducted to clarify the clinical implications of change of biomarker status in breast cancer patients treated with PST.Materials and MethodsThe pre-chemotherapeutic biopsy and post-chemotherapeutic resection specimens of 442 breast cancer patients who had residual disease after PST were included in this study. The association between changes of biomarker status after PST and clinicopathologic features of tumors, and survival of the patients, were analyzed.ResultsEstrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status changed after PST in 18 (4.1%), 80 (18.1%), and 15 (3.4%) patients,respectively. ER and PR mainly underwent positive to negative conversion,whereas HER2 status underwent negative to positive conversion. Negative conversion of ER and PR status after PST was associated with reduced disease-free survival. Moreover, a decline in the Allred score for PR in post-PST specimens was significantly associated with poor clinical outcome of the patients. HER2 change did not have prognostic significance. In multivariate analyses, negative PR status after PST was found to be an independent adverse prognostic factor in the whole patient group, in the adjuvant endocrine therapy-treated subgroup, and also in pre-PST PR positive subgroup.ConclusionER and HER2 status changed little after PST, whereas PR status changed significantly. In particular, negative conversion of PR status was revealed as a poor prognostic indicator, suggesting that re-evaluation of basic biomarkers is mandatory in breast cancer after PST for proper management and prognostication of patients.

HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation

“…Previous studies on HER2 change after NAC are summarized in Table 4. In our study, HER2 status was altered after NAC in 3.4% with positive to negative conversion in 0.9% and negative to positive conversion in 2.5% [52]. Most cases with negative to positive conversion of HER2 status after NAC showed low level of HER2 amplification, and the HER2/CEP17 ratio ranged from 2.2 to 4.4 (data not shown in a previous study) [52].…”

“…In our study, HER2 status was altered after NAC in 3.4% with positive to negative conversion in 0.9% and negative to positive conversion in 2.5% [52]. Most cases with negative to positive conversion of HER2 status after NAC showed low level of HER2 amplification, and the HER2/CEP17 ratio ranged from 2.2 to 4.4 (data not shown in a previous study) [52]. Cockburn et al [61] also reported the mean HER2/CEP17 ratio in resection specimens with HER2 positive conversion was 3.7.…”

“…Alteration of biomarker status after NAC is occasionally found in breast cancer [49,50]. Hormone receptor status changed more often than HER2 status, and as for hormone receptors, positive to negative conversion was more common than negative to positive conversion [51,52]. The frequency of HER2 change after NAC is reported in up to 15%, and both positive to negative conversion and negative to positive conversion were found with no preponderance [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66].…”

Effect of neoadjuvant therapy on breast cancer biomarker profile

“…We found a statistically significant decrease in PR expression values between biopsy and surgical specimens after NAT, which is consistent with other reports where the PR, along with the Ki67 index, are the most commonly altered biomarkers after NAT administration [7,15,16,31]. Contrary to what has been reported for Ki67, PR expression loss has been associated with worse tumor characteristics [15] and poor clinical outcomes [23,32,40]. It has also been shown that loss of PR expression may be an indicator of a decrease of hormone sensitivity in tumor cells, activation of alternate proliferation pathways such as PI3K/AKT/mTOR [41,42], and also, the induction of a non-functional ER state which could lead to a diminished response to endocrine therapy, specifically in ERpositive/PR-negative tumors [18,43].…”

“…In the current study, we aimed to analyze changes in IHC biomarker status and expression in paired biopsy and surgical samples in breast cancer cases treated and non-treated with NAT, given that changes in biomarker expression may have several clinical implications for disease outcome in breast cancer patients [31][32][33]. It may also affect adjuvant therapy regimen, as variation in breast cancer intrinsic subtype after NAT could lead to the addition or discontinuation of therapy schemes [16,34].…”