Progesterone receptor expression and its prognostic role in hormone receptor-positive/human epidermal growth factor receptor 2-positive breast cancer: a retrospective cohort study

Abstract

Purpose

While progesterone receptor (PR) negativity in luminal-type breast cancer is generally associated with worse oncologic outcomes, its prognostic role in estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains underexplored. This study aimed to evaluate the prognostic significance of PR expression in ER-positive, HER2-positive breast cancer.

Methods

A retrospective analysis was conducted on patients diagnosed with ER-positive, HER2-positive breast cancer who underwent primary surgery at Korea University Guro Hospital between January 2009 and December 2019. Patients were grouped by PR expression as negative/low (Allred score, 0–6) or strongly positive (Allred score,7 or 8). Prognostic outcomes, including disease-free survival (DFS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) were analyzed.

Results

A total of 223 patients were included. Patients in the negative/low PR group were older compared to the strongly positive PR group. The negative/low PR group showed significantly worse DFS (P = 0.005) and DRFS (P = 0.014) but showed no significant difference in BCSS (P = 0.153). On multivariate analysis, negative or low PR expressions were linked to inferior DFS (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.34–7.16; P = 0.008) and DRFS (HR, 9.55; 95% CI, 1.22–74.77; P = 0.032).

Conclusion

In ER-positive, HER2-positive breast cancer, negative or weak PR expression was associated with inferior DFS and DRFS compared to strong PR expression. These findings highlight the potential prognostic value of PR status in this group, underscoring its relevance in guiding treatment and follow-up strategies for more individualized patient care.

INTRODUCTION

Human epidermal growth factor receptor 2 (HER2) overexpression or gene amplification is observed in approximately 15%–30% of breast cancers [1,2,3]. In Korea, 2019 statistics showed that 24.9% of newly diagnosed breast cancers were classified as HER2-positive subtypes [4]. HER2-positive breast cancer represents a heterogeneous disease with significant variations in molecular features [5,6]. Expression of hormone receptors is one of its most marked heterogeneities. It has been recognized to have a predictive value in HER2-positive breast cancer [7,8].

The progesterone receptor (PR) is a marker of functional estrogen receptor (ER) [9]. Although its clinical role in breast cancer remains unclear, PR negativity in luminal-type breast cancers is generally considered to be associated with a higher risk of recurrence likely due to an accelerated development of endocrine resistance [9]. Considering that PR negativity is a high-risk factor, escalating endocrine therapy in patients with ER-positive, PR-negative breast cancer to improve disease-free survival (DFS) has been proposed and clinically tested [9].

Despite the idea that hormone receptor expression in HER2-positive breast cancer likely warrants distinct management approaches, few studies have specifically examined the role of PR in ER-positive, HER2-positive breast cancer. Thus, this study aimed to evaluate the prognostic significance of PR expression in ER-positive, HER2-positive breast cancer patients who underwent primary surgery.

METHODS

Study participants

Patients with newly diagnosed ER-positive, HER2-positive breast cancer who underwent primary surgery at Korea University Guro Hospital between January 2009 and December 2019 were enrolled. HER2-positive breast cancer was defined as a tumor with an immunohistochemistry score of 3+ or 2+ with subsequent confirmation of HER2 positivity by fluorescence in situ hybridization or silver in situ hybridization. ER-positive tumors were defined as those with an Allred score of 3–8. Data were collected retrospectively by reviewing medical charts and pathology reports.

Patients were excluded if they had received neoadjuvant chemotherapy, had a diagnosis of non-breast cancer, or had tumors with atypical histology (e.g., sarcoma or melanoma). Patients with less than one month of follow-up were also excluded. Demographic data such as age and cancer characteristics (subtype, grade, histology, and pathological stage) were collected. Information on adjuvant treatments was also included.

Guideline-concordant adjuvant treatment status was assessed based on the National Comprehensive Cancer Network (NCCN) treatment guidelines in effect at the time of diagnosis. This included receipt of adjuvant chemotherapy, HER2-targeted therapy, and/or endocrine therapy when clinically indicated based on tumor characteristics.

PR expression levels were determined using the Allred scoring system. Previous studies have classified Allred scores of 7/8 and 3 to 6 as strong positive and weak positive, respectively [10,11]. In this study, ER-positive, HER2-positive breast cancer patients were grouped for analysis based on PR expression: those with negative or low PR status (Allred score, 0–6) and those with strong PR expression (Allred score, 7 or 8).

Primary outcomes were DFS, distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS). DFS was defined as the time from breast cancer diagnosis to the first occurrence of any of the following events: breast cancer recurrence (locoregional, contralateral, or distant), diagnosis of a second primary cancer, or death from any cause. DRFS was defined as the time interval from diagnosis to the onset of distant metastasis such as metastasis in the bone, liver, or lung. BCSS was defined as the time interval from diagnosis to death attributed to breast cancer.

This study was approved by the Institutional Review Board of Korea University Guro Hospital (No. 2024GR0261). The requirement for informed consent was waived due to the retrospective nature of the study.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics ver. 20 (IBM Corp.). Clinical characteristics were compared using the chi-square test for categorical variables. DFS, DRFS, and BCSS were estimated using the Kaplan-Meier method, with survival curves compared with the log-rank test. The Cox proportional hazard model was used to assess associations of PR status with oncologic outcomes after adjusting for potential confounders. Factors with a P-value <0.2 in the univariate Cox proportional hazards model were included in the multivariate analysis. For all analyses, a P-value <0.05 was considered statistically significant.

RESULTS

A total of 470 patients underwent curative surgery for HER2-positive breast cancer. Among them, 209 patients with tumors negative for ER were excluded from the analysis. After excluding 39 patients who had undergone neoadjuvant chemotherapy, 223 patients who received primary surgery were enrolled.

Baseline characteristics

Clinicopathological features of each group are shown in Table 1. The median age of all patients with ER-positive, HER2-positive breast cancer was 53.0 years (interquartile range [IQR], 45.0–58.0 years) and the median follow-up period was 75.0 months (IQR, 59.0–103.0 months). The proportion of patients with negative or weak positive PR expression was 57.8%. Among clinical features, the median age differed according to PR status, with the negative or weakly positive PR group having an older median age than the strongly positive PR group (P = 0.006). There were no significant differences in histological grade, Ki-67, tumor size, and nodal status between the 2 groups.

Table 1. Clinicopathological features of patients with ER+ HER2+ breast cancer.

Values are presented as number only, median (interquartile range), or number (%).

ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.

Adjuvant treatments received by patients

Table 2 summarizes adjuvant treatments received following primary surgery for ER-positive, HER2-positive breast cancer. There were no marked differences in the receipt of postoperative radiotherapy, HER2-targeted therapy, or endocrine therapy between patients with varying levels of PR expression. However, chemotherapy administration differed, with fewer patients with negative or weakly positive PR expression receiving chemotherapy compared to those with strong PR expression (P = 0.019). Among the 15 patients who did not receive chemotherapy, 13 had negative or weakly positive PR expression, and 2 had strong PR expression. In the negative or weakly positive PR group, 5 patients declined chemotherapy despite clinical indications, while the remaining 8 had tumors measuring 0.5 cm or less, for which adjuvant chemotherapy is not recommended according to NCCN guidelines. In the strongly PR-positive group, both patients who did not receive chemotherapy had also declined it.

Table 2. Adjuvant treatments received by Patients with ER+ HER2+ breast cancer.

Values are presented as number (%).

ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.

In addition to the 7 patients who declined chemotherapy, one patient declined HER2-targeted therapy for personal reasons, and another could not receive HER2-targeted therapy due to severe preexisting heart failure. These patients were classified as having received guideline-discordant adjuvant treatment. After accounting for clinical context and patient preference, the overall proportion of patients receiving guideline-concordant adjuvant treatment did not differ significantly between the PR-low/negative and strongly PR-positive groups (P = 0.887).

Survival outcomes

During the follow-up period, a total of 33 DFS events were observed, comprising 25 breast cancer recurrences, 7 second primary malignancies, and 1 death unrelated to breast cancer. Among the 25 recurrence events, 20 occurred in patients with negative or weakly positive PR tumors, while 5 occurred in those with strongly positive PR tumors. Three patients died from breast cancer, all of whom had previously experienced recurrence and were therefore already included in the DFS event count.

Fig. 1 displays DFS by PR status, with the negative or weakly positive PR group showing an inferior survival (P = 0.005). As shown in Fig. 2, DRFS also differed significantly between the 2 groups (P = 0.014), with those having negative or weakly positive PR tumors exhibiting poorer outcomes. However, BCSS did not significantly differ between the 2 groups (P = 0.153, Fig. 3).

Fig. 1. Kaplan-Meier survival curves of the disease-free survival between different progesterone receptor (PR) statuses in hormone receptor-positive/human epidermal growth factor receptor 2-positive breast cancer.

Fig. 2. Kaplan-Meier survival curves of the distant recurrence-free survival between different progesterone receptor (PR) statuses in hormone receptor-positive/human epidermal growth factor receptor 2-positive breast cancer.

Fig. 3. Kaplan-Meier survival curves of the breast cancer-specific survival between different progesterone receptor (PR) statuses in hormone receptor-positive/human epidermal growth factor receptor 2-positive breast cancer.

Table 3 presents the univariable Cox proportional hazards analysis for DFS, and Table 4 shows both univariable and multivariable analyses for DRFS in HER2-positive breast cancer patients with hormone receptor expression. In the univariable analysis for DFS (Table 3), negative or low PR expression was significantly associated with a higher risk of recurrence (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.34–7.16; P = 0.008). Multivariable analysis for DFS was not performed, as PR status was the only variable significantly associated with DFS in univariable analysis. In the multivariable analysis for DRFS (Table 4), negative or low PR expression remained significantly associated with increased risk of distant recurrence (HR, 9.55; 95% CI, 1.22–74.77; P = 0.032). Additionally, receiving guideline-discordant treatment was associated with a higher hazard for distant recurrence (HR, 9.79; 95% CI, 2.04–46.86; P = 0.004), although it was not significantly associated with DFS in the univariable analysis.

Table 3. Univariate analysis for disease-free survival of ER+ HER2+ breast cancer.

ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; CI, confidence interval; PR, progesterone receptor.

Multivariable analysis was not performed for disease-free survival because only PR status was statistically significant in the univariable analysis.

Table 4. Univariate and multivariate analysis for distant recurrence-free survival of ER+ HER2+ breast cancer.

ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; CI, confidence interval; NA, not available; PR, progesterone receptor.

^a)Histologic grade was excluded from DRFS analysis due to estimation instability resulting from sparse events in certain subgroups, which led to inflated hazard ratios and standard errors.

DISCUSSION

Co-expression of ER and HER-2 can alter the clinical behavior of breast cancers [12] and modulate responses to endocrine and HER2-targeted therapies [13,14] through molecular crosstalk between ER and HER2 pathways [14,15]. To enhance treatment efficacy, efforts have been explored to block both pathways simultaneously in both adjuvant [16] and metastatic settings [17,18]. One notable example is the combined use of lapatinib, a dual epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, and letrozole, an aromatase inhibitor, as a first-line therapy for postmenopausal hormone receptor-positive, HER2-positive metastatic breast cancer [17]. This approach significantly improved clinical outcomes compared to letrozole alone [17]. Such advancements underscore the importance of considering hormone receptor status in HER2-positive breast cancer treatment decisions.

PR is widely regarded as a marker of functional ER activity [9]. In luminal breast cancer, the prognostic significance of PR expression has been extensively studied, with PR-positive tumors consistently linked to better clinical outcomes than PR-negative tumors [19,20,21,22,23]. Mohammed et al. [24] have elucidated the crosstalk between ERα and PR that regulates gene expression at the molecular level, thereby suppressing tumorigenic activity in ER-positive breast cancers. Despite the well-established role of PR expression in luminal breast cancers [21,22,25,26], its significance in HER2-positive tumors remains underexplored.

In this study, we found that both DFS and DRFS of ER-positive, HER2-negative breast cancer patients who underwent upfront surgery with a negative or weakly positive PR expression were inferior to those with tumors having a strong PR expression.

While the NCCN guidelines recommend neoadjuvant chemotherapy for HER2-positive breast cancer patients with tumor size greater than 2 cm or a node-positive disease [27], tumor size and nodal status did not significantly impact DFS or DRFS in our study. Although guideline-concordant treatment was relatively balanced between PR-positive and PR-negative groups, it significantly influenced DRFS of ER-positive, HER2-positive breast cancer patients. This highlights the critical role of chemotherapy and HER2-targeted therapy in this subtype, regardless of PR expression. Collectively, our findings aligned with prior studies on HER2-negative breast cancer, suggesting associations of poorer oncologic outcomes with low or negative PR expression in hormone receptor-positive, HER2-positive breast cancer.

In line with previous studies [12,28], we observed that patients with tumors expressing strong PR were younger than those with negative or weak PR expression. The median age of patients with strong PR expression was 49 years, younger than that (54 years) for the other group. This age difference may reflect a higher proportion of premenopausal women in the strong PR group. Premenopausal status is typically characterized by higher circulating levels of both estrogen and progesterone, which may stimulate PR expression in hormone receptor-positive tumors [12]. Clark et al. [29] previously reported that premenopausal women had significantly higher PR concentrations than postmenopausal women within the same age ranges, particularly among women in their 40s and early 50s, suggesting that elevated estrogen levels in younger women upregulate PR synthesis through ER activation. These findings support the hypothesis that strong PR expression in ER-positive tumors may indicate a greater functional estrogen dependence, particularly among younger, premenopausal patients.

While HER2-positive breast cancer is often treated as a single disease entity with a strong emphasis on chemotherapy and HER2-targeted therapy, our results suggest that hormone receptor expression, specifically PR status, deserves greater attention in clinical practice. PR status might be instrumental in tailoring treatment intensity and optimizing endocrine therapy approaches for hormone receptor-positive, HER2-positive breast cancers. Additionally, PR status could inform follow-up and surveillance strategies and help identify patients at higher risk of recurrence who might benefit from closer monitoring or additional therapeutic interventions.

The strength of this study lies in its focus on the prognostic role of PR expression in hormone receptor-positive, HER2-positive breast cancer, an area that has received inadequate attention. However, several limitations should be acknowledged. The retrospective nature of this study might have introduced potential biases. Its single-institution design might have limited the generalizability of findings to broader populations. Future prospective multicenter studies are warranted to validate our results and establish a consensus on the role of PR in HER2-positive breast cancer.

In conclusion, ER-positive, HER2-positive surgery-first breast cancer patients having a negative or weak PR expression had DFS and DRFS inferior to those with a strong PR expression. These findings suggest that PR status, even in HER2-positive breast cancer, might play a valuable role in guiding treatment decisions and follow-up strategies, paving the way for more individualized patient care.