Impact of shifting of hormonal receptor and human epidermal growth factor receptor 2 on survival of non-metastatic breast cancer

INTRODUCTION

The number of new breast cancer cases in India is 178,361 (13.5%), with 90,408 (10.6%) reported deaths, as per the global cancer observatory (GLOBOCAN) data (2020).^[1] The role of neoadjuvant chemotherapy (NACT) is now established for the treatment of locally advanced breast cancer. It helps to reduce the tumor size and, most importantly, decrease micrometastasis, increasing the chances of breast-conserving surgery.^[2,3] The receptor’s status needs to be determined as per protocol before initiating the treatment of breast cancer. These receptors include estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 neu (Her2neu), and Ki 67%. Hormone receptors (HR) and molecular markers are used to determine the status of breast cancer, and they may change after neoadjuvant chemotherapy.^[4] This retrospective study seeks to illustrate the variations in HR status between biopsy specimens and final histopathological reports post-operatively, along with assessing changes in HR status following NACT at a tertiary care center in Eastern India. Additionally, the study aims to establish a correlation between the alterations in HR status and the survival outcomes of the patients.

MATERIAL AND METHODS

The clinical data of breast cancer patients treated at the Institute of Post Graduate Medical Education and Research (IPGMER), Kolkata, from January 2013 to December 2018 were collected. The staging was done based on the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (7th edition, 2010).^[5] The diagnosis was validated by histopathological examination. The inclusion criteria for the patients were as follows: age > 18 years; females; unilateral histopathologically confirmed invasive breast carcinoma; availability of pre and post-operative histopathological examination report including the immunohistochemistry (IHC) report of ER, PR, Her2neu, and Ki67%; nonmetastatic breast carcinoma. Exclusion criteria were as follows: metastatic breast cancer; non-availability of pre and post-operative IHC report of ER, PR, Her2neu, and Ki67%; previous history of breast cancer treatment.

Data on age group, menopausal status, histopathological status, clinical stage, surgical information, post-operative staging, systemic chemotherapy information, IHC status, and follow-ups was collected. Disease-free survival (DFS) was defined from the start of primary therapy to the date of disease recurrence (local or distant). Overall survival (OS) was defined as the time from the date of the start of primary therapy to the date of death or the last follow-up.

RESULTS

Patients meeting the inclusion criteria were selected for analysis. The majority of the patients were in the age group > 40 years (68.2%). NACT was received by 300 patients whereas 182 were considered for upfront surgical intervention.

Survival analysis

The Kaplan-Meier survival analysis revealed a statistically significant difference in the DFS concerning changes in ER status (log-rank test, χ2 = 24.24; p < 0.001). The overall median DFS was 58.03 months. Patients maintaining ER positivity exhibited a median DFS of 76 months, while those remaining ER-negative had a median DFS of 35 months (CI of 29.56 – 40.43). ER changes from positive to negative resulted in a median DFS of 36 months (CI of 27.21 – 44.78), and DFS was not reached for ER changes from negative to positive [Figure 1]. Similarly, a significant difference in DFS was noted for changes in PR status (log-rank test, χ2 = 22.92; p < 0.001). PR-positive patients had a median DFS of 47 months (CI of 35.73–58.26), PR-negative patients showed a median DFS of 36 months (CI of 29.94–42.05), PR changes from positive to negative yielded a median DFS of 42 months (CI of 38.21–45.78), and those changing from PR negative to positive did not reach the median DFS [Figure 2]. No statistically significant difference in DFS was observed when comparing changes in Her2neu status

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Figure 1:

The Kaplan-Meier survival curve showing a statistically significant difference in the disease-free survival (DFS) concerning changes in estrogen receptor (ER) status (log-rank test, χ2 = 24.24; p < 0.001).

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Figure 2:

The Kaplan-Meier survival curve showing a statistically significant difference in the disease-free survival (DFS) concerning changes in progesterone receptor (PR) status (log-rank test, χ2 = 22.92; p < 0.001).

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DISCUSSION

This study mainly focuses on the change of ER and PR status in the specimens, but Her2neu status was also compared. Most important changes of receptor status are negative to positive as this change altered the treatment modality.^[7] Our study revealed that ER and PR receptor status conversion or change influences the recurrence of breast cancer, and similar findings in the other studies showed that the ER and PR receptor changes influence survival.^[8] In an Italian series of 904 patients, ER was lost in 5% of HR+ cancers compared with 67% showing loss of PR (cut-off 20%); change in PR status was associated with improved survival regardless of whether they received endocrine therapy.^[9]The study found that change in PR receptor status is associated with improved survival which is in concordance with the findings of our study. A review of 45 studies addressing ER, PR, and Her2neu expression found an average prevalence of discordant results of 32% for PR and 13% for ER local recurrences showed higher rates of ER and PR conversion than the immediate post-NACT specimens.^[10]

In our study, alterations in ER receptor status were observed in 8.5% (receptor changes of 1.88% in no NACT and 6.62% in the NACT group) of patients, while changes in PR receptor status were identified in 10.58% of patients. In a French series with 420 patients, ER status changed by 23%; 42% negative to positive and 13% positive to negative.^[11] An Indian study by Anand AS et al. reported that ER discordance was 8.7 % and PR discordance was 13 %. PR positive to PR negative discordance was the predominant one. These findings were in concordance with the results of our study.^[12] A study from China by WU YT et al. found a 15% change in ER status and 2a 7% change in PR status. These reports are higher than the findings of our study.^[13] In this study, a statistically significant difference in patient DFS was observed based on changes in ER or PR status. Patients maintaining ER positivity exhibited a median survival of 76 months, while ER-negative patients had a median survival of 35 months. ER changes from positive to negative resulted in a median survival of 36 months, and for ER changes from negative to positive, the median survival was not attained. For PR, those remaining PR-negative had a median survival of 36 months, PR changes from positive to negative showed a median survival of 42 months, and those changing from PR-negative to positive did not reach the median survival. A study by Yang Z et al. reported findings similar to those of our study, except that their study involved metastatic breast cancers.^[14]

A recent series of 482 patients by Ding et al. found changes in ER status in 10% of cases (36 positive to negative and 14 negative to positive) and PR status in 17% (57 positive to negative and 25 negative to positive). These changes influence the DFS and OS.^[15] Yang L et al. described in their study that for patients who received adjuvant hormonal therapy after surgery, the 5-year DFS estimates for patients in any receptor conversion group (55.2%) was worse than patients in the receptor stable group (73.7%, Log-rank test, P = 0.015). While the 5-year OS estimates for patients with or without receptor conversion were not statistically different (86.0 vs. 82.4%, Log-rank test, P = 0.587).^[16] We noted a lower survival rate in cases where ER expression was lost compared to those with continuous ER positivity. Likewise, DFS was compromised with the loss of PR expression and the shift from PR positive to PR negative. However, survival was higher in cases where PR initially tested positive but later converted to negative, in contrast to those where PR positivity was sustained. Matsumoto et al. found that patients exhibiting a switch to positive hormonal receptors in metastatic lesions experienced improved survival.^[17] In accordance with the recent recommendations from the National Comprehensive Cancer Network (NCCN), it is advised to tailor treatment based on recurrent ER/PR/HER2 status whenever possible.^[18] Ensure biopsy provision and optimize the treatment approach for patients experiencing recurrence and metastasis.

Limitations of our study including single center study, retrospective, and small sample size. Further studies on cumulative data are needed for confirmation.

CONCLUSION

In conclusion, changes in hormone receptor status, particularly ER and PR, significantly impacted recurrence and DFS. The study highlights the importance of personalized management strategies, with age, tumor grade, LVI, and changes in ER and PR status identified as key factors influencing prognosis. Further research is warranted to unravel the intricate relationships between molecular changes, treatment modalities, and long-term outcomes in breast cancer.