|ORIGINAL RESEARCH ARTICLE
|Ahead of print publication
Discordance of estrogen and progesterone receptors after neoadjuvant chemotherapy in locally advanced breast cancer
Surabhi Gupta1, Alvin Anto1, Juhi Singhal2, Pooja Agarwal3
1 Department of Radiation Oncology, Sarojani Naidu Medical College, Agra, Uttar Pradesh, India
2 Department of Surgery, Sarojani Naidu Medical College, Agra, Uttar Pradesh, India
3 Department of Pathology, Sarojani Naidu Medical College, Agra, Uttar Pradesh, India
|Date of Submission||30-May-2021|
|Date of Decision||16-Jun-2021|
|Date of Acceptance||02-Jul-2021|
|Date of Web Publication||28-Jan-2022|
Department of Radiation Oncology, Sarojani Naidu Medical College, Agra, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Aims and Objective: This study aimed to compare hormone receptor (HR) status before and after neoadjuvant chemotherapy that is discordance in locally advanced breast cancer patients, which are amenable for surgery. The secondary objective was to study the correlation between tumor response and HR expression.
Materials and Methods: The duration of the study was from August 2018 to December 2020. A total of 23 patients were selected as per certain inclusion criteria. American Society of Clinical Oncologys methodology was used to analyze estrogen receptor (ER) and progesterone receptor (PR) status of histopathology specimen. For study purposes, patients were classified into four groups after core biopsy of breast lump and after definitive surgery (post-NACT (neoadjuvant chemotherapy)) – Group A (ER+, PR+), Group B (ER+, PR−), Group C (ER−, PR+), and Group D (ER−, PR−).
Results: ER discordance was found to be (2/23) 8.69% (P value 0.76). PR discordance was (4/23) 17.39%. PR discordance was found to be higher than ER discordance. Changes in staining patterns in ERs were seen in 14 patients (93.33%). Changes in staining percentage in PRs were seen in eight patients (80%). It was found that both receptor-positive and negative diseases had an equal proportion of stable disease.
Conclusion: From the study, it is noted that performing ER PR study twice (before and after chemotherapy) is necessary as discordance is noted and this may impact the further treatment strategy.
Keywords: Estrogen receptor discordance, postsurgery, progesterone receptor discordance, pre neoadjuvant chemotherapy, staining pattern
|How to cite this URL:|
Gupta S, Anto A, Singhal J, Agarwal P. Discordance of estrogen and progesterone receptors after neoadjuvant chemotherapy in locally advanced breast cancer. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=336705
| > Introduction|| |
Worldwide, carcinoma breast is contributing to 11.7% of new cases and 6.9% mortality per annum among all cancer.
Breast cancer has ranked number one cancer among Indian females with age-adjusted rate as high as 25.8 per 100,000 women and mortality of 12.7 per 100,000 women. The Mortality-to-incidence ratio was found to be as high as 66 in rural registries whereas as low as 8 in urban registries.
In India, majority of patients present at locally advanced or at metastatic stages at the time of diagnosis. According to various studies, majority of carcinoma breast cases in the west report in Stages I and II of disease, whereas in India, 45.7% report in advanced stages.
Indian women having breast cancer are found a decade younger in comparison to western women suggesting that breast cancer occurs at a younger premenopausal age in India.[4.5] Cancers in the young tend to be more aggressive. Studies suggest that the disease peaks at 40–50 years in Indian women. Many of these cancers are human epidermal growth factor receptor 2 (HER) 2 positive and estrogen receptor (ER)/progesterone receptor (PR) negative, or triple negative and carry a poor prognosis.
ERs and PRs results are used to guide treatment so it is important that the results be accurate. The most common method currently used to test a tumor for ERs and PRs is called immunohistochemistry (IHC). For this, tissue may be achieved from a biopsy or from the surgery (breast-conserving surgery [BCS] or modified radical mastectomy [MRM]) specimen. ER- and PR-positive breast cancers are generally of good prognostic value. As they play a crucial role in the treatment of breast cancer, a change in its expression after chemotherapy is of significance. This seems therapeutically more significant when the discordance is from negative to positive receptor. Several studies have indicated that patients with hormonal receptor-positive status have significantly higher survival rates. Tumors that express both ER and PR receptors have the greatest benefit from hormonal therapy, but those containing only ER or PR still have significant responses. Patients with tumors negative for hormonal receptors have only a small probability of responding to hormonal therapy.
Thus, there is a strong need for the study of ERs and PRs mainly to know the prognosis of the disease and while planning chemotherapy and hormonal therapy after definitive treatment. Hence, the purpose of this study was to identify discordance of hormonal receptors after chemotherapy so that resultant receptor status helps in alteration of hormonal therapy accordingly and also helps in evaluating the prognosis of disease based on change of receptor status.
Aim and objectives
The primary objective of this study was to compare hormone receptor (HR) status before and after neoadjuvant chemotherapy that is discordance in locally advanced breast cancer patients, which were amenable for surgery. The secondary objective was to study the correlation between tumors response and HR expression.
| > Materials And Methods|| |
All locally advanced breast cancer patients presenting in the department and referred patients from the surgery department who fulfilled the eligibility criteria were enrolled in this study. The duration of the study was from August 2018 to December 2020. Patients were selected as per the following criteria.
- Primarily inoperable locally advanced female breast cancer patients
- Patients who underwent core biopsy/trucut biopsy before neoadjuvant chemotherapy
- ER/PR assay done by IHC as per the recommendations of the American Society of Clinical Oncology (ASCO)
- Patients who were amenable to undergo surgery after NACT.
Approval for the conduction of this study was obtained from the Institutional Ethics Committee. Informed consent was received from all the patients willing for the study at the time of enrolment.
A structured pro forma with variables such as age, patient characteristics, histological subtype, tumor size, grade, margins, tumor emboli, nodal status, stage, and molecular factors such as ER and PR status was used. Data were collected prospectively, starting from the day of registration for treatment. Patient master files, histopathology, and HR IHC reports were analyzed.
ASCO methodology was used to analyze ER and PR status of histopathology specimens. For study purposes, patients were classified into four groups after core biopsy of breast lump:
Group A (ER+, PR+)
Group B (ER+, PR−)
Group C (ER−, PR+)
Group D (ER−, PR−)
After core biopsy, patients underwent neoadjuvant chemotherapy in the form of anthracycline- or taxane-based regimen with proper pre and post medications up to four cycles followed by definitive surgery either in the form of MRM or breast conservative surgery. ER and PR receptors' study was done again on postoperative specimens and patients were reallocated into four groups again depending on the receptor status. Pre- and postchemotherapy receptor status and histopathological response with reference of receptor status of the individual patient were analyzed.
For statistical analysis, data were collected and entered into a Microsoft Excel spreadsheet. All care was taken to ensure that there is no data entry error. Categorical variables were described as frequency and proportion. Continuous variables were described as mean ± standard deviation. We compared proportions using the Chi-square test and Fisher's exact test as and when required. The means in the two groups were compared using Student's t-test. P <0.05 was considered statistically significant. The data were analyzed using SPSS version 20.0, manufactured by IBM, Armonk, New York, USA.
| > Results|| |
This prospective randomized study was conducted to assess the discordance of ER and PR receptors before and after chemotherapy. A total of 25 patients were enrolled in this study from August 2018 and December 2020. Two patients were excluded from the study due to achieving a pathological complete response, so the total number of evaluable patients was 23.
As shown in [Table 1], minimum number of patients were enrolled in the year 2020 due to COVID-19 pandemic.
As shown in [Table 2], majority of patients (65.19%) were of <50 years of age. No patients were under 30 years of age. Majority of the patients were of Stage IIIB, constituting 65.21% of the total. Almost equal distribution of patients was observed in view of laterality of tumors. Majority of patients (56.52%) were postmenopausal. All (100%) patients had invasive ductal carcinoma as histology in biopsy.
From [Figure 1], in prechemotherapy phase, most of the patients (39.13%) belonged to Group A (ER + PR+), while post chemotherapy, most of the patients, i.e. (39.13%) belonged to Group D (ER − PR−).
|Figure 1: Distribution of patients according to groups – pre and post chemotherapy|
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As shown in [Table 3], while assessing ER + tumors, 53.3% were strongly positive (80%–100%). About 60% of tumors showed 80%–100% staining for PR receptors.
From [Figure 2], ER discordance was found to be 8.69% (2/23) (Chi-square value was 0.0933 with P value 0.76.). The changes were 1 patient from ER − to ER + and 1 from ER + to ER − status.
From [Figure 3], PR discordance was 17.39% (4/23); Chi-square static was 0.3651 with P value of 0.54. Change in positive to negative was similar to change in negative to positive.
As shown in [Figure 4], PR discordance was found to be higher than ER discordance.
|Figure 4: Comparison of estrogen receptor and progesterone receptor discordance|
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As shown in [Figure 5], changes in staining pattern in ERs were seen in 14 patients (93.33%).
|Figure 5: Showing estrogen receptor staining before and after chemotherapy|
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As shown in [Figure 6], changes in staining pattern of PR receptors were seen in eight patients (80%).
|Figure 6: Showing progesterone receptor staining before and after chemotherapy|
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As shown in [Table 4], staining intensity details were available for 11 ER + tumors and 5 PR + tumors. Allred score was available only for five patients in prechemo phase so not included in observation.
|Table 4: Staining patterns in estrogen receptor/progesterone receptor discordance|
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As shown in [Table 5], while studying staining patterns of discordance, it was found that most of them have % between 80 and 100 in PR discordance.
As shown in [Figure 7], it was found that both positive and negative receptors had an equal proportion of stable disease, i.e. 62.5% each.
As shown in [Table 6], out of 25 patients, 2 showed pathological complete response and both belonged to Group D (ER − PR−).
| > Discussion|| |
Our study was prospective and randomized to compare discordance of ERs and PRs in locally advanced breast cancer patients before and after chemotherapy treated in the department.
Patients with locally advanced breast cancer who were amenable for surgery after induction chemotherapy were given neoadjuvant chemotherapy four cycles before surgery and were made to undergo MRM/BCS/mastectomy depending on the response. ER and PR receptors were studied first time from trucut biopsy/core biopsy specimen and second time from mastectomy/BCS specimen.
As per the literature, the studies that evaluated discordance of ER and PR receptors after NACT had a study population ranging from a minimum of 18 patients to a maximum of 459 patients. Twenty-five patients were enrolled in our study out of which two underwent pathologically complete response and were excluded from the analysis.
Most of the patients in the Indian study were in 46–55 years age group and in our study, most of the patients were in 40–49 years age group and the mean age was 45 years. This is approximately a decade younger than the west. This is likely to be due to the difference in the age distribution of the Indian population where 7% of the population are above 60 years.
In our study, majority of patients were postmenopausal and 57% and 43% were premenopausal, which was consistent with previous trials. Surakasula et al. trial showed that 52% of patients were postmenopausal in their study. There was an almost equal distribution of right- and left-sided breast tumors in our study, whereas left-sided tumors were common in previous studies conducted in the Indian subcontinent.
Percentage of patients in T3 N1-3 M0 was 35% and 65% of cases were of Stage T4 N1-3 M0. Most of the patients were inoperable at the time of diagnosis and NACT was given to downstage and make the tumor operable.
In our study, international data corporation (IDC) was the predominant histology type contributing about 100% of the total. A study by Aravindh Sivanadhan et al. also showed IDC as predominant histology (97.4%), whereas in a study by Ding et al., 93.8% were of IDC histotype.
In our study, pre chemo, 39.13% of patients belonged to Group A (ER + PR+) followed by 30.4% patients in Group D (ER − PR−), 26.08% patients in Group B (ER + PR−), and 4.3% patients in Group C (ER − PR+). Comparing to previous studies, majority of patients belonged to ER + PR + group followed by ER − PR − group. In a study by Aravindh et al., 49% of patients belonged to Group A (ER + PR + group), 37.2% in Group D (ER − PR−), and in Group B (ER + PR − group) and Group C (ER − PR + Group) 9% each. Therefore, the incidence of endocrine responsive breast cancer patients (prechemotherapy) in our study was 67.31%, when compared to the western population, the endocrine responsiveness of the Indian population was less. In a study by Yang et al., 55 patients (23.8%) had ER and/or PR conversion after NAC. Overall discordance of ER receptor in our study was found to be 8.69%, out of this, ER discordance from positive to negative was found to be 6% and from negative to positive was found in 12.5% of tumors and this result was similar to Neubauer et al. study where the ER discordance noted was 8%. In the study of Eladawei, et al.,100 patients were enrolled to see the discordance after NACT and it was observed that there was a statistically significant change of ER (P = 0.03). Fifty-five tumors were initially negative and 39 became negative after neoadjuvant chemotherapy.
In our study, the overall discordance of PR receptors was 17.39%. It was found to be higher than ER discordance with 20% of patients showing positive to negative change and 15.58% of tumors showing negative to positive changes. It was observed that PR discordance is significantly higher in all the studies reviewed, of which PR + changing to PR– was predominant one. Neubauer et al. study showed 18% PR discordance. Eladawei et al.'s study study revealed that PR status showed statistically significant change between before and after neoadjuvant chemotherapy (P = 0.04). The rate of conversion of PR from positive to negative was 15%.
In a study by Ding et al., the ER, PR, and Ki-67 expression changes observed were 10.4% (50/482), 17.0% (82/482), and 77.4% (373/448), respectively. These changes verify the presumption that the discordance in biomarker expression is elicited by NAC.
In a study by Aravidham et al., ER discordance following NACT was 8.7%. Change was more or less similar in ER-positive and ER-negative subgroup. Change was higher in PR positive to PR negative (21.6%) when compared to PR negative to PR positive (3.1%). Indian study by Tanuja et al. also reveals that PR discordance was higher, i.e. 20.5%, while ER discordance was only 12.8%.
The reduction in PR positivity may correspond to a decrease in PR expression, which could be explained by differential tumor sampling between the core biopsy and the final surgical specimen, chemotherapy-selective cytotoxicity of PR-expressing cells, small patient sample size, or inherent variability of PR IHC. Furthermore, interobserver variability with regard to stain interpretation could have contributed to observed differences in PR expression following neoadjuvant treatment. Overall, determination of both pretreatment and posttreatment PR IHC profile is merited due to the possible change in PR expression following neoadjuvant chemotherapy. The alteration of PR expression without change in ER status observed after neoadjuvant chemotherapy is of undetermined clinical significance, ER is generally considered a stronger predictor of response to hormone-directed therapy. Yang et al.'s study showed that the 5-year disease-free survival (DFS) estimates for patients in any receptor conversion group (55.2%) were worse than patients in the receptor stable group (73.7%, log-rank test, P = 0.015), while the 5-year overall survival estimates for patients with or without receptor conversion were not statistically different (86.0 vs. 82.4%, log-rank test, P = 0.587).
In our study, 62.5% of HR-positive tumors and 62.5% of HR-negative tumors showed either response or stable disease. The rest showed either metastasis or local recurrence.
In our study, two patients who underwent polymerase chain reaction (PCR) after chemotherapy were in ER − PR − group (Group D) which also correlated with other studies. Pathological complete remission was higher in nonendocrine responsive than the endocrine responsive group in the study done by Aravindh et al. Several other studies like Ring et al. have also shown that pCR rate is high after chemotherapy in endocrine nonresponsive patients.
| > Conclusion|| |
From the study, it is noted that performing ER PR study twice (before and after chemotherapy) is necessary as discordance is noted and this may impact the further treatment strategy. It eliminates the need for continuation of hormonal therapy after completion of treatment if the patient's hormonal status changes from positive to negative. It also helps in making a decision of starting hormonal therapy if receptor changes from negative to positive. ER PR discordance also helps in the prognosis of disease as noted from a study that most of the patients with a change of receptor from positive to negative have progressive disease or metastatic disease. Considering the patients' constraints, the study needs to be carried out with the enrolment of more number of patients and with a longer duration of follow-up to comment on the statistical significance of the study.
Younger patients (≤50 years) were more likely to have receptor conversion (P = 0.014). For 213 patients (92.2%) who received adjuvant endocrinotherapy after surgery, in multivariate Cox proportional hazard analyses, patients with any receptor conversion had worse DFS (hazard ratio, 1.995; 95% confidence interval, 1.130–3.521, P = 0.031).
The rate of conversion from negative to positive was 14%. Forty-seven of tumors were initially negative PRs and 62 became negative after NACT. PR status showed statistically significant change between before and after NACT (P = 0.04). The rate of conversion of PR from positive to negative was 15%. There is no statistically significant change of HER-2 before and after NACT (P = 0.98). There is a statistically significant change from high to low Ki 67 index (P = 0.006). The rate of conversion changes of Ki 67 from high to low was 20%. Conclusion: NACT changes receptor status and reduces K i67 expression. This change in HR status from negative to positive offers new endocrine therapy to this group of patients. Accordingly, reevaluation of HRs after NACT is required to guide further adjuvant treatment.
The authors would like to thank for departmental faculties (Dr. T. Samani, Dr.A. Tyagi) for patients' support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al
. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol 2017;13:289-95.
Globocan 2018. Lyon, France: International Agency for Research on Cancer; C2013. Available from: Available from: http://globocan.iarc.fr
. [Last accessed on 2018 Sep 23].
Thangjam S, Laishram RS, Debnath K. Breast carcinoma in young females below the age of 40 years: A histopathological perspective. South Asian J Cancer 2014;3:97-100.
] [Full text]
Sandhu DS, Sandhu S, Karwasra RK, Marwah S. Profile of breast cancer patients at a tertiary care hospital in north India. Indian J Cancer 2010;47:16-22.
] [Full text]
NCRP-Consolidated Report of Population Based Cancer Registries 2009-2011, National Cancer Registry Programme (Indian Council of Medical Research), Bangalore; 2013.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
Hirata T, Shimizu C, Yonemori K, Hirakawa A, Kouno T, Tamura K, et al
. Change in the hormone receptor status following administration of neoadjuvant chemotherapy and its impact on the long-term outcome in patients with primary breast cancer. Br J Cancer 2009;101:1529-36.
Neubauer H, Gall C, Vogel U, Hornung R, Wallwiener D, Solomayer E, et al
. Changes in tumour biological markers during primary systemic chemotherapy (PST). Anticancer Res 2008;28:1797-804.
Surakasula A, Nagarjunapu GC, Raghavaiah KV. A comparative study of pre- and post-menopausal breast cancer: Risk factors, presentation, characteristics and management. J Res Pharm Pract 2014;3:12-8.
] [Full text]
Anand AS, Velayudhan ST. Discordance of estrogen and progesterone receptors after neoadjuvant chemotherapy in breast cancer-An Indian study. Indian J Surg Oncol 2016;7:316-9.
Ding Y, Ding K, Qian H, Yu X, Zou D, Yang H, et al
. Impact on survival of estrogen receptor, progesterone receptor and Ki-67 expression discordance pre- and post-neoadjuvant chemotherapy in breast cancer. PLoS One 2020;15:e0231895.
Rhodes A, Jasani B, Balaton AJ, Barnes DM, Miller KD. Frequency of estrogen and progesterone receptor positivity by immunohistochemical analysis in 7016 breast carcinomas: Correlation with patient age, assay sensitivity, threshold value and mammographic screening. J Clin Pathol 2000;53:688-96.
Yang L, Zhong X, Pu T, Qiu Y, Ye F, Bu H. Clinical significance and prognostic value of receptor conversion in hormone receptor positive breast cancers after neoadjuvant chemotherapy. World J Surg Oncol 2018;16:51.
Eladawei GE, Elnady DA, Khater A, El-Taher SM. Impact of neoadjuvant chemotherapy on breast cancer biomarkers: A guide for further adjuvant treatment. Cancer Res J2019;7:8-17.
Shet T, Agrawal A, Chinoy R, Havaldar R, Parmar V, Badwe R. Changes in the tumor grade and biological markers in locally advanced breast cancer after chemotherapy--implications for a pathologist. Breast J 2007;13:457-64.
Ring AE, Smith IE, Ashley S, Fulford LG, Lakhani SR. Estrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer 2004;91:2012-7.
Van de Ven S, Smit VT, Dekket TJ, Nortier JW, Kroep JR. Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat Rev 2011;37:422-30.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]