|Year : 2016 | Volume
| Issue : 3 | Page : 366-371
Alteration in steroid hormone and Her-2/neu receptor status following neoadjuvant chemotherapy in locally advanced breast cancer: Experience at a tertiary care centre in India
P Ramteke1, V Seenu2, R Prashad2, SD Gupta1, V Iyer1, SVS Deo3, A Gogia4, S Mathur1
1 Department of Pathology, All Institute of Medical Sciences, New Delhi, India
2 Department of Surgery, All Institute of Medical Sciences, New Delhi, India
3 Department of Surgical Oncology, Dr. B.R.A Institute Rotary Cancer Hospital, All Institute of Medical Sciences, New Delhi, India
4 Department of Medical Oncology, Dr. B.R.A Institute Rotary Cancer Hospital, All Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||24-Feb-2017|
Department of Pathology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
CONTEXT: Use of neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC) enables tumor reduction and conservative surgery. It is proposed in some studies that there may be an alteration in the hormonal receptor (HR) status and human epidermal growth factor receptor 2 (Her-2)/neu immune-expression following NACT. AIMS: To study the status of estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu receptor before and after NACT in LABC. MATERIALS AND METHODS: HR and Her-2/neu status were evaluated by immunohistochemistry on 100 core needle biopsy of primary tumors and surgical specimens after receiving NACT (NACT group); fifty patients without NACT served as non-NACT group, and discordance was compared between the two groups. RESULTS: In the NACT group, discordance of 17%, 13%, and 11% was noted in ER, PR, and Her-2/neu status, while in non-NACT group, discordance seen in ER, PR, and Her-2/neu was 8%, 8%, and 4%, respectively. CONCLUSIONS: There was a significant alteration in ER and Her-2/neu status from the core biopsy to the treated resected tumor in the study group. As these changes may impact treatment, HR and Her-2/neu expression reanalysis in final surgical specimens is recommended.
Keywords: Breast carcinoma, human epidermal growth factor receptor 2/neu, neoadjuvant chemotherapy, steroid receptors
|How to cite this article:|
Ramteke P, Seenu V, Prashad R, Gupta S, Iyer V, Deo S, Gogia A, Mathur S. Alteration in steroid hormone and Her-2/neu receptor status following neoadjuvant chemotherapy in locally advanced breast cancer: Experience at a tertiary care centre in India. Indian J Cancer 2016;53:366-71
|How to cite this URL:|
Ramteke P, Seenu V, Prashad R, Gupta S, Iyer V, Deo S, Gogia A, Mathur S. Alteration in steroid hormone and Her-2/neu receptor status following neoadjuvant chemotherapy in locally advanced breast cancer: Experience at a tertiary care centre in India. Indian J Cancer [serial online] 2016 [cited 2017 Mar 25];53:366-71. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/366/200669
| » Introduction|| |
Breast cancer is the most commonly diagnosed cancer and the foremost cause of cancer death among females. Currently, neoadjuvant chemotherapy (NACT) is considered as the initial management of all patients with locally advanced breast cancer (LABC) followed by surgery (i.e., modified radical mastectomy or breast-conserving surgery).
It is postulated that there may be alteration in hormonal receptor (HR) status and human epidermal growth factor receptor 2 (Her-2)/neu immune-expression following NACT. There are many studies, which have been designed to address this query. However, there has been only one study in the Indian population in this regard. These studies lack uniformity in design, as well as different cut-off, and criteria for positivity have been used. Changes in expression of these biomarkers during NACT may influence the clinical decision of adjuvant molecular and hormonal therapy. Hence, revaluation of HR and Her-2/neu receptors has to be done to get actual receptor status after NACT to give a specific adjuvant therapy for patient benefit. The present study was designed to evaluate the alterations in HR and Her-2/neu receptor following NACT.
| » Materials and Methods|| |
This was a longitudinal study conducted in Department of Pathology. Clinical and investigation details were collected from records of Department of Surgery, Medical Oncology, and Surgical Oncology. Approval for the use of human cases in the present study was obtained from the Institutional Human Ethics Committee (Ref. No. IESC/T-201/01.06.2012). It was conducted in accordance with the guidelines set by the Institutional Ethical Committee. The study incorporated 150 cases of invasive carcinoma, no special type (NST). One hundred cases of LABC (Stage IIb, IIIa, and IIIb) who had received 4–8 cycles of anthracycline- and/or taxane-containing NACT followed by surgery (NACT group) and fifty patients who underwent primary surgery without receiving NACT (non-NACT group). All patients in NACT group had undergone core needle biopsy (CNB), received NACT with subsequent surgical treatment (radical or conservative surgery), and had a residual tumor with Miller–Payne grade ≤3 [Table 1].
|Table 1: The Miller–Payne system for classification of neoadjuvant chemotherapy-treated breast cancers|
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All specimens had a cold ischemic time not more than 1 h and were adequately fixed specimen for a duration between 8 and 24 h. Cases showing significant response following NACT (Miller–Payne grade ≥4) were excluded from the NACT group.
Formalin-fixed paraffin-embedded blocks were prepared from the biopsies and surgical resection specimens (RSs) of both groups and hematoxylin and eosin stained sections were examined. Appropriate blocks with adequate viable tumor tissue were selected for immunohistochemical (IHC) analysis. IHC was performed using commercially available monoclonal antibodies for estrogen receptor (ER) (Thermo Fisher Scientific, clone; RM-9101-S, dilution; 1:400), progesterone receptor (PR) (Thermo Fisher Scientific, clone; RM-9102-S, dilution; 1:400), and Her-2/neu (Thermo Fisher Scientific, clone; RM-9103-S, dilution; 1:100). Sections were cut from the selected blocks on 3-aminopropyltriethoxysilane-coated slides, and deparaffinization and antigen retrieval were done followed by 1 h incubation with primary antibody at 40°C. Polymer-based biotinylated secondary antibody followed by di-amino benzidine visualization and hematoxylin counterstain were done. With each batch, appropriate positive and negative controls (omitting the primary antibody) were also run.
IHC slides were reviewed by two pathologists (Ramteke P and Mathur S). For IHC interpretation of ER and PR, a validated semi-quantitative scoring system (the “Allred score”) was used to assess the proportion (0 = nil, 1= <1%, 2 = 1%–10%, 3 = 11%–33%, 4 = 34%–66%, and 5= ≥67%) and intensity (0 = no staining, 1 = weak, 2 = intermediate, and 3 = strong) of stained cells. The two scores are added together for a final score with eight possible values. Scores of 0–2 were considered negative, and scores of 3–8 were considered positive. IHC interpretation of Her-2/neu status was performed as four-graded system (0–3+) where, 0 (no staining or incomplete, faint/barely perceptible membrane staining in ≤10% of the tumor cells), 1+ (incomplete, faint/barely perceptible membrane staining >10% of invasive tumor cells), 2+ (incomplete and weak to moderate circumferential membrane staining in >10% of tumor cells or complete, intense, circumferential membrane staining in ≤10% of invasive tumor cells), and 3+ (complete, intense, circumferential membrane staining in ≥10% of invasive tumor cells). A score of 3+ was considered positive. Cases with equivocal (2+) score were confirmed by fluorescence in situ hybridization (FISH). FISH was performed using (Zytolight SPEC Her-2/NEU/CEN 17 Dual Color Probe Bremerhaven, Germany). The ratio of the number of copies of Her-2/neu gene to the number of chromosome 17 centromeric marker >2.2 was considered amplified.
The cases where discordant results of ER, PR, and Her-2/neu was observed between biopsy and its corresponding RS, a repeat IHC was performed in such cases.
Data were analyzed by Stata 11.2 software (StataCorp LP, Lakeway Drive College Station, Texas, USA) and presented in mean (standard deviation) and frequency percentage. Within change in a categorical variable was assessed by McNemar's test and between groups by Pearson's Chi-square and Fisher's exact test. P < 0.05 was considered as statistically significant.
| » Results|| |
All our patients were cases of invasive carcinoma, NST. The clinical and pathological characteristics are depicted in [Table 2]. All the cases were of locally advanced stage in NACT group. Among non-NACT group, 5 patients were in Stage Ia, 39 in Stage IIa, and 6 in Stage IIb. The entire study group patient received an average of five cycles of NACT. The ER, PR, and Her-2/neu positivity and their alterations in NACT and non-NACT groups are shown in [Table 2].
|Table 2: Clinical and pathological characteristics of cases in neoadjuvant chemotherapy and nonneoadjuvant chemotherapy group|
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The details of alterations in NACT and non-NACT group are documented in [Table 3]. Significant discordance in ER status was seen in 17% cases of the study group (P = 0.0016). In 15 cases, there was a loss of ER expression, while 2 cases showed ER immunopositivity in the RS. In the control group, only four cases showed discordance in ER expression, which was not significant.
|Table 3: Hormone receptor and human epidermal growth factor receptor 2/neu receptor changes after neoadjuvant chemotherapy|
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Overall change in PR status was seen in 13% cases in NACT group, of which 9% showed loss of immunoexpression in RSs, while 4% showed PR immunoexpression after NACT in RS. In non-NACT group, there was overall 8% change in PR status, out of which 6% showed a loss and 2% showed a gain of PR immunopositivity in RS [Table 3].
Her-2/neu expression remained unchanged in 89 out of 100 tested pre- and post-NACT sample pairs. Discordance in Her-2 expression was observed in 11% patients of the NACT group, which was statistically significant (P = 0.0348). In nine cases, there was a loss of Her-2/neu immunoexpression, while two cases showed a gain of Her-2/neu immunoexpression in RS. Of the nine cases, one case, which was 2+ in CNB showed Her-2/neu amplification on FISH, found to be Her-2/neu negative on RS. The discrepancy in the control group was 4%, of which 2% showed loss of Her-2/neu expression and 2% showed Her-2/neu overexpression in RS compared to biopsy results. Apart from this, there were 11 cases with equivocal (2+) results in NACT group, on which FISH was done; in 4 cases we found Her-2/neu amplification, while 7 cases were negative for Her-2/neu amplification. There were four cases of equivocal (2+) score in the control group; one case found to be Her-2/neu amplified, while three were negative for Her-2/neu amplification.
Overall there was no significant alteration seen in the status of ER, PR, and Her-2/neu in the study group compared to controls [Table 3].
| » Discussion|| |
Breast carcinoma accounts for 25% of all cancer cases and 15% of all cancer deaths among females. It is also the most common cancer in women in India and accounts for 27% of all cancers in women. According to GLOBOCON 2008, the number of new cases in India was 115,251 with the mortality rates being 53,592. However, there were 144,937 newly registered cases and 70,218 deaths due to breast cancer in India, according to the data published by GLOBOCON 2012. These data clearly point toward a steady rise in the cases of breast carcinoma.
Likewise, the management of cancer has significantly evolved over decades from radical mastectomy to breast-conserving surgeries after the introduction of NACT. In addition, antiestrogen and anti-Her-2 antibody therapy in patient having ER and Her-2/neu expression in tumor significantly improved overall survival in these patients., Hence, ER, PR, and Her-2/neu were the biomarkers routinely recommended in all the cases of breast carcinoma.
Before the era of NACT, prognosis of the LABC was very poor. Introduction of NACT leads to better local control of the disease, decreased lymph node metastasis, and increased the probability of breast-conserving surgery instead of mastectomy. It also helps to estimate the sensitivity to chemotherapy and to maximize distant disease-free survival. With the widespread use of NACT in cases of LABC, the effect of this therapy on ER, PR, and Her-2/neu receptor status has been questioned.
This study was undertaken to determine alterations in HR and Her-2/neu receptor status following NACT and also to compare the finds with patients operated without NACT. We followed standardized uniform protocol of fixation, antigen recovery, and same antibody clone with same dilution, uniform time, and temperature incubation for IHC. The IHC was repeated in all discordant cases.
We found alteration in ER, PR, and Her-2/neu status between CNB and RS in non-NACT group with discordance of 8% in ER, PR, and 4% in Her-2/neu. This discordance in non-NACT group may probably be caused by intratumoral heterogeneity. Although intra- and inter-observer variability can also lead to discordance to some extent, in the present study biopsies and resected specimens were interpreted independently by two pathologists (Ramteke P and Mathur S) and the final interpretation was made by consensus on a multiheader microscope. There are several studies which have demonstrated the concordance of ER, PR, and Her-2/neu between the CNB and excision specimen ranging from 61.7% to 99%, 61.5% to 91.3%, and 64% to 98.8%, respectively.,,,,
The present study demonstrated a significant discordance (17%) in ER status in NACT group. Among these, 15% of the patients who were ER positive on CNB were found to be ER negative upon resection, and 2% were ER negative on CNB were found to be ER positive upon resection. Discordance in PR was found to be 13%, out of which 9% were PR positive on CNB turn out to be PR negative on RS and 4% were PR negative on CNB turns out to be PR positive on RS. Discordance in HR in the present study could be due to sampling error within the heterogeneous tumor or direct effect of NACT targeting chemosensitive tumor cells leaving insensitive tumor cells with different biology behind in the residual disease.
A large study by Taucher et al., which included 214 patients who received preoperative chemotherapy, 14% of patients who were ER-positive on CNB turned out to be ER negative in RS. Likewise, 51.7% of patients who were PR positive on CNB were found to be PR negative on resection. For the controls, 5.4% of patients initially ER-positive and 26.8% of patients initially PR positive were found to be negative for the respective HR after evaluation of the RS. These differences between the patients receiving NACT and the controls were statistically significant. There are other similar studies which have found significant changes in the HR status after NACT.,,,,,,,
There was only one Indian study published in this regard, in which 73 cases were selected and no control group were taken, found 13% change in ER status (i.e., 5% cases changed from positive to negative status, 8% cases changed from negative to positive status) and 22% change in PR status (i.e., 7% cases changed from positive to negative, 15% cases changed from negative to positive).
There are relatively fewer studies which have reported no significant alterations in HRs following NACT. In a study by Lee et al., where they included 56 cases and 56 controls, found 18% and 21% change in ER or PR status in cases and controls, which was not statistically significant. Another study by Arens et al. compared a group of 25 patients who received NACT to a control group of 30 patients. No significant differences were noted between the CNB and the resected specimen regarding HR expression. In above studies, the sample size was small compared to the present study and they use a cut-off value of ≥10% for HR status. However, we used Allred score ≥3 as criteria for HR positivity. Similar results have been documented in few other studies.,,, The studies which showed a significant alteration in HR are outlined in [Table 4].
|Table 4: Studies which showed alterations in hormone receptor status following NACT|
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Among above-described studies, in only two studies the positivity criteria for HR evaluation similar to our study was used,, rest of the studies used ≥10% positivity criteria for HR. Hence, we recommend large studies to be done with uniform cut-off criteria. In our study, we selected only the cases of invasive carcinoma, NST for HR and Her-2/neu alteration study, while in most of the previous studies all subtypes were included.,,,, One important point to be emphasized in the current study is a low rate of ER-positive cases which was 51% in the study group and 46% in control group, in comparison to 75% as reported in literature. This could be possibly because of the ethnicity of the present sample.
Likewise, there are several studies which addressed the effect of NACT on Her-2/neu status. Findings of some of the key studies are depicted in [Table 5]. A study by Neubauer et al. (n = 87) using Her-2/neu positivity cut-off of 3+ found 15% change in the Her-2/neu status after NACT, out of these in 85% there was a loss of Her-2/neu expression. A study by Avci et al., (n = 100), concluded a significant change in Her-2/neu status after NACT. However, a study by Adams et al. found 23% increase in the expression of Her-2/neu in patients after NACT. In the current study, there was Her-2/neu alteration in 11% of the cases (out of these, in 9% there was a loss of Her-2/neu overexpression) in NACT group, which was significant (P = 0.0348). These alterations could be due to eliminated Her-2/neu overexpressing clones leaving only Her-2/neu negative tumor cells. Likewise, variable results were also observed in other studies.,,,, Taucher et al. analyzing an anthracycline/taxane-based neoadjuvant therapy regime found no significant change of Her-2/neu expression. Similarly, some studies did not found any significant alteration in the Her-2/neu status after NACT.,,,
|Table 5: Studies showed alterations in Her-2/neu receptor status following NACT|
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In most of these studies, FISH was not performed in equivocal (2+) cases.,,,,,, Although, at present, the data regarding Her-2/neu alteration after NACT are conflicting but based on our results we recommend that the Her-2/neu score should be re-evaluated in posttreatment tissue.
It is a known fact that trastuzumab-based neoadjuvant systemic therapy in patients with Her-2/neu overexpressing breast cancer achieved a high rate of pathological complete remission. A study by Mittendorf et al. and Hurley et al. found 32% and 43% loss of Her-2/neu amplification, respectively, in the residual tumor of the patients received trastuzumab-based neoadjuvant systemic therapy. However, in our study, none of our cases had received trastuzumab. FISH is the gold standard for detection of Her-2/neu amplification. In above two studies, FISH was used for Her-2/neu amplification detection. However, in the present study, we performed FISH only in Her-2/neu 2+ (equivocal) cases.
| » Conclusions|| |
Current guidelines do not recommend repeat performance of hormonal and Her-2/neu receptors following NACT. Notable alterations in hormonal and Her-2/neu receptors in patients receiving NACT were observed in this study. Although this did not achieve statistical significance, it may justify re-evaluation of these markers in RS given the alterations reported in this and other studies reported. Larger studies analyzing the impact of these alterations in patient survival need to be undertaken to know the significance of these alterations in patient management.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]