Abstract
Background
Breast cancer is a heterogenous group of diseases with steroid hormone dependant carcinogenesis. Along with Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2 (HER2), androgen receptor (AR) is now emerging to play key role in disease progression of various molecular breast cancer subtypes especially triple negative breast cancers. Aim of this study was to find out prevalence of AR positivity in all breast cancers, correlation of ER, PR, HER2 and Ki67 index with AR positivity. To find out correlation of AR positivity with histological grade.
Methods
This was a descriptive cross-sectional study done on 55 primary breast carcinoma cases. Routine Hematoxylin and Eosin stain as well as immunohistochemical ER, PR, HER2/neu, Ki67 and AR stain were done. The outcome was assessed in the form of relationship between AR and ER, PR, HER2 status and Ki-67 index and histopathological grade.
Results
AR positivity was seen in 69% of all breast cancers. AR positivity was seen in 8% of triple negative breast cancers. High Ki67 index showed 55% AR positivity. Grade II breast cancers showed 42% AR positivity.
Conclusion
Cases with triple negative breast cancers have worst prognosis. Unlike targeted novel hormone therapy (tamoxifen) in luminal cancers and monoclonal antibody (trastuzumab) in her2 enriched cancers, AR is looked upon as a target to treat triple negative breast cancer. However, the existing controversies demand more AR related studies.
Keywords: Androgen receptors, Prognostic marker, Predictive marker
Introduction
Breast cancer (BC) in females is the most common cancer and fifth cause of death in females worldwide. Mortality-wise, BC is greater in underdeveloped countries while incidence-wise, it is higher in industrialized countries, and it is attributed to availability of screening test for early detection and advanced treatment.1 Among Indian females, prevalence of primary BC is as high as 25 per 100,000 women.2 Younger women show aggressive features and worse prognosis, whereas post-menopausal women show more prevalence of BC.3 Pathogenesis of BC is steroid hormone-dependant; therefore, it shows large heterogeneity. PAM50 classification shows 4 different types of BC, depending on the mRNA levels of Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2 (HER2) and Ki67 index. Luminal BC is further subtyped as Luminal A and B depending on the expression of Ki67. HER2-enriched BC are characterized by more aggressive phenotype and worse prognosis compared to luminal BC. Basal-like triple-negative breast cancer (TNBC) have worst outcome among all the BCs.4 This heterogeneity explains why there is not a single therapy for BC treatment and highlights the need to develop new therapeutic strategies, alternative to the baseline drugs-Tamoxifen or Trastuzumab or Lapatinib useful only with ER or HER2 positive status. Where ER, HER2 are negative TNBC, the androgen receptor (AR) is emerging as a predictive marker and a potential new therapeutic target.5 AR is positive in 50–70% of overall BC.6 AR is positive in 84–91% of luminal A and luminal B (ER+ve, HER2-ve).7 AR is positive in about 59% of HER2-enriched subtype.8 AR is positive in 7–75% of TNBC.9 With this background, the present study was conducted to find out AR positivity in our set up.
Materials and methods
This study was a descriptive cross-sectional study conducted in the department of pathology, in a tertiary health care center. We studied a total of 55 primary BC cases from January 2020 to June 2021. The data was obtained from histopathological form that was received with the surgically resected BC specimen. The cases were selected after applying the selection criteria. Histopathologically confirmed cases of primary breast carcinoma either biopsy, lumpectomy or mastectomy specimens were included in our study. Cases of primary breast carcinoma who had received neoadjuvant therapy and secondary breast carcinoma (metastasis) were excluded. The study was approved by the institutional ethical committee. Informed consent was obtained from all the patients for use of data and figures in the study All good clinical practice guidelines as per declaration of Helsinki were followed during the study.
Tissue samples from primary tumor were fixed in 10% neutral buffered formalin for 24 h. Routine sections were taken and stained with Hematoxylin and Eosin (H&E). Histopathological study of H&E sections was done to assess histological subtype, axillary nodal status, lymphovascular invasion, Ductal carcinoma in situ (DCIS) and Lobular carcinoma in situ (LCIS) component. Histological grading of tumor was done according to modified Bloom–Richardson grading and staging according to pTNM classification designated by American Joint Committee on Cancer.10 Immunohistochemical stain for ER, PR, HER2/neu, Ki67 and AR was done on representative tumor paraffin blocks using a standard protocol. The immunostained slides were examined for nuclear staining in the case of ER, PR, AR and Ki-67, and membrane staining in the case of HER2/neu and recorded in CAP biomarker template.11 For hormone receptors, the proportion of positive staining tumor cells (expressed in percentage) and the average intensity of staining was evaluated based on Allred score method.12 HER2/neu staining was scored from 0 to 3+.13,14 Ki67 was scored as percentage of positively stained cells among the total number of malignant cells.15 AR expression was semi-quantitatively analyzed according to the percentage of cells showing nuclear positivity: 0, 0%; 1+, 1%–29%; 2+, 30%–69%; 3+, ≥70%. Scores ≥1 were considered positive, and a score of 0 was negative.16 The cases were evaluated for AR expression based on intrinsic subtypes- Luminal A, Luminal B, HER2 and TNBC.17
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Luminal A shows ER and PR positive expression with PR expressing high Allred score 5 to 8
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Lumina B, HER2-shows ER and PR positive expression with PR expressing low Allred score 0 to 4 and any Ki67 or ER positive with any PR and Ki67 high but with negative HER2.
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Luminal B, HER2+ is Luminal B as defined above but with overexpression of HER2.
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HER2-enriched is HER2 positive with no expression of ER and PR.
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TNBC is lack of all three hormone expressions—ER, PR and HER2.
The relationship between AR expression and various parameters such as age, menopausal status, tumor size, tumor extent, histologic type, histologic grade, lymph node status and the expression of ER, PR, HER2/neu and Ki-67 index was studied. The statistical analysis for correlation among these parameters was determined using tests like Pearson Chi-square test with the help of SPSS software. Significance was assumed at p < 0.05.
Results
We studied 55 primary breast carcinoma cases, mean age at diagnosis of these cases was 50.55 years. 84% (46/55) belonged to the age group above 40 years and 16% (9/55) were below 40 years.
In our study, the threshold for defining AR positivity was atleast 1% of tumor cell nuclei showing immunoreactivity for AR. All the clinicopathological features and immunohistochemical status were compared in AR positive and AR negative cases using 1% as cutpoint for AR positivity.
AR and clinicopathological characteristics in all breast cancer cases
Our study included 55 primary breast carcinoma cases, of which 38 cases (69.1%) were AR positive and 17 cases (30.9%) were AR negative (Table 1).
Table 1.
Histopathological features and expression of AR.
| Variables | Total No. (%) |
AR Positive No. (%) |
AR Negative No. (%) |
p value |
|---|---|---|---|---|
| Total no. | 55 pts | 38(69.1) | 17(30.9) | |
| Histological type | 0.000 | |||
| IDC, NOS | 44 (80.0) | 29 (76.0) | 15 (88.2) | |
| Invasive Carcinoma with Ductal and Lobular Features-Mixed Carcinoma | 6 (10.9) | 6 (15.7) | 0 (0) | |
| Invasive Lobular Carcinoma | 2 (3.64) | 2 (5.2) | 0 (0) | |
| Invasive Papillary Carcinoma | 1 (1.82) | 1 (2.6) | 0 (0) | |
| Metaplastic Carcinoma | 2 (3.64) | 0 (0) | 2 (11.7) | |
| Histologic Grade | 0.045 | |||
| Grade I | 26 (47.2) | 22 (57.9) | 4 (23.5) | |
| Grade II | 22 (40.0) | 13 (34.2) | 9 (53.0) | |
| Grade III | 7 (12.8) | 3 (7.9) | 4 (23.5) | |
| Tumor size | 0.8 | |||
| ≤2 cm | 4 (7.3) | 3 (7.9) | 1 (5.9) | |
| >2 and ≤5 | 31 (56.3) | 22 (57.9) | 9 (52.9) | |
| >5 cm | 20 (36.4) | 13 (34.2) | 7 (41.2) | |
| Pathological stage of primary tumor | 0.744 | |||
| pT1 | 6 (10.0) | 5 (13.1) | 1 (5.8) | |
| pT2 | 27 (49.0) | 17 (44.9) | 10 (58.8) | |
| pT3 | 14 (25.4) | 11 (28.9) | 3 (17.7) | |
| pT4 | 8 (14.5) | 5 (13.1) | 3 (17.7) | |
| Pathological stage of nodal spread | 0.362 | |||
| pN0 | 16 (29.0) | 9 (23.6) | 7 (41.1) | |
| pN1 | 15 (27.2) | 11 (28.9) | 4 (23.5) | |
| pN2 | 17 (30.9) | 14 (36.8) | 3 (17.7) | |
| pN3 | 7 (12.7) | 4 (10.5) | 3 (17.7) | |
| Lymphovascular invasion: Absent | 30 (54.5) | 19 (50.0) | 11 (64.7) | 0.227 |
| Present | 25 (45.4) | 19 (50.0) | 6 (35.3) | |
| Perineural invasion: Absent | 49 (89.0) | 34 (89.5) | 15 (88.2) | 0.892 |
| Present | 6 (10.9) | 4 (10.5) | 2 (11.8) | |
| Necrosis | 0.035 | |||
| Absent | 38 (69) | 30 (78.9) | 8 (47.0) | |
| Present | 17 (31) | 8 (21.1) | 9 (53.0) |
Age: Of the 69.1% (38/55) AR-positive cases, 92% of cases were in age group >40 yrs (35/38 cases) and 8% of cases (3/38 cases) were in age group ≤40 yrs.
Histologic grade: Our study had 57.9% (n = 22) grade I cases showing AR positivity, 34.2% (n = 13) grade II cases and only 7.9% (n = 3) grade III cases showing AR positivity.
DCIS and LCIS component: Of the total cases, DCIS was present in only 18(32.73%) cases, AR positivity was seen in 16(88.9%) cases, whereas no AR expression was seen in 2(11.1%) cases.
LCIS was seen in 1 case (1.82%). This case was histologically Invasive Lobular Carcinoma with 3+ AR status.
Age and necrosis were found to have significant statistical correlation with AR expression.
There was no statistically significant association between the tumor size, pathological stage of primary tumor, nodal spread, lymphovascular invasion, perineural invasion, necrosis, DCIS and LCIS component with AR (p value ≥ 0.05).
Histopathological and immunohistochemical characteristics stratified by AR status
Histopathological and immunohistochemical characteristics (IHC) subtypes: Among 44 IDC, NOS subtypes, 14 cases (32%) belonged to Luminal A subtype, 16 cases (36%) belonged to Luminal B, 4 cases (9.0%) belonged to HER2-enriched and 10 cases (23%) had triple-negative tumors. The one case of IDC, NOS with apocrine features belonged to the TNBC subtype. Among 6 invasive carcinomas with ductal and lobular features, 4 cases (67%) belonged to Luminal A and remaining 2 cases (33%) belonged to luminal B subtype. Among other subtypes, all cases of ILC (n = 2) and invasive papillary carcinoma (n = 1) belonged to Luminal A while all cases of metaplastic carcinoma (n = 2) belonged to triple-negative subtype (Table 2).
Table 2.
Relationship of AR positive and AR negative with IHC findings.
| Variables | Total | AR positive | AR Negative | p value |
|---|---|---|---|---|
| No. (%) | No. (%) | No. (%) | ||
| Total no. of pts | 55 (100) | 38 (69.1) | 17 (30.9) | |
| ER Status | 0.000 | |||
| Positive | 39 (72.7) | 36 (94.7) | 3 (17.7) | |
| Negative | 16 (27.3) | 2 (5.3) | 14 (82.3) | |
| PR Status | 0.000 | |||
| Positive | 32 (58.2) | 29 (76.4) | 3 (17.7) | |
| Negative | 23 (41.8) | 9 (23.6) | 14 (82.3) | |
| Her2 Status | 0.284 | |||
| Positive | 6 (11) | 3 (7.9) | 3 (17.7) | |
| Negative | 49 (89) | 35 (92.1) | 14 (82.3) | |
| Ki-67 | 0.003 | |||
| Low index | 19 (34.5) | 18 (47.3) | 1 (5.8) | |
| High index | 36 (65.5) | 20 (52.7) | 16 (94.2) | |
| IHC subtypes | 0.000 | |||
| Luminal A | 21 (38.1) | 20 (52.6) | 1 (5.8) | |
| Luminal B | 18 (32.7) | 16 (42.1) | 2 (11.7) | |
| Her2 enriched | 4 (7.3) | 1 (2.6) | 3 (17.6) | |
| TNBC | 12 (21.9) | 1 (2.6) | 11 (64.7) |
IHC subtypes and AR: AR positivity (Fig. 5) in IHC subtypes was more in luminal A and luminal B subtypes- 52.6% (20/38) and 42.1% (16/38), respectively. Whereas, Her2-enriched and TNBCs had a greater number of AR negative tumors- 17.6% (3/17) and 64.7% (11/17). Only one case of TNBC showing IDC with apocrine features was positive for AR and the rest (n = 11) were AR negative.
Fig. 5.
Microscopic image (100×) of AR Positive (score 3+).
Proliferation index: Of 19 cases with low Ki 67 index, 18 cases (47.3%) were AR positive while 1 case (5.8%) was AR negative. Of 36 cases with high Ki67 index (Fig. 4), 20 cases (52.7%) were AR positive while 16 cases (94.2%) were AR negative. We found highly significant statistical correlation of AR with Ki67 index.
Fig. 4.
Microscopic image (100×) of Ki67 index 80%.
Discussion
AR is now gaining recognition as the newly emerging biomarker in BCs.18 The selective AR inhibitors introduced recently for the treatment of prostate cancer has shown the possibility of their beneficial ecomonic use in BC cases that express AR.19 The molecular location of AR is on chromosome Xq11-12 that is a hormone regulating transcription factor.20 AR shows nuclear expression unlike ER and PR. In our study, tumor cells showing >1% AR expression were considered as AR positive. AR status was reported as positive with tumor cells showing >1% expression in the study by Fragomeni et al.21 In the study by Park et al.22 tumors with >10% positively nuclear-stained cells were considered AR positive. Astvatsaturyan et al.9 in their study used 1%, 10%, 20%, 25% and 30% as threshold for AR positivity.
The role of AR in BCs is variable, AR inhibits the tumor cell proliferation in ER positive BC, whereas it promotes tumor growth in ER-negative BC.23 So both the AR modulators or blockers can be used as per the scenario demands. AR antagonists like bicalutamide and enzalutamide have proved to be of use in advanced BC cases where they have an aggressive behavior, like in Tamoxifen-resistant BCs and TNBC.24
Unlike the role of AR, the expression of AR in BCs is also variable. It differs widely depending upon histological grade, histological type, immunohistochemical status and molecular subtype of BC. Most incidences reported uniform and diffuse AR expression in the intrinsic TNBC type. In these cases, the common histological type often found is carcinoma with apocrine features. It is a ductal tumor where the invasive cells exhibit extensive (>90%) apocrine cell change.9 We found AR positivity in 69% of overall BC cases, which was in line with study by Giovannelli et al.,6 and Tsang et al.25 who found AR positivity in 50–70% and 60–90% of overall BCs, respectively. We found statistically significant correlation of AR with grade of tumor (p = 0.045). In a study by Astvatsaturyan et al.,9 they found AR positive rate in tumor grades I, II and III was more than AR negative rate. In another study by Park et al.,22 they found highly significant statistical correlation with AR positive more in grade I and II while AR negative was more in grade III.
AR and ER expression: In our study, of 16 (27.3%) ER negative cases, 14 cases (82.3%) were AR negative and 2 cases (5.3%) were AR positive. Out of the 39 ER positive cases (Fig. 1), 94.7% were AR positive and 17.7% were AR negative. There was highly significant statistical association of AR with ER expression. AR and PR expression: In our study, out of 23 PR negative cases, 82.3% were AR negative while 23.6% were AR positive. And out of 32 PR positive cases (Fig. 2), 76.4% were AR positive while 17.7% were AR negative. There was a highly significant statistical correlation of PR expression with AR. This was comparable with the study by Park et al.,22 they found AR expression in ER positive was 86.9% compared to 13.1% in ER negative. This difference was found to be statistically significant (P ≤ 0.001), also AR expression in PR positive was 74.9% compared to 25.1% in PR negative. This difference was found to be statistically significant (P ≤ 0.001). AR and HER2 overexpression: In our study, out of 6 HER2 positive cases (Fig. 3), 7.9% were AR positive and 17.7 were AR negative. Among 49 HER2 negative cases, 35(92.1%) were AR positive and 14 (82.3%) were AR negative. There was no significant statistical correlation with HER2 and AR expression. A study by Park et al.,22 also showed no statistically significant correlation of AR and HER2(P = 0.150). Our study showed highly significant statistical correlation with TNBC and AR expression (P ≤ 0.000). In a study by Park et al.,22 of 34.6% of triple-negative cases only 3.9% were AR positive. There was a highly significant statistical correlation with TNBC and AR expression (P ≤ 0.001). In our study, we found AR positivity in 8% of TNBC cases. A study by Astvatsaturyan et al.9 found AR expression in TNBC with values ranging from 7 ± 75%.
Fig. 1.
Microscopic image (100×) of ER positive (score 8/8) with inset showing positive internal control.
Fig. 2.
Microscopic image (100×) of PR positive score (8/8).
Fig. 3.
Microscopic image (100×) of Her2 positive (3+).
Limitations: In our study, sample size was small (n = 55), cold ischemia time was not mentioned in the histopathological requisition form that we received. The data was collected from histopathological requisition form, many parameters like menstrual status, number of children, duration of lactation and other such parameters couldn't be assessed due to lack of information in the forms.
We assessed intrinsic subtypes of BC using IHC and not gene expression profile.
Summary and conclusion
AR showed statistically significant correlation with age, grade of the tumor and necrosis. In the spectrum of TNBC with uniform and diffuse AR expression, often histological type is manifested as carcinoma with apocrine features (a ductal tumor where the invasive cells exhibit extensive (>90%) apocrine cell change). We found significant statistical correlation between ER, PR and Ki67 with AR (with P value = 0.000, 0.0000 and 0.003, respectively). There was no significant statistical correlation of Her2 with AR expression. There was inverse relation between tumor size, DCIS, LCIS, lymphovascular invasion, perineural invasion, pathological stage and lymph node status and AR.
Cases with TNBCs have worst prognosis. Unlike targeted novel hormone therapy (tamoxifen) in luminal cancers and monoclonal antibody (trastuzumab) in her2-enriched cancers, AR is looked upon as a target to treat triple-negative BC. However, the existing controversies demand more AR-related studies.
In conclusion, AR is a prognostic and predictive marker and can be used in the treatment and follow-up of advanced BCs like Tamoxifen-resistant BCs and TNBC.
Patients/ Guardians/ Participants consent
Patients informed consent was obtained.
Ethical clearance
Institute/hospital ethical clearance certificate was obtained.
Source of support
None.
Disclosure of competing interest
The authors have none to declare.
Acknowledgements
The authors gratefully acknowledge Dr. Amit Mohite for statistical help.
References
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