Abstract
Breast cancer remains a significant cause of mortality globally, necessitating effective treatment strategies. Neoadjuvant chemotherapy (NAC) is widely employed to minimize tumor burden and prevent local spread, with treatment efficacy varying based on molecular subtypes. Despite advancements, resistance to conventional therapies persists, prompting the exploration of alternative approaches, including immune cell therapy. Tumor-infiltrating lymphocytes (TILs) have emerged as immunological biomarkers in breast cancer, exhibiting associations with molecular subtypes and treatment response. This retrospective study assessed the clinico-pathological relationship between stromal TILs and AR expression across molecular subtypes of invasive breast carcinoma in an Indian cohort. Thirty-seven patients receiving NAC followed by modified radical mastectomy were analyzed for TILs and molecular subtyping. Immunohistochemistry was used to determine hormone receptor status and AR expression. A higher AR positivity was observed in hormone receptor-positive/Her2neu-negative and hormone receptor-positive/Her2neu-positive tumors compared to triple-negative breast cancers (TNBCs). Significant associations were observed between AR expression and tumor grade, but not with age or Her2neu status. Although no significant correlation was found between AR and complete response to NAC, a weak negative correlation between AR and TILs was noted. Notably, TNBCs with negative AR and Ki67 index exhibited poorer responses to NAC, emphasizing the need for adjuvant therapy. These findings underscore the complex interplay between AR, TILs, and treatment response in breast cancer, highlighting the potential of personalized therapeutic approaches. Further research is warranted to elucidate the prognostic significance of AR and its implications for tailored treatment strategies in breast cancer management.
Keywords: Breast cancer, Neoadjuvant chemotherapy, Tumor-infiltrating lymphocytes, Androgen receptor, Molecular subtypes
Introduction
Breast cancer is the second most common cause of mortality in females, worldwide and to minimize this adversity, neoadjuvant chemotherapy (NAC) is widely used [1]. It reduces the overall tumor burden and prevents its localized spread [2]. Based on the hormone receptor status, treatment varies as Her2neu-positive tumors respond to a greater extent after Trastuzumab therapy [3]. But there are reports of resistance to traditional therapies as well [4]. This changing tumor dynamics needs to be investigated more thoroughly for the betterment of the patients. In this regard, immune cell therapy has gained significant importance in the recent past. Tumor infiltrating lymphocytes (TILs) are now used as immunological biomarkers in many human cancers including breast [5]. Studies are highlighting the association of TILs with molecular subtypes in breast cancer and its role in a pathological response post-NAC. TILs can be evaluated on hematoxylin and eosin (H&E) stained paraffin sections during routine reporting and have been used by researchers as a reliable and inexpensive method to assess the immune response in breast cancer [6]. For better uniformity and reporting, the International TIL Working Group (ITILWG) has given guidelines for reporting of TILs [7].
The continuous evolution of new targets for improved response in breast cancer is a never-ending task. Androgen receptors (AR) are steroid receptors and have a definite role in cell differentiation and proliferation. When androgen is present, the AR binds to hormone response elements which further regulates upregulation or downregulation of specific protein expression [8]. Previous studies showed the worst outcome in estrogen receptor (ER)-negative and Her2neu-enriched breast carcinomas having increased AR expression. Apart from this, in a few of the preclinical trials, a significant antitumor effect was observed when HER2neu and AR were targeted simultaneously [9, 10]. Contrary to this, in triple-negative breast cancer (TNBC), AR is supposed to be an important biomarker, and better survival was also noted in previous reports [11]. Overall, clinical utility and response to therapy in AR-positive breast cancer needs further evaluation. Although TILs had shown significant predictive value for pathological complete response (pCR) in TNBC, there is limited literature regarding its association with AR.
In this study, we intend to evaluate the clinico-pathological relationship between stromal TILs and AR across different molecular subtypes of invasive breast carcinoma, with no special subtype (IBC, NST) in the Indian cohort.
Materials and Methods
In this retrospective study of 1 year (November 2022 to October 2023), all the patients diagnosed with IBC and NST on core needle biopsy were reevaluated for sTILs and molecular subtyping. Only those patients who received NAC and then underwent modified radical mastectomy (MRM) were included in the study. We found 37 cases in our archives following the above inclusion criteria.
All the specimens were fixed in 10% neutral buffered formalin, and paraffin-embedded blocks were prepared followed by sectioning of 4 μm thickness. The slides were stained with H&E, and immunohistochemistry was applied for hormone receptor status and molecular subtyping. The positivity for estrogen receptor (ER) and progesterone receptor (PR) was defined when > 1% immunoreactivity was observed in tumor cells [12]. For Her2neu staining, guidelines of the College of American Society of Pathologists were used and hence 3 + positives were considered when ≥ 30% of cells showed uniform intense positivity. An additional IHC of AR was also done in all the cases, and the criteria for positivity were similar to that of the ER and PR [13].
All the cases were assessed for reconfirmation of the diagnosis of IBC, NST (based on the 5th edition of WHO [14] Blue Book Breast Pathology) and hormone status by two pathologists independently. The sections were also evaluated for lymphovascular invasion and modified Bloom Richardson score (BR). Furthermore, sTILs were evaluated, and the expression of AR was recorded in different molecular subtypes. The guidelines recommended by the ITILWG [7] were followed by the two pathologists for the evaluation of sTILs; the mean of which was considered as the final one. Lymphocytes and plasma cells within the tumor stroma excluding polymorphonuclear cells were considered as sTILs. The results of TILs were assessed in increments of 10, where 0 represented < 5%, 10 represented 5 to 10%, 20 represented 11 to 20%, and the rest scores were rounded up to the next higher 10%. The corresponding resection specimens were examined to see the residual tumor burden based on the Miller-Payne grading system for pCR [15]. Cases having no invasive or microinvasive foci and uninvolved axillary lymph nodes were considered as complete response after NAC.
Statistical Analysis
The presentation of the categorical variables was done in the form of numbers and percentages (%). The data normality was checked by using the Shapiro–Wilk test. In the cases in which the data was not normal, non-parametric tests were used. The association of the qualitative variables were analyzed using the chi-square test. If any cell had an expected value of less than 5, then Fisher’s exact test was used. The receiver operating characteristic (ROC) curve was used to assess the cut-off point, sensitivity, specificity, positive predictive value, and negative predictive value of Ki67 (%) for predicting positive AR. The ROC curve was also used to assess the cut-off point of TILs for predicting a complete response. Point biserial correlation was used for the correlation of AR with various parameters and for the correlation of LVI, ER, PR, and HER2 with TILs. Spearman rank correlation coefficient was used for the correlation of TILs with grade. Pearson correlation coefficient was used for the correlation of TILs with age and Ki67.
The data entry was done in the Microsoft EXCEL spreadsheet, and the final analysis was done with the use of Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, Ver 25.0. For statistical significance, a p-value of less than 0.05 was considered statistically significant.
Results
The median age of 37 patients was 51 out of which 22 (59.5%) were AR-positive on pre-NAC core needle biopsies. The distribution of age between AR-negative and AR-positive patients does not show any significant difference (p = 0.306). Furthermore, no significant differences were observed in the distribution of ER status (p = 0.315), PR status (p = 0.742), ki67 (p value = 0.118), LVI (p = 0.491), molecular subtypes (p = 0.107), and pCR (p = 0.08) between AR-negative and AR-positive patients. However, significant disparities were found in the distribution of tumor grade (p = 0.036), HER2 status (p = 0.035), and TIL percentage (≤ 10%) (p value = 0.006) (Table 1).
Table 1.
Association of parameters with Androgen Receptor Negative and Androgen Receptor positive status
| Parameters | AR-negative (n = 15) | AR-positive (n = 22) | Total | p value |
|---|---|---|---|---|
| Age (years) | ||||
| ≤ 50 | 8 (53.33%) | 8 (36.36%) | 16 (43.24%) | 0.306† |
| > 50 | 7 (46.67%) | 14 (63.64%) | 21 (56.76%) | |
| Grade | ||||
| Grade 2 | 7 (46.67%) | 18 (81.82%) | 25 (67.57%) | 0.036* |
| Grade 3 | 8 (53.33%) | 4 (18.18%) | 12 (32.43%) | |
| ER | ||||
| Negative | 10 (66.67%) | 11 (50%) | 21 (56.76%) | 0.315† |
| Positive | 5 (33.33%) | 11 (50%) | 16 (43.24%) | |
| PR | ||||
| Negative | 9 (60%) | 12 (54.55%) | 21 (56.76%) | 0.742† |
| Positive | 6 (40%) | 10 (45.45%) | 16 (43.24%) | |
| HER2 | ||||
| Negative | 13 (86.67%) | 11 (50%) | 24 (64.86%) | 0.035* |
| Positive | 2 (13.33%) | 11 (50%) | 13 (35.14%) | |
| Ki67 (%) | ||||
| ≤ 20 | 9 (60%) | 19 (86.36%) | 28 (75.68%) | 0.118* |
| > 20 | 6 (40%) | 3 (13.64%) | 9 (24.32%) | |
| LVI | ||||
| Negative | 11 (73.33%) | 13 (59.09%) | 24 (64.86%) | 0.491* |
| Positive | 4 (26.67%) | 9 (40.91%) | 13 (35.14%) | |
| TILs (%) | ||||
| ≤ 10% | 4 (26.67%) | 17 (77.27%) | 21 (56.76%) | 0.006* |
| > 10% | 11 (73.33%) | 5 (22.73%) | 16 (43.24%) | |
| Molecular class | ||||
| Luminal A | 3 (20%) | 3 (13.64%) | 6 (16.22%) | |
| Luminal B | 2 (13.33%) | 4 (18.18%) | 6 (16.22%) | |
| Luminal B (Her2 positive) | 0 (0%) | 4 (18.18%) | 4 (10.81%) | |
| Her2neu enriched | 2 (13.33%) | 7 (31.82%) | 9 (24.32%) | |
| Triple negative | 8 (53.33%) | 4 (18.18%) | 12 (32.43%) | |
| PCR | ||||
| No PCR | 8 (53.33%) | 18 (81.82%) | 26 (70.27%) | 0.08* |
| PCR | 7 (46.67%) | 4 (18.18%) | 11 (29.73%) | |
*Fisher’s exact test, †chi square test
When we compared various clinical and molecular characteristics with and without pathological complete response (pCR), a significant association was observed with tumor grade (p = 0.001), ki67 index (p = 0.0009), LVI (p = 0.003), and TIL percentage (p = 0.0002). (Table 2). The majority of the patients with pCR had grade 3 tumor, high ki67 index (> 20%), absence of LVI, and high TILs (> 10%). However, no significant association were seen with ER, PR, and HER2Neu status and molecular subtyping with pCR (Table 2).
Table 2.
Association of parameters with pathological complete response (pCR)
| Parameters | No PCR (n = 26) | PCR (n = 11) | Total | p value |
|---|---|---|---|---|
| Age (years) | ||||
| ≤ 50 | 9 (34.62%) | 7 (63.64%) | 16 (43.24%) | 0.151* |
| > 50 | 17 (65.38%) | 4 (36.36%) | 21 (56.76%) | |
| Grade | ||||
| Grade 2 | 22 (84.62%) | 3 (27.27%) | 25 (67.57%) | 0.001* |
| Grade 3 | 4 (15.38%) | 8 (72.73%) | 12 (32.43%) | |
| ER | ||||
| Negative | 13 (50%) | 8 (72.73%) | 21 (56.76%) | 0.285* |
| Positive | 13 (50%) | 3 (27.27%) | 16 (43.24%) | |
| PR | ||||
| Negative | 14 (53.85%) | 7 (63.64%) | 21 (56.76%) | 0.723* |
| Positive | 12 (46.15%) | 4 (36.36%) | 16 (43.24%) | |
| HER2 | ||||
| Negative | 14 (53.85%) | 10 (90.91%) | 24 (64.86%) | 0.057* |
| Positive | 12 (46.15%) | 1 (9.09%) | 13 (35.14%) | |
| Ki67 (%) | ||||
| ≤ 20 | 24 (92.31%) | 4 (36.36%) | 28 (75.68%) | 0.0009* |
| > 20 | 2 (7.69%) | 7 (63.64%) | 9 (24.32%) | |
| LVI | ||||
| Negative | 13 (50%) | 11 (100%) | 24 (64.86%) | 0.003* |
| Positive | 13 (50%) | 0 (0%) | 13 (35.14%) | |
| TILs (%) | ||||
| ≤ 10% | 20 (76.92%) | 1 (9.09%) | 21 (56.76%) | 0.0002* |
| > 10% | 6 (23.08%) | 10 (90.91%) | 16 (43.24%) | |
| Molecular class | ||||
| Her2neu enriched | 8 (30.77%) | 1 (9.09%) | 9 (24.32%) | 0.093* |
| Luminal A | 5 (19.23%) | 1 (9.09%) | 6 (16.22%) | |
| Luminal B | 4 (15.38%) | 2 (18.18%) | 6 (16.22%) | |
| Luminal B (Her2 positive) | 4 (15.38%) | 0 (0%) | 4 (10.81%) | |
| Triple negative | 5 (19.23%) | 7 (63.64%) | 12 (32.43%) | |
*Fisher’s exact test
The distribution of complete response across molecular subtypes was observed as Luminal A 9.09%, Luminal B 18.18%, Luminal B (Her2neu positive) 0%, and TNBC 63.64% and multivariate analysis revealed that TILs (> 10%) can be considered as an independent predictor of pCR (Table 3). Furthermore, AR expression does not significantly impact various clinicopathological and molecular characteristics of breast cancer in patients with PCR (Table 4). A significant weak positive correlation was seen between AR with HER2 with a correlation coefficient of 0.377, and a significant weak negative correlation was seen between AR with grade and TILs (%) with correlation coefficients of − 0.369 and − 0.344, respectively (Table 5).
Table 3.
Multivariate logistic regression to find out significant factors affecting complete response
| Variable | Beta coefficient | Standard error | p value | Odds ratio | Odds ratio lower bound (95%) | Odds ratio upper bound (95%) |
|---|---|---|---|---|---|---|
| Ki67(%) | − 0.042 | 0.071 | 0.554 | 0.959 | 0.835 | 1.101 |
| TILs (%) | 0.151 | 0.046 | 0.001 | 1.163 | 1.062 | 1.274 |
| LVI | − 2.071 | 1.600 | 0.195 | 0.126 | 0.005 | 2.900 |
Table 4.
Association of parameters with PCR in AR − and AR +
| Parameters | AR-negative (n = 7) | AR-positive (n = 4) | Total | p value |
|---|---|---|---|---|
| Age (years) | ||||
| ≤ 50 | 4 (57.14%) | 3 (75%) | 7 (63.64%) | 1* |
| > 50 | 3 (42.86%) | 1 (25%) | 4 (36.36%) | |
| Grade | ||||
| Grade 2 | 2 (28.57%) | 1 (25%) | 3 (27.27%) | 1* |
| Grade 3 | 5 (71.43%) | 3 (75%) | 8 (72.73%) | |
| ER | ||||
| Negative | 5 (71.43%) | 3 (75%) | 8 (72.73%) | 1* |
| Positive | 2 (28.57%) | 1 (25%) | 3 (27.27%) | |
| PR | ||||
| Negative | 4 (57.14%) | 3 (75%) | 7 (63.64%) | 1* |
| Positive | 3 (42.86%) | 1 (25%) | 4 (36.36%) | |
| HER2 | ||||
| Negative | 6 (85.71%) | 4 (100%) | 10 (90.91%) | 1* |
| Positive | 1 (14.29%) | 0 (0%) | 1 (9.09%) | |
| Ki67 (%) | ||||
| ≤ 20 | 2 (28.57%) | 2 (50%) | 4 (36.36%) | 0.576* |
| > 20 | 5 (71.43%) | 2 (50%) | 7 (63.64%) | |
| LVI | ||||
| Negative | 7 (100%) | 4 (100%) | 11 (100%) | NA |
| TILs (%) | ||||
| ≤ 10% | 0 (0%) | 1 (25%) | 1 (9.09%) | 0.364* |
| > 10% | 7 (100%) | 3 (75%) | 10 (90.91%) | |
| Molecular class | ||||
| Her2neu enriched | 1 (14.29%) | 0 (0%) | 1 (9.09%) | 1* |
| Luminal A | 1 (14.29%) | 0 (0%) | 1 (9.09%) | |
| Luminal B | 1 (14.29%) | 1 (25%) | 2 (18.18%) | |
| Triple negative | 4 (57.14%) | 3 (75%) | 7 (63.64%) | |
*Fisher’s exact test
Table 5.
Correlation of AR with various parameters
| Variables | Age (years) | Grade | ER | PR | HER2 | Ki67 (%) | LVI | TILs (%) |
|---|---|---|---|---|---|---|---|---|
| AR | ||||||||
| Correlation coefficient | 0.118 | − 0.369 | 0.165 | 0.054 | 0.377 | − 0.191 | 0.146 | − 0.344 |
| p value | 0.487 | 0.025 | 0.329 | 0.751 | 0.021 | 0.259 | 0.387 | 0.037 |
To assess the cut-off for the Ki67 index to predict AR expression ROC curve was used which showed that if the Ki67 index is < 20%, then there was a 67.90% probability of AR positivity and 66.70% probability of AR negativity when the Ki67 index is > 20%. Overall, the performance of the Ki67 index (%) was not significant for predicting AR expression (Fig. 1). However, a significant strong positive correlation was seen between sTILs (%) and Ki67 index (%) with a correlation coefficient of 0.635. A weak positive correlation between sTILs (%) and the grade of tumor was also noted. A negative correlation was observed between sTILs (%) with ER, PR, and Her2neu status with the coefficient correlation of − 0.487, − 0.392, and − 0.408 (Table 6).
Fig. 1.
Receiver operating characteristic curve of Ki67 (%) for predicting positive AR
Table 6.
Correlation of TILs with various parameters
| Variables | Age (years) | Grade | ER | PR | HER2 | Ki67 (%) | LVI |
|---|---|---|---|---|---|---|---|
| TILs (%) | |||||||
| Correlation coefficient | − 0.253 | 0.528 | − 0.487 | − 0.392 | − 0.408 | 0.635 | − 0.507 |
| p value | 0.131‡ | 0.001§ | 0.002¶ | 0.017¶ | 0.012¶ | < 0.0001‡ | 0.001¶ |
‡Pearson correlation coefficient, §Spearman rank correlation coefficient, and ¶point biserial correlation
Discussion
In the recent past, the role of AR signalling has gained importance. In this study, we found that AR positivity was higher in hormone receptor-positive/Her2neu-negative and hormone receptor-positive/Her2neu-positive tumors rather than TNBCs. These findings were concordant with the previously conducted studies [16]. However, the biology behind the decreased expression of AR in TNBCs is still not studied well and needs future research.
In this study, no significant association between age and AR expression, but the majority of the AR-positive patients were of the older age group which was in line with the previous studies [17]. One of the previous studies showed that a significantly higher pCR was noted in AR-positive patients having Her2neu molecular subtype when compared with AR-negative patients [18]. Contrary to this, we found no significant association between Her2neu status and AR expression. The above difference is possibly due to different sample sizes in these two studies. However, observations similar to our study were described by Lee et al. [19] Furthermore, as per the study on AR mRNA expression in patients receiving NAC, a lower pCR is noted with higher expression of AR [20]. Nakashoji et al. [21] observed that patients responding to NAC having molecular subtype TNBC had negative AR and a ki67 index. Similar findings were observed in our study also. It is noteworthy that TNBCs not responding to NAC have an overall poorer prognosis, and they require adjuvant therapy and close follow-up. Overall, the available literature of the evidence regarding the prognostic significance of AR in TNBC is controversial as few observations support good outcomes in AR-positive patients [22], whereas others found inverse relation [23], and many studies were not able to define any significant association [24, 25]. These disparities across studies could be explained by many factors which include, ethnic variation, cohort size, and variability in the threshold for AR expression [13].
In this study, we found a significant weak negative correlation between AR and sTILs although we did not perform the genetic subtyping of the AR positive cases. A lower median sTILs were observed in non-metastatic TNBC of luminal androgen receptor in a study of a large cohort by Dieci et al [26].
In this study, expression of AR was analyzed across all molecular subtypes, and correlation with various clinicopathological parameters was analyzed. Although we could not establish the prognostic significance of AR, there are certain results which highlight the significance of AR, ki67 index (%), and sTILs and their associations with pCR.
Author Contribution
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Adil Aziz Khan, Sana Ahuja, Kiruthikasri G., and Sufian Zaheer. The first draft of the manuscript was written by Adil Aziz Khan, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Data Availability
The data that support the findings of this study are included in the article.
Declarations
Ethical Approval
The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Consent to Participate
The authors certify that they have obtained all appropriate patient consent forms.
Consent for Publication
Informed consent was sought from patient regarding participation and publication.
Competing Interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This study has not been presented and published previously.
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Data Availability Statement
The data that support the findings of this study are included in the article.