|Ahead of print publication
Correlation of B-cell lymphoma 2 immunoexpression in invasive carcinoma of breast, no special type with hormone receptor status, proliferation index, and molecular subtypes
Henna Azmat1, Javeria Faridi1, Hafiz Muhammad Habib1, Umair Jan Bugti1, Ahmareen Khalid Sheikh1, Syeda Kiran Riaz2
1 Department of Pathology, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
2 Department of Pathology, Shaheed Zulfiqar Ali Bhutto Medical University; Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
|Date of Submission||08-Jun-2020|
|Date of Decision||13-Aug-2020|
|Date of Acceptance||30-Sep-2020|
|Date of Web Publication||15-Oct-2021|
Syeda Kiran Riaz,
Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad
Source of Support: None, Conflict of Interest: None
Background: B-cell lymphoma 2 is involved in various cancers including breast carcinoma. Its expression in breast cancer has been associated with good prognostic factors such as hormone receptor expression, low Ki-67, low grade, and earlier stage. It is also considered to be an independent prognostic factor for luminal and triple-negative tumors.
Objective: We aimed to determine the expression of B-cell lymphoma 2 (BCL2) in different molecular subtypes of invasive ductal carcinoma of breast and its association with prognostic indicators.
Materials and Methods: Fifty samples of invasive carcinoma of breast, no special type (NST), were categorized into molecular subtypes according to immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), and Ki-67 and then evaluated for BCL2 expression. The expression of BCL2 was correlated with ER, PR, HER2, and Ki-67 and compared between luminal and nonluminal subtypes.
Results: The BCL2 expression was seen in 68% of the cases with a significant association with ER, PR, and luminal subtypes. No significant association of BCL2 expression was seen with grade, HER2 and Ki-67 status of the tumor, or age group of the patients. BCL2 expression is significantly associated with ER, PR, and luminal subtypes in breast cancer.
Conclusion: BCL2 is a marker of good prognosis in invasive carcinoma of breast, NST.
Keywords: B-cell lymphoma 2, estrogen receptor, human epidermal growth factor 2, invasive breast cancer, progesterone receptor, triple-negative breast cancer
|How to cite this URL:|
Azmat H, Faridi J, Habib HM, Bugti UJ, Sheikh AK, Riaz SK. Correlation of B-cell lymphoma 2 immunoexpression in invasive carcinoma of breast, no special type with hormone receptor status, proliferation index, and molecular subtypes. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 7]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=328262
| > Introduction|| |
A substantial amount of morbidity and mortality across the globe is attributed to breast cancer.,, Apoptosis is the main mechanism by which cells self-regulate their survival. Disruption of apoptosis is the key event in development of carcinogenesis. Apoptosis is mainly regulated by a family of pro-apoptotic and anti-apoptotic proteins collectively known as the B-cell lymphoma 2 (BCL2) family. Among this family, BIM, PUMA, BAD, BID, BIK, BMF, HRK, and NOXA are pro-apoptotic initiator proteins, while BCL2, BCLXL, BCLW, MCL1, and BFL1/A1 are anti-apoptotic proteins., BCL2 was the first anti-apoptotic protein discovered in any species. In humans, it was first described in association with acute B-cell leukemia and follicular lymphoma caused by translocation t (14;18) which leads to fusion of immunoglobulin heavy chain locus on chromosome 14 and BCL2 gene locus on chromosome 18. This leads to overexpression of BCL2 and hence inhibition of apoptosis. Overexpression of BCL2 has been found in a number of carcinomas. The mechanisms leading to its overexpression in addition to translocations are gene amplification, increased gene transcription, and altered posttranslational processing of the BCL2 protein.
The numerous carcinomas which overexpress BCL2 include breast, colorectal, endometrium, prostatic, squamous, and basal cell carcinoma as well as lymphomas and leukemias. In addition to inhibition of apoptosis, BCL2 is also thought to be responsible for metastasis and invasion in various carcinomas of lung, glioma, neuroblastoma, and hepatocellular carcinoma by inducing matrix metalloproteinases. BCL2 is overexpressed in approximately 75% of breast carcinomas. The role of BCL2 in breast cancer prognosis is considered to be a paradox. Despite functioning similar to an oncogene, BCL2 has been extensively linked to favorable prognostic factors and better survival. BCL2 is an independent prognostic factor in estrogen-positive and triple-negative breast cancer. Studies have shown a strong link to estrogen receptor (ER) and progesterone receptor (PR) positivity, human epidermal growth factor 2 (HER2) negativity, low mitotic index, low grade, earlier stage, lack of p53 expression, absence of tumor necrosis, and lymphovascular invasion., The lucidity for BCL2 relation to favorable prognosis lies in its strong association with hormone receptor status. This may be explained due to the fact that BCL2 gene is an estrogen-responsive gene, highlighting that BCL2 positivity can indicate an intact estrogen signaling pathway. In both the luminal types A and B, BCL2 is expressed in high levels, with luminal A showing a slightly greater expression. On treatment grounds, the expression of BCL2 is essentially associated with better response to endocrine therapy. This may be due to the fact that in BCL2-positive tumors, endocrine therapy would also target BCL2, thereby inducing apoptosis of the tumor cells.,,,
This study was conducted for evaluation of BCL2 in breast cancer in a cohort, as few studies have been conducted in this regard. This was done in view of the fact that in tumors showing a co-expression of hormone receptors and BCL2, potential target agents against BCL2 could also be used in therapy regimes, as anti-BCL2 agents have been reported to increase the response to tamoxifen. We also wanted to assess the correlation of BCL2 expression with prognostic parameters in breast cancer in our population.
| > Materials and Methods|| |
Cases of tru-cut breast biopsies and modified radical mastectomy specimens received in the Department of Pathology were collected from January 2018 to October 2019. Fifty cases following inclusion and exclusion criteria diagnosed as invasive carcinoma, no special type (NST), were taken for the study. Female patients without age limitation, no clinical, radiological, and pathological evidence of lymph node metastasis, and adequately fixed tissue were included in the study, keeping in view diminished immunohistochemical staining for hormone receptors in unfixed tissue sections. Excluded from the study were male patients, patients with clinical, radiological, and pathological evidence of lymph node metastasis and inadequately fixed tissues, unfit for immunohistochemical staining. After fixation of the specimen in 10% formalin, gross examination was done according to AJCC protocols, followed by sectioning, embedding in paraffin blocks, cutting, slide preparation, and staining of the tissue with hematoxylin and eosin. The slides were examined under light microscope by 3 surgical pathologists with minimum 5 years post fellowship experience. Histopathological diagnoses with Nottingham histologic grade assessing intrinsic tumor properties of tubule formation, nuclear pleomorphism, and mitosis with their respective scores and sum of these values to ascertain histologic grade were recorded. For immunohistochemistry, four-micron sections of these blocks were prepared. Heat-induced epitope retrieval method was used for antigen retrieval. Immunohistochemical stains were applied for ER (PA0151, Leica Bond, IL, USA), PR (PA0321, Leica Bond, IL, USA), HER2 (PA0571, Leica Bond, IL, USA), proliferation index Ki-67 (PA0230, Leica Bond, IL, USA), and BCL2 (BCL2/100/D5, Leica Bond, IL, USA). Both ER and PR were scored according to the Allred scoring system utilizing the intensity of staining on a scale of 0–3 and proportion of tumor cells being stained on a scale of 0–5, for a possible total score of 8 on summation, indicative of positivity and increased potential benefit from hormone therapy. For Ki-67, nuclear staining was considered positive, with 14% being the cutoff value between low, i.e., ≤14%, and high >14% proliferation index. HER2 overexpression is assessed using scoring criteria by the College of American Pathologists. A faint or strongly perceptible membranous staining detected in ≤10% or 30% of tumor cells shall be considered negative or strong positive on a scale of 0–3+, respectively. These hormone receptor assessments, i.e., ER/PR, HER2, and Ki-67, are carried on histologically evident viable tumor foci using ×10 magnification. For BCL2 immunostain, IHC was then examined under light microscope for analysis of expression by the tumor cells. Cases were categorized into molecular types including luminal types A and B and nonluminal (HER2-enriched and basal-like) subtypes using IHC analysis as a surrogate, where luminal A-like breast carcinomas are ER and/or PR positive and HER2 negative with low proliferative index, i.e., <14% Ki-67 staining. Similarly, luminal B-like carcinomas are ER and/or PR positive with variable expression of HER2 and high proliferative index, i.e., Ki-67 >14%. Likewise, HER2-enriched type encompasses tumors showing high expression of HER2 and is ER/PR negative. Finally, basal-like type is triple-negative breast carcinoma showing no ER/PR and HER2 expression and is CK5/6 and EGFR positive. Basal-like molecular subtype was confirmed immunohistochemically with CK5/6, taking diffuse cytoplasmic staining as positive. For positive control of BCL2, a case of basal cell carcinoma was used. Cytoplasmic brown-colored staining if present in greater than 10% of tumor cells was to be considered positive for BCL2. Chi-squared test was used to assess the association between different variables with SPSS software (IBM, Armonk, NY, USA), and P < 0.05 was considered statistically significant.
| > Results|| |
A total of 50 samples of invasive carcinoma of breast, NST, were taken. The mean age of the patients was 53.2 ± 13.4 years. Of the 50 cases, 27 were of age group >53 years while 23 were of age group ≤53 years. Almost 14% (7) of the cases were of Grade I, 76% (38) Grade II, and 10% (5) Grade III. Of 50 cases, 76% (38) were positive for ER, 58% (29) were positive for PR, and 62% (31) were positive for HER2. About 68% (34) of the cases showed a high proliferative index, i.e., >14%. Of the 38 ER-positive cases, 10 cases were PR negative, while of the 12 ER-negative cases, only 1 was PR positive. By classifying into molecular subtypes, luminal cancers were 78%, while nonluminal (HER2-enriched and basal-like) cancers were 22%. Of these, 24% (12) cases were luminal A, 54% (27) cases were luminal B, 8% (4) were basal like, and 14% (7) were HER2 enriched [Table 1]. It was observed that 42% (5) of luminal A cases, 48% (13) of luminal B cases, 50% (2) of basal-like cases, and 43% (3) of HER2-enriched cases were of age group less than 53 years. However, there was no significant association of age group with grade of tumor and molecular subtypes (P = 0.9 and P = 0.9, respectively).
|Table 1: Clinicopathological parameters of invasive carcinoma of breast, no special type|
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BCL2 positivity was seen in 68% (34) of the cases. Of the BCL2-positive cases, 94.4% of the cases fell in age group >40 years, however, the correlation of BCL2 with age group was not significant (P = 0.1). Of the ER-positive cases, 79% were BCL2 positive, and of the ER-negative cases, 66.6% were BCL2 negative [Table 2]. Of the PR-positive cases, 89.7% were BCL2 positive, and of the PR-negative cases, 62% were BCL2 negative [Table 3]. Among the molecular subtypes, 58.3% of luminal A, 88.9% of luminal B, 75% of basal-like, and none of the HER2-enriched cases were BCL2 positive [Table 4] and [Figure 1], [Figure 2], [Figure 3], [Figure 4]. The BCL2 expression was significantly associated with ER and PR (P = 0.00). By categorizing the tumors into luminal and nonluminal types, 77% of the luminal subtypes and 36.3% of the nonluminal subtypes were BCL2 positive. This difference was statistically significant, with P = 0.01 [Table 5] and [Figure 5]. Of the HER2-positive cases, 38.6% were BCL2 positive. Among the grades of tumor, 85.7% of Grade I, 65.7% of Grade II, and 60% of Grade III tumors were BCL2 positive. Seventy percent of the cases with high proliferation index and 62.5% of the cases with low proliferation index showed BCL2 positivity. The BCL2 expression was not significantly associated with HER2, Ki-67, or grade of the tumor (P = 0.5).
|Table 2: Correlation of estrogen receptor with B-cell lymphoma 2 expression|
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|Table 3: Correlation of progesterone receptor with B-cell lymphoma 2 expression|
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|Figure 1: Invasive ductal carcinoma of not otherwise specified type, luminal A; (a) H and E (×400). (b) Estrogen receptor positive (×400). (c) Progesterone receptor positive (×400). (d) Human epidermal growth factor 2 negative (×400). (e) Ki-67 5% (×400). (f) B-cell lymphoma 2 positive (×400)|
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|Figure 2: Invasive ductal carcinoma of not otherwise specified type, luminal B; (a) H and E (×100). (b) Estrogen receptor positive (×100). (c) Progesterone receptor positive (×100). (d) Human epidermal growth factor 2 negative, score 1+ (×400). (e) Ki-67 50% (×100). (f) B-cell lymphoma 2 positive (×100)|
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|Figure 3: Invasive ductal carcinoma of not otherwise specified type, human epidermal growth factor 2 enriched; (a) H and E (×100). (b) Estrogen receptor negative (×400). (c) Progesterone receptor negative (×400). (d) Human epidermal growth factor 2 positive score 3+ (×400). (e) Ki-67 30% (×400). (f) B-cell lymphoma 2 negative (×400)|
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|Figure 4: Invasive ductal carcinoma of not otherwise specified type, basal like; (a) H and E (×100). (b) Estrogen receptor negative (×100). (c) Progesterone receptor negative (×100). (d) Human epidermal growth factor 2 negative score 1+ (×400). (e) Ki-67 20% (×400). (f) B-cell lymphoma 2 positive (×100)|
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|Table 5: Comparison of B-cell lymphoma 2 expression between luminal and nonluminal subtypes|
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|Figure 5: Comparison of B-cell lymphoma 2 expression between luminal and nonluminal subtypes of invasive carcinoma of breast, no special type|
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| > Discussion|| |
The mean age of the patients in our study, i.e., 53.2 years, was comparable with Zubair et al. who reported a mean age of 49 years. Ninety percent of the patients were of age >40 years, while 10% were of age group ≤40 years. Widodo et al. categorized the patients into age groups ≤50 years and >50 years. Similar to our study, they found a higher overall frequency of breast cancer in higher age group, while Kadivar et al. found a greater frequency of breast cancer in lower age group.
In our study, luminal cancers (luminal A and B) were more frequent as compared to nonluminal (basal-like and HER2-enriched) cancers. This is similar to the results reported by Widodo et al. from Indonesia and Fragomeni et al. from the USA., However, from Pakistan, a study by Khokher et al. conducted in Lahore stated that nonluminal cancers were more frequent.
Among the nonluminal cancers in our study, HER2-enriched subtypes were more common as compared to triple-negative subtype, similar to results reported by Akbar et al. from Mansehra, Pakistan, and in contrast to results reported by El Fatemi et al., Widodo et al., and Khokher et al.,, Fragomeni et al. reported a near similar frequency of basal-like and HER2-enriched subtypes.
Our study showed a higher frequency of luminal B cancers similar to El Fatemi et al. from Morocco, Hashmi et al. from Karachi, and Khokher et al. from Lahore, Pakistan.,, In contrast, Fragomeni et al. from the USA, Widodo et al. from Indonesia, and Akbar et al. from Abbottabad, Pakistan, reported a higher frequency of luminal A subtypes.,,
There was no significant association of luminal subtypes with age group of the patients, in contrast to the results reported by Widodo et al. who showed that luminal A subtypes were more common in higher age group.
The overexpression of BCL2 was seen in 68% of the cases in our study. This is in concordance with Merino et al. who state that BCL2 overexpression is seen in about 75% of breast cancers. The expression of BCL2 was not significantly associated with age of the patient in our study, however, the older age group showed a higher frequency of BCL2 expression. This was similar to the results reported in American, Swiss, and Swedish patients.,, In contrast, a higher frequency of BCL2 positivity was reported in lower age groups of Pakistani and Korean cohorts., The reason for this difference may lie in the fact that the majority of our study patients were of older age group, i.e., >40 years. Moreover, the cutoff value for distinguishing age groups was also variable in different studies.
ER and PR positivity is associated with a better prognosis and overall survival. The correlation of BCL2 positivity with hormone receptor status, i.e., ER or PR positivity, has been well recognized. Our study further adds to the cemented evidence that BCL2 expression is significantly associated with ER and PR expression in the tumor, similar to the results reported earlier.,,, All these studies have provided evidence that BCL2 has a good prognostic influence and increased overall survival in ER- and PR-positive breast cancer.
In our study, BCL2 was not significantly associated with HER2 and Ki-67 expression. HER2 expression and high Ki-67 are both considered poor prognostic factors in breast cancer. The absence of correlation between HER2 and BCL2 is similar to the results stated by Mitrović et al. who showed no correlation between HER2 and BCL2 in breast carcinoma by gene analysis. This is in contrast to results reported by Hwang et al. and Kallel-Bayoudh et al. who showed a positive correlation between HER2 and BCL2., Zubair et al. found an inverse relation of HER2 with BCL2 expression. Ki-67 in most of other studies has been known to show an inverse relation with BCL2 expression, and a high BCL2/Ki-67 is associated with worse outcomes.,, However, similar to Fulga, there was no correlation between Ki-67 and BCL2 in our study.
No correlation was found between grade of the tumor and BCL2 expression in our study, similar to Fulga. In contrast, BCL2 expression has been reported to be associated with low-grade tumors by Tawfik et al. and Zubair et al.,, while Hwang et al. showed BCL2 expression in high-grade tumors.
In literature, luminal-type cancers are reported to have a better prognosis and survival as compared to nonluminal. The difference of BCL2 expression in molecular subtypes was significant in our study. BCL2 was significantly higher in luminal subtypes as compared to non-luminal subtypes. The highest frequency of BCL2 in our study was found in luminal B subtypes, similar to Fulga. This was due to the fact that most of the tumors in our study were luminal B type. In contrast, most of the studies have shown a higher frequency of BCL2 expression in luminal A subtypes and have also reported the prognostic value of this correlation. Escórcio-Dourado et al. compared the expression of BCL2 in luminal A- and triple-negative breast cancers and found a significant difference in its expression between the two subtypes with strong association with luminal A. Zubair et al. from Peshawar, Pakistan, reported a higher expression of BCL2 in nontriple-negative breast cancers as compared to triple negative. Tawfik et al. have shown that BCL2 expression was associated with better prognosis in luminal subtypes while it predicts a worse prognosis in triple-negative cancers. Hwang et al. state a prognostic value of BCL2 expression in luminal A and luminal B but not in basal-like or HER2-enriched subtypes.
| > Conclusion|| |
We aimed to determine the expression of BCL2 in different molecular subtypes of invasive carcinoma of breast and its association with prognostic indicators. BCL2 was found to be associated with favorable prognostic factors in breast cancer patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]