**3. Short review, results and discussion**

The chapter contributor's work in this field over the 50 cases of invasive ductal carcinoma is depicted in a tabular forms below.

The Bcl-2 immunoexpression was seen in 33 of 50 cases (66%). There were 30 (60%) women who were below age of 51 and 20 (40%) were 51 and above years. The age versus Bcl-2 immunoexpression is charted in **Table 1**.

Of the 30 women who were below age of 51 showed Bcl-2 immunoexpression on 21 instances (70%) while 12 of 20 (60%) showed Bcl-2 immunoexpression in women more than 50 years of age. The youngest patient of invasive ductal carcinoma was 26 years while oldest one was 84 years. The immunoexpression of Bcl-2 was observed to be 100% in women of invasive ductal carcinoma in between the age of 31 to 40 years.

The distribution of Bcl-2 immunoexpression across BR grade is shown in **Table 2**.

It was observed that Bcl-2 immunoexpression is independent of BR grade.

TNM stage and immunoexpression in 50 cases of invasive ductal carcinoma is shown in **Table 3**.

The TNM stage of invasive ductal carcinoma when plotted against Bcl-2 immunoexpression revealed 15 Bcl-2 immunoexpressions in 20 cases of stage II disease and 7


#### **Table 1.**

*Bcl-2 Immuno-expression and age range of invasive ductal carcinoma.*


#### **Table 2.**

*Bcl-2 Immuno-expression and BR-grade.*

*Bcl-2 Immunoexpression in Invasive Ductal Carcinoma and Its Evaluative Correlation… DOI: http://dx.doi.org/10.5772/intechopen.109297*


#### **Table 3.**

*Bcl-2 Immuno-expression and TNM stage.*


#### **Table 4.**

*Bcl-2 Immuno-expression and molecular sub-type.*

of the 9 stage III disease thus the comparisons of Bcl-2 immunoexpression in between TNM stages was found to be non-specific.

The molecular subtype of invasive ductal carcinoma and its relationship with Bcl-2 is shown in **Table 4**.

It was observed that Bcl-2 immuno-expression by percentage was more in Luminal A molecular subtype of invasive ductal carcinoma followed by Luminal B and Her2 enriched (**Figure 2**).

The higher frequency of correlation between the Bcl-2 immunoexpression with molecular subtype Luminal A of breast cancer as observed in present study is attributed to oestrogen up regulating of Bcl-2 imuunoexpression. The higher frequency of immunoexpression of Bcl-2 with molecular subtype of Luminal A of breast cancer too has been observed in the other studies.

The p-value distribution of the various studies for relationship between molecular subtype of invasive ductal carcinoma and Bcl-2 immunoexpression is shown in **Table 5**.

The studies depicted in **Table 5** concluded of evidences of Bcl2 immunoexpression correlates well with molecular subtype of Luminal A of invasive ductal carcinoma to which the contributors of present chapter agree.

The included studies for their observations are cited below paragraphically explaining about Bcl-2 immuno-expression and its evaluative correlation with BR Grade, TNM stage and molecular subtypes of invasive ductal carcinoma including comparisons.

**Figure 2.** *IHC Bcl-2, invasive ductal carcinoma (luminal a molecular subtype, 40×).*

Sharmila, Praba [2] have studied 30 cases of invasive ductal carcinoma for expression of Bcl-2 in immunohistochemistry (IHC). The immunohistochemistry was carried out by standard methods. The objective of study was to analyse Bcl-2 expression and its relationships with ER, PR, HER-2 status, histological grade and Nottingham prognostic index. The study observed that 7 cases of the Invasive Ductal Carcinoma showed intense Bcl-2 staining while 23 cases showed no expression. The Grade I tumour showed 45.5% positive immuno-expression followed by Grade II at 14.3%. The correlation of Bcl-2 expression with ER status showed that 7 out of 12 ER positive cases expressed Bcl-2 with statistically significant values. The study concluded that BCl2 expression in invasive ductal carcinoma, directly related with lower histological grade, small tumour, size, ER and PR positive status. It is inversely related to HER-2 nu status.

Cecka, et al. [3] did study on expression of Bcl-2 in 57 females suffering from primary breast cancer who were treated with neo-adjuvant chemotherapy. The immunohistochemistry for BCl2 were performed either on the surgical specimens or core cut biopsies with Streptavidin and Biotin method with peroxidise detection system. The results of immunohistochemistry when correlated with the findings of Bcl-2 have shown the following p-values with individual variables.

Tumour size (0.56), grading (0.53), ER (0.003), PR (0.36), Ki-67 score (0.07), Her-2 nu (0.24) and p53 (0.88). Hence the study concluded that there exists no significant association of Bcl-2 expression with clinical variable except ER status.


*Bcl-2 Immunoexpression in Invasive Ductal Carcinoma and Its Evaluative Correlation… DOI: http://dx.doi.org/10.5772/intechopen.109297*


**Table 5.** *Study and results (p-value) distribution.*

#### *Breast Cancer Updates*

#### *Bcl-2 Immunoexpression in Invasive Ductal Carcinoma and Its Evaluative Correlation… DOI: http://dx.doi.org/10.5772/intechopen.109297*

Callagy et al. [4] did study to evaluate that in first 5 years after diagnosis, Bcl-2 is predictor of breast cancer outcome independently, and serves as a useful tool as prognostic marker besides Nottingham prognostic index. A total of 13 markers expression was evaluated in 930 breast cancer patients on a tissue microarray. Out of all the markers Bcl-2 was the best marker. Through this study it's also evaluated that whether a single marker or a series of markers could improve prognostic potential of Nottingham prognostic index.

Kamaruzman, et al. [5] published study related to nanotherapeutics in breast cancer wherein they observed that the expression of Bcl-2 was observed in 22.4% of molecular subtype of Luminal a of invasive breast cancer.

Adams, Cory [6] did a new study which was innovative as it encouraged to ponder us upon that most of cytotoxic stresses imposed on a cell lead to activation of BH3 only proteins as important signal of stress. These BH3 proteins belong to Bcl-2 family which help us to understand their role in cancer development, and through this search for important class of anticancer drugs can be done.

Eom et al. [8] did study to evaluate the relation between the prognostic outcomes and Bcl-2 expression among the molecular sub-types. A study was conducted taking into account 1356 patients who were newly diagnosed with breast cancer between November 2006 and November 2011. Mainly Immunohistochemistry (IHC) was used to measure status of - ER, progesterone receptor, human epidermal growth factor receptor 2, and Bcl-2 expression. In this study breast cancer was classified into five molecular sub-types namely, luminal A, luminal B with positive status, luminal B with negative status, human epidermal growth factor receptor 2 expression, and triple negative sub-types. The clinico-pathological variables were analysed which assessed the correlation between Bcl-2 expression and clinical outcomes such as relapse free survival and disease- specific survival according to the five molecular sub-types.

Dawson et al. [9] have established the rationale of performing Bcl-2 immunohistochemistry in prognostic stratification of invasive ductal carcinoma. Their work included the conglomeration of 5 studies wherein the relationship between Bcl-2 and molecular subtypes of breast carcinoma was followed. The study observed the significant p-value (p < 0.01) in ER positive breast cancer (Luminal A subtype).

Lehmann et al. [10] observed 43.1% of their cases showing Bcl-2 immunoexpression. However, the study observed no relationship between Bcl-2 immuno-expression and molecular subtype of breast cancer. A similar observation of discordant relationship in between molecular subtype of luminal A and Bcl-2 immuno-expression by Wijesinghe et al. [13] and Bayoudh et al. [14]

The study of Hwang et al. [11] observed the Bcl-2 immunoexpression in 51.2% cases and luminal A subtype held its association with significant p-value (p < 0.01).

Min et al. [12] observed 34.2% of the breast cancer expressing Bcl-2 and its significant correlation with luminal A subtype of breast cancer (p < 0.05).

Rashid, AL-Sakkal [15] studied 61 cases of primary breast cancer in which 71% of ER positive cases and 59% of PR positive cases depicted positive Bcl-2 oncoprotein expression, having p-values (p = 0.030) and (p = 0.001) respectively.

#### **4. Conclusion**

Bcl-2 is an independent prognostic marker for breast cancer although its expression frequency may differ but it plays definite prognostic role in breast cancer. It is observed that Luminal A molecular subtype of invasive ductal carcinoma has a

frequent association with Bcl-2 immuno-expression. There are some limitations to use of immunohistochemistry staining method as the results may be affected by intratumoral heterogeneity.
