|Year : 2018 | Volume
| Issue : 1 | Page : 31-38
|Expression of breast cancer type 1 and its relation with expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu in breast carcinoma on trucut biopsy specimens
Deepti Verma1, Kiran Agarwal2, Sanjeev Kumar Tudu3
1 Department of Histopathology, Dr Lal Path Labs, New Delhi, India
2 Department of Pathology, Lady Hardinge Medical College, New Delhi, India
3 Department of Surgery, Lady Hardinge Medical College, New Delhi, India
Click here for correspondence address and email
|Date of Web Publication||22-Mar-2018|
| Abstract|| |
Objective: (1) The objective is to study the immunohistochemical expression of Breast cancer type 1 (BRCA1) in breast carcinoma on trucut biopsy specimens and (2) To relate its expression with that of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER-2)/neu and the clinicopathological parameters. Settings and Design: A cross-sectional hospital-based study was performed in Lady Hardinge Medical College and Shrimati Sucheta Kriplani Hospital, New Delhi, with collaboration of the Departments of Pathology and Surgery from the period of November 2008 to March 2010. Materials and Methods: The study group included 54 cytologically proven cases of breast carcinoma. The immunohistochemical expression of BRCA1 was studied and related with expression of ER, PR, and HER-2/neu on their trucut biopsies. Results: The altered expression of BRCA1 (i.e., reduced or absent expression) was seen in 44.4% cases of breast carcinoma while 55.6% had positive expression. About 83% of breast carcinomas with altered BRCA1 expression were larger than 3 cm in size. The breast carcinomas showing altered expression were found to be mostly high grade (63.6%). This was statistically significant. The ER and PR negativity were seen in 62.5% and 79.2% breast carcinomas with altered BRCA1 expression, respectively. The score 3 positivity of HER-2/neu was more common among carcinomas with altered BRCA1 expression (21% vs. 16.7%). The triple negativity was found in 41.7% breast carcinomas having altered BRCA1 expression. This was statistically significant. Conclusion: The combination of immunohistochemical expression of BRCA1, ER, PR, and HER-2/neu and clinicopathological details may be helpful in predicting the individuals more likely to carry BRCA1 mutations and thus selecting the candidate and family members for genetic screening for BRCA1 mutations.
Keywords: Breast cancer type 1, breast carcinoma, trucut biopsy
|How to cite this article:|
Verma D, Agarwal K, Tudu SK. Expression of breast cancer type 1 and its relation with expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu in breast carcinoma on trucut biopsy specimens. Indian J Pathol Microbiol 2018;61:31-8
|How to cite this URL:|
Verma D, Agarwal K, Tudu SK. Expression of breast cancer type 1 and its relation with expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu in breast carcinoma on trucut biopsy specimens. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Oct 18];61:31-8. Available from: https://www.ijpmonline.org/text.asp?2018/61/1/31/228172
| Introduction|| |
Breast cancer is one of the most common causes of cancer and death among women. Breast carcinomas can be sporadic or hereditary; latter are associated with family history or germline mutations and account for 5%–10% of all breast carcinomas.,, Breast cancer susceptibility is generally inherited as an autosomal dominant trait. Breast cancer type 1 (BRCA1) mutations account for approximately 45% of families with a significantly high breast cancer incidence., More than 600 mutations have been identified in BRCA1 gene located on chromosome 17q21;, BRCA1 mutation carriers carry a lifetime risk of 50%–85% for breast cancer and 15%–60% for ovarian cancer.,,, They show an early age of onset and an increased risk for colon and prostate cancers.,,, Thus, detection of this mutation makes screening for these tumors also important.
Majority of breast carcinomas are sporadic. Sporadic breast carcinomas rarely show somatic mutations. About 30% of these show downregulation of BRCA1 mRNA and protein expression.,, Since BRCA1 gene is large and hundreds of different mutations have been identified, genetic screening is expensive. Moreover, not all mutations are likely to be clinically important. Results of research suggest that screening methods only detect 60%–70% of BRCA1 mutations for several reasons. The correlation of morphological findings and immunohistochemical profile helps decide the individuals likely to show BRCA1 mutations. This thus helps by providing a better patient selection and thereby increasing the possibilities of obtaining more rapid informative genetic screening results.
There are very few studies in the past depicting the immunohistochemical expression of BRCA1 in breast cancer patients and that too on trucut biopsy specimens and its relation with estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER-2)/neu expression.
Trucut biopsy besides being a sensitive outpatient procedure has many benefits. It gives information not only about the tumor type but also about grade and hormone receptor status. Unnecessary frozen sections can be avoided plus it allows biopsies from different sites of the lesion. Early diagnosis is thus made and an adequate definite plan of management can be decided for the patient. In the present study, the immunohistochemical expression of BRCA1 has been studied in breast carcinoma patients on trucut biopsy specimens along with its relation with an expression of ER, PR, and HER-2/neu and various other clinicopathological parameters.
| Materials and Methods|| |
A cross-sectional hospital-based study was performed that included all 54 cytologically proven cases of breast carcinoma between November 2008 and March 2010 in Lady Hardinge Medical College and Shrimati Sucheta Kriplani Hospital, New Delhi, with collaboration of the Departments of Pathology and Surgery. Patient's clinical history and cancer characteristics including tumor type, histological grade, tumor size, and lymph node status were available for all patients. These patients were selected irrespective of family history, sex, age, or recurrence at the time of diagnosis.
The trucut biopsy was performed on breast lump using 14 gauge and 7.6 cm long needle under aseptic precautions. Minimum time of fixation required was 6 h in 10% neutral buffered formalin. The tissue sections were taken from these specimens. The paraffin-embedded tissue blocks were cut on poly-L-Lysine coated slides at 3–4 microns thickness and hematoxylin and Eosin staining and manual method of immunohistochemistry for BRCA1, ER, PR, and HER-2/neu were performed using the Super sensitive polymer–HRP ready to use kit (biogenex systems). MS 110 clone (Biocare Medical) was used for BRCA1 immunostaining at 1:100 dilution. The antibody clones used for ER, PR, and HER-2/neu immunostaining were 1D5 (DBS), hPRa2+ hPRa3 (DBS), and BV5 (DBS), respectively. These were used at 1:50 dilution. The antigen retrieval was done by pressure cooker for nuclear antigens such as ER, PR, and BRCA1. The microwave was used as means for antigen retrieval in HER-2/neu immunostaining.
Analysis of immunostaining
Estrogen receptors/progesterone receptors scoring system (quick score)
This is based on assessment of proportion (score 0–5) and intensity of nuclear staining (score 0–3). The scores 0, 1, 2, 3, 4, and 5 are given for 0, <1, 1–10, 11–33, 34–66, and 67%–100% nuclei showing staining, respectively. The scores 0, 1, 2, and 3 are given for absent, weak, moderate, and intense nuclear staining, respectively. The scores are summed to give a maximum of 8. Tumors scoring 2 or less are considered negative. Positive control tissue taken for ER and PR staining was fibroadenoma.
Scoring for breast cancer type 1
In the breast, BRCA1 staining is observed as brown nuclear staining in parenchymal cells with no cytoplasmic or membranous staining. In the malignant tissues, unlike breast, the expression intensity is heterogenous and frequently less intense than in normal breast. For scoring BRCA1 staining, scoring system given by Yoshikawa et al. were follows:
Score 0: 0% nuclear staining (absent staining)
Score 1: <20% nuclear staining (reduced staining)
Score 2: 20%–80% nuclear staining
Score 3: >80% nuclear staining
The score 0 and score 1 were taken to be the altered expression of BRCA1 protein. The positive control tissue taken for BRCA1 staining was normal breast tissue.
Scoring for human epidermal growth factor receptor 2/neu
The HER-2/neu staining is seen as brown, membranous staining. The score 0 is given if no staining is observed or incomplete faint/barely perceptible membrane staining is observed within ≤10% of tumor cells. An incomplete membrane staining that is faint/barely perceptible and within >10% of tumor is scored as 1+. The circumferential membrane staining that is incomplete and/or weak/moderate and occurring within >10% of tumor cells or complete and circumferential membrane staining that is intense and occurring within ≤10% of tumor cells is scored 2+. A circumferential membrane staining that is complete, intense, and occurring within >10% of tumor cells is scored as 3+. The scores 0 and 1+ are negative while scores 2+ and 3+ are taken to be equivocal and positive, respectively.
The Elston and Ellis modification of Scarff-Bloom-Richardson grading was followed for microscopic grading of breast carcinoma.
The association of BRCA1 expression with various clinicopathological parameters and ER, PR, and HER-2/neu expression was analyzed using SPSS software version 16 and P values were calculated for each parameter; P < 0.05 was taken to be statistically significant.
| Results|| |
Breast carcinoma and clinical parameters
The patients ranged in age from 22 to 85 years. The mean age at presentation was 48.14 years. Fifty-three out of 54 patients were females and one patient was male. The majority of patients (62.3%) included in the study were postmenopausal.
The family history was present in 6 out of 54 cases (11.1%). Two out of 54 (3.7%) breast cancers were bilateral at the time of presentation. Majority (90.7%) were >2 cm in size. Three out of 54 (5.5%) breast cancers were the recurred cases of previously diagnosed and treated breast carcinoma. The axillary and supraclavicular lymph nodes involvement were observed in only 25 (46.3%) and 5 out of 54 (9.26%) patients, respectively.
Breast carcinoma and morphological parameters
Twenty-seven out of the 54 (50%) breast cancers were Grade 2 while 16 out of 54 (29.6%) and 11 out of 54 (20.4%) were Grade 1 and 3, respectively.
Breast carcinoma and estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu expression
The ER and PR positivity was seen in 46.3% of the tumors while 18.5% were HER-2/neu positive. Both ER and PR negativity was observed in 40.7% breast carcinomas. Fifteen out of 54 (27.8%) patients were triple negative, i.e., ER, PR, and HER-2/neu negative.
Breast cancer type 1 expression
Out of total 54 breast cancers, 24 (44.4%) were found to have altered BRCA1 expression (reduced and absent) while 30 (55.6%) were BRCA1 positive. Among 24 breast cancers showing altered BRCA1 expression, 12 (22.2%) had score 0, and an equal number (22.2%) had score 1 BRCA1 positivity. Various immunohistochemical expressions of BRCA1 have been depicted in [Figure 1].
|Figure 1: (a-d) Breast cancer type 1 nuclear immunostaining in breast carcinoma tissue sections (×400): score 0: 0% staining (absent), score 1: <20% staining (reduced), score 2: 20%–80% staining, score 3: >80% staining. Altered breast cancer type 1 expression includes scores 0 and 1|
Click here to view
Breast cancer type 1 expression and clinical parameters
The mean age of presentation for breast carcinomas with altered and positive BRCA1 expression was 47.3 and 50.2 years, respectively. Only 1 out of 54 patients was a male who showed score2 BRCA1 positivity. Six breast (11.1%) cancers were familial; out of which 4 (66.7%) had altered expression. No significant association was found between BRCA1 expression and family history of breast cancer (P = 0.245). Majority of breast carcinomas 62.3% (33/53) presented in postmenopausal group. Among these, 57.6% (19/33) were positive for BRCA1 expression while 42.4% (14/33) had altered BRCA1 expression. However, no association was found between BRCA1 nuclear expression and menopausal status, P = 0.591.
Twenty out of 24 (83.3%) breast carcinomas showing reduced or absent (altered) BRCA1 expression were found to be >3 cm in size. The larger size showed a significant association with altered BRCA1 expression, P = 0.011.
The frequency of uninvolved nodes was more common among breast carcinomas showing positive BRCA1 expression than those showing altered BRCA1 expression. Seventeen out of 29 (58.6%) showing uninvolved lymph nodes had positive BRCA1 expression. However, no significant association could be found out between BRCA1 expression and axillary lymph node involvement (P = 0.625). Five out of 54 patients had supraclavicular lymph node involvement; out of which only single had altered BRCA1 expression. No significant association could be established between the two, P = 0.248.
Breast cancer type 1 expression and morphological parameters
Seven out of 11 (63.6%) breast carcinomas with absent and reduced BRCA1 expression were Grade 3, in contrast to, 4 out of 11 (36.4%) BRCA1 positive breast carcinomas. Grade 1 tumors were more frequent in BRCA1 positive tumors (13/16, i.e., 81.3%) than tumors with altered BRCA1 expression (3/16 i.e., 18.7%). This has also been shown in [Figure 2]. There was a significant association established between BRCA1 expression and grade of the breast cancer (P = 0.038).
|Figure 2: Relationship between breast cancer type 1 expression and grade of the tumor|
Click here to view
The morphological features considered included lymphocytic infiltration, higher nuclear pleomorphism, less tubule formation, and high mitotic count; out of which the latter 3 are considered while calculating microscopic grade of the tumor by Nottingham Modification of the Bloom-Richardson system with which positive association was observed as discussed above. The positive association was seen between BRCA1 expression and lymphocytic infiltration of the tumor (P = 0.0005).
Breast cancer type 1 expression and estrogen receptors status
Majority of the breast cancers with altered BRCA1 expression were ER negative (15/24, i.e., 62.5%) while 46.7% (14/30) of breast cancers with positive BRCA1 expression were ER negative. However, no significant association could be established between the two (P = 0.246). The findings have been illustrated in [Figure 3].
|Figure 3: Relationship between breast cancer type 1 and estrogen receptors expression|
Click here to view
Breast cancer type 1 expression and progesterone receptors status
Nineteen of 24 (79.2%) breast cancers with altered BRCA1 expression had negative PR expression, in comparison to, 10 out of 30 (33.3%) in breast cancers with positive BRCA1 expression. BRCA1 nuclear expression showed a positive significant association with PR status, P = 0.001. The observations have been depicted in [Figure 4].
|Figure 4: Relationship between breast cancer type 1 and progesterone receptors expression|
Click here to view
Breast cancer type 1 expression and HER-2/neu status
Equal frequency of breast carcinomas with altered and positive BRCA1 expression showed negative HER-2/neu expression (66.7% in each group). No significant association was seen between BRCA1 nuclear expression and HER-2/neu expression (P = 0.869). This has been shown in [Figure 5].
|Figure 5: Relationship between breast cancer type 1 and human epidermal growth factor receptor 2/neu expression|
Click here to view
Breast cancer type 1 expression and triple-negative status
Out of 54 breast carcinomas, 15 were found to be triple negative (27.8%). Out of these 66.7% (10/15) had altered BRCA1 expression. Among breast carcinomas showing altered BRCA1 expression (24 cases), 10 (41.7%) were triple negative. This was found to be statistically significant (P = 0.042).
The results of the study in relation to BRCA1 expression and its relation with various parameters such as clinical characteristics, morphological features, and hormone receptor status has been illustrated in [Table 1].
|Table 1: Summary of the results of the study in relation to breast cancer 1 expression and relation with various parameters such as clinical characteristics, morphological features, and hormone-receptor status|
Click here to view
| Discussion|| |
Breast carcinoma is one of the most common cancers among females worldwide. The trend is toward an increase during the past two decades. There are many different treatment options available including chemotherapy, radiotherapy, and hormonal therapy. Although surgery is the mainstay of treatment of early breast cancer, the main focus after surgical resection is to determine which women will gain benefit from adjuvant therapies, for example, chemotherapy, radiotherapy, and hormonal therapies. At present, treatment decisions are made on histological tumor characteristics and the molecular markers such as ER, PR, and HER-2/neu are used to predict the treatment response in both early and metastatic breast cancer disease. Still, a search for other better biomarker is continuing including the research on the role of BRCA1.
It is very important to define morphological, immunohistochemical, and molecular features of BRCA1 associated tumors to improve genetic testing and also gain further insight into biological characteristics of tumors. The morphological and immunohistochemical data can be combined to predict risk of a young patient harboring a germline mutation in BRCA1.
The BRCA1 protein may play a crucial role in the development and progression of sporadic breast carcinomas and can be a promising biomarker to select a more targeted and effective chemotherapeutic regime to the patients of breast carcinoma. Thus to study its immunohistochemical expression becomes important.
The BRCA1-associated breast carcinomas are particularly chemosensitive. BRCA1 could be a predictive marker of response to different types of chemotherapeutic agents.
In the present study, 24 (44.4%) patients were found to have altered BRCA1 expression. Six breast cancers were familial, out of which 4 had altered expression. Although a number of cases with family history were less, altered expression of BRCA1 was observed to be higher (66.7%) in familial as compared to sporadic cases (41.7%). No significant association could be established between BRCA1 expression and family history. However, more number of cases with family history would be required to establish any association with BRCA1 expression.
Rakha et al. reported complete loss of nuclear expression of BRCA1 in 15% breast carcinomas and reduced nuclear expression in 39% of the cases. Similarly Pérez-Vallés et al. reported that among 38 breast cancer cases with no germline mutations, 63% of the familial cases showed absent staining for BRCA1, in contrast to, 50% cases without family history which was quite high. Among breast carcinoma with germline mutations, 43% and 28% showed absent and reduced staining, respectively. Yang et al. demonstrated 34.3% of the 175 sporadic breast cancers to be negative for BRCA1 nuclear staining. Lambie et al. in their group of 100 breast carcinoma patients found 79% cases to be showing weak to moderate nuclear staining for BRCA1 while it was completely lost in 5% of the tumors.
On the contrary, Lee et al., Yoshikawa et al., Mitrovic et al., and Hosni  and Hedau et al. noticed this in relatively lesser proportion of cases. Lee et al. found absence of nuclear staining of BRCA1 in 18.5% sporadic breast carcinomas.
Yoshikawa et al. noticed that 30 (28%) of 108 sporadic and 6 (17%) of 35 hereditary breast tumors with unknown BRCA1 mutation status showed reduced expression of BRCA1 protein. None of the cases among these groups showed complete loss of BRCA1 expression. Of the 19 breast cancer tissues with known BRCA1 mutation, 8 (42.1%) cases showed reduction and 7 (36.8%) showed complete loss of BRCA1 expression.
Mitrovic et al. studied Topoisomerase 2 alpha (TOP2A) amplification (using fluorescence in situ hybridization methods), and TOP2A and BRCA1 protein overexpression (immunohistochemistry) in four molecular subtypes of breast cancer. Of 53 patients, 32 showed TOP2A and 38 showed BRCA1 overexpression. Fifteen (27%) cases were negative for BRCA1.
Hosni et al. evaluated 30 cases of female breast cancer immunohistochemically for the expression of both aldehyde dehydrogenase 1 (ALDH1) and BRCA. BRCA1 expression was positive in 18 cases (60%) and negative in 12 (40%) cases. Thirty percentage showed positive cytoplasmic expression for ALDH1.
Hedau et al. evaluated the level of expression of the BRCA1 and BRCA2 proteins immunohistochemically in 40 sporadic breast cancer cases. Out of the 40 breast cancer, 12 cases (30.0%) showed a decreased BRCA1 protein expression compared to their respective normal adjacent controls.
The larger size was found to have a significant association with altered BRCA1 expression. Similar results have also been reported by Pérez-Vallés et al. They found tumors measuring ≥4 cm to correlate with the absence of BRCA1 staining. Rakha et al. also found a positive correlation between larger tumor size and nuclear expression of BRCA1. They found that 58.2% of cases with reduced and absent (altered) staining to be associated with larger size than 41.8% of cases with strong staining (P< 0.001). Comănescu et al. observed 64.29% of breast tumor (carrying BRCA1 gene mutation) to be >2 cm in size. However, Lee et al., Lambie et al., and Yang et al. did not find any correlation between tumor size and BRCA1 nuclear expression.
In our study, no significant association could be found out between BRCA1 expression and axillary or supraclavicular lymph node involvement. Similarly, Pérez-Vallés et al., Yoshikawa et al. did not find any significant association between the two. On the contrary, Yang et al. and Rakha et al. found a significant negative correlation between lymph node status and nuclear BRCA1 expression.
In the present study, among Grade 3 breast carcinomas 63.6% (7/11) showed reduced and absent BRCA1 expression. On the contrary, among Grade 1 tumors, majority were BRCA1 positive (81.3%) as compared to those with altered BRCA1 expression (18.7%). This was statistically significant. This was consistent with results of Rakha et al., Yang et al., Lambie et al., Lee et al., and Hedau et al.
However, Pérez-Vallés et al. observed no association of negative BRCA1 expression with grade of tumor in patients with no germline mutations. However, patients with germline mutations belonged to Grade 2 (2/7) and Grade 3 (5/7). Similarly, Yoshikawa et al. did not find any significant association between BRCA1expression and grade of the tumor.
Positive ER expression is considered as a good prognostic marker and gives a good response to Tamoxifen. In this study higher proportion of cases with altered BRCA1 expression (62.5%) showed ER negativity. However, it was not statistically significant. Similar findings were also obtained by Lee et al., who demonstrated loss of BRCA1 nuclear expression more commonly to be present in ER-negative tumors (12.2% vs. 27.1%), but without any significant association (P = 0.056). In addition, Yang et al. and Pérez-Vallés et al. observed ER negativity a more common feature among BRCA1-negative breast tumors but without any significant association. Similar results have been reported by Lambie et al. and Yoshikawa et al. However, Rakha et al. noticed a significant association between ER negativity and altered BRCA1 expression.
The PR negativity was significantly seen to be associated with tumors showing altered BRCA1 expression. Similar results were also obtained by Rakha et al. and Comănescu et al., who noticed a significant association between negative PR expression and altered BRCA1 expression on immunohistochemistry in breast carcinomas. However, no significant association between serum PR levels and BRCA1 staining was found by Yoshikawa et al.
The score 3 positivity of HER-2/neu was more common among breast carcinoma with altered expression (21%) than breast carcinoma with positive BRCA1 expression (16.7%). Yoshikawa et al. depicted similar results that breast carcinoma with reduced BRCA1 expression to have a trend toward HER-2/neu overexpression. HER-2/neu expression and BRCA1 nuclear staining were not found to be significantly associated by Yang et al. and Rakha et al.
In the present study, 15 out of 54, i.e., 27.8% breast carcinomas were found to be triple negative; of which 66.7% (10/15) were found to have altered BRCA1 expression. This was statistically significant. A significant association was also found by Rakha et al. between altered nuclear BRCA1 expression and triple-negative phenotype where 80% showed altered BRCA1 nuclear expression. Comănescu et al. depicted in their study that 78.6% (11/14) breast carcinoma which were positive for the presence of BRCA1 gene mutations on immunohistochemistry cases showed triple negativity for ER, PR, and HER-2/neu.
Various morphological characteristics possessed by tumors showing altered BRCA1 expression include large size, higher grade, less tubule formation, high mitosis, high nuclear pleomorphism, lymphocytic infiltration, smooth noninfiltrative margins, and vascular invasion. Out of these, in our study, we found that breast cancer cases with altered BRCA1 expression had significant association with lymphocytic infiltration, higher grade, and larger size. Tubule formation, mitoses and nuclear pleomorphism are considered in modified Bloom Richardson grading system, and we found a positive significant association of altered BRCA1 expression with grade. However, the characteristic pushing margins and vascular invasion can not be reliably commented on trucut biopsy specimens on account of smaller amount of tissue.
Mitrovic et al. demonstrated that TOP2A and BRCA1 positive phenotypes were in significant correlation in Luminal B and triple-negative breast cancer subtypes and that patients from these groups could benefit from epirubicin-based therapy.
The study by Hosni et al. revealed a significant inverse correlation between expression of ALDH1 and BRCA1 and established phenotypes combining expression of ALDH1, BRCA1, ER, PR, and HER2, which correlate with prognosis and outcome. They found that the protein expression profile; (ALDH1-, BRCA+, ER+, PR+, HER2-) was correlated with good prognosis and outcome of tumor while (ALDH1+, BRCA-, ER-, PR-, HER2+) was correlated with worse prognosis as well as tumor outcome. The study emphasizes the possible utility of ALDH1 as a biomarker to screen family members at risk for BRCA1 mutation and a possible therapeutic target in breast cancer as well.
Vaz et al. suggested BRCA1 immunohistochemistry a rapid and easy test that can be used before the expensive mutation screening, to select which high-risk cases should be submitted to analysis of this gene; they found that BRCA1 immunohistochemistry was 100% specific and 80% sensitive to predict for BRCA1 mutations.
Mangia et al. carried out an immunohistochemical study on tissue microarray samples from 93 sporadic and 94 familial breast cancer patients with (7/94) and without BRCA1 germline mutations. BRCA1 protein expression level was evaluated using the monoclonal MS110 antibody. All the tumors from patients carrying BRCA1 mutations showed complete loss of both BRCA1 and ERα expression, regardless of the type of mutation. The percentage of MS110 positive cases was significantly lower in mutated versus wild-type BRCA1 familial cases (P = 0.02) while the percentage of patients with higher ERα expression was significantly lower in BRCA1-mutated versus BRCA1-wild type familial patients (P = 0.05).
| Conclusion|| |
In our study, we found that altered BRCA1 expression is significantly associated with larger size (>3 cm), higher grade, PR positivity, triple-negative status, and lymphocytic infiltration while higher number of cases with altered expression had ER negativity and HER-2/neu overexpression. As BRCA1-related tumors are chemosensitive and respond very well to certain chemotherapeutic drugs, knowing BRCA1 expression status before initiation of chemotherapy is important in tailoring a proper chemotherapeutic regime.
The trucut biopsy of breast lump is a convenient method to obtain sample for this as it is less invasive than open biopsy and immunohistochemistry can be put up but it has certain limitations that margins of carcinoma can not be commented owing to smaller tissue.
The combination of immunohistochemical expression of BRCA1 in breast carcinomas with morphological findings, other immunohistochemical features, and clinical history may be of great help in finding individuals more likely to carry BRCA1 mutations and selecting the candidate and family members to genetic screening for BRCA1 mutation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lambie H, Miremadi A, Pinder SE, Bell JA, Wencyk P, Paish EC, et al.
Prognostic significance of BRCA1 expression in sporadic breast carcinomas. J Pathol 2003;200:207-13.
James CR, Quinn JE, Mullan PB, Johnston PG, Harkin DP. BRCA1, a potential predictive biomarker in the treatment of breast cancer. Oncologist 2007;12:142-50.
Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-24.
Newman B, Austin MA, Lee M, King MC. Inheritance of human breast cancer: Evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A 1988;85:3044-8.
Easton DF, Bishop DT, Ford D, Crockford GP. Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families. The breast cancer linkage consortium. Am J Hum Genet 1993;52:678-701.
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al.
Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-9.
Kennedy RD, Quinn JE, Johnston PG, Harkin DP. BRCA1: Mechanisms of inactivation and implications for management of patients. Lancet 2002;360:1007-14.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al.
Astrong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71.
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast cancer linkage consortium. Lancet 1994;343:692-5.
Hilakivi-Clarke L. Estrogens, BRCA1, and breast cancer. Cancer Res 2000;60:4993-5001.
Marquis ST, Rajan JV, Wynshaw-Boris A, Xu J, Yin GY, Abel KJ, et al.
The developmental pattern of brca1 expression implies a role in differentiation of the breast and other tissues. Nat Genet 1995;11:17-26.
Yang Q, Sakurai T, Mori I, Yoshimura G, Nakamura M, Nakamura Y, et al.
Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas. Cancer 2001;92:54-60.
Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 1995;9:444-50.
Comănescu M, Popescu CF. BRCA1 expression in invasive breast carcinomas and clinicopathological correlations. Rom J Morphol Embryol 2009;50:419-24.
Fletcher DM. Tumors of the breast. In: Diagnostic Histopathology of Tumors. 3rd
ed. Philadelphia: Elsevier; 2007. p. 948-9.
Yoshikawa K, Honda K, Inamoto T, Shinohara H, Yamauchi A, Suga K, et al.
Reduction of BRCA1 protein expression in Japanese sporadic breast carcinomas and its frequent loss in BRCA1-associated cases. Clin Cancer Res 1999;5:1249-61.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al.
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013.
Palacios J, Honrado E, Osorio A, Cazorla A, Sarrió D, Barroso A, et al.
Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: Differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 2003;9:3606-14.
Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, et al.
The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20:2310-8.
Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO, et al.
Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 2008;39:857-65.
Pérez-Vallés A, Martorell-Cebollada M, Nogueira-Vázquez E, García-García JA, Fuster-Diana E. The usefulness of antibodies to the BRCA1 protein in detecting the mutated BRCA1 gene. An immunohistochemical study. J Clin Pathol 2001;54:476-80.
Lee WY, Jin YT, Chang TW, Lin PW, Su IJ. Immunolocalization of BRCA1 protein in normal breast tissue and sporadic invasive ductal carcinomas: A correlation with other biological parameters. Histopathology 1999;34:106-12.
Mitrovic O, Mićić M, Čokić V, Koko V, Đikić D, Budeč M, et al
. BRCA1 and TOP2A
gene amplification and protein expression in four molecular subtypes of breast cancer. Arch Biol Sci 2013;65:511-8.
Hosni HN, Daoud AS, Bassam AM. Immunohistochemical study of stem cell marker ALDH1 and BRCA1 in breast cancer. Acad J Cancer Res 2014;7:1-7.
Hedau S, Batra M, Singh UR, Bharti AC, Ray A, Das BC, et al.
Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer. J Cancer Res Ther 2015;11:158-63.
Vaz FH, Machado PM, Brandão RD, Laranjeira CT, Eugénio JS, Fernandes AH, et al.
Familial breast/ovarian cancer and BRCA1/2 genetic screening: The role of immunohistochemistry as an additional method in the selection of patients. J Histochem Cytochem 2007;55:1105-13.
Mangia A, Chiriatti A, Tommasi S, Menolascina F, Petroni S, Zito FA, et al.
BRCA1 expression and molecular alterations in familial breast cancer. Histol Histopathol 2009;24:69-76.
Dr Lal Path Labs, Sector-18, Rohini, New Delhi - 89
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
|This article has been cited by|
||From Editoręs desk
| ||Ranjan Agrawal |
| ||Indian Journal of Pathology and Microbiology. 2018; 61(1): 1 |
|[Pubmed] | [DOI]|
| Article Access Statistics|
| Viewed||3099 |
| Printed||41 |
| Emailed||0 |
| PDF Downloaded||181 |
| Comments ||[Add] |
| Cited by others ||1 |