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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 35  |  Issue : 3  |  Page : 103-107

Molecular subtypes of breast carcinoma and its relation with clinicopathological features: A single-center initial experience


Department of Pathology, Regional Institute of Medical Sciences, Imphal, Manipur, India

Date of Submission18-Jan-2022
Date of Acceptance21-Feb-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Babina Sarangthem
Department of Pathology, Regional Institute of Medical Sciences, Imphal, Manipur
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jms.jms_5_22

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  Abstract 


Molecular subtypes of breast carcinoma and its relation with clinicopathological features: A single centre initial experience.
Background: Breast carcinoma is the most common malignancy in female in the world. They are a group of heterogenous diseases with diverse clinical, morphological and gene expression profile. Molecular subtyping of histological types of breast carcinomas based on the expression receptors estrogen receptors (ER), progesterone receptors (PR), HER2 neu and Ki67 act as a surrogate marker for gene expression profiling. This helps in specific prognostic and predictive targeted therapy.
Objective: Identification of various molecular subtypes and correlate with the clinicopathological parameters.
Methods: This cross sectional study comprising of thirty four cases is conducted at Department of Pathology, Regional Institute of Medical Sciences, Imphal during a period of three years from August 2016 to July 2019. The histomorphological diagnosis and clinical parameters are correlated with immunohistochemical findings for ER, PR, Her2 Neu and Ki 67. Statistical analysis done by chi square test.
Results: The commonest histological type is invasive carcinoma of no special type (88.2%). After molecular sub typing, Luminal B type (LUMB) is the most common type (38.2%). LUMA type found to be associated with smaller tumor size, grade 1-2 and seen mainly in 6rd and 7th decade of life. LUMB and Her-2 Neu enriched, triple negative type commonly associated with larger tumor size, grade 2-3 and seen in 4th to 6th decade of life.
Conclusion: Some differences in clinicopathological profile of the molecular subtypes from other studies seen. A larger multicentric study with genetic analysis will help in understanding the disease pattern in our area helping in targeted and personalized treatment.

Keywords: Breast carcinoma, estrogen receptors, HER-2 neu, molecular subtypes, progesterone receptors


How to cite this article:
Joute Z, Debnath M, Pukhrambam GD, Khuraijam S, Sarangthem B. Molecular subtypes of breast carcinoma and its relation with clinicopathological features: A single-center initial experience. J Med Soc 2021;35:103-7

How to cite this URL:
Joute Z, Debnath M, Pukhrambam GD, Khuraijam S, Sarangthem B. Molecular subtypes of breast carcinoma and its relation with clinicopathological features: A single-center initial experience. J Med Soc [serial online] 2021 [cited 2022 Aug 7];35:103-7. Available from: https://www.jmedsoc.org/text.asp?2021/35/3/103/347643




  Introduction Top


Breast carcinoma is the most common malignancy in females in the world and accounts for 502,000 deaths every year according to the WHO.[1] It is also the most common malignancy in females in Manipur, India (PBCR 2016) and 2nd most common cancer next to cervical cancer in India as a whole.[1],[2] Breast carcinoma is a heterogeneous disease with diverse clinical, histomorphological, and genetic profiles. Sørlie et al., in the early 2000s have classified breast tumors based on gene expression profiling (GEP) into five major types, Luminal A (LUMA), Luminal B (LUMB), HER-2 neu enriched, basal, and triple-negative (TN) type.[3] They have shown that tumors displaying similar histomorphology have different molecular signature and gene expression profiles resulting in different clinical behavior, prognosis, and treatment response.[3],[4] As GEP is neither applicable or economical in day-to-day practice, molecular classification of breast tumors based on immunohistochemical (IHC) analysis by St Gallen consensus 2011 based on the expression of pathological biomarkers estrogen receptors (ER), progesterone receptors (PR), HER-2 neu, and Ki67 is widely adopted.[4],[5] This also classifies breast tumors into five types and stresses on the importance of ki67 index in differentiating LUMA from LUMB. This classification act as a surrogate marker for gene expression profile as they have comparable clinical outcome even though they are not identical. Ethnic variation in the presentation of various subtypes of carcinoma breast is also seen.[5],[6],[7] As these molecular subtypes are associated with different disease courses and treatment responses, identification is important for prognosis and prediction of therapy.[8],[9] Our study attempts to identify and study the molecular subtypes of breast carcinoma seen in our center and correlate the different subtypes with clinicopathological features.


  Materials and Methods Top


This is a cross-sectional study carried out in the Department of Pathology, Regional Institute of Medical Sciences, Imphal, during a period of 3 years from August 2016 to July 2019. Ethical approval from the Institutional Ethical committee was taken. A total of 34 cases of breast carcinoma reported during the study are included in the study. This includes 30 cases of mastectomy and four cases of trucut biopsy specimens. Those cases with history of neoadjuvant therapy, recurrence, and without incomplete data are excluded from the study. The relevant clinical data, Hematoxylin and Eosin stained sections are studied. The histomorphological diagnosis is reported based on latest version of the College of American Pathologist (CAP) protocol.[5] IHC studies for ER, PR, and HER-2 neu, Ki 67 are done and interpreted with negative and positive control. PathnSitu reagents of rabbit monoclonal antibody for ER, PR, and mouse monoclonal antibody for Ki67 are used. Thermo scientific reagent for monoclonal antibody used for HER-2 neu. The CAP reporting guidelines system of scoring used for ER and PR (Allred system of scoring) and HER-2 neu receptors. Grading for Ki67 done from Ki67 index calculated by comparing the number of positive cells with the total number of cells and multiplying by 100.[5] Molecular subtyping done on the basis of ER, PR, HER-2 neu, and Ki 67 profile as LUMA (ER/PR+, HER-2, low ki67, <14%), LUMB (ER/PR+, HER-2+, high ki67 >14%), HER-2 neu enriched (ER/PR/HER-2+), and TN (ER/PR/HER-2).[4],[5] IHC studies for cytokeratin 5 (C5) and cytokeratin 7 (C7) not done as reagents are not available in the department. Hence, the basal and TN types could not be distinguished and are grouped together as TN tumors.

Histological grading done based on Nottingham histologic score (NHG). Hence, based on the gland formation, nuclear pleomorphism, and mitotic figures, the cases are scored and then graded.[10] Molecular subtypes are then correlated with the histomorphological diagnosis and clinicopathological parameters such as age, size of tumor, lymph node involvement, and stage of the disease. The data obtained are analyzed using descriptive variables such as mean and percentage. Moreover, association analyzed by the Chi-square test.


  Results Top


A total of 43 cases of breast carcinoma are diagnosed during the study. Thirty-four cases are included in the study after applying the exclusion criteria. The most common histological type seen is invasive breast carcinoma of no special type (88.2%) [Figure 1]. The maximum number of cases are seen in the 40–50 years age group with a mean age of 44.1%. Ductal carcinoma in situ component seen in 44.2% of the total cases. After molecular subtyping, LUMB type is found to be the most common type (38.2%) [Figure 2], followed by LUMA type 32.3% [Figure 3], HER-2 neu enriched 26.5% [Figure 4], and TN type 2.9% [Figure 5]. In the association of the molecular subtypes with age, the LUMA type is seen most commonly in the 61–70 years age group, whereas other subtypes are seen in the younger age group as depicted in the bar diagram [Figure 6]. This association is not found to be statistically significant (P = 0.606). When the molecular subtypes are correlated, LUMA and HER-2 neu enriched type found to be associated with smaller tumor size with a mean size of 3.3 and 3.6 cm, respectively. The TN type is associated with the largest size, i.e., 4.5 cm, whereas the LUMB type has a mean tumor size is found to be 4.03 cm. However, this association is not found to be statistically significant (P = 0.601). Of the total cases, 76% of the cases show lymph node positivity. In the molecular subtypes, TN (1/1, 100%) and HER-2 neu (5/6, 83.3%) types showed maximum lymph node positivity. LUMA and LUMB types showed 75% and 70% positivity, respectively. However, when correlated, this association is not found to be statistically significant (P = 0.875). After grading the tumors by NHG score, HER-2 neu and TN are found to be associated with a higher grade than LUMA and LUMB types as shown in the bar diagram [Figure 7]. This is found to be statistically significant (P = 0.012). Staging of the tumors is done based on the American Joint Committee on Cancer 8th Edition and maximum number of tumors presented in Stage II (44.0%). The association of the molecular subtypes and stage are shown in the bar diagram given below [Figure 8]. The P is not found to be statistically significant (P = 0.586).
Figure 1: Microphotograph showing infiltrating duct carcinoma not otherwise specified (H and E stain, ×400)

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Figure 2: Immunohistochemical stain showing Luminal B subtype with high proliferation (×400)

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Figure 3: Immunohistochemical stain showing Luminal A subtype with low proliferation (×400)

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Figure 4: Immunohistochemical stain showing HER-2 neu enriched subtype (×400)

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Figure 5: Immunohistochemical stain showing triple-negative subtype (×400)

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Figure 6: Association of molecular subtypes of breast carcinoma with age group (P = 0.606)

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Figure 7: Association of molecular subtypes with histologic grade of breast carcinoma (P = 0.012)

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Figure 8: Molecular subtypes with stage of breast carcinoma (P = 0.586) (not significant)

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  Discussion Top


Molecular classification of breast tumor has become an essential tool for better prognostic and prediction of breast cancer therapy. In our study comprising of 34 cases of invasive breast carcinoma, invasive ductal carcinoma (88%) is found to be the most common histologic type and maximum number of cases are seen in the 40–50 years age group. These findings are similar with most of the studies.[1],[6],[7],[10] A higher age Group >50 years involvement is seen in studies conducted by some workers from Indonesia, Iran, and China.[9],[11],[12] After molecular subtyping of the tumors, LUMB subtype is found to be the most common type (382%) followed by LUMA subtype (32.3%). This finding is similar with those of Mittal and Mani,[1],[13],[14] the majority of the workers from India and other parts of the world have found LUMA to be the most common type.[8],[15],[16] The difference may be due to our small sample size or ethnic variation. A Pakistani study has found HER-2 neu enriched type as the most common tumor.[17] TN tumors found to be the most common subtype as reported by Walke Vand Gunjkar.[18] Hence, LUMA subtype is found to be the most common type seen in most of the studies. When age is correlated with the molecular subtypes, LUMA cases are found maximum in the 61–70 years age group whereas LUMB, HER-2 neu enriched, and TN types are seen in 41–50 years of age. This finding is similar with most studies wherein LUMA cases are seen in the older age group whereas HER-2 neu enriched and TN types are seen in slightly younger age group.[19],[20],[21] This association of molecular subtypes with age is found to be statistically insignificant (P = 0.606) in our study.

In our study, tumor size is found to be more than 2 cm but <5 cm. Some workers have found larger tumor size to be associated with HER-2 neu enriched and TN types.[2],[9],[20] This is similar with our finding. However, no association noted between the size of tumor and molecular subtype. Highest lymph node positivity cases found in HER 2 neu (83.33%) and TN which is also similar to most of the studies.[3],[6],[7],[8]

When tumor grading is done by modified Nottingham scoring system, most of the cases in our study presented with histologic grading of Grade II. The lone TN subtype presented in Grade III. These findings are similar with most studies.[2],[8],[18],[21] HER-2 neu enriched and TN types are aggressive tumors and usually present in higher grade. This association is found to be statistically significant (P = 0.012). Similarly, most of the molecular subtypes presented in Stage 2 and 3 which is similar with most studies.[7],[19],[22] This late presentation is commonly seen in Indian studies whereas developed countries showed an earlier presentation.[16] This may be due to the lack of awareness or social factors prevalent in our country.[8] The differences in clinicopathological profile of the molecular subtypes from other studies may be due to ethnic variations, genetic factors, or small sample size of our study.


  Conclusion Top


Breast carcinoma is a heterogeneous disease with various molecular subtypes having different clinicopathological features and clinical responses to therapy. Hence, an attempt has been made to subtype at the molecular level. Most of the findings in our study are found to be similar with other studies with some differences, a larger multicenter study with genetic analysis is the need of the hour to understand the disease for better prognosis and prediction of breast cancer therapy in our state. This will help in more targeted and personalized treatment of the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mittal A, Mani NS. Molecular classification of breast cancer. Indian J Pathol Oncol 2021;8:241-7.  Back to cited text no. 1
    
2.
PBCR, Manipur (under NCDIR-NCRP, ICMR). Annual report, Imphal: PBCR, Manipur; 2016:16-7.  Back to cited text no. 2
    
3.
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-74.  Back to cited text no. 3
    
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Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, et al. Strategies for subtypes – Dealing with the diversity of breast cancer: Highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Annls Oncol 2011;22:1736-47.  Back to cited text no. 4
    
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Tang P, Tse GM. Immunohistochemical surrogates for molecular classification of breast carcinoma: A 2015 update. Arch Pathol Lab Med 2016;140:806-14.  Back to cited text no. 5
    
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Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med 2016;13:496-504.  Back to cited text no. 6
    
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Rahman MZ, Karim A. Profile of molecular subtypes of breast cancer among Bangladeshi women. Chattagram Maa-o-Shishu Hosp Med Coll J 2017;16:1-4.  Back to cited text no. 7
    
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Tiwari S, Malik R, Trichal VK, Nigam RK, Rai A, Balani S. Breast cancer: Correlation of molecular classification with clinicohistopathology. Sch J App Med Sci 2015;3:1018-26.  Back to cited text no. 8
    
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Widodo I, Dwianingsih EK, Triningsih E, Utoro T, Soeripto. Clinicopathological features of Indonesian breast cancers with different molecular subtypes. Asian Pac J Cancer Prev 2014;15:6109-13.  Back to cited text no. 9
    
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Effi AB, Aman NA, Koui BS, Kouadio DK, Traore ZC, Kouyate M. Breat cancer molecular subtypes defined by er/pr and her-2 neu status: Association with clinicopathologic parameters in ivorian patients. Asian Pac J Cancer Prev 2016;17:1973-8.  Back to cited text no. 10
    
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Kadivar M, Mafi N, Joulaee A, Shamshiri A, Hosseini N. Breast cancer molecular subtypes and associations with clinicopathological characteristics in Iranian women, 2002- 2011. Asian Pac J Cancer Prev 2012;13:1881-6.  Back to cited text no. 11
    
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Sohn YM, Han K, Seo M. Immunohistochemical subtypes of breast cancer: Correlation with clinicopathological and radiological factors. Iran J Radiol 2016;13:e31386.  Back to cited text no. 12
    
13.
Raychaudhuri S, Bajaj A, Agarwal C, Pujani M, Singh K, Chauhan V, et al. Immunohistochemistry based molecular subtyping of breast carcinoma in industrial population in India, Haryana: A correlation with clinicopathological parameters. Middle East J Cancer 2021;12:357-67.  Back to cited text no. 13
    
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San TH, Fujisawa M, Fushimi S, Soe L, Min NW, Yoshimura T, et al. Molecular subtypes of breast cancers from Myanmar women: A study of 91 cases at two pathology centers. Asian Pac J Cancer Prev 2017;18:1617-21.  Back to cited text no. 14
    
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Yao C, Liu Y, Huang H, Zhang J. Correlation between clinicopathological features and postoperative prognosis in patients with breast cancer J Clin Exp Med 2018;11:2483-8.  Back to cited text no. 15
    
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Priyanka A, Sudalaimuthu M, Shivashekar G. Surrogate molecular subtyping of breast carcinomas – A study on recent modifications and their clinicopathological significance. Trop J Pathol Microbiol 2021;7:71-7.  Back to cited text no. 16
    
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Akbar M, Akbar K, Naveed D. Frequency and correlation of molecular subtypes of breast cancer with clinicopathological features. J Ayub Med Coll Abbottabad 2014;26:290-3.  Back to cited text no. 17
    
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Walke Vand Gunjkar G. Immunohistochemical profile and its association with clinicopathological parameters in carcinoma breast: A prospective study in central India. Int J Res Med Sci 2019;7:1796-802.  Back to cited text no. 18
    
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Hashmi AA, Aijaz S, Khan SM, Mahboob R, Irfan M, Zafar NI, et al. Prognostic parameters of luminal A and luminal B intrinsic breast cancer subtypes of Pakistani patients. World J Surg Oncol 2018;16:1.  Back to cited text no. 19
    
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Cheng HT, Huang T, Wang W, Yue JQ, Shen N, Guo H, et al. Clinicopathological features of breast cancer with different molecular subtypes in Chinese women. J Huazhong Univ Sci Technolog Med Sci 2013;33:117-21.  Back to cited text no. 20
    
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Ansari M, Mittal A, Mehta J, Niharika J. Molecular subtypes of breast cancer according to immunohistochemicl expression of hormone receptors in a region of North West India: A comparative study with other regions in India and around the globe. Int Arch BioMed Clin Res [Internet]. 2019;5:26-30. Available from: https://iabcr.org/index.php/iabcr/article/view/460. [Last accessed on 2019 Mar 21].  Back to cited text no. 21
    
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Dewan K, Mandal AK. Surrogate molecular classification of breast carcinoma: A classification in need or a dilemma indeed. Oncol J India 2020;4:79-86.  Back to cited text no. 22
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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