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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 79-86

Surrogate molecular classification of breast carcinoma: A classification in need or a dilemma indeed

Department of Pathology, Dr. Baba Saheb Ambedkar Medical College and Hospital, Government of NCT of Delhi, New Delhi, India

Date of Submission08-Nov-2019
Date of Decision09-Oct-2020
Date of Acceptance02-Nov-2020
Date of Web Publication26-Nov-2020

Correspondence Address:
Ashish K Mandal
Director, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair - 744 104, Andaman and Nicobar Islands

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/oji.oji_46_19

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The biological heterogeneity of breast cancer accounts for variations in natural course of disease and differences in response to various therapeutic modalities. These variations pose as major challenges in clinical management of patient. The quest for markers that would accurately define prognosis and response to particular therapeutic modality has led us to the molecular makeup of these tumors. The technique of gene expression profiling has been pivotal in this regard. With the study of thousands of genes simultaneously in breast cancer patients, a molecular classification of breast carcinoma was proposed in the early 21st century. High-throughput commercial assays proved to be useful in predicting prognosis for the patients but are expensive. Classification of breast cancers using immunohistochemistry that can be used as a surrogate of this molecular classification is inexpensive, easier, and more convenient to use. However, the accuracy of this classification is closely dependent on accurate immunohistochemical measurement of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki67. The initial surrogate classification has undergone revisions to make it more relevant in the 13th St Gallen International Breast Conference. Newer molecular subtypes such as claudin low have also been identified but are included in the basal-like subtype in surrogate classification due to its triple-negative nature. The utility of the surrogate classification in the Indian setting is immense due to limited access to molecular techniques. This review covers in detail the evolution, prognostic, and therapeutic implications of the surrogate molecular classification of breast cancers.

Keywords: Breast carcinoma, immunohistochemistry, intrinsic molecular subtypes, surrogate molecular classification

How to cite this article:
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

How to cite this URL:
Dewan K, Mandal AK. Surrogate molecular classification of breast carcinoma: A classification in need or a dilemma indeed. Oncol J India [serial online] 2020 [cited 2021 Dec 5];4:79-86. Available from: https://www.ojionline.org/text.asp?2020/4/3/79/301588

  Introduction Top

Cancer is the most dreaded disease in present times. Worldwide, breast cancer is the second most common cancer in the population and the most common cancer in females.[1] Although bracketed under a common heading of breast cancer, the biological heterogeneity that this term encompasses is evident on the variations in morphology, varying natural course of disease, and differences in response to various therapeutic modalities. Over the past two decades, identification of biological heterogeneity has moved from the cellular level to the molecular level due to advances in molecular research. The role of the surgical pathologist is also evolving and is gaining increasing momentum in patient management for this reason. The surgical pathology report now serves a purpose much beyond offering a diagnosis and includes prognostic molecular markers. It also includes molecular markers that may predict chances of satisfactory response of a particular therapeutic modality in an individual, avoiding unnecessary adverse side effects in others, making it possible to offer individualized customised therapy in true sense. This has been worked upon to draw diagnostic, prognostic, and predictive implications with the ultimate aim of benefitting the patient.

The present review aims to summarize the changing taxonomy of breast cancer based on molecular studies in the past decade. It highlights the evolution of the currently relevant surrogate molecular classification of breast carcinoma beginning from the description of intrinsic molecular subtypes and multigene signature assays. The significance of the classification in making therapeutic decisions and predicting prognosis is explained elaborately.

  Intrinsic Molecular Subtypes of Breast Cancer Top

Gene expression profiling (GEP), that is analyses of thousands of genes simultaneously, has been instrumental in discovering numerous genes that play a role in the pathogenesis of various human cancers. Numerous researchers worldwide are making fresh attempts toward taxonomy of almost all cancers based on the vast expanse of data generated by GEP and to correlate this genetic profiling with the already known clinicopathological classification. In the early 21st century, studies on variation in gene expression patterns in human breast cancers using complementary DNA microarrays revolutionized the way these tumors are classified. In the year 2000, Perou et al. published their study on gene expression patterns in 65 surgical specimens of human breast tumors from 42 different individuals, using complementary DNA microarrays representing 8102 human genes. Each of these breast tumors portrayed a unique molecular makeup, and yet, these tumors clustered into groups based on GEP patterns to form the basis for classification of breast carcinomas.[2] In 2001, the same set of researchers published a refinement of this classification by analyzing a larger sample size and using 456 cDNA clones that were actually selected from the earlier set of 8102 genes on the basis of higher variability in expression between different tumors and minimal variance within repeated samplings of the same tumor. These characteristics made these 456 genes accountable for the phenotypic characteristics of the tumor. Careful analysis of the patterns of gene expression revealed clustering of tumors into groups. This clustering, called hierarchical clustering, primarily classified breast tumors into two main types based on estrogen receptor (ER) expression – ER positive and ER negative [Figure 1]a. The ER-positive group, constituting the right branch of the hierarchical clustering showed the largest cluster. It was characterized by the expression of genes normally expressed by luminal breast epithelial cells and therefore called luminal type. Further classification into two main subgroups was possible. The first subgroup, Luminal subtype A, demonstrated high expression of ER, X-box-binding protein 1, trefoil factor 3, GATA-binding protein 3, estrogen-regulated LIV-1, hepatocyte nuclear factor 3 alpha, and low expression of proliferation-related genes and human epidermal growth factor receptor 2 (HER2) negative. The second group of tumors showed lower expression of luminal-specific genes and was further broken into two units – Luminal B and C. Luminal C was characterized by high expression of a novel set of genes with unknown function.[3] The ER-negative tumors, constituted the left branch of the hierarchical clustering, contained three subgroups which were characterized by low/absent expression of ER and other genes normally expressed by luminal epithelial cells and strong expression of basal epithelial genes. The three left branch tumors were basal-like subtype (characterized by lack of expression of ER and HER2 and high expression of keratins 5, keratin 17, laminin, and fatty acid-binding protein 7); ERBB2 subtype (high expression of genes such as ERBB2 and GRB7 located on chromosome 17q22.24); and normal breast-like group (characterized by triple negativity and high expression of genes expressed by fat and nonepithelial cell types). The prognostic significance of this classification was shown by shorter survival rates and relapse-free survival for basal-like and ERBB2-positive breast cancers, while the luminal subtype had a favorable clinical outcome.[3] The potential significance of this intrinsic subtyping of breast cancers was not limited to survival rates. Further research suggested a relation between intrinsic subtypes and response to various therapeutic modalities in adjuvant and neoadjuvant settings. It has also been suggested that different intrinsic subtypes originate from cells in differing stages of maturation with activation of different molecular pathways. This genetic information based on molecular profiling is more clinically useful in guiding therapy and defining prognosis in an individual than morphology alone.
Figure 1: (a) Hierarchical clustering of breast tumors by gene expression profiling. (b) Immunohistochemistry for estrogen receptor (×400)-positive in a case of Luminal A tumor. (c) Immunohistochemistry for progesterone receptor (×400)-positive in a case of Luminal A tumor. (d) Immunohistochemistry for human epidermal growth factor receptor 2 neu (×400)-positive in a case of human epidermal growth factor receptor 2-enriched tumor

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  Multigene Signature Assays Top

GEP of breast tumors was closely followed by the development of high-throughput microarray-based commercial assays to quantify gene expression of multiple genes obtained from formalin-fixed paraffin-embedded breast tumor tissue.[4] These assays use a collection of genes (known as a “gene signature”) rather than individual genes to identify a particular tumor in relation to its biological behavior. The three commercially available arrays are

  1. Oncotype DX assay
  2. Prediction analysis of microarray (PAM) 50
  3. Mammaprint.

Oncotype DX assay

Oncotype DX assay (Genomic Health, Redwood City, CA, USA), also known as 21-gene recurrence score (21-gene RS), is based on quantitative reverse transcriptase–polymerase chain reaction analysis of expression of 21 genes. Sixteen of these 21 genes have been proven to be associated with breast cancer behavior and included genes that regulate cell proliferation (Ki 67, STK 15, Survivin, CCNB1, and MYBL2), tumor invasion (stromelysin 3 and cathepsin L2), HER2 group (GRB7 and HER2), estrogen group (ER, PgR, BCL2, and SCUBE2), and others such as GSTM1, CD68, and BAG1. The expression of the rest of the five included genes is known to remain stable during the test process and they serve as internal controls for the test and are called reference genes (ACTB, GAPDH, RPLPO, GUS, and TFRC). The gene expression result is reported as a numerical value, known as RS, the value of which ranges from 0 to 100. Patients are classified into low risk (21-gene RS <18), intermediate risk (21-gene RS 18–30), and high risk (21-gene RS >30) where higher RSs imply a greater chance of distant recurrence of the tumor. The 21-gene RS also correlated with overall patient survival. The RS was found to quantify the chances of distant recurrences in newly diagnosed early-stage breast cancer (ER-positive lymph node-negative breast cancers) that had been treated with tamoxifen therapy.[4],[5],[6]

It has been observed that only 15% of all ER-positive/HER2-negative patients on long-term follow-up have distant recurrences at 10 years. If this subset of patients is treated with adjuvant chemotherapy, we would actually be overtreating 85% of patients and exposing them to side effects of chemotherapy. Patients with high 21-gene RS were proved to have a larger benefit from chemotherapy in comparison to patients with intermediate RS. Patients with low RS derived minimal benefit from chemotherapy if any.[7] This finding is especially important in making crucial decisions regarding the administration of chemotherapy in ER-positive/HER2-negative cases. Therefore, 21-gene RS has emerged as a useful tool in limiting chemotherapy to high 21-gene RS patients only who are most likely to benefit from chemotherapy.[7]

Baseline 21-gene RS is proven to correlate with response to neoadjuvant chemotherapy using ixabepilone with cyclophosphamide in locally advanced HER2-negative breast cancer patients. Achievement of pathologic complete response, which is taken as a measure of response to neoadjuvant chemotherapy, was seen in a total of 17% cases, but the response rate increased to 27% in patients with high 21-gene RS and no response was seen in patients with low or intermediate 21-gene RS.[8]

Prediction analysis of microarray 50

PAM 50 was introduced in 2009 and measured the expression of 50-genes to identify the intrinsic molecular breast cancer subtypes with 93% accuracy.[9] It also provides a proliferation score and a risk of relapse (ROR) score. The ROR score is predictive of response to neoadjuvant therapy in all breast cancer patients, including both ER-positive and ER-negative tumors.[9],[10],[11],[12] This is in comparison to Oncotype Dx, which is proven to be predictive of response to adjuvant and neoadjuvant chemotherapy in ER-positive patients only. Based on the ROR score, very low-risk group of breast cancer that may not need chemotherapy at all is identified and overtreatment is avoided.[10]


Mammaprint (Agendia, Huntington Beach, CA, USA), also known as 70-gene breast cancer gene signature, is a US Food and Drug Administration-approved commercial assay that uses tumor RNA analysis of 70 genes regulating cell cycle (e.g., CCNE2 and ECT2), invasion (e.g., GPR 180 and GPR126), metastasis (e.g., SCUBE 2, WISP 1, and transforming growth factor beta-3), and angiogenesis (e.g., ALDH4A1, GMPS, COL4A2, and MMP9). 70-gene signature test classifies tumors into those with a good prognosis or poor prognosis. According to the clinical criteria, young age of the patient and early stage of breast carcinomas are known good prognostic parameters. However, when the 70-gene signature test was used on this set of clinically good prognosis patients, the tumors classified as “poor prognosis” group by 70-gene signature had significantly lower 10-year survival rates and the probability of remaining free of distant metastasis at 10 years than those classified as “good prognosis” group.[12] It was thereby proven that 70-gene signature adds independent prognostic information to that provided by clinicopathologic factors but not vice versa.[13] In addition to the prognostic value, this test is also used as a factor in guiding judicious use of adjuvant therapy in breast cancer patients to reduce rates of both overtreatment and undertreatment.

These commercial assays based on GEP, although provide a high-throughput powerful research tool, have come with their own set of drawbacks. Standardization of protocols for analysis and interpretation of the vast amount of data generated is a matter of concern. In addition to the technical concerns, the tests are expensive, costing around 4000 US$ per test, not available widely for this reason, and have a turnaround time of around 2 weeks. All these factors combined together discouraged routine use of these tests despite encouraging results regarding their role in patient management. As more and more researchers were investigating the utility of these commercial assays in patient care, there were others who were striving to find alternatives that were more conveniently available, but that would also be comparable in predicting prognosis and response to various therapeutic modalities. Immunohistochemistry was the closest alternative to these gene expression-based assays and has the advantage of being economical, widely available, and shorter turnaround time. In addition, it shows protein expression in relation to tumor morphology, and most pathologists are better versed with this technique.

  Surrogate Molecular Classification Using Immunohistochemistry Top

In 2009, Cheang et al. designed a clinically practical panel of immunohistochemistry markers to distinguish between the two subgroups (Luminal A and B) of ER+ tumors defined by GEP and used it to separate breast cancer according to their recurrence-free and disease-specific survival.[14] Using a Ki67 index of 14% as a cutoff point, they classified ER+ tumors as Luminal A subtype (ER and/or PgR positive, HER2 negative, and Ki67 <14%) [Figure 1]b and c] and Luminal B (ER and/or PgR positive, HER2 negative, and Ki67 ≥14%). They also described a category of “Luminal HER2 positive” that were ER and/or PgR positive and HER2 positive [Figure 1]d, as these tumors would benefit from anti-HER2 therapy. The 10-year relapse-free survival and 10-year breast cancer-specific survival were maximal for patients with Luminal A and lowest for patients with luminal HER2-positive tumors. They found Luminal B subtype to show increased expression of HER2-associated genes (e.g., ERBB2 and GRB2) and cell proliferation markers (e.g., MKI67, CCNB1, and MYBL2), accounting for its poor prognosis and for the fact that it is more likely to benefit from chemotherapy.[14]

Nielsen et al. were working to develop an immunohistochemical (IHC) assay for identification of basal-like breast tumors and demonstrated that these tumors are negative for ER and HER2 and positive for cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR), and/or c-kit. They proved that an immunopanel comprising ER, HER2, EGFR, and CK5/6 can accurately identify basal-like breast carcinomas with 76% sensitivity and 100% specificity. While CK5/6 and EGFR expression are associated with poor survival rates in basal-like breast tumors, c-kit expression does not influence prognosis.[15]

This research work on the IHC markers for defining various molecular subgroups of breast cancer laid down the foundation of the surrogate molecular classification of breast carcinoma using IHC markers. This was formally accredited in 2011 by the 12th International Breast Cancer Conference. It was attended by 4300 participants from 96 countries, and a 51-member expert panel put forth recommendations for testing and treatment in breast cancer patients.[16] The expert panel noted that it was not always practically feasible to conduct gene expression tests, and therefore, breast cancer subtypes defined using immunohistochemistry were accepted as cheaper and more realistic surrogate markers for therapeutic purposes. The surrogate definitions of intrinsic molecular subtypes of breast cancer using immunohistochemistry were mostly based on the research published by Cheang et al. and Nielsen et al. and are given in [Table 1].[14],[15],[16],[17]
Table 1: Surrogate Molecular Classification of Breast Cancer along with treatment[16],[17]

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  Interpretation of Immunohistochemical Results Top

The accuracy of the surrogate molecular classification is closely dependent on accurate measurement of ER, PR, HER2, and Ki67.

  1. A tumor is positive for ER or PgR if >1% of tumor cell nuclei are reactive on a validated IHC assay.[18]
  2. A tumor is positive for HER2 if any of the following is true:

    • IHC staining (complete, intense circumferential membranous staining is observed in a homogeneous and contiguous population in >10% of invasive tumor cells, readily appreciated on low-power objective), these are labeled as 3+
    • Average HER2 copy number ≥6.0 signals/cell on a validated single probe in situ hybridization (ISH) assay
    • HER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 with average HER2 copy number ≥4.0 signals/cell on dual-probe assay
    • HER2/CEP17 ratio ≥2.0 with average HER2 copy number <4.0 signals/cell on dual-probe assay
    • HER2/CEP17 ratio <2.0 with an average HER2 copy number ≥6.0 signals/cell on dual-probe assay.

  3. A tumor is negative for HER 2 if any of the following is true:

    • IHC staining is 0 (no staining or faint/barely perceptible incomplete membranous staining in ≤10% of invasive tumor cells)
    • IHC is 1+ (faint/barely perceptible incomplete membranous staining in >10% of invasive tumor cells)
    • Average HER2 copy number <4.0 signals/cell on a validated single probe ISH assay
    • HER2/CEP17 ratio <2.0 with average HER2copy number <4.0 signals/cell on dual-probe assay.

  4. If a tumor is not discretely positive or negative according to the above-mentioned criteria and one of the following is true, the tumor is said to be equivocal for HER2

    • IHC is 2+ (incomplete and/or weak/moderate circumferential membrane staining in >10% of invasive tumor cells or Intense, complete circumferential membrane staining in ≤10% invasive tumor cells)
    • Average HER2 copy number ≥4.0 and <6.0 signals/cell on a validated single probe in situ hybridization (ISH) assay
    • HER2/CEP17 ratio <2.0 with average HER2copy number ≥4.0 and <6.0 signals/cell on dual-probe assay.

For all HER2 equivocal cases, a repeat HER2 test is recommended on the same specimen using the alternative test – IHC/ISH unless the specimen handling is suspected to be inappropriate (long ischemic time and short time in fixative).[19] If the latter be true, a repeat HER2 test should be performed on a new specimen using either of the tests (ISH/IHC). The repeat HER2 test is now referred to as “reflex test.”[19] Reflex testing is also recommended if there is a disagreement between the HER2 test result and the histopathologic findings. In case of a Grade 1 tumor of infiltrating ductal or lobular type ER positive/PgR positive/tubular type/mucinous type/cribriform type/adenoid cystic type, HER2 positivity is not expected. However, if HER2 is positive in association with any of these histopathologic findings, a false positive HER2 result must be ruled out and a new HER2 test should be ordered to confirm. Similarly, if the initial HER2 test in a core needle biopsy of primary breast carcinoma is negative, but a histopathologic examination of excision specimen shows Grade 3 tumor or a high-grade carcinoma morphologically distinct from that in the core or if the amount of invasive tumor in core biopsy is small, a new HER2 test on the resection specimen is a must.[19] Tumors that are recurrent and those that have metastasized should undergo repeat IHC testing. Measures to minimize sources of variation at all levels -preanalytical, analytical, and postanalytical in HER2 testing must be taken to give a valid result.[20] The sample meant for HER2 testing must be immersed in a fixative within 1 h of sampling (called cold ischemic time). It should be fixed in adequate volume of 10% neutral buffered formalin for 6–72 h and then processed and stained according to standardized operating protocols. Sections should be sliced at 5–10 mm intervals and those cut >6 weeks earlier must be rejected.[19]

  Revised Surrogate Molecular Classification Top

The surrogate molecular classification underwent revisions in the subsequently held 13th St. Gallen International Breast Conference.[17] The significance of distinguishing between Luminal A and B disease was already evident in terms of prognosis and treatment since the inception of the molecular classification for breast tumors. The basis of this distinction between Luminal A and B was improved using quantification of progesterone receptor (PgR), as proven by Prat et al.[21] Discussing the IHC-defined Luminal A tumors alone, considerable decrease in survival rates was reported if PgR <20% was expressed by the tumor.[21] This difference was independent of the administration of endocrine therapy.[21] It was therefore proposed to revise the definition of Luminal A tumors to ER positive/HER2 negative/Ki67 <14% and PgR ≥20%.[21] Endocrine therapy alone was advised in this group of patients.[21] The remaining tumors defined as Luminal A type by IHC (using criteria recommended by the 12th St Gallen conference) but with PgR <20% were re-classified as Luminal B (HER2 negative) tumors in the revised classification. The Luminal A and B definitions were also revised in reference to commercial assays. Patients who cannot be clearly classified as low risk (tumor size <1 cm with negative lymph nodes) or high risk (tumor size >5 cm, inflammatory breast cancer, >4 involved lymph nodes or very low ER) using clinical data, administration of chemotherapy is of uncertain clinical indication and these patients are most likely to benefit from multigene assay 21-gene RS or 70-gene signature to predict responsiveness to chemotherapy. A low 21-gene RS was included in the definition of Luminal A-like breast tumors and high RS was included in definition of Luminal B-like (HER2 negative) tumors [Table 1].

With availability of IHC surrogate markers, frequency of various subtypes of breast cancer has been found. Among all the breast carcinomas, hormone receptor-positive breast cancers that express ER and/or PgR constitute approximately 60%.[22] The Luminal A subtype is most common, represents 50%–60% of breast cancer cases, and is characterized by low histological grade and good prognosis. Histologically, most of the cases are tubular/cribriform/low-grade invasive ductal carcinoma/classic lobular carcinoma.[23] Luminal B represents 10%–20% of all breast cancers and is more aggressive with a higher grade and worse prognosis as compared with the Luminal A subtype. HER2/neu is overexpressed in 20%, and basal-like accounts for another 20% of breast cancer cases.[22] The basal-like subtype is characterized by high proliferation, high histological grade, and poor prognosis. Histologically, they include high-grade ductal carcinoma and metaplastic carcinoma, both of which bear a poor prognosis.[23],[24]

  Treatment Recommendations Top

The significance of the surrogate molecular classification of breast tumors has been acknowledged by the 15th St. Gallen International Breast Cancer Expert Consensus Conference held in Vienna, Austria, 2017, and lies in the fact that it provides information about the biological behaviour of the disease in an individual and is an important factor in deciding modalities of treatment to be administered in that individual.[25] Patients with Luminal A-like disease are best treated with endocrine therapy alone as they are less responsive to chemotherapy. However, chemotherapy may be offered to a subset of patients with large tumor volume or on the basis of patient preference. For Luminal B-like (HER2 negative) disease, chemotherapy based on anthracyclines and/or taxanes, in addition to endocrine therapy, is recommended. Treatment of HER2 disease must also include 1 year of trastuzumab in addition to taxane-based chemotherapy regimen. Chemotherapy based on carboplatin along with anthracyclines and taxanes may be useful for the treatment of triple-negative (basal like) disease.[25] Chemotherapy regimens including alkylating agents are not specifically required for this group.[17]

Triple-negative molecular subtype and HER 2 positivity in breast tumors have been proven to be independent predictors for the achievement of pathologic complete response. Pathologic complete response is defined as the absence of residual invasive tumor cells in the breast and regional draining lymph nodes in response to neoadjuvant therapy.[26]

According to the latest recommendations, additional postoperative adjuvant chemotherapy following a full course of neoadjuvant chemotherapy is not required irrespective of the achievement of pathologic complete response.[25] For patients with HER2-positive disease, neoadjuvant treatment should include antiHER2 drugs. Neoadjuvant endocrine therapy is recommended in postmenopausal patients with strongly positive hormone receptors and low proliferating disease and should be continued until maximal response.[17]

  the Indian Scenario Top

The utility of surrogate molecular classification of breast cancer in the Indian setting is immense. Multigene expression assays due to their costs and lack of availability are hardly accessible in the Indian scenario. In the Indian population, Luminal A-like disease is seen in 20%–34%, triple-negative tumors in 16%–38%, Luminal B-like disease and Her2-enriched tumors in 17%–37% each, and unclassified type in 5% of all breast tumors [Table 2].[27],[28],[29],[30] In comparison to the worldwide data, the Luminal A subtype is much less common and HER2 enriched and basal like are more common in the Indian setting. This is in corroboration with the fact that most breast cancers in India are high grade and high stage which is similar to the natural history of basal-like and HER2-enriched tumors.[31] Kunikullaya et al. studied the pattern of distant metastasis in molecular subtypes of breast cancer and found the bone to be the most common site of metastasis in Luminal A, Luminal B like, and Luminal B like (HER2 positive) and the brain as the most common site of metastasis in HER-2 enriched tumors.[30]
Table 2: The Indian scenario

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  Additional Molecular Subtypes of Breast Carcinoma Top

In addition to the already known intrinsic molecular subtypes of breast cancer, a new molecular subtype was identified in the year 2007 and called “claudin-low” because of low expression of cell adhesion proteins – claudin 3, 4, and 7 and E-cadherin. This subtype accounts for 10%–15% of all breast cancers and shows high expression of genes associated with epithelial-mesenchymal transition, immune response, cell communication, angiogenesis, interferon-gamma activation, tumor-initiating cells/breast stem cells, and lymphocyte and endothelial cells. Histologically, they show medullary-like and metaplastic-like features. They bear a poor prognosis and are resistant to conventional chemotherapy.[29] The loss of claudin molecule is more frequently seen in invasive disease as compared to in situ carcinoma, but an in situ carcinoma that shows low claudin expression has a worse prognosis than the one with a high claudin expression.[32],[33] In current molecular classification, these tumors are typically classified as basal like (or normal breast like) due to its triple-negative nature.

Two molecularly distinct defects in the cell cycle checkpoint including impairment of the GAP 2 checkpoint and spindle cell assembly checkpoint were noted specifically in Luminal B and basal-like intrinsic breast subtypes, respectively.[34]

  Conclusion Top

Breast cancer bears a heterogeneous genetic makeup that accounts for variation in the natural course of disease and in the intensity of response to various therapies, both of which are clinically relevant for the patient and the treating doctor. The conventional classification systems based on clinicomorphological parameters, on the other hand, are less accurate in predicting prognosis or response to therapy. Molecular classification is based on intrinsic molecular subtypes of breast cancer defined by GEP and commercial multigene assays are useful in predicting prognosis and response to various therapies. In the Indian setup, their application is limited by their cost and availability. IHC surrogate of this molecular classification is useful in guiding clinically relevant decisions. An IHC panel comprising ER, PgR, HER2, and Ki67 would assist in therapeutic decision-making process in most cases of breast carcinoma.

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  [Table 1], [Table 2]


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