‘Genomic profiling will change the management of breast cancer’

Dr Maheboob M Basade & Dr Ajay Jhaveri

Till recently, breast cancer was treated according to the anatomic stage of the disease i.e. tumour size, lymphnode involvement and extent of the disease (TNM staging). But with the advent of new gene signature and molecular technology, it is now possible to classify breast cancer on a molecular level such as luminal, basal like, ERBB+, HER-2.

Hormone receptors and HER-2 are critical in defining distinct subtypes of breast cancers. The completion of the human genome project and advances in computational biology has provided a powerful tool in breast cancer research. Investigators have looked for genes of which the expression significantly varied between different tumours. In this way they identified the intrinsic gene list designed to identify subtypes of breast cancers. Hormone receptors, until recently were the most important molecular feature that is a mandatory aspect of tumour evaluation.

Incidence of ER positivity increases with age (80 per cent of breast carcinomas occurring after the age of 65 years on immunotyping is ER positive). There is a significantly higher ER expression in low grade than high-grade tumour. Proliferation as measured by a number of techniques e.g. S-phase, mitotic index is negatively correlated with ER expression levels.

However research has shown that ER positive tumours exhibit substantial molecular, biologic and clinical heterogeneity. The concentration of ER is known to affect the benefit of Tamoxifen. Mortality reductions with the use of five years of Tamoxifen were 23 per cent and 36 per cent for low and high ER positive tumours respectively. Several well-characterised individual features, such as progesterone receptor and HER-2 status, appear significantly to affect the biology of ER positive breast cancer.

Most recently, the application of comprehensive m-RNA, profiling of breast carcinomas has led to the definition of subgroups, according to the relative expression of many hundreds of genes. The ER positive group is further divided into three main subtypes A, B and C. The luminal A of ER positive subgroup has the highest expression of ER, GATA binding protein 3, X- box binding protein- 1, hepatocyte nuclear factor 3 alpha and estrogen regulated gene LIV-1. Luminal B and C tumours showed moderate expression of genes in ER cluster. And among all the subgroups A has the best prognosis. There are several other biomarkers that have been found to be estrogen dependent in the laboratory studies and to be expressed almost exclusively in ER positive tumours.

The absence of expression of such markers in some ER positive tumours could assist in identifying ER positive tumours that have little chance of responding to endocrine therapy. BCL 2 is one such marker, which was identified as involved in regulating apoptosis. BCL 2 suppresses apoptosis and expression might be expected to relate to tumour with poor prognosis although this is not borne out in practise. PS2 (trefoil factor 1) is also expressed to greater degree in ER positive tumour and its expression is markedly suppressed by estrogen deprivation therapy. The availability of new analytic platforms that allow the simultaneous measurements of the m-RNA expression of many thousands genes has made it possible to classify breast (and other) tumour according to the results of such analyses. Although there have been a remarkable consistency in their segregation of two major families that are distinguished by the presence or absence of ER expression indicating the dominance of ER as a molecular feature of breast cancer.

The type 1 growth factor receptors HER-2 (c- erb B2/ neu) and EGFR (c-erb B1/ HER 1) have an inverse correlation with ER expression and play an important role in the biology of breast cancer. The HER-2 receptor, as other receptors initiates and modulates a complex pathway with many negative and positive feed back loops. The HER-2 signal influences proliferation, survival, elaboration of proteolytic and angiogenic molecules, alterations in cytoskeletal and motility functions and responses to hormonal and cytotoxic therapies.

Two general strategies have been used to characterise HER-2 positive breast cancer. One is to systematically assess individual components of HER-2 pathway and the other to use multiparametric analysis at the genomic, gene expression and protein levels to identify individual genes and proteins or pattern and profiles that correlate with prognosis. Both of these approaches have also been used to study outcome and to understand the predictive factors to trastuzumab, kinase inhibitors, chemotherapy and hormone therapy.

The HER-2 receptor is phosphorylated at specific residues on activation and assays using phosphoHER-2 specific antibodies that have been performed on tumour tissue have shown that it correlates with higher HER-2 levels and worse outcomes. Molecular classifications of HER-2 positive breast cancer that identify trastuzumab sensitive and resistant patients are important given the side effects and costs of transtuzumab. Presently on HER-2 expression itself has emerged as reliable marker to response to trastuzumab. Based on these observations, we can definitely predict that genomic profile would immensely alter the management of breast cancer and other cancers in future.

Dr Maheboob M Basade is consultant medical oncologist and Dr Ajay Jhaveri is resident at Jaslok Hospital, Mumbai. Email: basade@vsnl.com