Prognostic tests can guide the treatment of people who are suffering from Breast Cancer

Globally, breast cancer is the most common type of cancer in women. The prevalence in Asian countries including India has been on the rise forming nearly one-third of all cancers detected in Indian women.

As of today, there are nearly eight million women suffering from breast cancer.

Certain inherited gene mutations like BRCA1, BRCA2 and PALB-2, greatly increase the risk of breast cancer.

About 50 percent of breast cancer cases occur in women with no prior identifiable cause or hereditary basis. Some of the major factors implicated include age, obesity, alcohol and tobacco consumption, family history and postmenopausal hormone therapy among others.

Over the years, it has been understood that breast cancer is a molecular disease with different genetic signatures. Thus, each patient needs a different approach to treatment and management based on many factors. One of the pivotal factors is the molecular and genetic profiling of the tumour cells. These prognostic factors determine the clinical course, outcome and overall survival in the patient. It will also determine how long a person will remain disease-free in the future.

Hence, once a patient is diagnosed with breast cancer, doctor’s first try and determine their individual risk of recurrence and if any particular patient would benefit from adjuvant therapy.

Prognostic factors and tests

For breast cancer patients, the American Joint Committee on Cancer’s (AJCC) defines two types of staging.

• An anatomic stage depends upon the size of the tumour (T), nodal status (N) and distant metastasis (M).
• A more valuable, prognostic stage, which includes the grade of the tumour, hormone receptor and oncogene expression status and the molecular signature based on multigene testing.

Thus, the first step in determining the prognostic stage and treatment course is to determine the molecular subtype of breast cancer based on hormone receptor status through immunohistochemistry (IHC). The markers done are Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth factor Receptor -2 (HER-2) and Ki67 proliferation index. Based on the expression of markers, each case falls into one of the following subtypes:

• Luminal A: ER and/or PR positive, HER2 negative, and low Ki-67. These cancers tend to grow slowly and have the best prognosis. They are treated with Hormonal Therapy.
• Luminal B: ER and/or PR positive, HER2 positive or negative, and high Ki-67. These cases follow a more aggressive course than luminal A-type and carry a relatively worse prognosis.
• HER2-enriched: ER/PR negative and HER2 positive. These are more aggressive than their luminal counterparts but show good treatment response to targeted therapies aimed at the HER2 protein, such as Trastuzumab (Herceptin).
• Triple-negative/basal-like: ER, PR and HER2 negative. This type of cancer is associated with BRCA1 gene mutations. These are extremely aggressive tumours. Since hormone receptors are negative in these cases, they don’t respond to hormonal therapy and need chemotherapy.
• Normal-like: Shows profile similar to Luminal A-type. ER and/or PR positive, HER2 negative, and has low levels of Ki-67. It carries a slightly worse prognosis than luminal A subtype.

Tissue heterogeneity, variation in operator handling of the tissue and staining, and inter-observer variation amongst pathologists can all cause issues with an evaluation of recurrence using IHC.

This is where the recent multigene panels which serve as a multivariate prediction model have made a breakthrough in predicting recurrences and guiding treatment. These molecular tests help to distinguish different prognostic groups among patients with similar tumour characteristics; thus predicting response to various therapeutic agents. Molecular testing and multi-gene panels help in selecting patients with a higher likelihood of response and spare the cost burden and potential toxicity in those who are unlikely to respond.

The most popular and well-validated molecular assays are the Oncotype DX and Mammaprint. Oncotype DX is a 21 gene molecular tool that predicts the risk of recurrence in node-negative, hormonally treated breast cancer. It also predicts the benefit of adding chemotherapy (with cyclophsosphamide, doxorubicin and florouracil) to Hormonal therapy (Tamoxifen). Mammaprint on the other hand is a 70 gene molecular assay that predicts five and 10 years prognosis based on the risk of recurrence.

The American Society of Clinical Oncology (ASCO), in 2017 included some of these prognostic tests in their guidelines for predicting whether patients with breast cancer will derive benefit from adjuvant chemotherapy. Other tests which are commercially available include Endopredict and Prosigna which also carry the added advantage of being easy to perform in a local laboratory.

These tests, from an Indian scenario, are still expensive costing in lakhs. Also as discussed before, breast cancer patients show significant differences in the behaviour of the disease in different ethnicities mainly due to the variation in expression of different genes like p53. Indian patients, for instance, show a younger age at presentation and are more commonly triple negative. It is thus, imperative to develop prognostic tools which are more cost-effective and have been also validated in the local ethnic population. CanAssist Breast (CAB) is one such test that is validated primarily on the Indian population.

There is a lot of research focusing on developing markers that guide treatment by understanding the gene signature and tumour biology in each patient through Next Generation Sequencing (NGS), microarray, epigenetics, proteomics and metabolomics. The result has been the identification of newer molecular targets like PIK3CA and the development of molecules that benefit patients harbouring these mutations.

There are also newer tests being evaluated like detection of circulating tumour DNA (ctDNA) in plasma both before and after treatment, which is associated with a high risk of relapse and shorter Disease-Free Survival. These can be easily performed and provide a detailed analysis mitigating the issues of tumour heterogeneity.

To conclude, recurrence is a major cause of death in breast cancer patients. Also, breast cancer treatment carries a major risk of debilitating adverse effects and financial burden related to overtreatment. Prognostic markers help to identify patients carrying a significant risk of recurrence, in whom the benefit from adjuvant therapy far outweigh the risk of serious adverse effects related to overtreatment.

With the advent of newer prognostic tests some of which, like Oncotype DX, have a direct consequence on cancer staging and treatment in breast cancer patients, and identification of newer molecular targets through sequencing, the future of personalised medicine looks promising with higher cure rates and a significant reduction in breast cancer mortality.

The author is the Section Head of Histopathology & COE, SRL Diagnostics

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