When is chemotherapy required?

Dr Chris Maske compares genomic profiling testing to the laboratory equivalent of a crystal ball – where we can predict now what may happen with a cancer over the next 10 years, and intervene in the best way to reduce risk.

Main goal of therapy

Some breast cancers (BC) require treatment with chemo because the disease is advanced (metastatic to other parts of the body); chemo will reduce the size, relieve symptoms and, sometimes, even reduce the cancer to undetectable levels.

You may ask, but if the BC is confined to the breast and can be cut out, why would chemo be necessary? Unfortunately, even when a BC is confined to the breast and there is no evidence, with the best available tools for investigation, that it has spread, there is still a risk that it can recur in distant sites at some point in the future.

This risk is due to cancer that may have escaped from the breast before it was removed that can grow in other sites. Preventing distant recurrence and metastasis after a cancer has been removed is the main goal of therapy, after the initial treatment and removal of an early BC.

Insurance chemo

Having chemo when the primary cancer in the breast has been removed and there is no evidence of any disease remaining is essentially ‘insurance chemo’ (adjuvant chemo). Like any insurance, if you had a crystal ball or perfect sight of the future, you could avoid paying the premiums because you know the fender bender is never going to happen.

Wouldn’t it be great to have a crystal ball for your BC and predict the future perfectly, so you can act accordingly? If your BC was never going to recur, you could avoid chemo. If your BC was going to recur in the future, of course you would endure chemo now to prevent that from happening, if you could.

We might not have a crystal ball but we do have a microscope lens and other tools that can predict, with increasing accuracy, the risk of BC recurring and whether the use of adjuvant chemo will reduce that risk down the line.

Current understanding

BC includes four biological groups with different collective behaviour, which informs decisions on taking adjuvant chemo. Two of these groups, HER2-positive and triple-negative cancers, are aggressive subtypes that usually require adjuvant chemo to reduce the long-term risk of recurrence. Many studies show that using adjuvant chemo in these situations reduces the number of women getting metastatic cancer in the future.

The remaining two groups share a property; they are hormone receptor, also called ER for oestrogen receptor, positive. This group comprises about 80% of breast cancer. The biological behaviour is varied and is a continuum. Some ER positive cancers are low grade, have a very low-risk of spread in the body, and show little incremental benefit from adjuvant chemo. These are luminal-A type cancers.

Others are more aggressive, have a significant risk of distant recurrence over time, and the use of adjuvant chemo will reduce this risk and is recommended. These are luminal-B type cancers.

Much of modern early BC management obsesses around the categorisation of ER positive cancers into luminal-A/-B subtypes with one purpose in mind: to decide whether to give adjuvant chemo now to reduce the risk of recurrence later.

Scientific tools

The tools for making this decision  are becoming increasingly precise. Pathological (microscopic) grading of the tumour, hormone receptor analysis in the tumour cells, and determination of the number of cancer cells that are active in the cell cycle and are proliferating are now standard for assessing BCs.

In many cancers, this will be sufficient to make the decision for adjuvant chemo. The individuals with very low-grade luminal-A cancers (considering all parameters) will be spared and will benefit from ER blockade alone with tamoxifen or equivalent.

The individuals with very high-grade luminal-B cancers will be offered adjuvant chemo now to reduce the risk of recurrence later. Unfortunately, this only takes care of the extremes of low and high grade and we’re left with the agonising intermediate-risk tumours that sit somewhere between luminal-A and -B tumours. Enter the modern world of genomics and personalised medicine, and we have new tools to assist with this decision.

Genomic testing

Much scientific work has focused on how to predict more accurately the biology or aggressiveness of a BC. The resolution and accuracy of this prediction increases as we go from looking down a microscope at the cells, to measuring the cancer cell cycle with molecular stains, and, even greater, when looking at which genes are active in cancer cells.

Gene analysis in BC is now applied with increasing frequency to score a cancer on the spectrum of biological aggressiveness and give an accurate risk of recurrence. The Oncotype DX test does just that – analysing 21 different genes in the cancer.

When BCs are analysed with Oncotype DX, the score will predict the percentage risk of recurrence and the incremental benefit that may be expected from adjuvant chemo. This test is used most frequently in the group where traditional parameters don’t provide clear guidance and only in hormone receptor positive cases.

The Oncotype DX test is allowing us to take the middle ground of hormone receptor positive BC and make more accurate decisions regarding the benefit of adjuvant chemo. Using such tools reduces the number of patients requiring adjuvant chemo, reducing morbidity and cost of treatment.

This test is taking us closer to a laboratory equivalent of a crystal ball – where we can predict now what may happen with a cancer over the next 10 years, and intervene in the best way to reduce risk.

Even when such tests are applied, there are cases where the answer is not perfectly simple. Where a cancer can recur despite a low-risk signature in the gene test; this is the complexity of biological systems gone wrong in the form of cancer cells. I have no doubt that we can expect increasing precision as we go forward in this era of the biotechnology revolution.

Dr Christopher Maske

MEET OUR EXPERT – Dr Chris Maske

Dr Christopher Maske is the founder and managing director of QLAB, a pathology consultancy specialising in tissue and molecular diagnostics. He qualified in medicine from the University of Cape Town and did his PhD at Oxford University in Molecular Cell Biology, and worked as a research scientist in the university before moving into diagnostic pathology.  His main interest is in molecular biomarkers in solid tumours for treatment, diagnosis and therapy decisions.