One of the best-known things about cancer is that it’s good to catch it early. By that, of course, we don’t mean that you should make an effort to get cancer when you’re young but that, if it does arise it’s a good idea to find out before the initial growth has spread to other places in the body. That’s because surgery and drug treatments are very effective at dealing with ‘primary’ tumours — so much so that over 90% of cancer deaths are caused by cells wandering away from primaries to form secondary growths — a process called metastasis — that are very difficult to treat.
The importance of tumour spreading is shown by the figures for 5-year survival rates. Overall in the USA it’s 90% but this figure falls to below 30% for cancers that have metastasized (e.g., to the lungs, liver or bones). For breast cancer the 5-year survival rate is 99% if it is first detected only in the breast (most cases (62%) are diagnosed at this stage). If it’s spread to blood and lymph vessels in the breast the 5-year survival rate is 85%, dropping to 27% if it’s reached distant parts of the body.
What’s the cause of the problem?
The other thing most people know about cancers is that they’re caused by damage to our genetic material — DNA — that is, by mutations. This raises the obvious notion that secondary tumours might be difficult to deal with because they have accumulated extra mutations compared with those in primaries. And indeed, there have been several studies pointing to just that.
Very recently, however, François Bertucci, Fabrice André and their colleagues in various institutes in France, Switzerland and the USA have mapped in detail the critical alterations in DNA that accumulate as different types of breast cancers develop from early tumours to late, metastatic forms. As is the way these days, their paper contains masses of data but the easiest form of the message comes in the shape of ‘violin plots’. These show the spread of results — in this case the number of mutations per length of DNA.
Metastatic tumours have a bigger mutational load than early tumours. These plots are for one type of breast tumour (HR+/HER2−) and show results for 381 metastases and 501 early tumours. Red dots = median values: these are the “middle” values rather than an average (or mean) and they show a clear upwards shift in burden as early tumours evolve into metastases. From Bertucci et al., 2019.
The violin plots above are for one subtype of breast cancer (HR+/HER2−). Recall that breast tumours are often defined by which of three types of protein can be detected on the surface of the cells: these are ‘receptors’ that have binding sites for the hormones estrogen and progesterone and for human epidermal growth factor. Hence they are denoted as hormone receptors (HRs) and (human) epidermal growth factor receptor-2 (HER2). Thus tumours may have HRs and HER2 (HR+, HER2+) or various receptors may be undetectable. Triple negative breast cancer (TNBC) is an absence of receptors for both estrogen and progesterone and for HER2.
The plots clearly show an increase in mutation load with progression from early to metastatic tumours (on average from 2.4 to 3.8 mutations per megabase of DNA). Looking at individual genes, nine ‘drivers’ emerged that were more frequently mutated in HR+/HER2− metastatic breast cancers (we described ‘driver’ and ‘passenger’ mutations in Taking Aim at Cancer’s Heart).
For now these findings give us just a little more insight into what goes on at the molecular level to turn a primary into a metastatic tumour. The fact that some of the acquired driver mutations are associated with poor patient survival offers some guidance as to treatment options.
Don’t get carried away
It’s a familiar story in this field: another small advance in piecing together the jigsaw that is cancer. It doesn’t offer any immediate advance in treatment — mainly because most of the nine ‘driver’ genes identified are tumour suppressors — i.e. they normally act as brakes on cell growth. Mutations knock out that activity and at the moment there is no therapeutic method for reversing such mutations. (The other main class of cancer promoters is ‘oncogenes‘ in which mutations cause hyper-activity).
But such steps are important. The young slave girl in Uncle Tom’s Cabin gave us the phrase “grew like Topsy” — meaning unplanned growth. Cancer growth is indeed unplanned and a bit like Topsy but it’s driven by molecular forces and only through untangling these can we begin to design therapies in a rational way.
Bertucci, F. et al. (2019). Genomic characterization of metastatic breast cancers. Nature 569, 560–564.