Explainer: why do some breast cancers come back?

Cancer is a collection of many hundreds of diseases. The common factor is that once-normal cells have undergone a series of mutations in their genes that has led to uncontrolled growth and an impaired ability to die when they normally should.

Cancers may also spread into other organs, forming secondary cancers, called metastases. When patients die of cancer, it’s usually due to these metastases.

Breast cancer is one of the most common cancers in the Western world, with 15,000 women (and about 70 men) diagnosed each year in Australia. Fortunately, with modern treatments, more than 90% of women with breast cancer go on to have a normal life expectancy, though the side effects of both the cancer and its treatment affect many aspects of their lives.

When detected, cancer can be classified into stages, based on how advanced the disease is in the body.

In breast cancer, the important factors include the aggressiveness of the cells (the grade) and specific proteins that they make. These proteins drive the growth of the tumour cells, including some that bind to female hormones such as oestrogen and growth-promoting proteins such as HER2. Whether a tumour has involved lymph nodes under the arm is also of great importance in assessing its likely potential to spread further.

These markers guide us closely in what drug treatments to consider but also suggest a “prognosis” – that is, how likely the cancer is to be cured or to come back.

So, a patient with breast cancer may undergo surgery to remove the lump and any involved lymph nodes, radiotherapy to try to ensure the cancer does not come back in the breast or lymph nodes nearby, and drug treatments that depend on these markers of aggressiveness. This is done as an “insurance” to increase the chances that the tumour never returns. Scans such as computed tomography (CT scans) are not usually helpful to monitor for recurrence, as small numbers of tumour cells can still be present, but cannot be seen.

Yet for 10% of patients the disease will return – often many years later – and this person is likely to die eventually of cancer. Even though other treatments may shrink the cancer, they cannot get rid of it all together, so unfortunately cure is not possible.

It is assumed that before this recurrence occurs, tiny microscopic nests of cancer cells are lying dormant somewhere in the body. A major quest for cancer researchers has therefore been to find where these cells are hiding and what causes them to wake up and cause secondary cancer.

One intriguing observation has been that in up to 10% of patients previously treated for cancer who are apparently “cancer free”, very careful examination of both blood and bone marrow reveals a few residual cancer cells. This is strongly linked with a more likely chance of cancer coming back.

However, this is not universal. And we know that many supposed cancer cells floating in the bloodstream will in fact be mopped up by the bodies’ immune system or will die “of natural causes”. So, can we better define which are which?

One promising feature under intense scientific scrutiny is the so-called mesenchymal state of the cells. This indicates the cancer cells have changed from looking even less like their cell of origin – in this case, a breast cell – to more primitive cells that can move uninhibited in blood and spread through tissues. This is the same process the body uses in developing embryos and in other situations such as wound healing.

These mesenchymal features allow cancer cells to survive in the toxic environment of the bloodstream, to evade many of our current treatments such as chemotherapy and to set up home in distant organs – the process of metastasis, or secondary cancers.

We still don’t know what causes cancer cells to undergo mesenchymal change (termed epithelial-mesenchymal plasticity or EMP), but understanding it means we are a step closer to developing drugs that can modify or stop the process. It also takes us closer to identifying a biomarker, so we can determine which patient may benefit from these as-yet-undeveloped drugs.

Christobel Saunders has previously received grants from NHMRC, National Breast Cancer Foundation and Cancer Council WA.

Rik Thompson receives funding from the National Breast Cancer Foundation, the NHMRC and Princess Alexander Hospital Foundation.

Robin Anderson receives funding from NHMRC, National Breast Cancer Foundation, Cancer Australia, Cancer Council Victoria.

Anthony Dowling does not work for, consult to, own shares in or receive funding from any company or organisation that would benefit from this article, and has no relevant affiliations.