Aggressive breast cancer protein discovered

In In The News by Barbara Jacoby

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“A breakthrough by scientists could lead to a new treatment for one of the most aggressive forms of breast cancer,” the Mail Online reports.

Researchers have identified a protein called integrin αvβ6, which may help trigger the spread of some types of breast cancer.

Up to a third of breast cancers are HER2-positive cancers. These are cases of breast cancer where growth is driven by a protein called human epidermal growth factor receptor 2 (HER2). These types of cancer can be particularly aggressive.

Seventy percent of people with HER2-positive breast cancers develop resistance to Herceptin, the main drug treatment for these cancers, effectively leaving them with no treatment options.

This laboratory study examined samples of breast cancer tissue from two cohorts of women with breast cancer. Researchers looked at the expression of a protein called integrin αvβ6, which has been shown to interact with HER2 to stimulate cancer growth.

The researchers found women who had higher expression of integrin αvβ6 in their breast cancer tissue had poorer five-year survival rates, particularly when they were also HER2 positive.

The researchers then studied mice that had been grafted with breast cancer tissue. But a potential new treatment called 264RAD was found to block integrin αvβ6 in the rodents.

Giving this treatment in combination with Herceptin stopped cancer growth, even in breast cancer tissues resistant to Herceptin.

Clinical trials of 264RAD in women with this particularly high-risk type of breast cancer are now required.
Where did the story come from?

The study was carried out by researchers from Barts Cancer Institute, Queen Mary, University of London, and was funded by the Breast Cancer Campaign and the Medical Research Council.

It was published in the peer-reviewed Journal of the National Cancer Institute, and is open access and available to read for free online.

Both the Mail Online and The Daily Telegraph’s reporting of the study is accurate and informative.
What kind of research was this?

This was a laboratory study examining samples of breast cancer tissue from two cohorts of women with breast cancer. Researchers looked for the expression of a particular protein called integrin subunit beta6 (integrin αvβ6). They then looked at how the expression of this protein was associated with cancer survival.

The researchers explain that in up to a third of all breast cancers, a particular protein called human epidermal growth factor receptor 2 (HER2) is overexpressed. This is associated with a very aggressive breast cancer.

These cancers are aggressive because HER2 triggers signalling pathways that stimulate breast cancer cells to grow out of control. This means the cancer cells are more likely to spread into the lymph nodes or to other major organs of the body (known as metastases or metastatic cancer).

Currently, some HER2-positive breast cancers can be treated using the biological antibody treatment Herceptin (trastuzumab). Herceptin works by binding to the protein receptors and blocking them so HER2 cannot stimulate the growth of the breast cancer cells.

However, as the researchers point out, more than 70% of people have developed resistance to Herceptin, leaving them without other treatment options. New treatments are therefore needed for people with HER2-positive breast cancers.

A molecule called TGFβ has been shown to promote HER2-driven cancer by increasing the migration, invasion and spread of breast cancer cells. Integrin αvβ6 has been identified as an activator of TGFβ and implicated in promoting the growth of various types of cancer.

With this knowledge, this research aimed to see whether integrin αvβ6 could influence HER2-positive breast cancer and if inhibiting its action helped reduce the cancer size and spread.
What did the research involve?

The research included two cohorts of people with breast cancer:

a Nottingham cohort that included 1,795 consecutive women treated from 1986 to 1998
a London cohort that included 1,197 women mostly treated from 1975 to 1998

The researchers were able to gather complete information on the women’s tumour types, including whether they were HER2 positive.

They examined tissue samples for the expression of integrin αvβ6 and looked at how this was associated with survival by seeing whether the women were still alive at five-year follow-up checks.

The researchers also looked at survival rates when there was co-expression of both HER2 and integrin αvβ6.

Further laboratory experiments using mice grafted with breast cancer tissue examined treatment options using Herceptin (trastuzumab), the antibody known to block HER2, and an antibody called 264RAD, which was found to block integrin αvβ6.
What were the basic results?

High expression of integrin αvβ6 was found in 15-16% of breast cancer tissue samples from the two cohorts of women.

The researchers found a significant association between the expression of integrin αvβ6 and survival.

In women with a high expression of integrin αvβ6, five-year survival dropped from 75.6% to 58.8% in the London cohort, and from 84.1% to 75.0% in the Nottingham cohort.

In statistical terms, this meant that high expression was associated with an almost doubled risk of mortality.

Even with adjustment for tumour stage, size and grade, integrin αvβ6 was an independent predictor of overall survival.

For the Nottingham cohort, the researchers also had data available on distant spread (metastases) – 39.5% of those who were integrin αvβ6-positive had metastases, compared with 30.9% who were integrin αvβ6 negative.

When looking at co-expression of both integrin αvβ6 and HER2, they found this combination was associated with a particularly poor prognosis. In women who were HER2 positive, five-year survival was 65.1%, but it dropped to 52.8% if integrin αvβ6 was also strongly expressed.

The studies in mice grafted with human tumour tissue found both Herceptin and the study molecule 264RAD individually slowed tumour growth, but the combination of the two effectively stopped tumour growth, even in breast cancer tissues resistant to Herceptin.
How did the researchers interpret the results?

The researchers conclude that the overexpression of integrin αvβ6 in breast cancer is a poor prognostic factor associated with lower survival and the development of distant metastases.

They say the overexpression of both integrin αvβ6 and HER2 is associated with an even poorer prognosis.

The researchers feel the likely biological explanation is integrin αvβ6 and HER2 co-operate within the same molecular complex and integrin αvβ6 mediates the invasive behaviour of HER2-positive cancer.

They suggest targeting αvβ6 using the antibody 264RAD, either alone or in combination with Herceptin, may provide a novel therapy for people with this very high-risk breast cancer sub-type (HER2/αvβ6 positive), particularly if it is resistant to Herceptin.

This is a valuable laboratory study that furthers our understanding of the way HER2 may promote the growth, proliferation and spread of breast cancer cells, possibly through the influence of the protein integrin αvβ6.

The researchers suggest up to 40% of people with HER2-positive breast cancers may also have a high expression of integrin αvβ6.

The discovery that integrin αvβ6 may play a role in mediating the growth and progression of these cancers hopefully opens up new treatment possibilities for people with HER2-positive cancers.

As the researchers suggest, their study supports the proposal that testing breast tissue biopsies for the expression of αvβ6 should become a routine procedure to stratify women with breast cancer into this new very high-risk αvβ6-positive/HER2-positive group.

The laboratory experiments in mice with human breast cancer tissue grafts suggested the combination of Herceptin with the antibody 264RAD could be effective in stopping tumour growth in this group.

However, the development of the 264RAD treatment is still in the very early stages. Clinical trials in people with αvβ6-positive and HER2-positive breast cancer are now awaited. These will tell us whether 264RAD – either alone or in combination with Herceptin – could be an effective treatment option for this very high-risk sub-group.

Analysis by Bazian. Edited by NHS Choices.