Counting copies: HER2 and the development of Herceptin

Sadie Sweeney has never met Professor Bill Gullick. But he had a major impact on her life.

Sadie conquering more than just cancer

A scientific paper published by Professor Gullick in The Lancet in 1987 was an important step in the development of Herceptin – a drug that Sadie would need two decades later.

Sadie told us her story. ”I turned 50 in Sept 2007 and I was ready to relax, work part time, join the ladies who lunch and enjoy the next 30 years or so – or so I thought.

“A few months after my 50th birthday I got an invitation to attend a free NHS mammogram – it turned out to be the best belated birthday gift ever, life-saving in fact. In April 2008 I was diagnosed as having HER2 positive breast cancer.

“The diagnosis was a huge shock to me and my family. I had no symptoms or health issues to speak of. But found myself at a turning point. I had lost control of my health to cancer.

“But help was at hand…Cancer Research UK had been on the case all along.”

Time for a change

So where does Professor Gullick come into the story? Let’s take a step back in time to the 1980s, when he was still Dr Gullick and Sadie was approaching her 30s. Margaret Thatcher was re-elected for a third term in office and Rick Astley was at number one in the charts.

Our scientists were also never gonna give up – they were making major advances that would change the face of cancer research forever. At this point, many people still believed that the majority of cancers were caused by viral infections – a view that was about to change.

In 1984 a research paper by one of our scientists, revealed the structural code of a protein called EGFR. This molecule is a ‘receptor’ that sits on our cell surfaces and transmits signals into the cells to make them grow and divide.

This structural code gives the protein its functional properties. And EGFR was found to be almost identical to the viral protein v-erbB, a protein that causes cancer in chickens, suggesting that EGFR might play a similar role in humans.

This was groundbreaking because it showed that our own genes and the proteins they encode had the potential to cause cancer – it wasn’t just caused by viruses. You can read more about the discovery in our previous high-impact series blog post.

From EGFR to HER2

After this discovery, EGFR was linked to a myriad of different types of cancer. Not only that, it was also found to have a molecular sibling – HER2. Straight away, scientists started finding out whether this receptor, which works in a similar way to EGFR, was also involved in cancer.

In the US, Dr Dennis Slamon found that some human breast cancers had too many copies of the HER2 gene, and having an excessive number of copies correlated with a poor outlook for the patient. Soon after Dr Slamon published his findings, Dr Bill Gullick, based at the Institute of Cancer Research in London and funded by the Cancer Research Campaign (the forebear of Cancer Research UK), found precisely the same thing – some breast cancer cells had many more copies of the HER2 gene than their non-cancerous counterparts.

But Dr Gullick’s study went one step further, and showed for the first time that not only was the HER2 gene over-represented in breast cancer cells, but the HER2 protein was also found at unnaturally high levels. He discovered this using antibodies that specifically recognise the HER2 protein, revealing exactly where it is and how much is there.

Working with another of our researchers, Dr Diana Barnes from the Imperial Cancer Research Fund Unit at Guys Hospital, Dr Gullick found that tumours with the most copies of the HER2 gene also had the most protein. And he found that areas of tumours that were starting to spread had more HER2 protein than other areas. This was different from other studies, as it showed a direct match between having too many copies of the gene and levels of the subsequent protein, and that this correlated with how aggressive the tumour was.

Today around one in eight women with breast cancer in England and Wales* are diagnosed with HER2-positive disease, adding up to many thousands of women in the UK, and many more worldwide with this type of cancer.

The next step was to turn this laboratory finding into new hope for these patients.

From HER2 to Herceptin

The Herceptin antibody

Most drugs work by blocking or interfering with the activity of a protein molecule. So the fact that the HER2 protein was present at a very high level in some breast cancer cells highlighted it as a good target for potential drugs to treat HER2 positive tumours.

Building on the research from our scientists and others around the world, Dr Mark Sliwkowski and his colleagues at the biotechnology company Genentech developed a way to target HER2 with an antibody – the same kind of molecule that Professor Gullick first used to reveal the location of HER2 in cancer cells.

The antibody blocked the receptor activity of HER2, stopping it transmitting signals into the cells that made them grow and divide. This eventually became the drug Herceptin (also known as trastuzumab).

Herceptin was approved as a drug for HER2 positive breast cancer in 1998, 10 years before Sadie got her diagnosis.

Sadie’s treatment

Sadie had surgery, chemotherapy and radiotherapy before she started Herceptin treatment. It wasn’t the easiest road for her to walk down, as she explains.

“The long haul began, I wrote ‘be brave, a faint heart never won the day’ on my first day of chemotherapy, but my resolve was tested as I became more and more unwell during the treatment. Would I make my daughter’s graduation and my nephew’s wedding? Both of which required photos – and I’d lost my hair!

“But as the months went by I started to look and feel a bit more normal. After all, I’d got cancer but it had not got me.”

Sadie started Herceptin treatment in 2009, getting the drug every 3 weeks. Because it can sometimes affect the heart muscle, Sadie also had heart scans to keep an eye on things. The first Herceptin delivery went as planned, at first, until Sadie started having a bad reaction to the treatment. But doctors and nurses responded quickly, and avoided any serious problems.

Sadie abseiling down the Forth Rail Bridge in South Queensferry.

“I continued on with another five treatments, together with heart scans, and all seemed to go to plan – but I started to show signs of problems with my heart, so I was taken off the drug for a three month recovery period. Then I completed my full course of Herceptin without any further difficulties. I even managed to abseil down the Forth Rail Bridge during my year of treatment!’

What does the future hold?

Researchers are working hard to make new variants of Herceptin. The next generation of treatments are being developed to make them kinder, with fewer side effects for patients.

The so-called son-of-Herceptin (trastuzumab emtansine) is one example. It’s a combination of the Herceptin antibody linked to a chemotherapy drug, forming a single potent package. This double whammy means the drug can seek out the cancer cells (thanks to the antibody) and then deliver a toxic dose of chemotherapy exactly where it’s needed. We’ve covered the trials pointing to this being an effective treatment for women with more advanced HER2 positive breast cancer elsewhere on the blog, back when the drug was known as T-DM1.

And other research is looking at wider uses of Herceptin. It’s now used to treat HER2 positive stomach cancer patients. And there have been studies indicating that the drug might be beneficial for patients with lung cancer, pancreatic cancer and even some HER2 negative breast cancers. What’s for sure is that Herceptin will continue to benefit thousands of patients, and possibly many more in the future as we find new uses for it.

As for Sadie, this year she celebrated 5 years cancer free by once again joining the Edinburgh Race for Life.

“It was the most beautiful day and the crowds were mighty pink! Crossing the finish line I could not help but cry…but tears of joy on this occasion. The finish line banner said “We did it” ….we sure did.”

Sarah

With special thanks to Sadie for sharing her story with us.

*In England and Wales between 10 per cent and 15 per cent of breast cancers in women are HER2 positive. This is based on a subset of surgically-treated breast cancer cases and so the estimate includes some adjustment by Cancer Research UK. National Cancer Intelligence Network (2011). Second All Breast Cancer Report.

Reference

Venter D.J., Tuzi N.L., Kumar S. & Gullick W.J. Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistological assessment correlates with gene amplification., Lancet, PMID: 2885574