January 21, 2006

Here’s a story Emma Kearns has told 50 times before, and each time she tells it she never knows how it will turn out. “I was on my mobile phone, and I had my arm resting against the side of my breast, and I felt something there that shouldn’t be. More of a mass really than a bump. I mentioned it to Dave, my partner, and my mum, and they said it would be best to get it checked out to be safe.”

This was in December 2004, when she was 27. She went to her doctor in the middle of January, and was told that the breast changes quite a lot during the menstrual cycle, so the best thing would be to come back in two weeks. “I went back two weeks later, and by then the mass had more of a harder, rounder shape. My doctor referred me straight to the Marsden, and I was really lucky: the Marsden has got a rapid diagnostic unit which means you’re tested and get the results on the same day. I made an appointment for 8 February.”

Emma Kearns was born in Long Eaton, near Nottingham. She grew up in Cambridge and Bristol, and met her boyfriend Dave at university in Bradford. They live in a small house in Sutton, Surrey. The Royal Marsden is just up the road.

“The first inkling I had that things weren’t quite right was when a breast cancer specialist nurse came to get me, with a blue uniform and a special badge, rather than a white uniform and the regular badge.”

Each year, about 40,000 women are diagnosed with breast cancer in the UK, accounting for about a third of all cancers in women. One in nine women will get breast cancer at some stage in her life.

“A little later, the Royal Marsden’s head surgeon said, ‘I’m afraid you have breast cancer, as we suspected,’ and my mother was sitting beside me and I remember thinking, ‘I’m going to look at her, and if she’s crying then I really am done for.’ But she wasn’t crying, and I thought, ‘OK, maybe I can get through this day.’ ”

Emma Kearns’s type of breast cancer was particularly aggressive, but unusually common among those who are diagnosed under the age of 40. Her cancer was formed at least partly by the presence of too many copies of a gene called HER2. A few years ago this knowledge would have been superfluous, and her prognosis would have been bleak. But at the beginning of 2006, our new understanding of her genetic pathways may save her life.

In 1986, when Emma Kearns was settling into primary school, a 36-year-old cancer specialist called Dennis Slamon found a new way to examine what it was that distinguished a cancer cell from a normal cell, and specifically what it was that made a cancer cell replicate at an uncontrollable rate. Slamon worked at the University of California at Los Angeles, and spent much time attending scientific conferences.

After one symposium in Denver he had met the German biologist Axel Ullrich, and the two men realized they might be able to help each other. Ullrich was an emerging star in the field of genetic cloning, and had contributed to the landmark discovery that certain growth factors and receptors in cells are related directly to cancer.

This is a cornerstone of oncology we now take for granted, but when the research was first published in Nature in 1984, it not only confirmed what scientists had suspected for decades, but also held the potential for revolutionary breakthroughs in treatment. If specific cancer-causing genes could be isolated, then in time they could also be targeted and blocked and corrected.

This was the great hope for the start-up biotechnology companies of the Seventies. But for a decade or so the chances of success seemed remote; the haystack was the size of a mountain with more than 100,000 genes in every human cell involved in growth rate alone.

Thankfully, science has always been populated by mavericks and true believers. At UCLA, Dennis Slamon had amassed a large collection of breast, lung, liver and colon tumours, a collection which some considered a ghoulish passion, but Slamon regarded as a research bank. For a few years it wasn’t quite clear what purpose the bank would yield, but in the summer of 1986 the collection found its use.

He asked Axel Ullrich to send him DNA samples from his growth factor genes — oncogenes — and Slamon and his assistant would attempt to match them against the DNA extracted from his tumours. After a while, Slamon got a hit from his breast and ovarian cancers. Ullrich revealed that the oncogene in question was called HER2, first identified a few years earlier (the initials indicated it was the human epidermal growth factor receptor 2).

This was a momentous leap, but it didn’t answer all the questions. The scientists found that HER2 was linked to breast cancer growth when copies of the normal HER2 gene mutated and ‘overexpressed’ its protein. This protein appeared as a receptor on a cell’s surface, and sent a signal within the cell for it to grow and divide. A healthy breast cell has about 50,000 HER2 receptors on its lining, but on a mutated gene this may increase to more than a million.

But Slamon’s own collection of breast cancer tissues (from about 30 tumours) had no case histories attached to them, and it was impossible for him to tell what sort of breast cancer HER2 mutation caused. So Slamon turned to another collaborator who had oncogene protein samples linked to many patients’ case notes, and from these it was possible to detect that HER2 disease was not only aggressive and common in younger patients, but was linked to the frequent recurrence of tumours. Ullrich and Slamon published their findings in the magazine Science. At first, fellow researchers couldn’t believe what they read. It all seemed so simple. All they had to do now was find a way for their discovery to benefit patients.

“My tumour was initially 3cm by 4cm,” Emma Kearns says. “And so the first chemo was an attempt to shrink it, which hopefully would mean only a lumpectomy rather than a mastectomy.”

The treatment worked, and her breast was saved. When the tumour was removed it measured only 8mm. Her first course of chemotherapy consisted of a combination of two drugs known as AC — Adriamycin and Cytoxan. She did lose a lot of her hair at the front and top, but the use of a helmet resembling a horse-riding hat froze and saved some follicles at her crown. She wore the occasional wig and head scarf, “and in the summer I just looked like a boho chick”.

The second chemotherapy after surgery in June 2005 was Taxotere, whose active ingredient is derived from the yew tree. She underwent radiotherapy at the same time, and the whole process made her nails turn white and snap off.

Compared to the promises of biotechnology, familiar cancer therapies can sometimes seem like something from a darker age, best summed up by a doctor as a combination of “slash, poison and burn”. The surgical removal of breast tumours is still regarded as the best line of defence.

Chemotherapy has advanced greatly since the blunt instrument first wielded in the late Fifties and early Sixties, but the great range of treatments designed for the various types and stages of cancer are inexact weapons, as is radiotherapy: the side effects — severe nausea, bone marrow disease, loss of hair, fevers, diarrhoea — are the clearest indication that in the process of killing diseased cells, immune-boosting and healthy growth cells perish, too. In the longer-term, infertility would be another blow.

The commercial use of tamoxifen in the mid-Seventies signalled a new way forward for breast cancer care. This therapy, manufactured originally by ICI under the trade name Nolvadex before its mechanism was fully understood, blocked oestrogen production by adhering to the oestrogen receptors in breast cancer cells, thus interrupting one of the pathways of tumour growth. Initially licensed for late-stage cancer treatment, seven years ago it was also approved as a preventative treatment for those considered at high risk from breast cancer, not least if there is a family history of the disease. Tamoxifen is taken in pill form over two to five years, and it can have many side effects, not least those commonly associated with the menopause.

Because it is rarely effective in women under 35, Emma Kearns was not a good candidate for tamoxifen. But now there was something new. She was copied into all the letters the Royal Marsden sent to her doctor, and her correspondence was invariably headed with the code HER2+, which put her in a group of between 25 to 30 per cent of women with breast cancer (rising to 40 per cent of women younger than 40). Until a few years ago most women with breast cancer would not be tested for the HER2 gene, and not just because the technology was complex and expensive. There was no point because there was no treatment.

This position had changed by the time Emma Kearns presented herself. “They were saying that there is this research going on,” she remembers, “ ‘and we don’t know how it will affect you, but you are a suitable candidate. We’ll let you know, because the results of the research aren’t in yet.’ ”

That was in April 2005, and the results of the research were but days away. But the trials in question were a specific inquiry into the efficacy of a drug for use in early-stage breast cancer. The same drug’s dramatic impact on late-stage and metastatic breast cancer (cancerous cells that have spread beyond the breast), had already been proven, and it had far exceeded the wildest hopes of Dennis Slamon and Axel Ullrich.

In the late Eighties, the two scientists took their work on HER2 one stage further — into mice. Slamon worked in his lab at UCLA, while Ullrich developed his research with his colleagues at Genentech, the biotechnology company that had been founded in 1976 and had later adopted the corporate slogan “In Business For Life”. The goal was to develop a monoclonal antibody effective against mutating HER2 — a synthetic drug, made in large quantities, designed specifically to block the receptors on the cell surface. The progress was swift. In 1989, an HER2 antibody was shown to work in human breast tumour cells; in 1991 the first anti-HER2 antibody that had initially been developed in mice was tested in humans, and reported a few months later in the journals. This phase 1 trial showed no damaging side effects and enabled the researchers to work out a suitable dosage. The phase II trials, testing the drug’s effectiveness in a small group of patients recruited by Dennis Slamon at UCLA and other sites, commenced in 1993 and ended a year later, and the results were very encouraging. About 15 per cent of the women benefited from the drug (their tumour either shrunk or didn’t increase), but this gave Slamon confidence that the biological theories were at least correct. Much of the money at UCLA came from the cosmetics company Revlon, which contributed about $13m to the university’s cancer work under Slamon’s leadership between 1989 and 1997. As it entered the phase II trials, the drug finally had a name: trastuzumab. And Genentechhad also registered a trade name for it: Herceptin.

“There was little doubt in our minds that it would work,” Dennis Slamon told me one morning before he left home for his office at UCLA’s Jonsson Cancer Centre. “We knew that if we understand what’s broken, and target that specifically, then in theory we’ll have more effective and less toxic therapies. But there was a lot of doubt in the field, because monoclonal antibodies had traditionally failed.”

In the phase II studies, Slamon says the 15 per cent success rate was encouraging because he was seeing patients who’d failed with everything else. “Everyone now believes this is the crest of the wave,” he says. “Before the Herceptin data it was only a big promise, and after it, it became a reality.”

But the big test was yet to come. The phase III trials, which had great difficulty recruiting just a few hundred women to such a novel experiment, began in 1995, and would be the first big test of Herceptin delivered alongside traditional chemotherapy drugs. The results were revealed publicly in 1998.

The day before I talked to Dr Slamon, I had been to see Mark Sliwkowski, director of translational oncology at Genentech in San Francisco. The company was so big it had its own street: DNA Way. Dr Sliwkowski joined Genentech in 1991, not long after it had been bought by Roche Holding Ltd, the Swiss company that owned the giant pharmaceutical company Roche.

He was one of the first at Genentech to learn the results of the phase III Herceptin trials in November 1997. “It was unbelievable,” he says. “I knew that it worked, but I was told not to tell anybody.”

The data showed one thing above all others: Herceptin could delay the recurrence of breast cancer and extend the life of patients. — Dawn/The Guardian News Service (c) The Observer

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