January 28, 2008
Forbes Health

The Cancer That Shouldn't Be

Cervical cancer is almost entirely preventable with a new genetic test. Yet doctors still cling to the highly unreliable Pap smear. Something is very wrong here.

Christine Baze and her husband of seven years were planning to start a family in 2000 when she found out she had cervical cancer. At 31 she underwent a hysterectomy followed by three months of drugs and radiation.

Baze was, as she describes it, "the girl who was doing everything right," getting annual Pap smears that screen for pre-cancerous cervical cells. But the Pap test missed the cancer that had been growing inside her for a decade. Each test had returned a negative result. With early detection, Baze could have treated her cancer with chemotherapy and radiation."I was devastated, and incredibly pissed at my doctor's office. If they'd found the tumor three years earlier, I could have kept my uterus and had a child," says Baze, now 39 years old and executive director of the Yellow Umbrella, a cervical cancer prevention group she founded in 2002.

It borders on the scandalous that cervical cancer, among the few cancers that are preventable, kills 310,000 women a year worldwide. In 2007, 11,150 women in the U.S. were diagnosed with it. Half of them had not had a recent Pap test. Another third did get tested but got false negatives from the 65-year-old Papanicolaou biopsy. The Pap test is valuable, having cut the rate of cervical cancer by 70%, but it is archaic. It calls on a lab technician or machine to peer at a daub of cervical cells under a microscope to spot the abnormal precancerous ones. This artisanal approach yields false negatives between 13% and 45% of the time.

The persistence of the Pap--55 million are performed each year--is especially frustrating for Qiagen, the German diagnostic tools firm that paid $1.6 billion in cash and stock to buy Digene, a Gaithersburg, Md. biotech firm that invented a far more accurate test.

For $49, 12 bucks more than a Pap, Qiagen's HPV test can spot the genetic fingerprint of the human papilloma virus that hides within cervical cells. HPV infection is a necessary precursor to cancer. Catch it early and you won't get cervical cancer. The Food & Drug Administration approved Digene's HPV test in 2003 for cervical cancer screening alongside the Pap for women over 30. It gives a false negative for precancer only 5% of the time. Yet three-quarters of women in the U.S. have never taken it.

One reason doctors like the Pap is that it brings patients back every year. The HPV test is needed only once every three years because the test is so accurate and most women fight off HPV infections on their own. Without Pap as a draw, doctors are concerned their patients will fall behind on other checkups like breast exams. Docs are also afraid of losing the income from annual visits, says Walter Kinney, a gynecologic oncologist at Kaiser Permanente in Sacramento, Calif.

Kaiser added the HPV test in 2004 for routine screening alongside the Pap. That move saved Kaiser's doctors from having to go back and remove more cells from patients in the 6% of Paps that return inconclusive results. For every dollar spent doing Paps, it was spending another on follow-ups, which are often unnecessary: Irregular Paps are often the result of inflammation that goes away on its own.

Ellen Sheets, chief medical officer of Pap maker Hologic, says that, while the Pap does produce more false negatives than the HPV test, it produces fewer false positives. "We believe your best bet is to get the Pap so you know what's wrong today, not find out what might go wrong in the future."

Other clinicians disagree. "The time has come that we need to make a conversion [to the HPV test]. It would be doing women a disservice not to," says Cosette Wheeler, a University of New Mexico School of Medicine professor who has spent her career studying HPV.

Three studies published in October, two in the New England Journal of Medicine and one in Lancet, supported using the HPV test in place of or in tandem with the Pap. Roche also has an HPV test now under FDA review, and biotechs Third Wave, Gen-Probe and SensiGen are developing tests.

Merck's heavy marketing of its two-year-old Gardasil HPV vaccine ($1.3 billion in annual sales) has educated young women about the link between HPV and cervical cancer, but it may also create problems for Qiagen, which now has to convince vaccinated patients that they still need to be screened. Gardasil protects against only 2 of the 15 types of cancer-inducing genital HPV strains, and its long-term effectiveness is unproved.

HPV gets picked up eventually by nearly all sexually active people through skin-to-skin contact. Researchers discovered in the mid-1980s that the virus was linked to cervical cancer. A decade later they determined that 15 of the more than 100 HPV types caused virtually all cases of cervical cancer.

Digene's test, shepherded by marketer Douglas White and researcher James Godsey, uses a chemical reagent to separate a cervical cell's DNA into two strands in a vial. A robotic arm squirts in RNA molecules culled from 13 high-risk HPV strains. The RNA is designed to bind to the cell's DNA if the virus is present, forming a hybrid molecule. Antibodies and enzymes added to the sample will light up if they find the hybrid.

Qiagen, which grossed $560 million in the last 12 months from sales of diagnostic test components, says the HPV test will add $265 million next year. Its chief executive, Peer Schatz, says the potential market is $1.5 billion worldwide and could grow as countries replace the Pap with the HPV test.

Qiagen is developing a genotyping test that would tell the patient whether she has one of the two more virulent types of HPV that cause 70% of cancers. It could be available by 2009. Qiagen is also readying for delivery a briefcase-size device called FastHPV for use in developing countries. Funded by the Gates Foundation and developed with global health not-for-profit path, the FastHPV machine requires no electricity or potable water, is simple to use and returns results in two hours, so women can get treated immediately. One Harvard study predicts that the test could halve cervical cancer rates in the developing world. The test could be introduced in China in 2009. Trials in India are under way.

Christine Baze is confident that, with the combination of the HPV test and the vaccine, cervical cancer like hers will someday be a thing of the past. "I truly believe we can eliminate this cancer."

By the Numbers

• 555,100 New cervical cancer cases worldwide in 2007.
• 309,800 Deaths from cervical cancer worldwide in 2007.
• 83% of deaths are in the developing world.
• 75% of women in the developed world screened recently.
• 5% screened in the developing world.

Sources: American Cancer Society; Qiagen.