Chin noticed a glitch in communication between let-7 and the KRAS gene in about 20 percent of the tumors. In these cases, the team identified a mutation of the KRAS gene — they called it the KRAS-variant — that prevented let-7 from controlling how much KRAS protein was made. In KRAS-variant patients, let-7 simply could not connect to the KRAS gene well enough to stop it from producing too much protein. The excess protein led to unchecked cellular division and cancer.
Weidhaas and Chin spent months poring over medical records, cross-checking what they had learned from the genetic signatures of the tumors with the progress of each patient’s disease. What they found was startling — and chilling.
The 20 percent of lung cancer patients who carried the KRAS-variant had more aggressive cancers that affected multiple organs. “We’d go through their charts and see the same things over and over. They’d beat the lung cancer, but then they’d get head and neck cancer, or breast cancer or colon or pancreatic cancer,” says Weidhaas. “I remember thinking, ‘Holy cow — this is real.’ ”
When Weidhaas and Slack presented their initial findings at several major cancer conferences, they were treated like rock stars by their audience of fellow researchers. “We had people running up on the stage, asking to collaborate,” recalls Weidhaas.
They looked beyond lung cancer, and discovered the KRAS-variant played a key role in half a dozen other particularly lethal malignancies, especially in women.
Women with the variant were at much higher risk for cancer, had more recurrences, were often hit with multiple cancers and were more likely to die from aggressive forms of these diseases.
Recognizing their discovery’s significance and hoping to speed up the process of taking it from lab bench to bedside, Weidhaas and Slack founded the company MiraDx in 2008. Using about $3 million in seed money cobbled together from friends and family members, they planned to commercialize their diagnostic test. The goal was to make it standard practice, much like BRCA screening for women with a family history of breast and ovarian cancer.
By 2010, they had launched their first test, PreOvar, which uses either saliva or blood samples to evaluate ovarian cancer risks, including screening for the KRAS-variant. PreOvar was the forerunner of the current KRAS-variant test, which is also based on saliva or blood samples.
The new diagnostic tool is used in research, but is also available to individuals for considerably less than many other genetic tests. The KRAS-variant test must be ordered through MiraDx by the individual’s physician, who then collects the patient’s sample and sends it to the company’s certified lab for processing. Although some direct-to-consumer genetic testing has come under FDA scrutiny recently, the KRAS-variant test does not require the agency’s approval because it is given only in these controlled conditions.
Making the test widely available and keeping it affordable were Weidhaas and Slack’s goals from the start. Making the test standard practice was also their hope, but they quickly ran into the harsh realities of the marketplace: It can cost upward of $150 million to hire a sales force and do the years of clinical trials that both insurance companies and leading oncology groups demand before incorporating a diagnostic test into professional practice guidelines.
Without the time or money for this traditional route to get the test into standard practice, Weidhaas and Slack thought they would use the $3 million in seed money to promote the test in hopes of attracting more investors with deeper pockets. They hired a staff to run the company day to day, trying to drum up interest. It worked: Venture capitalists came calling three times between 2009 and 2011. But Weidhaas and Slack turned down all three offers. They were committed to keeping the fee low and felt the interested parties saw it only as a cash cow — other cancer genetic tests can cost $5,000 or more.
Thanks to the cost of research, test development and promotion — as well as a refusal to abandon their commitment to putting mission above profits — Weidhaas and Slack quickly burned through their funds.
Women Especially at Risk
Yet even as their goal of wider KRAS-variant testing foundered, research supporting the need for such a test was piling up. Study after study — eventually involving more than 65,000 participants — confirmed the life-saving potential of this diagnostic tool.
Doctors have had little success diagnosing ovarian cancer at its earliest, most treatable states or identifying women at risk for the disease, for example. But Weidhaas and Slack’s studies showed how the KRAS-variant increases a woman’s risk of ovarian cancer — more than 27 percent of women with this type of cancer carried the variant. “More than 700,000 women get their tubes tied every year,” says Weidhaas. “If they had the variant, they might consider having their ovaries removed, too.”