Ontology engineering

news feature© 2010 Nature America, Inc. All rights reserved.Others wonder whether HER2 is eventhe right thing to test. Strategic Medicine’sLiebman, who was at Vysis (now part of AbbottLaboratories of Abbott Park, Illinois) whenthe first FISH test was developed, says that forcertain patients, the immunohistochemistryand FISH results never agree. “Just becauseyou have a change in gene copy number, thatdoesn’t mean it’s expressed,” he says. The factthat a significant fraction of HER2-positivepatients with metastatic disease fail to respondto the drug also suggests that it is not a causalmarker but a surrogate.There may be room for yet more tests.Microarray studies indicate that between 20to 30 distinct classes of breast cancer exist,according to Charles Perou, of the LinebergerComprehensive Cancer Center in Chapel Hill,North Carolina. A few of those make up themost clinically relevant subtypes, but there areenough differences between those types thatmore and better tests are urgently needed.“Our array data show that there are at leasttwo kinds, and maybe many more, of patientswith HER2-positive disease,” he says. The differencecan be seen in how the patients respondto chemotherapy, with 80% responding in onegroup and only 30% in the other.Son of HerceptinOne other HER2-targeting drug, the smallmoleculeTykerb (lapatinib from London-basedGlaxoSmithKline), is now approved for use inbreast cancer, but a bevy of next-generationversions of Herceptin and new combinationswith the drug are nearing the market, potentiallygiving oncologists even more choiceswhen deciding which drug to use and whento use it.Genentech currently has two new HER2-targeting drugs in phase 3 trials. Pertuzumabis a HER2 dimerization inhibitor that binds toa different epitope on HER2 than Herceptin.The drug inhibits HER2 dimer formation withother HER family members, such as HER3and HER1. Genentech is currently studying acombination of both HER2 inhibitors in breastcancer. “With this approach, we are addressingthe question of what happens when youhave more complete HER2/neu blockade,” saysGenentech’s Sliwkowski. The drug has alreadyshown promise in early trials. In one study,about a quarter of women whose disease hadprogressed while they were taking Herceptinhad their tumors shrink by >50% when pertuzumabwas added to their treatment regimen.The company is also optimistic aboutT-DM1 (trastuzumab-DM1), a drug conjugatethat combines Waltham, Massachusetts–basedImmunoGen’s antimitotic maytansinederivativeDM1 cancer-killing agent withHerceptin. In earlier studies, this drug madetumors shrink even in some women withadvanced breast cancer who had been treatedwith a median of seven different drugs. Thedrug is being “moved up the line,” accordingto Sliwkowski, and will be tested in a randomizedphase 2 trial comparing TDM-1 versusHerceptin plus chemotherapy. “We think it isso active that it’s important to try this,” saysSliwkowski. To be able to use a targeted therapywithout chemotherapy is the dream and it maybe very close to realization.Dennis Slamon, a University of California,Los Angeles, oncologist who was part of theteam that developed Herceptin back in the1980s, is enthusiastic about combining it withGenentech’s vascular endothelial growth factor(VEGF) inhibitor, Avastin (bevacizumab).Slamon points out that the two pathways arelinked. When HER2 is amplified, “one of thepathways that consistently goes up is VEGF,”he says. Trials of the combination (Avastin plusHerceptin) have been encouraging. In phase2 trials, “the two antibodies alone, with nochemo, are giving objective response rates in54% of women with metastatic disease.” Usedat earlier stages, Slamon believes the combinationcould be even more powerful and he isoptimistic that this regimen will eventually betested in a phase 3 trial without concomitantchemotherapy.Growing understanding of the pathwaysrelating to HER2 are also leading to new drugtargets. Phosphatidyl inositol 3-phosphate(PI3) kinase and PTEN (phosphatase andtensin homolog) are two other players thatseem connected to HER2. Mutations in PI3kinase occur in 30% of breast cancers andcause the enzyme to be turned on all the time.“It’s a classic oncogenic activating mutation,”says William Sellers, head of oncology researchat Novartis Institutes for Biomedical Researchin Cambridge, Massachusetts. PTEN, meanwhile,is a tumor suppressor gene which canact by blocking the activation of PI3 kinase.Mutations in that gene can again lead to overactivation.“In many instances, the amplificationof HER2 leads to signaling through thispathway,” Sellers says. This has become thenumber one pathway of interest in cancer.The most advanced new compounds targetingthe pathway are mTOR inhibitors, but thesework far downstream, and researchers wouldlike to hit it earlier on. Novartis’ BKM120 is aselective PI3 kinase inhibitor that the companyhopes will do just that. All these targets, includingHER2, are found in other cancers, whichmeans they could have wider use. Herceptin isbeing tested in stomach cancer, for example. Ifthese drugs are used more broadly, new testswill be needed. The question then, Sellers says,will be, “How do we know which therapeuticto use?”Improving outcomesControversy about testing has doggedHerceptin from the beginning. “Slamon battledfor ten years to prove HER2 was important,”recalls Shak, who worked on Herceptin’sdevelopment while at Genentech. “He had tofight that hard because so many groups weredoing their tests without quality control.” Butexperts are adamant that testing for HER2must be improved. “In the adjuvant setting,you are giving a woman absolutely substandardcare if you are wrongly denying her thedrug,” says Ross. Norton concurs: “We mustdo better.”Although standardizing immunohistochemistryseems to be the most obvious next step,it may not necessarily be the best way toimprove outcomes. “Even when countrieswith a national health service do everythingthey can to standardize this test, we still seeunacceptable margins of error,” says Liebman.Strategic Medicine is working with The MayoClinic and Thompson Reuters, headquarteredin New York, to build data models that willreveal which steps are most likely to improvethe quality of HER2 testing. Most laboratoriesare using immunohistochemistry, andthe cost of making improvements across theentire community, he points out, would likelybe prohibitive. “Our goal is to find the weakestpoints in the system, whether it is an issuewith reimbursement, diagnostic developmentor education. What should be the priority fixthat gets us the biggest impact in improvingpatient care?”Others think the answer clearly lies inapplying some newer technologies. “I thinksequencing will give us the final answer, oncewe have inexpensive-enough techniques,” saysNorton.Malorye Allison, Acton, Massachusetts1. Phillips, K.A. et al. Cancer 115, 5166–5174 (2009).2. McArthur, H.L. & Hudis, C. Clin. Cancer Res. 15,6311–6313 (2009).3. Perez, E.A. et al. J. Clin. Oncol. 25, 512, Suppl. 18S(2007).4. McArthur, H.L. et al., abstract 1005, presented atEuropean CanCer Organization 15 and 34th EuropeanSociety for Medical Oncology MultidisciplinaryCongress, Berlin, Sept. 20–24, 2009.nature biotechnology volume 28 number 2 february 2010 119