OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

	Johan Lennartsson, PhD, is an associate professor at Uppsala University and leader of the Section for Signal Transduction at the Uppsala Branch of the Ludwig Institute for Cancer Research in Uppsala, Sweden. His research focuses on platelet-derived growth factor receptor (PDGFR) and mitogen-activated protein kinase (MAPK) signaling in normal physiology and cancer. He is an expert in a wide variety of oncogenic signaling pathways, including the SCF/KIT pathway, to which he has made numerous seminal research contributions.

	What role does SCF/KIT signaling play in normal cells?

	SCF/KIT signaling most likely has different functions in different cell types. Major functions regulated by this pathway include cell survival and acting as a guiding cue for migrating cells expressing the KIT receptor. Examples of the types of cells that express KIT are primitive hematopoietic cells, germ cells, and melanocytes.

	How important is it in cancer development, and in what kinds of cancer?

	Overactivity of SCF/KIT signaling occurs through a number of different mechanisms, for example, mutational activation, SCF expression in an autocrine fashion, or receptor overexpression. In human cancer, aberrant activation of KIT has been detected in mastocytosis, gastrointestinal stromal tumors, acute myeloid leukemia, certain lymphomas, and in germ cell tumors. These tumor types reflect the normal expression pattern of KIT.

	What are the major targeted therapies available or in development?

	It has become clear that a large number of tumors have aberrant expression of receptor tyrosine kinases, and that this class of cell surface receptors frequently regulates functions such as proliferation, migration, and survival—functions that are deregulated in tumor cells. Therefore, these receptors have been used as targets for drug development, including low-molecular-weight kinase inhibitors (eg, the clinically used drug Gleevec), but other possibilities are neutralizing antibodies against the receptor (similar to the HER2-targeting antibody Herceptin) or ligand (similar to the vascular endothelial growth factor—targeting antibody Avastin). Furthermore, it is likely that these targeted therapies will be most efficient in combination with classical radio- and/or chemotherapy.

	What is the future for this signaling pathway in cancer research?

	I believe it is important to identify which signaling circuits are activated by KIT, and how these circuits contribute to the observed effects on cell survival, growth, and migration. This knowledge may then be used to develop drugs that interfere with these pathways, with the ultimate goal of simultaneously striking against both KIT receptor activity as well as intracellular circuits. This will increase the likelihood of a response and make it more difficult for resistance to evolve.

	Another avenue of exploration is to identify drugs that have multiple targets, thereby inhibiting several signaling pathways essential for the cancer cell.

Articles

Johan Lennartsson's research focuses on platelet-derived growth factor receptor (PDGFR) and mitogen-activated protein kinase (MAPK) signaling in normal physiology and cancer. 

4 Questions for Johan Lennartsson, PhD

	The importance of the stem cell factor (SCF)/ KIT signaling pathway in the normal human body is relatively well understood, but the breadth of its oncogenic functions and potential role as a therapeutic target are only just becoming clear.

	Agents targeting this pathway have proved more successful in some tumor types than in others; particularly variable has been the role of imatinib (Gleevec, Novartis). More recently, the evolution of a new paradigm of cancer therapy, in which the molecular characteristics of a tumor are used to guide therapeutic regimens for each individual patient, has seemingly brought the story of the SCF/ KIT pathway full circle and is driving increased interest in these agents.

	The significant genetic player in this pathway is the 

 gene, whose KIT protein product is a member of the class III receptor tyrosine kinases (RTKs), a family that includes other receptors such as platelet-derived growth factor receptor (PDGFR). As with other RTKs, the binding of a specific ligand, in this case SCF, leads to receptor dimerization (one receptor molecule binding to another), which activates the intrinsic tyrosine kinase activity of the receptor, leading to its phosphorylation at key amino acid residues.

		SCF indicates stem cell factor; STAT3, signal transducer and activator of transcription 3; K, tyrosine kinase domain. The MAPK pathway is denoted as RASRAF- MEK-ERK and the PI3K pathway is PI3K-AKT-mTOR.

		Adapted from Lovly C, Pao W, Sosman J. KIT in thymic carcinoma: what is KIT? Vanderbilt-Ingram Cancer Center. 

. Updated June 30, 2011. Accessed July 25, 2011.

	These residues subsequently act as binding sites for signaling molecules within the cell; thus, the process of signal transduction is initiated downstream of the receptor. A number of important downstream signaling cascades are activated by the SCF/KIT pathway including mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling.

	Researchers have identified 2 isoforms of the SCF ligand that are quite different in the signaling outcomes they initiate. The isoforms differ in the presence or absence of a proteolytic cleavage site, and their resulting solubility (let’s call them “SCF ” and “SCF-” for simplicity’s sake). SCF initiates a rapid and transient activation of KIT, followed by a rapid degradation, while SCF- leads to a more sustained activation and prolonged downstream signaling.

	The SCF/KIT pathway is believed to have a number of major in vivo functions in humans. Like the JAK/STAT pathway described in last month’s “Pathways” article, SCF/KIT signaling is crucial for hematopoiesis, the formation of blood cells. It plays a particularly vital role in the development of primitive hematopoietic cells such as stem and progenitor cells, becoming less important once they have differentiated, such that less than 0.1% of peripheral blood cells express KIT. One important exception is the mast cells, which continue to express KIT at high levels and are dependent on SCF/KIT signaling for their growth, survival, and proper function.

	Another important function of the SCF/KIT pathway is in pigmentation, since it has a very well-established role in melanocyte development. Mice with reduced KIT expression have defective pigmentation, and mutations in the 

 gene have been detected in the majority of humans with piebaldism, a rare inherited condition characterized by a patch of white hair above the forehead.

	SCF/KIT signaling is also important in the gastrointestinal tract (specifically in the development of the interstitial cells of Cajal [ICC]), in fertility, and in the nervous system.

	This myriad of important cellular functions of course translates into a darker side of this pathway, when mutations or altered expression of its component parts lead to the development of cancer.

	Unsurprisingly, KIT is associated with several malignant human diseases, which mirror its major in vivo functions, including melanoma, mastocytosis (characterized by an accumulation of mast cells in various tissues), gastrointestinal stromal tumors (GISTs; the most common form of mesenchymal tumor of the digestive tract, thought to arise from the ICC), acute myelogenous lymphoma (AML), and small cell lung carcinoma (SCLC). It also has been described in a range of other tumors such as neuroblastoma, cervical, testicular, thyroid, breast, colon, bladder, renal, pancreatic, and non-small cell lung carcinoma.

	However, the precise role of KIT in these different tumors is often complex and poorly understood. While 

 is overexpressed in some melanomas, progression to invasive and metastatic stages has also been shown to correlate with reduced levels of the protein, suggesting a tumor-suppressive function.

	In the majority of cases, however, tumors arise from activating mutations in 

 or its overexpression. For example, between 50% and 80% of GISTs have an activating mutation in 

, and between 28% and 88% of SCLC cell lines have been reported to overexpress 

. Furthermore, mutations in the kinase domain (D816V) of 

 have been identified in the mast cells of patients with mastocytosis.

	No KIT-specific inhibitors have been generated to date; however, the tyrosine kinase inhibitor (TKI) imatinib is multitargeted, and also inhibits KIT activity. When it comes to tumors associated with KIT abnormalities, GISTs have been the real success story for imatinib.

	Prior to the 2001 approval of the so-called “magic bullet,” patients with GISTs that harbor a 

 mutation had a particularly poor prognosis. Imatinib revolutionized the treatment of these tumors, with more than 80% of patients responding. At the 2011 American Society of Clinical Oncology (ASCO) meeting, the results of an Australian population-based study put the impact of imatinib on GISTs into perspective, showing a 64% improvement in survival of GIST patients subsequent to imatinib approval.

	Not all KIT-defective tumors have displayed such dramatic effects, however. Imatinib proved relatively ineffective in the treatment of mastocytosis and controversial in the treatment of melanomas, with several phase II studies reporting no clinical activity in metastatic melanoma. Furthermore, a new problem developed in GIST patients being treated with imatinib: resistance.

	For these reasons, researchers began to look for alternative treatments for cases in which imatinib fails to work or when resistance develops. Sunitinib (Sutent, Pfizer) was the first targeted therapy to show effectiveness in treating imatinib-refractory GISTs.

	However, a wealth of clinical trial data presented at this year’s ASCO meeting in Chicago highlight the number of second-generation TKIs that are now being tested in this respect, including sorafenib (Nexavar, Bayer Health- Care and Onyx Pharmaceuticals), nilotinib (Tasigna, Novartis), dasatinib (Sprycel, Bristol- Myers Squibb), and regorafenib (BAY 73- 4506, Bayer HealthCare), all TKIs that include KIT among their multiple targets.

	The studies presented at ASCO demonstrated that these agents have significant activity in patients with imatinib-resistant GISTs. Some studies also examined patients with sunitinib-resistant GISTs, and these patients also responded well to other second-generation TKIs.

	In addition to these alternative agents, the molecular analysis of tumors has now led us full circle back to imatinib, and the case is slowly being made for reassessment of this agent for treatment of melanomas.

	Many of the original trials that demonstrated limited clinical activity were carried out prior to the discovery that activating mutations in 

 were important in melanoma development, and therefore did not screen for patients with these mutations. Substantial evidence now suggests that 

-mutated melanomas can respond to treatment with imatinib.

 mutations are sensitive to imatinib, and numerous studies show that patients with melanoma harboring 

 mutations can have significant and durable clinical responses, with even greater activity in tumors that have certain types of mutations. It is left to the future of SCF/KIT pathway research to determine precisely which 

 alterations may be of particular functional relevance in leading to tumor formation and determining response to treatment.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

			Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327-2334.

			George S, von Mehren M, Heinrich C, et al. A multicenter phase II study of regorafenib in patients with advanced gastrointestinal stromal tumor (GIST) after therapy with imatinib and sunitinib. J Clin Oncol. 2011;29(suppl; abstr 10007).

			Goldstein D, Lee C, Tracey E, et al. Validating innovation: A population-based study of gastrointestinal stromal tumors (GIST) to estimate the survival benefit of imatinib. J Clin Oncol. 2011;29(suppl; abstr 10060).

			Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification [Epub ahead of print]. J Clin Oncol. 2011;29(21):2904-2909.

			Kindler HL, Campbell NP, Wroblewski K, et al. Sorafenib in patients with imatinib and sunitinib-resistant gastrointestinal stromal tumors (GIST): final results of a University of Chicago phase II consortium trial. 

			Lennartsson J, Voytyuk O, Heiss E, et al. C-Kit signal transduction and involvement in cancer. 

			Lennartsson J, Rοnnstrand L. The stem cell factor receptor/c-Kit as a drug target in cancer. 

			Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). 

The breadth of the stem cell factor (SCF)/ KIT signaling pathway oncogenic functions and potential role as a therapeutic target are just now becoming clear.

The SCF/KIT Pathway's Roles: Interest in Therapeutic Targets Is Growing

	7th Annual Multidisciplinary Symposium on Head and Neck Cancer Is Set for Philadelphia

		Ezra W. Cohen, MD University of Chicago

	The 7th Annual Multidisciplinary Symposium on Head and Neck Cancer will be held on November 19, 2011, at the Hyatt at the Bellevue in Philadelphia, Pennsylvania. The symposium, chaired by Ezra W. Cohen, MD, co-director of the head and neck cancer program at the University of Chicago, will present recent data from international oncology conferences, with a strong emphasis on the use of prognostic/ predictive biomarkers in diagnosis and treatment.

	Faculty members will discuss the latest developments in minimally invasive surgical techniques, new agents and biomarkers under investigation, and state-of-the-art treatment for thyroid cancer and nasopharyngeal carcinoma. This symposium will also feature case-based discussions, questionand- answer sessions with the faculty, and multidisciplinary case management sessions.

		Joyce O’Shaughnessy, MD Baylor Charles A. Sammons Cancer Center

	The School of Breast Oncology conference was developed to address the growing specialization in breast cancer and to better advance patient care in practice centers across the country. Led by Joyce O’Shaughnessy, MD, the co-director of breast cancer research at the Baylor Charles A. Sammons Cancer Center in Dallas, Texas, the School of Breast Oncology is a curriculum-based program that focuses exclusively on the clinical management of breast cancer.

	This 4-day interactive program, which runs from November 3-6, 2011, in Atlanta, Georgia, provides a comprehensive review of the most recent data on aspects of breast cancer biology, diagnostics, prevention, and advances in treatment. The evidence-based curriculum will examine topics such as breast carcinogenesis and the management of high-risk disease, adjuvant chemotherapy and endocrine therapy, imaging modalities and their use, the management of HER2-positive disease, treatment of metastatic disease, and survivorship.

The 2 upcoming conferences include the 7th Annual Multidisciplinary Symposium on Head and Neck Cancer and the School of Breast Oncology.

Conference Corner: 2 Upcoming Physicians' Education Resource Conferences

	It’s hard to tell which moves more quickly: Edith Perez’s feet, or her mind.

	A devoted runner, Edith A. Perez, MD, strides along the beaches of northern Florida whenever she gets the chance. A translational researcher who spends her time designing clinical trials of potential breast cancer treatments and studying the biology of the disease, Perez maintains the same swift pace as she travels the globe, interspersing projects at her home base, the Mayo Clinic in Jacksonville, with frequent trips to speak and consult.

	Luckily, Perez is able to apply her mind just as nimbly to solving problems in breast cancer treatment. Rotating her sharp focus through the broad range of tasks that make up her typical day is a joy for the 55-year-old scientist who loves to read about any subject, is a whiz at math, and completed high school in 2 years and college in 3 years.

	“My brain works fast,” said Perez. “It’s nice to be able to work for an hour, come up with something, then do something else, and something else. I enjoy that.”

	The doctor’s intellectual appetite has made a marked difference for patients with breast cancer everywhere. Every day, she puts her mind to finding better treatments for the disease and conducting research that will help others in the oncology community move forward with science aimed at improving people’s lives.

	Much of her work has concentrated on the study of compounds designed to fight HER2-positive breast cancer, leading to a 2005 discovery that changed the way the disease is treated. A study that Perez led and helped design showed that the use of Herceptin (trastuzumab), a monoclonal antibody that helps counteract a genetic mutation of the HER2 gene, in concert with chemotherapy—rather than chemotherapy alone&mdash;resulted in a 52% decrease in the recurrence of HER2- positive breast cancer in patients who had undergone surgery for the condition, and improved their survival by 33%.

	“We presented those data at the largest meeting ever of the American Society of Clinical Oncology, with about 16,000 people in attendance— people who had been involved in funding and some of my patients who were in the trial,” Perez recalled. “I realized that not too many physicians have the opportunity to affect that many lives to this degree, no matter how dedicated they are or how incredibly good their ideas. It was humbling, actually.”

	Using tumor and blood samples collected during the study, Perez and her colleagues have continued to consider the potential applications of Herceptin. In May, the doctor presented results demonstrating that the therapy works for P10-postive or P10-negative patients whose tumors do not express the HER2 protein.

	Perez also is proud of a study she concluded 7 months earlier. The study of trastuzumab-DM1, or T-DM1, a drug antibody conjugate that combines chemotherapy agent docetaxel with Herceptin, demonstrated that the conjugate is half as toxic as the same drugs given separately to patients with HER2- positive metastatic breast cancer who had not received prior chemotherapy for metastatic disease.

	“I routinely explore things that I hope will be more efficacious and lower toxicity,” Perez said, “because that’s huge for people’s lives.”

	The doctor accomplishes that through a variety of roles at the Mayo Clinic. For more than a year, she has served as deputy director of the Mayo Clinic Cancer Center, and also is director of the institution’s Breast Program and chair of its Breast Disease Oriented Group, which brings together researchers from all Mayo Clinic sites to review research opportunities related to breast cancer prevention, treatment, and survivorship.

	She is a Serene M. and Frances C. Durling Professor of Medicine at the Mayo Medical School; the first Mayo physician to serve on the Board of Scientific Advisors of the National Cancer Institute (NCI); and, in 2007, was given her institution’s top honor for investigators when she was named a Mayo Clinic Distinguished Investigator. She chairs the Breast Committee for the North Central Cancer Treatment Group, sponsored by the NCI.

	Finally, an annual marathon Perez helped to launch has led to the creation in January 2009—and continued funding&mdash;of Mayo’s Breast Cancer Translational Genomics Program, which aims to unravel, categorize, and catalog all the mutations present in breast cancer. The goals of the work include gaining a better understanding of what drives the disease’s growth, learning what may predict sensitivity or resistance to different treatments, and identifying targets that can be used to develop new treatments, Perez said.

			Claims The Little Prince as a favorite book because it involves “someone looking at the world, experiencing new places, talking to people, getting insight, and having a positive outlook.”

			Enjoys the movie Up Close and Personal because it’s also “a beautiful story about being positive. The main character was positive about herself and her potential through work.”

			Has a favorite saying: “Being lucky means being ready when the opportunity arises.”

			Spent 2 months exploring England between her first and second years of medical school, paying for the trip by working as a maid at a 5-star hotel.

			During medical school, played on her university’s tennis team.

			Since 1998, has been receiving grant funding from the Breast Cancer Research Foundation originated by Evelyn Lauder, who has served as senior corporate vice president of the Estée Lauder Companies. She describes Evelyn Lauder as a “renaissance woman.”

			Is “very respectful of the contribution of other people” to her work and her field. “You need teams to be able to implement ideas,” she said.

			Is proud to have earned an honorary doctorate of letters from the University of North Florida, among other awards.

			In donating to cancer research, thinks it’s often more constructive to give to an existing nonprofit than to start a new charity in a loved one’s memory.

			Has published 550 research articles in journals and books, and abstracts.

	Her myriad roles make for a whirlwind schedule of 10-hour days.

	In addition to her clinical trial work, Perez’s schedule includes organizing, attending, and speaking at meetings all over the globe; participating in conference calls; conducting grant reviews on behalf of the National Institutes of Health (NIH); advising scientists and companies throughout the world on studies, research, and patient care; writing manuscripts; mentoring younger scientists; and making videos for YouTube to explain her current research.

	Perez also heads Mayo teams in conducting basic research projects funded by the NIH, including one focused around tissue biomarkers for responsiveness to adjuvant trastuzumab and another aimed at understanding the role of the immune system in response to anti-HER2 therapy—trastuzumab and lapatinib (Tykerb)&mdash;in adjuvant and metastatic settings. In large part, the projects involve analyzing the proteins and genes in tissue and blood specimens and correlating them with patient outcomes.

	“My work doesn’t feel like a lot of sacrifice. It’s what I can do best,” Perez said. “Although I would like more hours to play tennis, run on the beach, read, be with good friends, and volunteer my time, it’s not a sacrifice at all.”

	Perez also manages to find time to see breast cancer patients, including 3 who periodically return for follow-up care, and new patients who are seeking second opinions about diagnoses.

	Seeing patients on a regular basis would be difficult, Perez said, due to her travel schedule. Those she has treated, though, remain fixed in the doctor’s memory.

	“Some of their stories are really amazing,” Perez said. “I just respect what they have to go through, because most of them thought they were healthy until, one day, this happened to them.”

	The doctor was moved recently when she received an email from the husband of a deceased patient. “She died before Herceptin was available, and I thought, ‘If she had lived a few more months, we would have had this,’” Perez recalled. “This kind of thing has served as my inspiration all these years. Whenever I see a patient, I wonder, ‘Is this the patient I’m going to help next?’”

Florida Marathon Supports Genomics Program

		For Edith Perez, MD, running is an opportunity to exercise, clear her mind, and think about her work.

		For the oncology community, the hobby is a lucky break.

		Without it, the translational researcher might never have helped found 26.2 with Donna, the National Marathon to Finish Breast Cancer, which in turn led to the creation—and continued funding&mdash;of Mayo’s Breast Cancer Translational Genomics Program. Under Perez’s direction, the Genomics Program aims to unravel, categorize, and catalog all the mutations present in breast cancer.

		Seventy percent of the marathon’s proceeds go to the Genomics Program, with the remaining 30% helping to pay the living expenses of local patients who are unable to work because they are undergoing treatment for breast cancer. So far, the run has raised $2.5 million and helped pay the expenses of 4500 patients.

		“The marathon is an event for everybody to get healthier and to get others healthier while doing some fundraising for two tremendously important causes: research and helping underserved women while they go through breast cancer treatment,” Perez said. “We’re looking for advances for the future, so everybody should be part of this run/walk event.”

		Perez came up with the idea for the annual marathon in collaboration with her patient, friend, and running buddy Donna Deegan, a Florida television news anchor who serves as coordinator of the run that launched in 2008.

		Perez runs in the marathon every year, and is involved in its planning and organization. She is proud of what it has accomplished on the research front, describing the Genomics project—which is now also supported by additional grants&mdash;as “a model for how to develop and perform translational research here at Mayo Clinic.”

		“The Genomics project involves 20 people at different levels: a fantastic team of basic researchers, bioinformatics specialists, biostatisticians, and lab technicians,” Perez said. “Specifically, we intend to identify every genomic abnormality in tumors and develop therapeutic strategies based on the full range of genomic abnormalities, beyond just estrogen receptor, progesterone receptor, and HER2.

		“The goals of our program also include utilization of these genomic technologies to serve as infrastructure for investigators here at Mayo Clinic to conduct translational research related to breast cancer as well as pancreatic, lung, thyroid, renal, and colon cancer, amongst others,” she said.

		As of the close of 2010, Perez wrote in a progress report, the Genomics Program had already seen success.

			Hundreds of people run through beachfront communities near the Mayo Clinic in Florida during the 26-mile marathon to raise funds for cancer research.

		The program had “completed total messenger RNA sequencing of 24 primary breast tumors, 8 nontransformed human breast epithelial cells, 8 pairs of tumor-normal pancreatic tumors, and 15 lung cancers,” Perez wrote at the time, and had “a manuscript published, one submitted, and two in preparation.”

		Looking ahead, Perez expects the Genomics Program to use its findings to identify new biomarkers and therapeutic targets in triple-negative, HER2- positive, and estrogen-receptor-positive breast cancer; identify risk factors and predictors of breast cancer; shed light on the reasons drugs do not work for some patients; and begin translational clinical trials.

		“The financial support from the 26.2 with Donna foundation has made this program possible,” Perez wrote. “We look forward to continued, careful stewardship of the money in the context of our visionary strategy.”

	It was a similar thought that inspired Perez to study medicine. She was a freshman in college when her grandmother died suddenly.

	“I thought, ‘If I had been a doctor, I could have helped her,’” Perez recalled.

	Growing up on the east coast of Puerto Rico, close to the beach and the rainforest, Perez exhibited all the skills she would later need to pursue a medical degree.

	“I really enjoyed science very early in my life, although I was going to be a mathematician, not a physician,” she said. “I was really good at math, which I got from my father. Even when I was in college, I took a calculus class, and in the whole semester, I missed one question in one test. I could see the solutions easily.”

	By the time Perez was an intern, she was considering a specialty in breast cancer.

	“I thought it was interesting because it was evolving and complex, it had to do with people, and I realized that someone who liked to read could do well,” she said. “I thought I could be doing this for a while, and I was right.”

	The child of a father who owned a grocery store and a mother who was a teacher-turned-librarian, Perez started school early, advanced an extra year during high school and graduated in 2 years, and, at 16, enrolled as a premed student at the University of Puerto Rico, Rio Piedras, where she earned a bachelor of science degree in biology 3 years later.

	Perez stayed at the university to earn her medical degree, and then completed her residency in internal medicine at Loma Linda University Medical Center in California. Having decided to pursue oncology, Perez began a fellowship in hematology and oncology at the Martinez Veterans Administration Medical Center, School of Medicine, University of California, Davis. There, she did work related to lung cancer, and began to explore breast cancer.

	Then, one evening in 1995, a phone call altered her path to the top of that field.

	“I got a call asking if I’d be interested in transferring to the Mayo Clinic,” she said. “I was extremely happy, and I accepted the opportunity. I was very fortunate because it’s a great institution.”

	Before moving to Mayo’s facility in Jacksonville, Perez spent 6 months working at the institution’s Rochester, Minnesota, location, where she devoted mornings to lab research and afternoons to patients.

	In Mayo’s lab, her focus was “combinatorial chemistry,” Perez recalled, “treating cancer cells with different medicines or new compounds and seeing how you can best kill tumor cells—is it best to combine medicines or use one? These are ideas I carry today when I do lab bench work that can be translated into clinical trials.”

	Since moving to Jacksonville, Perez has bolstered Mayo’s breast cancer program by attracting continuous grant funding from Evelyn Lauder’s Breast Cancer Research Foundation, becoming a founder of the genomics center, and helping to make numerous discoveries about the mechanisms of the disease.

	For instance, “many people thought that the more copies a patient had of the 

 gene, the better their response would be to Herceptin,” Perez said. “But we found that, up to a threshold, more copies of the gene didn’t make for a better outcome.”

	In addition to the work Perez has done to help test anti-HER2 agents and other cancer drugs, she is contributing to studies of newer investigational compounds that may help patients who have breast cancer.

	“The compounds have no names yet, just numbers,” Perez said. “I’m really excited about being involved in their development.”

	Perez is proud of the progress she has made during her time at Mayo, and she is eager to build on it.

	“I love what I do, and I want to do more,” the doctor said. “These days, I’m much more productive than I ever was, and I’m having more fun than ever. It’s all very interesting to try to put together.”

	One thing Perez hopes she’s accomplished is to use her positivity to inspire others to help fight breast cancer.

	“Most important is to get other people to understand that things are getting better, and that it’s worthwhile for them to join the effort,” she said. “I want people who are scientists and mathematicians to be involved with us, and for the lay public to understand that if we continue working together, things will get better quicker. That can include donations of funding, or the willingness of patients to participate in clinical trials or allow us to use their tumor specimens to test for proteins and genes so we can optimize our understanding of cancer.”

	“I want people to know,” she said, “that we are committed to having a better future related to the understand ing of cancer.”

	Beth Fand Incollingo is a New Jersey-based writer and editor, and owner of the communications firm Texterity, LLC.

It's hard to tell which moves more quickly: Edith Perez's feet, or her mind.

Racing Against Breast Cancer: A Conversation With Edith A. Perez, MD

		Histopathologic image of gastrointestinal stromal tumor of the stomach. Hematoxylin-eosin stain.

	The strategy of using targeted therapies to attack tumors has demonstrated signifi cant results in the past decade, and biological markers that help clinicians choose which treatment options to pursue for particular patients are attracting increased research interest.

	Here is a summary of 5 key areas in which biomarkers are either already in clinical use or are showing promise as future signposts.

	Established Breast Cancer Marker Explored

	Human epidermal growth factor receptor 2, also known as HER2/neu (ERBB2), is a receptor tyrosine kinase that helps regulate cell survival and proliferation. Extra copies of the 

 gene are found in 20% to 25% of breast cancers, and they cause excess production of HER2, prompting tumors to grow faster and recur more frequently. Overexpression of HER2 also occurs in some ovarian, stomach, lung, and uterine cancers.

	HER2 bulges outside affected cancer cells rather than hiding inside, making it a good target for drugs. Trastuzumab (Herceptin) binds with HER2, suppressing the 

 gene, reducing HER2 production, and blocking signaling pathways. The drug, which is being studied for use in other HER2-positive cancers, also promotes immune response, stimulating the body to attack cancers directly.

	Another HER2-targeting drug is lapatinib (Tykerb), a dual tyrosine kinase inhibitor that disrupts different cell signaling pathways. Unlike trastuzumab, lapatinib is a small molecule that can cross the blood-brain barrier for cancers that have spread there. It binds to mutated 

, where the receptor does not protrude properly from the cell.

	Another monoclonal antibody, pertuzumab, which inhibits dimerization of HER2 with other HER receptors, is in advanced clinical trials. Genentech, a member of the Roche Group, recently announced that the pivotal phase III CLEOPATRA trial demonstrated that the combination of pertuzumab and Herceptin plus docetaxel chemotherapy significantly improved progression-free survival compared with Herceptin and docetaxel alone for patients with HER2-positive metastatic breast cancer.

	The targeted agents are not likely to be effective against breast cancers that do not exhibit an excess of HER2, nor are they effective in all HER2-positive cases. Patients are screened for potential eligibility through immunohistochemistry and either silver, chromogenic, or fluorescence in situ hybridization. 

	Gastrointestinal stromal tumors (GISTs), which are newly diagnosed in 3000 to 6000 people in the United States annually, are associated with several different oncogenes and proteins that can help improve diagnosis and determine treatment for individual patients.

	About 85% of all GIST cases can be attributed to 2 types of mutations: a mutation in the KIT gene and a mutation in platelet-derived growth factor receptor alpha (PDGRFα).

 gene, whose protein products are KIT or CD117, are observed more frequently than the PDGRFα mutation, being found in 80% to 85% of all GIST cases. The most common of those mutations generally respond well to treatment with imatinib (Gleevec), though secondary mutations are often spotted after patients develop resistance to that drug.

	Mutations in PDGFRα occur in about 5% of all GIST cases. Of the 4 common mutations, only the PDGFRα exon 18 mutation in GIST (D842V) confers lowered responsiveness to standard treatments, most often imatinib.

	Mutations in BRAF—a serine/threonine protein kinase involved in cell proliferation, differentiation, and transcriptional regulation&mdash;are rare but deadly. They occur in less than 1% of cases but carry an increased risk of malignancy and resistance to existing KIT/PDGFRα tyrosine kinase inhibitors.

	For the approximately 10% to 15% of patients whose GIST tumors show no abnormalities in any of these proteins, treatment with sunitinib (Sutent), which is the second-line treatment for most GISTs, has been demonstrated to be effective in 1 of 3 patients who are resistant to imatinib.

	Other targeted therapies that have been tested against different types of GIST include sorafenib (Nexavar), nilotinib (Tasigna), and dasatinib (Sprycel). 

	Protein Emerges as Target, Particularly in Lung Cancer

	Epidermal growth factor receptor, also known as ERBB1 or HER1, is a cell-surface receptor protein that is frequently found to be mutated and overactive in lung cancer, colorectal cancer, and glioblastoma multiforme.

	EGFR exists on the cell surface and is activated by binding of its ligands, including epidermal growth factor and transforming growth factor. Mutations involving EGFR can lead to its constant activation and bring about uncontrolled cell division.

	EGFR protrudes from cells enough to make it an attractive binding target for drugs that prevent activation or binding with other cells and stop the cycle of dysfunction. Panitumumab (Vectibix) was approved in 2006 for the treatment of colorectal cancer. Cetuximab (Erbitux) is another EGFR-inhibiting antibody that is also approved for colorectal cancer and for treatment of squamous cell carcinoma of the head and neck.

	Gefitinib (Iressa) and erlotinib (Tarceva) are EGFR inhibitors approved for use against lung cancer. Lapatinib targets both EGFR and HER2 and is often used in combination with trastuzumab in treating breast cancer. These last 3 agents are all small-molecule medications rather than antibodies, so they can be taken as pills rather than injected.

	In April, the American Society of Clinical Oncology issued a provisional opinion about how EGFR testing should guide treatment choices for patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC).

	Patients whose tumors test positive for EGFR gene mutations have higher response rates to erlotinib and gefitinib while tumors that test negative exhibit better responses to standard chemotherapy. Earlier this year, the National Comprehensive Cancer Network similarly called for EGFR testing of patients with NSCLC tumors of all histologies except squamous cell carcinoma.

	Pharmaceutical companies hope to win approvals for new indications of existing drugs and bring new EGFR inhibitors to market to fight other cancers. Most other cancers do not have EGFR as the sole regulator in certain downstream pathways found in breast cancer and lung cancer, so they are resistant to the effects of EGFR inhibitors. 

	Overexpression of the protein products of the 

 gene (KIT or CD117) has been associated with GISTs, testicular seminoma, mast cell disease, melanoma, acute myeloid leukemia, and thymic malignancies. KIT molecules normally live on the outside of various cells, especially hematopoietic stem cells, and serve to identify those cells to antibodies and to communicate with other cells. Mutations of the 

 gene or overexpression of the molecule occur at varying rates in different cancers.

 mutations are found in GIST, collectively appearing in about 85% of all cases. KIT is overexpressed in 87% of thymic malignancies, enough that it might be used in diagnosis to distinguish them from thymoma or lung carcinoma.

 mutations or overexpression respond well to imatinib, which is now approved for use against 10 cancers, with more tests underway. For patients with imatinib-resistant KIT-positive leukemia, there is the kinase inhibitor nilotinib.

	Another antibody that inhibits KIT is pazopanib (Votrient), which was approved for the treatment of renal cell carcinoma 2 years ago. Pazopanib may also be effective in ovarian cancer, soft tissue sarcoma, and NSCLC. The small-molecule KIT inhibitor suntinib is approved as a treatment for renal cell carcinoma, as a second-line medication for GIST, and in advanced pancreatic neuroendocrine tumors. 

	Activity Attracting Keen Research Interest

	This protein, encoded by a gene of the same name and designed to serve as a molecular on/off switch, mutates in some people to increase the virulence of certain cancers and decrease the efficacy of targeted medications.

	Under normal circumstances, the KRAS protein is involved in regulating cell division. Mutations of the gene are associated with lung adenocarcinoma, colorectal carcinoma, mucinous adenoma, and ductal carcinoma of the pancreas.

	The role of KRAS in colorectal cancer has attracted the greatest interest to date, because it can help determine whether patients will respond to a pair of treatments that inhibit EGFR, which is amplified in many cases of colorectal cancer. Panitumumab and cetuximab have produced striking results against many of those cancers. KRAS, however, may work to reduce the effectiveness of either drug and worsens colorectal cancer results by nearly every metric. The activating mutations that predict poor performance—at least 17 distinct mutations have been noted&mdash;occur in about 40% of colorectal cancers.

	Approximately 15% to 25% of patients with lung adenocarcinoma also have 

 mutations. Those mutations are shown to reduce or eliminate responses to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, but it has not been shown whether they reduce response to antibody-based EGFR inhibitors. 

	There is no single regulatory repository for information about cancer biomarkers. US regulatory procedures for approving biomarker tests vary depending upon whether the test is to be sold as a product or a laboratory service; the only FDA-approved biomarkers available for clinical use are protein molecules.

	This list consists of FDA-approved and other clinically used biomarkers compiled from the sources cited below.

			Diagnosis, staging, detecting recurrence, monitoring

			Prognosis, detecting recurrence, monitoring

			Monitoring, prognosis, detecting recurrence, screening for hepatic metastases

Biological markers that help clinicians choose which treatment options to pursue for particular patients are attracting increased research interest.

PERSONALIZED CANCER CARE5 Key Areas Where Biomarkers Point the Way to Personalized Care

		Visualization of a molecular network integrated with a gene profile.

	In recent years, the sequencing of the human genome and advances in supercomputer technology have helped drive hopes that a deeper understanding of the biology of cancer would yield the markers needed to truly usher in the long-awaited era of personalized medicine.

	Biomarkers offer great potential for improving management of cancer at every point from screening and detection, to diagnosis, staging, prognosis, and the assessment of treatment response. Striking advances have been made in several fields, particularly breast cancer, and fresh research suggests significant steps forward in lung cancer.

	Yet progress has been slow in the vast, ever-changing, and controversial frontier of biomarker research, with fewer than 2 dozen cancer biomarkers approved so far by the FDA among the thousands researchers have explored.

	Experts have advanced a brew of reasons for the gap between potential and performance, in a complex field that requires the coordination of a diverse team of pathologists, molecular biologists, and biostatisticians.

	Last year, the AACR-FDA-NCI Cancer Biomarkers Collaborative described a “growing imperative” to modernize the drug development process, and made 27 recommendations in 8 different areas for doing so.

	Meanwhile, the pharmaceutical industry is exploring ways to improve biomarker development, with some industry analysts seeing regulatory issues as a significant sticking point in economically feasible biomarker development (

Industry Testing New Models for Developing Biomarkers

	Sudhir Srivastava, PhD, MPH, the founding chief of the Cancer Biomarkers Research Group at the National Cancer Institute, said in an interview with 

 that one of the challenges in biomarker research is the unrealistic expectations promoted by many study investigators.

	“With almost every paper, even if there is a remote chance of success, you see a press release hyping a discovery, but later on they fail,” Srivastava said. “The public gets so excited about it that they demand we must succeed as soon as possible. But the fact of the matter is, the hype usually does not translate into clinical studies.”

	At the same time, Srivastava said, the scientific community is getting organized and gaining momentum. “The infrastructure is in place to move forward in the right direction. More breakthroughs are a matter of time,” he said.

		Adapted from Mishra A, Mukesh V. Cancer biomarkers: are we ready for the prime time? Cancers 2010; 2:190-208; doi:10.3390/cancers2010190.

	Many researchers who have reviewed the progress made on biomarkers thus far have found much to criticize.

Biomarkers offer great potential for improving management of cancer at every point from screening and detection, to diagnosis, staging, prognosis, and the assessment of treatment response.

August 2011 | Oncology Live®

4 Questions for Johan Lennartsson, PhD

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Racing Against Breast Cancer: A Conversation With Edith A. Perez, MD

PERSONALIZED CANCER CARE5 Key Areas Where Biomarkers Point the Way to Personalized Care

The Great Biomarker Chase: Promise & Pitfalls Along the Path to Personalized Care

In the Pipeline

Industry Testing New Models for Developing Biomarkers

New Clinical Trial Designs Needed for Marker-Based Studies