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The concept of personalized medicine is not new. As doctor Ogan Gurel points out in an article published in 2007 on 

, personalized medicine has been practiced since ancient times in the form of surgery. He astutely notes, “While an abdominal or scalp incision has a fairly generic codification, once that surgeon makes that fateful cut, the operation becomes unique to that patient. Every medical student learns from the first days of anatomy about anomalous hepatic arteries, that an appendix can even be found on the left-hand side of the abdomen, and so on. Every patient is unique.” As researchers started to unravel genomics, just how unique the human species is, down to the molecular level, began to surface. Although surgeons may have represented the epitome of personalized medicine throughout the ages, physicians across all specialties have always tried to tailor their patients’ treatments based on all the clinical information available to them; however, the information was always limited to the visually obvious, such as physical signs and symptoms, and, eventually, laboratory, radiographic, and pathologic data. Following the mapping of the human genome in 2003, considerable progress has been made in understanding the “person the disease has” rather than “what disease the person has,” allowing more targeted therapies to be developed for complex diseases, such as cancer, thereby moving away from the “one size fits all approach.”

Just a few years ago, researchers predicted we’d one day be able to identify those patients for whom a drug would be effective at the outset, rather than having to go through a process of trial and error, which is costly and mentally and physically taxing for patients. This prediction has come true on many disease fronts, especially cancer, and the field of pharmacogenomics has exploded. In “The Case for PersonalizedMedicine,”

 put out by the Personalized Medicine Coalition, Paul Stoffels, MD, Company Group Chairman, Global Pharmaceutical Research and Development, Johnson & Johnson, is quoted as saying “The pharmacogenetic approach is used for almost every compound we develop... We are now looking for markers for response and for adverse events to better understand our current compounds and to improve the effectiveness of future compounds.” As demonstrated by the vast number of abstracts presented at the recent 2009 ASCO Meeting, which had “Personalizing Cancer Care” as its theme, it is clear that considerable investments are being made to decode gene signatures and develop targeted therapies, including vaccines, to combat diseases that historically have been difficult to treat. So, how far have we truly come, and what does the future hold? Let’s examine a few of the recent findings presented at the 2009 ASCO Meeting regarding melanoma and breast, gastrointestinal, hematologic, lung, prostate, and thyroid cancers, which could eventually translate to more effective treatment options for more patients with cancer.

According to the American Cancer Society, the incidence of melanoma is increasing more quickly than that of other cancers. It is 

 that 68,720 people will receive a melanoma diagnosis in 2009, with 8,650 succumbing to their illness

. There has been a paucity of treatments for melanoma, and the majority of patients do not respond to chemotherapy. A new study that examined the tumor tissue of 21 patients with metastatic melanoma—some of whom responded to treatment and some of whom did not&mdash;found eight genes that one day may be able to determine which patients will respond to treatment (

). To isolate these genes, researchers used a mathematical tool called Neural Network Analysis to survey over 25,000 genes and regulators that turn the genes on and off. According to Hussein Tawbi, MD, University of Pittsburg, who presented the findings, “The genes that we isolated in this study could be potential targets for new therapies down the road,” noting “this work takes us one step closer to doing so.”

Vaccines are gaining ground in the treatment of numerous cancers, and a randomized, phase III clinical trial has for the first time shown promising results for the use of a vaccine in treating advanced melanoma (

Considerable advancements in personalized medicine have been made on the breast cancer front for both prevention and treatment. Tests to determine the presence of BRCA1 and BRCA2 mutations, both of which considerably increase the risk of developing breast cancer, allow more preventative measures to be taken in women who are found to be at high risk, such as increased frequency of monitoring, chemoprevention, or prophylactic surgery. There are already over 1300 genetic tests on the market, testing for a wide range of conditions or for use to guide treatment in the disease setting.

One test that has been widely adopted for breast cancer is Onco

DX. This assay was recently used in a study that compared 347 male breast cancers with 82,434 female breast cancers to assess the gene signatures of male versus female breast cancers (

). Although the study found many similarities between the sexes, including comparable low, intermediate, and high risk of recurrence when using the Recurrence Score, there were also a few differences. Male patients tended to be older, were less likely to have lobular breast cancer, and had a higher mean expression of the hormone receptor genes. According to George Sledge, MD, Indiana University, Indianapolis, lead investigator of the study, “[these] results support the clinical utility of Onco

DX in providing quantitative information to help guide treatment decisions for men with breast cancer.”

Numerous advancements have been made in developing targeted therapies for breast cancers that are difficult to treat or do not respond to traditional therapies, such as HER2-positive breast cancer, which affects approximately 20% to 30% of women with breast cancer

. In these patients, targeted therapy with trastuzumab (Herceptin) has beenfound to be effective. Trastuzumab works by attaching to HER2 proteins and blocking the chemical signals that stimulate tumor growth. Studies have shown that trastuzumab reduces the risk of recurrence by about 50% in early-stage HER2-positive breast cancer, and a trastuzumab-based therapy is also being investigated for patients with more advanced disease, who have had few to no options available to them. The results of a phase II study revealed a new agent, known as trastuzumab- DMI (T-DMI), to be effective in patients with advanced HER2-positive breast cancer (

). The study enrolled 112 US patients whose breast cancer had progressed despite treatment with two or more HER2-targeted therapies. Of these patients, 35% experienced tumors shrinkage or disease stabilization for 6 months after receiving T-DMI, which represents the first treatment for breast cancer in a new class of drugs known as antibody-drug conjugates. By having trastuzumab deliver DMI directly to the tumor, the agent is able to specifically target the cancer cells, maximizing the clinical benefit while minimizing side effects. In February 2009, a phase III study (EMILIA) evaluating T-DMI for second-line advanced HER2-positive breast cancer was initiated, which will compare T-DMI monotherapy with lapatinib plus capecitabine. This 

Another form of breast cancer that has been particularly difficult to treat is triple- negative disease. A recent phase II clinical trial of BSI-201, an investigational cancer drug that represents a new class of agents known as PARP1 (poly[ASP-ribose] polymerase) inhibitors, showed significant clinical benefit in patients with this form of breast cancer (

The impact of imatinib mesylate (Gleevec) on gastrointestinal stromal tumors (GIST) has been profound, with up to 80% of patients showing a response; however, a small subset of patients with GIST have little or no response to this therapy. Researchers at Fox Chase Cancer Center, Philadelphia, have uncovered a genetic pattern that may help clinicians predict how their patients will respond to imatinib. The researchers followed 63 patients enrolled in the Radiation Therapy Oncology Group (RTOG) trial, who received imatinib before surgery for primary or recurrent tumors. Using tumor samples collected before and after the patients were given the drug, the researchers studied which genes were active in the tumors and then compared these profiles of gene expression to how well the tumors responded to short-term imatinib treatment. The researchers found 38 genes that were expressed higher in tumors that did not respond to imatinib. Of these, 20 were KRAB-zinc finger genes that encode for proteins that typically act as transcriptional repressors of other genes; 10 of these 20 were isolated on a single section of chromosome 19. While these findings are not yet applicable at the bedside, they indicate that future studies are warranted and that an agent that alters the activity of the KRAB-zinc finger proteins may improve the efficacy of imatinib therapy in these patients.

	In 2008, the evidence for a correlation between stomach cancer and HER2 expression started to mount, and just as in breast cancer, HER2-positive stomach cancers had been solidly correlated to more aggressive disease and poorer outcomes. It is estimated that approximately 22% of stomach tumors are HER2-positive. Patients with advanced disease have a poor prognosis, with a median survival time after diagnosis of approximately 10 months using currently available therapies. The findings of a new international, phase III study, known as ToGA, found that when trastuzumab was added to chemotherapy with capecitabine (Xeloda or intravenous 5-FU and cisplatin, the risk of death was reduced by 26%, with survival extended by about 3 months compared with those not receiving trastuzumab; the higher the level of HER2 expression, the greater the benefit, with median survival reaching 16 months in patients with higher levels. According to Eric Van Custem, MD, University Hospital Gasthuisberg, Leuven, Belgium, the principle investigator, who presented these findings, “There is a high unmet need in advanced stomach cancer. The data from the ToGA study show that targeted therapy with Herceptin delivers a major advance in this therapeutic area.”

In the early 20th century, leukemia and lymphoma were the only two diagnoses available when it came to hematologic cancers. Currently, cellular and genetic analyses can distinguish between 38 types of leukemia and 51 types of lymphoma, allowing for more effective treatments. As a result, there has been considerable improvement in survival for patients with many of these blood cancer subtypes

	Based on an 8-year, randomized, controlled, phase III clinical trial, a new patient-specific vaccine, known as BiovaxID, has been shown to considerably improve disease-free survival in patients with follicular non-Hodgkin’s lymphoma, with patients receiving the vaccine experiencing a median-disease free survival of approximately 44 months compared with approximately 30 months for those who received the control vaccine (

). The vaccine works by using the patient’s own tumor cells to stimulate the immune system. 

Maintenance therapy is a relatively new concept in non-small cell lung cancer (NSCLC). A recent, randomized, double-blind, phase III lung cancer trial sought to determine whether adding erlotinib (Tarceva) to bevacizumab (Avastin) maintenance therapy in patients with advanced NSCLC would improve outcomes (

). The study randomized 768 patients with nonsquamous histology to receive bevacizumab plus erlotinib or bevacizumab plus placebo. Patients treated with the erlotinib-bevacizumab combination saw their cancer growth slow more than those in treated with bevacizumab alone, with patients experiencing a progression-free survival of 4.8 months versus 3.7 months for those not receiving erlotinib. This 29% reduced risk of disease progression for patients who took the erlotinib and bevacizumab combination compared with bevacizumab alone demonstrates that maintenance therapy with two targeted therapies may be superior to one.

Another recent study found that adding the experimental targeted therapy vandetanib (Zactima) to docetaxel (Taxotere) improves progression-free survival in advanced NSCLC patients who experience progression after first-line treatment (

). The phase III trial randomized 1390 patients who had previously been treated with chemotherapy to receive docetaxel plus vandetanib or docetaxel plus placebo. After a median follow-up of 12.8 months, patients in the vandetanib group experienced a 21% reduction in the risk of disease progression compared with those in the placebo group. The vandetanib arm had a median progression-free survival time of 17.3 weeks versus 14 weeks in the control arm. This study is the first phase III trial to show that adding a targeted therapy to second-line chemotherapy with docetaxel results in a clinical benefit for patients with NSCLC. According to Roy S. Herbst, MD, PhD, University of Texas MD Anderson Cancer Center, and the study’s lead investigator, “In a disease as heterogeneous as lung cancer, the need to target multiple pathways has become clear—hence, this agent targeting two key pathways critical for NSCLC growth and metastasis is novel and could play a key role.” He indicated that the drug could be important for the future management of this disease.

Two important prostate cancer studies conducted at Fox Chase Cancer Center were released at ASCO. The first identified a genetic marker that may predict the early onset of prostate cancer (

). Over 50% of prostate tumors carry a fusion gene called TMPRSS2-ERG. Recently, scientists reported that a single nucleotide polymorphism, called Met160Val SNP (also known as rs12329760), is associated with gene fusion, and patients who carry the T allele of Met160Val are more likely to have a prostate tumor with the gene fusion than those who have the C allele. Researchers at Fox Chase genotyped 631 men enrolled in the institution’s Prostate Cancer Risk Assessment Program to determine if the T allele is clinically relevant in men who are at high risk of developing prostate cancer. While differences in the distribution of alleles were observed between black and white patients, the risk allele did not have a major contribution to disease development in either of these patient cohorts; however, when the risk allele was evaluated in 183 white men with a family history of prostate cancer, these patients were found to have a more than two-fold increased risk of developing prostate cancer. Additionally, more men carrying the high-risk allele experienced earlier onset of prostate cancer compared with men not carrying the risk allele. Researchers are planning to see if the association holds up in a larger white patient population and to assess whether a similar association between the T allele and prostate cancer may exist in black men with a family history of this disease. According to Veda Giri, MD, an investigator of the study, “Genetic testing for prostate cancer is not yet clinically well characterized as it is for breast, ovarian, and colon cancer. Markers such as this one are useful because they may help clinicians distinguish between men who are at risk for earlier onset of disease where intensive screening approaches can be discussed.”

The second study presented was a long-term study that showed prostate cancer recurrence can be predicted by low oxygen levels in the tumors (

). While researchers have long known that hypoxia in tumors is a risk factor for radiation resistance in solid tumors, with numerous studies having been conducted on this subject, this study provides more long- term data to validate the link between hypoxia and radioresistance. To monitor the amount of oxygen the prostate tumors and the surrounding normal healthy tissue were receiving, researchers built a custom probe, which was used on 57 patients with low or intermediate risk of cancer just before undergoing a form of localized radiotherapy. Patients were tracked over time to determine whether there was a correlation between the amount of oxygen in the prostate tumor relative to the muscle tissue at the time of therapy and whether there was an increase in prostate-specific antigen (PSA) levels. Of the patients, eight experienced an increase in PSA levels after prostate cancer treatment, which was defined as an increase of 2 ng/mL above the lowest PSA reading after brachytherapy. Overall, average muscle oxygenation of normal tissue was 12.5-times higher than that of the tumor (30 mm Hg versus 2.4 mm Hg). Using a statistical model that accounted for such risk factors as tumor grade, PSA level, and tumor size, the investigators determined that hypoxia was a significant independent predictor for an increase in PSA levels, and potentially tumor recurrence. According to Aruna Turaka, MD, lead author of the study, “the future goal is to interpolate that to relate to the expression of molecular markers [such as hypoxia-inducible factor-1-alpha] and attack those tumors with dose escalation radiation oncology strategies and targeted agents.”

Thyroid cancer is more common in women, and its incidence appears to be increasing. Approximately 37,000 new cases and 1590 deaths were 

. Although patients with thyroid cancer generally have a good prognosis, with the vast majority of patients responding to surgery and follow- up treatment with radioiodine, a small subset of patients (about 5%) experience rapidly progressing, life-threatening disease that does not respond to conventional treatment. An ongoing study from the Mayo Clinic has found that use of pazopanib—a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1,-2, and-3; platelet-derived growth factor receptor-

; platelet-derived growth factor receptor-ß; and C-kit—which inhibits the growth of new blood vessels, provided dramatic benefits for some patients with aggressive differentiated thyroid cancer (

). The study initially included 37 patients, of whom two-thirds had their tumors shrink or stop growing following treatment. The trial has been conducted for over a year, and researchers have yet to determine the long- term effects of the drug, including whether it will have a clinically significant impact on survival. Pazopanib is also being investigated for medullary and anaplastic thyroid cancer and advanced kidney and ovarian cancers.

According to research conducted at the University of Pennsylvania, sorafenib (Nexavar) is another agent that has shown promise for treating thyroid cancer that is resistant to radioactive iodine. Like pazopanib, sorafenib inhibits the growth of blood vessels. An interim analysis of this trial was 

, and the updated results were presented at ASCO. The latest data indicate that responses to sorafenib translated into a median overall survival of more than 140 weeks, a three- fold improvement over doxorubicin (

). Based on the results of this and other phase II trials, the National Comprehensive Cancer Network Clinical Guidelines now recommend the use of sorafenib for patients with radioactive iodine- refractory thyroid cancer who are not able to enter clinical trials. According to Marcia S. Brose, MD, who presented the results of the sorafenib study, “This is the first significant progress in 30 years, since doxorubicin was approved in 1974, which is toxic and produces responses in only 5% of patients.”

The global cancer burden continues to increase, and it is expected to triple by 2030. Fortunately, the arsenal to combating cancer is becoming increasingly powerful through advances in pharmacogenetics, nanotech, biotech, and robotics, as well as the increased understanding of the distinct biology of various cancers and their subsets. Based on how rapidly each of these sciences is evolving and medical technologies are converging, it may not be too farfetched to envision us in the very near future knowing our medical prospects without having to consult a crystal ball, allowing us to have greater control over our individual and collective medical destiny.

Articles

The concept of personalized medicine is not new. As doctor Ogan Gurel points out in an article published in 2007 on WTN News, personalized medicine has been practiced since ancient times in the form of surgery. 

Personalized Medicine: What does the future hold?

	In the April 10, 2009 issue of Science, Dr Xiong and colleagues published their promising findings regarding secondary glioblastoma multiforme (GBM), one of the most deadly cancers. According to the authors, 75% of low grade gliomas and secondary GBMs have mutations in the isocitrate dehydrogenase-1 (IDH1) gene, resulting in a reduced level of a compound called α-ketoglutarate (α-KG). Low levels of α-KG promote tumor growth in part because of induced HIF-1α pathway that leads to increased nutrient and oxygen supplies to the tumor. Dr Xiong and colleagues discovered that when an α-KG analog is added to the tumor cells, these effects caused by the mutant IDH1 gene are reversed.

1) How did you and your team discover the α-KG compound? 

	Was it one of many compounds tested? The α-KG analog has been described in the literature, and after chemical modification, α-KG can enter the cells. The discovery that tumor- derived mutations in IDH1

	gene reduce the catalytic activity and the level of α-KG led us to test whether adding the α-KG analog back to the cultured cells would reverse the effect caused by the mutant IDH1. Although several α-KG analogs are reported in the literature, we have only tested one thus far.

2) Can you tell us a little bit about the effects you observed when α-KG was added to tumor cells? 

	We’ve only tested the effect of α-KG analog in cultured tumor cells, not yet in primary tumors. The test was relatively straightforward: tumor-derived mutations in IDH1 reduced the catalytic activity of IDH1 enzymes, resulting in a decrease of its product, α-KG. A decreased α-KG is known to cause stabilization, resulting in an accumulation of HIF-1α, which is a transcription factor that regulates many genes involved in nutrient and oxygen supplies. We used the level of HIF-1α as the test and found that the α-KG analog can reverse the accumulation of HIF-1α caused by the expression of the IDH1 mutant.

3) Are you working on developing a mouse model to test α-KG as a treatment for secondary GBMs, and, if so, when do you anticipate being able to start conducting this study?

	 Also, should such studies go well, how long do you think it would be before such treatments become available to patients with secondary GBMs? We are currently working on developing a mouse model based on this discovery, and one of the major goals of developing this model is to test α-KG analog as a treatment for low grade gliomas and secondary GBMs. If things move well, we anticipate having the mouse model in less than 2 years, and the subsequent test of the α-KG analog would take about a year. In the meantime, we are in discussions with clinical doctors and experts from medicinal chemistry on how to move this finding to the bedside more quickly for patients.

4) Based on your preliminary results, what effect on survival do you think α-KG may have for secondary GBM patients with the IDH1 mutation?

	It’s difficult to predict. Given the highly restricted spectrum of the IDH1 gene mutation (only found in low grade glioma and secondary GBM, not in many other types of tumors examined), there is a reason to expect a strong effect if we can develop an α-KG drug and figure out a way of deliver it to the right place in patients.

5) Your study was conducted in collaboration with researchers and students at Fudan University in Shanghai, China. Were there any challenges and/ or benefits in working with a team located so far away?

	The actual experiments were carried out in Fudan University, and such a long distance did pose some new challenges to me and my colleague, Dr. Kun-Liang Guan from UCSD. Fortunately, both the junior faculty and graduate students who worked with

	us are highly motivated and skillful. One unique aspect of this study is the terrific collaboration among the faculty with different expertise, including biochemistry, cell biology, protein structure, and tumor biology.

 about what Yue Xong, PhD, and his team are doing.

The beat on the people, devices, trends, and companies shaping healthcare... with Yue Xiong, PhD, Professor of Biochemistry and Biophysics, UNC Lineberger Comprehensive Cancer Center.

June 2009 | Oncology Live®

Personalized Medicine: What does the future hold?

5 questions with Yue Xiong