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Oncologists’ Guide to Genomics

Stay current on the latest trends in genomics and molecular diagnostics for oncology.

Monday, October 22, 2018

Despite months of aggressive treatment involving surgery and chemotherapy, about 85 percent of women with high-grade widespread ovarian cancer will have a recurrence of their disease. This leads to further treatment, but never to a cure. About 15 percent of patients, however, do not have a recurrence. Most of those women remain disease-free for years. Recently, researchers have identified an independent prognostic factor—cancer/testis antigen 45 (Cell 2018;175(1):159).

CT45 is associated with extended disease-free survival for women with advanced ovarian cancer. The team of physicians and scientists found that patients with high levels of CT45 in their tumors lived more than seven times as long as patients who lacked sufficient CT45. Data from long-term survivors averaged 2,754 days (7.5 years), compared to only 366 days for patients who had little or no CT45.

Cancer Proteomics

The study authors attribute their discovery to the emerging field of multi-level cancer proteomics. The researchers relied on minute pieces of tissue acquired from the University of Chicago ovarian cancer tissue bank, which has been following patient outcomes for 20 years.

They used pieces of these samples to isolate, identify, and characterize thousands of proteins. The most interesting of those proteins was CT45. They determined that higher levels of this biomarker were closely linked to treatment success and excellent patient outcomes.

"We believe this is the first example of mass spectrometry-based proteomics leading to the discovery of a prognostic and functionally important cancer biomarker," said co-lead author Ernst Lengyel, MD, PhD, an ovarian cancer specialist and Chairman of the Department of Obstetrics and Gynecology at the University of Chicago.

"Our goal was to find reliable biomarkers that could predict treatment response," said the study's co-lead author Matthias Mann, PhD, Chairman at the Max-Planck Institute. The team quantified more than 9,000 proteins and "identified CT45 as an independent prognostic factor for patients with high-grade serous ovarian cancer."

"Using mass spectrometry, we can identify, for the first time, almost all of the proteins in the tumor tissue of the patients," Mann said. "Our highly sensitive methods now enable us to profile thousands of proteins simultaneously, allowing us to search for the proteins that are critical to the disease by comparing the tissue samples."

It was encouraging for the research team to find the first significant biomarker in tissues from ovarian cancer patients who responded to platinum-based chemotherapy. "CT45," Lengyel said, "was completely unknown until then."

Study Details

To validate their initial findings, the researchers studied tissues collected from more than 200 patients from the University of Chicago. They found no CT45 in 82 of those patient samples, but they found high levels in 42 patients, all of whom had much longer disease-free survival.

A larger study, using sequence data from The Cancer Genome Atlas, confirmed their initial results, leading to their conclusion that "CT45 expression is a novel prognostic indicator for advanced stage high-grade serous ovarian cancer."

Since little was known about CT45's role in cellular functions, the study authors tried to understand the molecular mechanisms that improved responses to chemotherapy. They found that the standard chemotherapy for ovarian cancer, carboplatin, caused DNA damage, particularly in tumor cells expressing high levels of CT45. This lead to cell death in tissue culture and tumor reduction in treated mice.

"We suspect that CT45 plays a major role in the response of tumors to carboplatin. This gives us hope that future strategies that activate CT45 expression in the tumor could make it more sensitive to carboplatin treatment," said Marion Curtis, PhD, a postdoctoral scholar in the Lengyel laboratory.

They also found two peptides from CT45-positive ovarian cancer cells that stimulated a solid immune response against the cancer. T cells collected from a CT45-positive patient with high-grade ovarian cancer were able to kill cancer cells in vitro "in a dose-dependent manner."

"We have evidence that tumor-specific expression of CT45 stimulates the patient's immune system to fight the cancer, as would a virus or bacterial-infected cells," Lengyel added. "Our long-term goal is to find new ways to improve patient outcomes based on these exciting insights."

The clinical implications from this study "could be significant," the authors noted. Expression of CT45 improves the efficacy of platinum-based chemotherapy, and potentially immunotherapy, for patients with advanced stage ovarian cancer. "CT45 may be particularly relevant to long-term survival," they added.

"This study," researchers concluded, also "highlights the power of clinical cancer proteomics to identify targets for chemo and immunotherapy, define their mechanisms, and contribute to the development of effective cancer therapies."

Friday, September 21, 2018

By Joel Diamond, MD, FAAP

Few advances in recent decades have the potential to change health care practice as significantly as genomics and precision medicine. Not surprisingly, oncology is proving to be the standard bearer in the charge.

In recent years, and certainly since the human genome was mapped in the early 2000s, uptake and progress in clinical practice have been swift:

  • Oncologists have greater insight into disease mechanisms, which supports targeted diagnosis and treatment.
  • Rather than viewing cancer as a site-specific disease, physicians now can base clinical decision-making on molecular classifications.
  • These considerations allow treatment to be individualized so therapeutic benefit is achieved faster.
  • Cancer specialists are equipped to prospectively evaluate risk, and likewise can detect the disease and intervene earlier.

The picture is bright and promises to get only brighter as advances in the science of genomics accelerate.

Bringing Genomics Into Workflow

Yet the industry faces one significant barrier: Bringing the value of genomic data into the oncology workflow so physicians can access and use the information at the point of care. Forward-looking health care leaders are seeking an informatics strategy as the basis for ensuring both clinicians and patients are able to leverage the full value of genomic results.

Three factors contribute significantly to this obstacle:

1. Lack of standardized nomenclature. Despite tremendous inroads made by health care IT professionals and policy makers, the industry lacks standardized nomenclature to make information meaningful and useful. Oncology itself presents its own set of challenges. Naming conventions for specific cancers vary significantly. Cancer staging is not reflected consistently across clinical IT software. Other considerations such as toxicity and disease recurrence likewise are not integrated uniformly.

Efforts to standardize genomic nomenclature are even more immature—and vocabularies around molecular immunotherapy lag further still. This is due, in part, to the rapid pace of scientific discovery. The health care industry struggles to understand terms that are already in use, while emerging vocabularies around new concepts like proteomics have yet to be undefined. While it is never easy to "issue" a medical vocabulary (consider the lingering strain surrounding the move from ICD-9 to ICD-10), the task is nevertheless critical for oncology to fully exploit genomics and precision medicine at the point of care.

2. Too much paper and too little foresight. Integrating genomic information into the EHR, where it is readily available for the clinician, is critical if oncologists are to fully benefit from precision medicine.

Right now, precision medicine is in danger of taking a giant step backwards when it comes to electronic data sharing. Incredible amounts of genomic information continue to be communicated via paper, a practice that simply is not sustainable. Obvious inefficiencies aside, paper-based documents greatly limit how the information can be accessed and how it can be leveraged. Genomic information must be shared as discrete data so it can be mined and applied across treatment and research activities, and so it can be referenced and factored as physicians follow patients longitudinally.

Oncology thought leaders increasingly talk about the value of application platforms like SMART on FHIR—and they are, without a doubt, a necessary next step. But, alone, they are insufficient in propelling the industry where it needs to go. We have likewise learned from the past that waiting for government consensus on industry IT standards requires patience. The wheels of progress turn slowly.

Instead, oncology and other specialists can achieve "speed to value" by considering a different informatics strategy, including implementation of existing vendor-neutral solutions that consume genomic data from any knowledge base or source, and deliver it directly into any EHR.

3. Data silos. Health care is in danger of building another generation of data silos around genomics, repeating the mistake made when other clinical information systems emerged. Already, some health systems are exploring disease-specific precision medicine technologies, such as those available to oncology departments. This may prove to be a shortsighted strategy, however.

Consider the disadvantages a precision oncology data silo might represent. Optimal use of genomics in the care of cancer patients is not limited to somatic data. Some cancer susceptibility is tied to germline data—clinicians may benefit from insights contained in epigenetic information as well, for example. In addition, pharmacogenomics supports better clinical decision-making by revealing how a patient might respond to specific medications (e.g., pain or anti-nausea drugs), and whether or not toxicity might be an issue. It also reveals non-cancerous comorbidities and how they are being addressed, which might impact the oncologist's recommended course of treatment.

Adaptive Clinical Trials

Bringing genomic information to the point of care via an intentional informatics infrastructure will enable oncology to make strides in other key areas as well.

Precision medicine holds the promise of dramatically changing clinical trial matching, for instance. Industry leaders are considering the fact that genomics may accelerate a move away from certain randomized clinical trials towards greater reliance upon adaptive trials. Consider the benefit to the patient—and the researcher—if matching began with biology rather than the drug.

When a treatment is intended for patients with specific markers, perhaps only those individuals should be included in the trial. The oncologist, at the point of care, can access the genomic data and refer only those patients most likely to respond to therapy. Why waste clinical resources, as well as the patient's time and possibly quality of life, if the oncologist already knows that the treatment is ineffective, based on biology? This, of course, means patient cohorts would be smaller, and researchers may also eliminate the need for control groups receiving only placebos.

Addressing Disparity

Disparity around which patients do or do not receive genetic testing is rapidly becoming a point of discussion and contention among industry thought leaders. EHRs, as an example, don't enable oncologists (or any physician) to identify at-risk patients easily or effectively. Critical information—like comprehensive family history—is often limited or incomplete and, even when present, typically not stored as discrete data integrated with the workflow and appropriate decision-support tools.

The result of this information gap was perhaps best articulated by Kevin S. Hughes, MD, FACS, Co-Director of the Avon Foundation for Comprehensive Breast Evaluation at Massachusetts General in Boston, in a recent article in the Journal of Clinical Oncology (2017;35:3789-3791): "Our problem, which desperately cries out for a solution, is that huge numbers of high-risk patients who could be identified by genetic testing are instead developing cancer and often dying of that disease."

Bringing access to genomic testing into the workflow would go a long way to save lives because "out of sight, out of mind" affects physicians just like all other segments of the population. If the opportunity to consider the option of genetic testing…and the functionality to order these tests…and the ability to review the results all presented themselves at the point of care, within the workflow, oncologists and all clinicians would constantly be reminded of their option to leverage genomics.

With access to genomics at the point of care, physicians could ensure every patient for whom testing is appropriate would have access.

Few doubt that genomics and precision medicine will soon be recognized as the standard of care in oncology and other specialties.  To reap its full value, however, clinicians must have meaningful access to all genomic and clinical information that could impact testing, diagnostic, and therapeutic decisions. Moreover, it must be available within the workflow and in formats that empower oncologists to leverage it to its fullest potential. To do that, we must evaluate our informatics strategy, and build a precision care platform to meet today's needs and accommodate the discoveries just over the horizon.

JOEL DIAMOND, MD, FAAP, is Adjunct Associate Professor of Biomedical Informatics at the University of Pittsburgh. He is a diplomat of the American Board of Family Practice and a fellow in the American Academy of Family Physicians. He cares for patients at Handelsman Family Practice in Pittsburgh.

Monday, August 20, 2018

Treating early-stage lung cancers with drugs that unleash the immune system's ability to attack malignant cells may hinder tumor growth and improve overall survival, according to new research by Weill Cornell Medicine and NewYork-Presbyterian investigators.

The study suggests that immunotherapy that blocks PD-1—a protein that inhibits immune response to tumors—could be successfully incorporated into early-stage non-small cell lung cancer (NSCLC) treatment (JCI Insight 2018;3(13):e96836). Currently, the FDA has approved these immune checkpoint inhibitors only for late-stage NSCLC cases either alone or in combination with chemotherapy. Treatment is based on the proportion of tumor cells expressing PD-L1, a protein that together with PD-1 triggers the deactivation of the immune response. By initiating this therapy earlier in the disease course, clinicians can take advantage of patients' healthier immune systems before tumors progress or other treatments physically weaken patients.

"The standard of care for early-stage lung cancer is surgery, and removing a localized tumor has a therapeutic benefit. But 50 percent of patients relapse eventually," said senior author Vivek Mittal, PhD, Professor of Cell and Developmental Biology in Cardiothoracic Surgery, and Director of the Neuberger Berman Foundation Lung Cancer Laboratory at Weill Cornell Medicine. "If we could do something in the early stages to generate an active immune response, we might be able to prevent recurrence in the future."

NSCLC comprises about 80 percent of all lung cancers, with a 5-year survival rate of only 15-20 percent. About 20-25 percent of the 220,000 people diagnosed with NSCLC in the U.S. each year present with early-stage disease.

Checkpoint inhibitor drugs are designed to release the immune system's built-in brakes, known as checkpoints, which impede the immune system's ability to attack cancer cells.

"Integrating these drugs into the treatment of patients with early-stage lung cancer, preferably before surgery, can result in a powerful immune response that may persist even after the tumor is surgically removed," said co-senior author Nasser Altorki, MD, Chief of the Division of Thoracic Surgery at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center and the Gerald J. Ford-Wayne Isom Research Professor in Cardiothoracic Surgery at Weill Cornell Medicine. "This will hopefully reduce or prevent the chance of future recurrence of the cancer after surgery."

Focusing on Immune Cells

The study aimed at testing the utility of these drugs in early-stage NSCLC was completed in two parts. First, Mittal and his colleagues evaluated molecular components of the immune system in early-stage NSCLC by comparing tumor and healthy lung tissue samples taken from 20 NSCLC patients treated at Weill Cornell Medicine. All of the patients had been diagnosed with stages I through IIIA of the disease—considered early-stage cases—and hadn't yet undergone non-surgical treatment. The team found that tumor tissues contained large numbers of T cells, indicating an anti-tumor immune response.

However, that immune response was rendered ineffective when the checkpoint proteins, PD-1 on the T cells and PD-L1 on the tumor cells, interacted. This indicated immune suppression in patients—even at this early stage of cancer development.

Next, the researchers treated mice with lung cancer with immune checkpoint inhibitors. The lung cancer in these mice was driven by a mutation in the KRAS gene that occurs in about 30 percent of cases of human lung cancer. There are no FDA-approved targeted therapies currently available for these patients, Mittal noted. "Rodents treated with checkpoint inhibitors lived about 25 percent longer than those not treated with the drugs."

The team found that immune cells called CD4 T cells, which coordinate the immune response by signaling other T cells to collectively fight invaders, grew in number and activity with checkpoint inhibitor treatment. They discovered that treatment also increased the number of CD8 T cells, which directly kill tumor cells. They further showed that loss of both populations led to a diminished response to the drug and enhanced tumor progression. Their data demonstrated that these checkpoint inhibitors are affecting not only the CD8 T cells that do the killing, but also the CD4 T cells that coordinate the response. And more importantly, they work together, which has yet to be appreciated.

This dual approach yielded key insights about how checkpoint inhibitors influence immune system T cells, which recognize and fight invaders.

Few other scientists nationwide are examining the role of checkpoint inhibitors in early-stage NSCLC, Mittal said, and clinical trials in humans are already underway at Weill Cornell Medicine.

"For early-stage lung cancer patients, there's a lot of excitement to begin to look into the effectiveness of immune checkpoint inhibitors," he said. "We need to refine the use immunotherapies, preferably in combination with other therapies to hopefully stop the cancer from coming back."

Wednesday, July 18, 2018

An international team of researchers including University of Southern California (USC) scientists has found scores of new genetic markers in DNA code that increase prostate cancer risk—powerful knowledge likely to prove useful to detect and prevent the disease.

Focusing on DNA of more than 140,000 men worldwide, researchers were able to identify 63 new genetic markers associated with prostate cancer risk. That greatly increases the number of genetic risk regions, bringing the total to more than 170 and moving scientists closer to using genetic information for clinical treatment.

The results will help bridge the gap between cancer research diagnosis and treatment, equipping physicians with tools to screen at-risk patients. The study, based at USC with collaborators worldwide, including the London-based Institute of Cancer Research (Nature Genet 2018;50:928-936).

"This is not a cure, but the information can help to identify men at high risk of developing prostate cancer who may benefit from enhanced screening and future targeted prevention," said Christopher A. Haiman, ScD, Professor of Preventive Medicine at the Keck School of Medicine of USC and a principal investigator for the project.

DNA Analysis

Prostate cancer is the second-most common cancer in American men, with one in nine men being diagnosed in their lifetime, and the third-leading cause of cancer death for men.

To identify genetic markers associated with prostate cancer risk, the researchers used OncoArray, a new DNA analysis, to compare more than half a million single-letter changes in the DNA code of nearly 80,000 men with prostate cancer and more than 61,000 men without the disease. The researchers identified 63 new variants in DNA, which when inherited increased a man's risk of prostate cancer. Each individually had only a small effect on risk, but the combined effect of inheriting multiple variants could be dramatic.

Study Results

The findings show that 1 percent of men at highest risk were 5.7 times more likely than the general population to develop prostate cancer—an increase in absolute risk from about one in 11 to one in two. The researchers were able to identify that high-risk population because it inherited many of the harmful genetic variants.

And the top 10 percent in the population risk distribution were 2.7 times more likely to develop the disease than the general population—corresponding to a risk of almost one in four.

With the addition of dozens more genetic markers to previously known markers, almost 30 percent of a man's inherited risk of prostate cancer has been accounted for—which may now be enough to start using the information in practical testing strategies, according to the study.

"We now have the ability to identify men at greater risk of prostate cancer," Haiman noted. "We now need to figure out how to use this genetic information to prevent the disease."

These genetic markers may also one day help guide treatment for prostate cancer. Many of the new genetic variants were found in the region of genes involved in communication among cells of the immune system and other cells in the body. This implies that genetic errors in immune pathways may be affecting prostate cancer risk, which could have important implications for potential future treatment of prostate cancer with immunotherapies.

The study comes with caveats. For example, it focuses on white males only. Haiman said parallel studies are underway to study other ethnic groups. For reasons unknown, African-American men face a 74 percent greater risk of prostate cancer than in non-Hispanic white men, according to ASCO.

The global scope of the project enabled researchers to collect massive amounts of DNA and compare genetic variants, which was key to achieving critical mass to make new discoveries. About 200 researchers worldwide participated, including experts from the U.S., U.K., Sweden, Canada, Germany, China, Finland, Belgium, Spain, Poland, Malaysia, and Croatia, among others.

Wednesday, June 20, 2018

By Catlin Nalley

How can oncologists address treatment resistance in brain cancer?

"This is one of the key questions the cancer research community is currently trying to solve," noted Damian A. Almiron Bonnin, MD-PhD candidate at the Geisel School of Medicine at Dartmouth. "High-grade gliomas are the most common and aggressive primary brain tumors in adults, and unfortunately, current medical therapies are largely ineffective against this type of tumor."

Initially, targeted therapy with receptor tyrosine kinase (RTK) inhibitors appeared like a promising approach in this type of tumor, he explained. "However, despite abundant evidence implicating RTKs, including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma, the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance.

"Despite the initial responsiveness of high-grade gliomas to these state-of-the-art therapies, these tumors virtually always become resistant and eventually recur," Almiron Bonnin continued. "This is one of the reasons why [high-grade gliomas] have one of the worst survival rates (less than 2 years)."

Mechanisms of Resistance

Researchers at Dartmouth's Norris Cotton Cancer Center, along with Almiron Bonnin, are looking for new approaches to prevent brain tumors from becoming resistant to anti-tumor drug treatment Almiron Bonnin and his team found that "insulin signaling functions as a 'tumor-growth signal' in brain cancer cells that have been treated with a targeted therapy, which allows the tumor to grow despite continued treatment (Mol Cancer Ther 2017;16(4):705-716).

"In this study, we have successfully identified a pathway that mediates the resistance of the most aggressive brain tumors, glioblastoma multiforme, to targeted anti-tumor drugs," Almiron Bonnin noted. "Importantly, there are drugs currently available that can block this pathway to resistance."

In order to study the mechanism of resistance to RTK inhibition in high-grade gliomas, researchers utilized a "mouse model of glioma that we develop in our lab to produce proneural glioblastomas as a direct result of inappropriate PDGF/PDGFR activation in glial cells," Almiron Bonnin explained. "We engineered this mouse model so that the PDGF/PDGFR could be turned on or off at the discretion of the investigator to mimic important aspects of the therapeutic activity of RTK inhibitors.

"We analyzed the response of these tumors to RTK inhibition utilizing different biomolecular techniques such as immunoblotting arrays, microarrays, western blotting, RT-PCR, cell culture, and immunohistochemical techniques," he elaborated. "To dissect large datasets produced by these experiments, we used several bioinformatics approaches. With the insights and knowledge we gained from these computational studies, we queried the cancer genome atlas database which contains clinical and genomic data of large cohorts of glioblastoma multiforme patients."

This study, according to Almiron Bonnin, "will lead to a better understanding of cancer mechanisms of drug resistance that will hopefully translate into improved clinical therapies for the treatment of high-grade gliomas."

The next step for researchers is to pursue a clinical trial to test the efficacy of this new approach on patients diagnosed with proneural glioblastoma with PDGF/PDGFR alterations.

"An important concept this study highlights was that when signaling from a specific secreted factor is blocked (such as PDGF), an alternative secreted factor can maintain the oncogenic functions of the secreted factor that was blocked (such as insulin and IGF1)," Almiron Bonnin added. "Multiple studies suggest that the capacity of cancer cells to secrete a wide range of soluble factors with redundant functions significantly limits the efficacy of current antineoplastic treatments including targeted therapies.

"Therefore, targeting the secretory mechanisms of cancer cells could potentially simultaneously reduce the levels of multiple prooncogenic secreted factors and, consequently, diminish cancer drug resistance and increase patient survival."

Glioma Stem Cells

The cancer stem cells within glioblastoma multiforme tumors are thought to be important drivers of resistance and recurrence.

"To put it simply, if you eliminate most of the tumor with standard treatments, but leave even one cancer stem cell behind, that cell could, in theory, give rise to an entire new tumor," explained Almiron Bonnin. "Therefore, making sure these cells are being effectively targeted is an important goal of cancer research."

According to Osuka, et al (J Clin Invest 2017;127(2):415-426), "certain glioma stem cell (GSC) populations display higher intrinsic chemo- and radioresistance than non-GSCs, indicating that a fraction of the primary tumor GSC population can survive the initial therapy and initiate recurrent tumor formation. GSCs can overcome the damage induced by chemotherapy and radiotherapy not only through innate properties (e.g., genetic heterogeneity), but also through adaptive resistance pathways.

"Because of their tumor-sustaining capacity and resistance to conventional therapies, GSCs represent an important target in the quest to find more effective therapies for GBM."

Almiron Bonnin's team recently uncovered a therapeutic approach that targets aggressive brain cancer stem cells (Oncogene 2018;37(8):1107-1118). "The presence of glioma stem cells within high-grade gliomas is one of the reasons they are so difficult to treat," noted Almiron Bonnin, in a statement. "In this study, we have successfully identified a secretion-mediated pathway that is essential for the survival of glioma stem cells within aggressive brain tumors."

"Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew," study authors wrote. "We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 axis to enhance the self-renewal of glioma stem-like cells."

Pharmacological blockade of the identified pathway leads to a noticeable reduction in tumor growth, according to Almiron Bonnin. "Being able to target the cancer stem cells within these tumors, like we did here, could potentially improve response to current chemotherapies and prevent recurrences, which would translate into an increase in patient survival rates."

Looking forward, the team is finalizing the preclinical experiments needed to initiate the clinical trial that will test drugs targeting glioma stem cells of patients diagnosed with this type of tumor.

Ongoing Research

The oncology community continues its efforts to unlock a better understanding of treatment resistance in brain cancer and new ways to combat it.

"Studies like ours demonstrate that it is not enough to target primary drivers of tumorigenesis such as PDGFR in proneural glioblastomas, for example," Almiron Bonnin concluded. "Effective anticancer therapies will have to be thoughtfully designed to also target the appropriate mechanisms of resistance, which vary depending on specific tumor types and therapeutic agent utilized."

Catlin Nalley is associate editor.