Genomic navigators key to proper interpretation of sequencing data

Dramatic advances in the quest to identify genetic mutations that drive cancer growth have provided the scientific community with an unprecedented understanding of how to diagnose, treat or prevent malignancies.

In the past year alone, researchers with The Cancer Genome Atlas — the largest whole-genome sequencing program in the United States — have heralded breakthroughs identifying potential treatment targets in acute myeloid leukemia, lung adenocarcinoma, bladder cancer, ovarian cancer and glioblastoma.

The progress comes with a price, however — both in terms of financial investment and the time that front-line clinicians must invest to stay abreast of each new discovery that offers the promise of personalized cancer treatment.

“Even those of us who do this for a living don’t always know what to do with much of the genetic and genomic information that is potentially available,” Elena Martinez Stoffel, MD, MPH, director of the cancer genetics clinic at University of Michigan Health System, told HemOnc Today. “Keeping up with this field is a full-time job.”

Some support mechanisms are in place. Genetic counselors have long been a key piece of the treatment puzzle, but their role traditionally has been to help patients understand inherited risk factors and guide them through the testing process. Tumor boards also have become increasingly prevalent, helping clinicians with diagnosis and decision-making.

Still, the sentiment expressed by Stoffel and echoed by others in the field has prompted speculation about whether a new specialty — genomic navigation — will become a necessary intermediary between the laboratory and the bedside to help oncologists and hem/oncs better understand the implications of mounting genomic data and apply them to patient care.

“My feeling is that we do need a navigator — either human or an automated system — to guide us,” Jean Claude Zenklusen, MS, PhD, director of The Cancer Genome Atlas Program Office, said in an interview. “There is no way an everyday clinician who sees 30 or 40 patients a day can be responsible for all of their treatment decisions, in addition to the overwhelming amount of genetic information that is available.”

Potential solutions may take different forms.

“Given the large amount of data that genomic testing generates and the associated growing scientific literature, the solutions to this information-management challenge will not be solely human solutions,” Mary Nesline, MS, director of genomics clinical support informatics at Roswell Park Cancer Institute told HemOnc Today. “There are systematic approaches and informatics tools that can help ferret out nonrelevant information so that the report that goes to an oncologist is not intimidatingly long or complex.”

HemOnc Today spoke with several leaders in the field about the rapid acceleration of genomic sequencing, the challenges it poses to clinicians, the likely evolution of genetic counselors and tumor boards, and the need for additional resources to interpret genetic and genomic data.

Rapid growth of testing

In the early stages of genomic sequencing, researchers hypothesized that a few mutations served as the drivers for most cancers.

In the early 2000s, however, researchers began to realize the number of mutated genes that influence cancer development and progression far exceeded early expectations.

In a study published in Nature in 2007, Greenman and colleagues cited figures that were — at the time — astonishing. They reported more than 1,000 somatic mutations found in 274 megabases of human DNA, corresponding to coding exons of more than 500 protein kinase genes in 210 different cancers.

“Systematic sequencing of cancer genomes, therefore, reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated,” Greenman and colleagues wrote.

Inherited mutations play a major role in 5% to 10% of all cancers, and researchers have identified genetic mutations associated with more than 50 hereditary cancer syndromes, according to a fact sheet produced by the NCI.

Most clinicians are familiar with commonly occurring mutations, such as those that occur in the BRCA1, BRCA2, TP53 and PTEN genes. Other mutations — such as those associated with Lynch syndrome, Wermer syndrome, Von Hippel-Lindau syndrome — are less broadly understood.

Consequently, the NCI encourages patients to speak with professionals trained in genetics before deciding whether to undergo genetic testing. This strategy ensures patients and their families understand the risks, benefits and limitations of genetic testing. Expert consultations post-testing also help patients understand their results and ensure they have access to support groups and other appropriate resources.

Patients, however, are not the only ones who face challenges.

Best practices and Level I evidence serve as the foundations of cancer treatment. When clinicians become overwhelmed with genetic data — and do not know how to apply it to practice — there can be consequences.

“Ordering and receiving information, when neither the clinician nor the patient has any idea what should be done with it, can lead to pitfalls,” Stoffel said. “We know a lot about certain genetic conditions, but there are gene alterations that can be detected through next-generation sequencing that we don’t know a lot about — and we don’t know how to treat. This can cause anxiety among clinicians as well as patients.”

A study published earlier this year in the Journal of Clinical Oncology illustrated that anxiety.

Stacy W. Gray, MD, a medical oncologist at Dana-Farber Cancer Institute, and colleagues surveyed 160 physicians who practiced at Dana-Farber Cancer Institute/Brigham and Women’s Hospital at the initiation of Profile, an institution-wide genomic database project. Survey respondents included medical oncologists (57%), surgeons (29%) and radiation oncologists (14%). The majority of respondents (83%) were research principal investigators.

Twenty-two percent of respondents indicated they were “not very confident” or “not confident at all” in their knowledge of genomics. Fourteen percent indicated they had little to no confidence in their ability to explain genomic testing to patients, and 26% expressed little to no confidence in their ability to use genomic testing results as a basis for treatment decisions.

“Some physicians want testing for almost all of their patients and other physicians plan to test very few, if any, patients,” Gray told HemOnc Today when the study was published. “These findings, combined with the finding that not all physicians were confident in their knowledge about genomics or ability to make treatment recommendations based on genomic data, highlight the fact that it is unlikely that this kind of test will be used in routine cancer practice in the near future.”

Clinicians’ responsibilities

As the volume of genetic and genomic data grows, the responsibilities front-line clinicians will bear regarding interpreting that information will evolve. The only question is how.

“We can’t possibly expect every oncologist to be as knowledgeable as a genetic expert,” Stoffel said. “Cancer genetics is a field in and of itself. Studies done as far back as the 1990s have shown that clinicians can sometimes misinterpret genetic results. There are high stakes here from a patient care perspective and a medical legal perspective.”

Davendra Sohal, MD, MPH, associate staff physician in the department of solid tumor Oncology at Cleveland Clinic, agreed.

“It used to be one mutation test and one drug. Now, there are 200 mutation results and there are not always drugs [for those mutations],” Sohal said. “Doctors are scratching their heads. They often do not have access to ‘Drug X’ to treat ‘Tumor Y,’ and there are no trials open to test ‘Drug X’ in ‘Tumor Y.’ It is a big problem.”

For now, regardless of how oncologists receive genetic data, they often are responsible for synthesizing them and applying them to clinical decision-making.

However, that will change soon, according to Robert D. Daber, PhD, director of research and development and director of cancer genetics at BioReference Laboratories Inc., and former director of clinical genomics at the Center for Personalized Diagnostics at University of Pennsylvania’s Perelman School of Medicine.

“The clinician will still be the patients’ primary point of contact, but given the expanding knowledge, patient care will rely on a team of experts,” Daber told HemOnc Today. “As time goes on, clinicians won’t have all that knowledge, nor will they be responsible solely for it.”

Laboratories that conduct genomic testing increasingly will be expected to help physicians interpret the resulting data and to guide them with regard to therapeutic implications, Nesline said.

“Just because high-throughput technologies can be used to test hundreds of genes or the entire genome doesn’t mean that results that have little or no clinical utility should be reported back to clinicians,” she said.

Role of genetic counselors

The question of whether some type of navigator or interpreter is necessary to help front-line clinicians understand genomic data is not up for debate, Howard McLeod, PharmD, medical director of the DeBartolo Family Personalized Medicine Institute at Moffitt Cancer Center, told HemOnc Today.

“There are going to be results of tests that most clinicians will be very comfortable interpreting or applying to patients,” McLeod said. “For others, they will need that expert advice.”

Genetic counselors likely will be more involved, moving beyond a role that requires them to translate test results for patients into one that increasingly provides insights that clinicians can use to establish appropriate treatment plans.

In a study published this year in the Journal of Genetic Counseling, Profato and colleagues suggested that medical genetics is transitioning to genomics.

The researchers conducted an online survey and phone interviews with 16 program directors to assess their opinions about the inclusion and responsibilities of genetic counselors.

“[Fifteen of 16 respondents] reported that it is important to include genomic medicine in program curricula,” Profato and colleagues wrote.

Most topics of genomic medicine either are currently taught or under development in all of those directors’ programs, the researchers added.

“This vacuum needs to be filled by commercial enterprise,” McLeod said. “[The National Comprehensive Cancer Network] is not going down that road, and ASCO is not going down that road.”

Genetic counselors are prevalent at large academic centers, but that may not be the case at small or rural community hospitals, McLeod said.

Sohal raised the issue of volume. In some community settings, a genetic counselor may see very few patients per month, leading to questions about whether the specialty is always financially viable.

“In those cases, a regional referral center may be preferable,” he said. “If it’s a large area, you can serve a lot of people.”

One option is for genetic counselors to be employed by laboratories that perform genetic testing. Companies that develop assays also employ counselors, as do insurance companies.

Still, another formidable barrier remains: Demand far outpaces supply.

There are an estimated 2,400 genetic counselors in the United States, according to the National Business Group on Health, a nonprofit organization that provides solutions to health care and related benefits issues. According to the Council for Responsible Genetics, however, another 20,000 to 30,000 qualified personnel are needed.

“A lot more genetic counselors are being trained,” Stoffel said, “but there are still not enough.”

Role of tumor boards

The other resource on which clinicians often rely is a tumor board.

Yet, tumor boards — created to produce multidisciplinary consensus about a patient’s condition and treatment options — will not always be the ideal solution, McLeod said.

“They will mainly be dealing with outliers,” McLeod said. “The clinical community has no idea what is going on with some of these tumors. There are too many variants [and] we don’t know what to do with them. It is necessary to develop a consensus based on large numbers of patients, but this is challenging because it can take years to accrue enough patients.”

A review by Rustgi and colleagues, published in Genes & Development in January, illustrates this point.

The researchers explained how subsets of familial pancreatic cancer involve several types of mutations, such as germline cationic trypsinogen (PRSS1), BRCA2, CDKN2 or DNA repair gene mutations.

“However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts,” Rustgi and colleagues wrote.

Team approaches ultimately will help clarify the confusion surrounding these and other mutations, said Jennifer Morrissette, PhD, clinical director at the Center for Personalized Diagnostics in the University of Pennsylvania’s Perelman School of Medicine.

“General tumor boards are beneficial but, as we move forward, specialty-specific boards are going to evolve, as well,” Morrissette said.

Despite widespread acceptance of tumor boards as an important or even essential step in the patient management process, there has been pushback, and some data are conflicting.

Keating and colleagues investigated whether tumor boards improved outcomes in the Veterans Affairs health system. They published their results in 2013 in the Journal of the National Cancer Institute.

Presence of a tumor board was associated with only seven of 27 outcome measures assessed, and only one outcome measure demonstrated a statistically significant association with tumor boards in terms of use, quality or survival.

The results suggest “no effect or an effect that varies by structural and functional components,” coupled with the expertise of tumor board participants, Keating and colleagues concluded.

“Most community hospitals won’t have the kind of staff to evaluate tumors,” McLeod said. “They really need someone to help make these decisions. In some cases, tumor boards will be locally constituted, but we need other solutions.”

Consistent terminology

One potential solution lies in the choice of language. The NCI has created a dictionary of terminology to help clinicians improve their understanding of genetic and genomic information.

“Pathology guidelines change from year to year, but although genetic reporting is the same, we are still a few years away from anything being reported in the same standardized way,” Zenklusen said.

Zenklusen’s research has focused on genetic pathways.

“One gene may be responsible for about 2% to 5% cancers, but there are a lot of genes along that pathway, so the proportion of tumors affected by that pathway may be higher if you account for all the small players,” he said. “The problem is, the definition of ‘pathway’ is still up in the air.”

The term “pathway” may change to “function,” Zenklusen said, and the distinction is important.

“We have information about a number of mutations — such as the way the BRAF gene transforms, for example — but coding of it can be confusing, as not all reports will call the change with the standardized form,” he said. “Although there is a standardized vocabulary, the disparate use of terms is creating another layer of obstacles for clinicians.”

Continued education is essential, according to Vincent A. Miller, MD, chief medical officer of Foundation Medicine, a molecular information company that strives to transform cancer care based on an understanding of patients’ genomic composition.

“At the moment, clinicians and researchers in various specialties are readily interchanging terms surrounding cancer genomics, assuming things are synonymous when they are not,” said Miller, who served as an attending physician at Memorial Sloan Kettering Cancer Center for nearly 20 years. “Comprehensive education will standardize this language.”

Training programs for medical oncologists are evolving, Miller said.

“We are trying to get them more up to date on genomics, testing platforms, signaling and other aspects of our field,” he said. “This will help everyone communicate more effectively.”

A new intermediary

A far more comprehensive option worth exploring, according to experts, is the creation of a new level of support — dedicated genomic navigators — to help translate the vast quantities of data emerging from research laboratories and help clinicians apply them to patient care.

Such a venture would require considerable financial investment in training and staffing, but proponents suggest the expense must be evaluated in the context of value.

“These people cost money, but it is a lot more costly to put a patient on the wrong regimen,” Zenklusen said. “It is a burden on the system, and it is burden of time and loss of health placed on the patient.”

These complications can compound, Zenklusen said.

“Treating the tumor in the incorrect way can have consequences down the line,” he said. “The cost of not doing it is a lot greater than the cost of doing it.”

One key will be reimbursement.

“It will not be long before genomic tests will be covered under Medicare and Medicaid,” Zenklusen said. “Many insurance agencies require a genetic counselor when genetic testing is done. Money speaks. The minute insurance reimburses for this, it will become more prevalent.”

Private industry likely will play a role, McLeod said.

“Companies will sprout up and offer some of the interpretation piece,” he said. “The good ones will be incredibly useful. Ultimately, electronic medical records will contain some of this data, but that could be 20 years from now. For now, community clinicians are relying on local experts, but it is not enough.”

A tipping point

The inadequacies of the current structure likely will become more apparent with time, McLeod said.

“Right now, the lack of a genetic navigator is an inconvenience,” McLeod said. “But if you are seeing a lot of rare or unusual tumors, then you have a problem. This field is growing in importance every week. There will be a tipping point in the future, and some day it will impair efficiencies of practice.”

Nesline agreed to an extent but predicted that a slightly different scenario will unfold, suggesting that as many solutions may come from medical informatics and information technology as from professional services.

As more molecular-diagnostic tests become available, it is reasonable for oncologists to expect that the nature of genomic test reports will change significantly, Nesline said.

“We’re quickly coming to a place where genomic testing is more a matter of filtering what results to report based on proven clinical utility rather than what genes to test,” she said. “The question going forward is what authoritative data sources and standards will be used to do this. In the interim, we are going to see focused testing, where a lab will only identify known alterations that are clinically relevant because they’re associated with a particular therapeutic option. We’ll also see better, more accessible informatics tools that direct oncologists to the latest information about clinical options and availability of clinical trials. The focus will be on information that’s actionable, not overwhelming.”

Morrissette emphasized the need for communication.

“We like to help all clinicians who are starting to get genomic data and give them a chance to … listen to how other oncologists are incorporating these data in the care of their patients,” Morrissette said. “When you are at a large academic medical center, it is easier for medical oncologists to be involved. For people in smaller centers or in private practice, it is a little more difficult. It is important for all clinicians to have a voice.”

McLeod said the role of genetic testing and genomic sequencing must be kept in perspective, and the effort to treat patients in the best way possible must remain the focus.

“I use genetics as a tool, but I’m not so in love with DNA that I believe it is the answer to every question,” McLeod said. “We have to keep that in perspective and make sure we are doing whatever it takes to personalize medicine.” – by Rob Volansky

References:

Council for Responsible Genetics. Genetic testing: Preliminary policy guidelines. 2006. Available at: www.councilforresponsiblegenetics.org/ViewPage.aspx?pageId=84. Accessed on July 16, 2014.

National Cancer Institute. Genetic testing for Hereditary Cancer Syndromes. Available at: www.cancer.gov/cancertopics/factsheet/Risk/genetic-testing. Accessed on July 16, 2014.

Gray SW. J Clin Oncol. 2014;32:1317-1323.

Greenman G. Nature. 2007;446:153-158.

Keating NL. J Natl Cancer Inst. 2013;105:113-121.

National Business Group on Health. Genetic testing and counseling: Recommended benefit or practice. Available at: www.businessgrouphealth.org/cancer/planbenefits/genetic.cfm. Accessed on July 16, 2014.

Profato J. J Genet Couns. 2014;23:679-688.

Rustgi AK. Genes Dev. 2014;28:1-7.

Santillan AA. J Clin Oncol. 2010;3:481-486.

For more information:

Robert D. Daber, PhD, can be reached at BioReference Laboratories, 481 Edward H. Ross Drive, Elmwood Park, NJ 07407.

Howard McLeod, PharmD, can be reached at DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.

Vincent A. Miller, MD, can be reached at Foundation Medicine Inc., 150 Second St., Cambridge, MA 02141.

Jennifer Morrissette, PhD, can be reached at Center for Personalized Diagnostics, Hospital of the University of Pennsylvania, 3020 Market St., Suite 221C, Philadelphia, PA 19104; email: jennifer.morrissette@uphs.upenn.edu.

Mary Nesline, MS, can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263; email: mary.nesline@roswellpark.org.

Davendra Sohal, MD, MPH, can be reached at Cleveland Clinic, 9500 Euclid Ave., R35, Cleveland, OH 44195; email: sohald@ccf.org.

Elena Martinez Stoffel, MD, MPH, can be reached at A. Alfred Taubman Health Care Center, 1500 E. Medical Center Drive, Room 3912, Ann Arbor, MI 48109.

Jean Claude Zenklusen, MS, PhD, can be reached at The Cancer Genome Atlas Program Office, National Cancer Institute at NIH, 31 Center Drive, Building 31, Suite 3A20, Bethesda, MD 20892; email: jz44m@nih.gov.

Disclosure: Daber, McLeod, Miller, Morrissette, Nesline, Sohal, Stoffel and Zenklusen report no relevant financial disclosures.

 

Will all hem/oncs need to be board certified in genetics to provide effective care?

 

New genetic information that informs more effective treatment decisions will absolutely be on the boards.

The changes from the first time I took my boards to the second were quite striking, and they were reflective of advances in molecular and genetic knowledge. I see no reason why that trend would not continue.

If we look back over the history of those key genetic observations from the last few decades, we see a rise in findings that were testable that ended up being incorporated into everyday practice. Specific mutations like EGFR or BRCA or the Philadelphia chromosome in CML rapidly ended up in the body of information that was taught in medical school and put into practice by clinicians. In the past, all you needed to know was age and grade stage, but now we need to know HER-2 status, etc. Newer genetic observations keep getting added to that checklist. This information became part of the boards and part of the general lexicon, so I think the process of becoming more familiar with genetic information has been in place in the clinical oncology community for many years.

In recent years, we have seen an explosion in this kind of genetic information, and we have every reason to believe that will continue. It certainly complicates our treatment approaches to patients, as the new molecular findings are generally disease specific and not necessarily applicable across multiple tumor types. This is making it more difficult to be a general oncologist [and] to keep up with the specifics of every kind of tumor.

The body of knowledge you need to be familiar with in terms of actionable drugs to effectively treat a patient is exploding. It has made it really hard to be a jack-of-all-trades, and we are seeing a growing trend of oncologists specializing in one disease or disease site. Of course, there have always been disease-specific specialists in academic centers, but we are seeing this kind of specificity more and more in the community, as well.

Most clinicians these days are comfortable with the new molecular and genetic information on a conceptual level. They understand tumor suppressors, oncogenes and pathways. This has been reflected in the boards, and it is likely that it will continue to be so.

 

Glenn J. Lesser, MD, is a professor of hematology and oncology at Wake Forest Baptist Medical Center and Brain Tumor Center of Excellence. He can be reached at Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157; email: glesser@wakehealth.edu. Disclosure: Lesser reports no relevant financial disclosures. 

I do not think it will be necessary for hematologists and oncologists to become board certified in clinical genetics to provide effective care in the future.

However, it will be important for hematologists and oncologists — as well as most other health care providers — to continue to update their training in genetics.

We have already seen an increased emphasis on basic and clinical genetics in many medical school, residency and fellowship training programs. Professional societies offer many educational opportunities for practicing hematologists and oncologists pertaining to clinical genetic testing in general, as well as to genetic testing for specific disorders.

I think it is also important to recognize that hematologists and oncologists have been using genetic information in the care of their patients for a long time (eg, the detection of the somatic BCR/ABL1 translocation in CML or screening for germline mutations in mismatch repair genes for Lynch syndrome).

Admittedly, the number of available tests and the complexity of genetic testing for hematology and oncology applications is increasing, so educational efforts may need to be supplemented by more of a team-based approach, incorporating the expertise of hematologists and oncologists, as well as other physicians and health care providers with formal training in medical genetics or laboratory genetics.

Finally, it is important that guidelines continue to incorporate updated genetic testing into their algorithms when supported by sufficient evidence.

 

Jason D. Merker, MD, is co-director of the Clinical Genomics Service at Stanford University School of Medicine. He can be reached at Department of Pathology, 300 Pasteur Drive, L235 MC 5324, Stanford, CA 94305; email: jdmerker@stanford.edu. Disclosure: Merker has performed consultant work for the Gerson Lehrman Group. He also is a co-patent holder for an approach for measurement and monitoring of cell clonality.