Dana-Farber Oncologists Differ Widely on the Use of Multiplex Tumor Genomic Testing

A new study by researchers at the Dana-Farber Cancer Institute suggests that not all doctors are ready to embrace tests that may identify hundreds of genomic changes in a patient’s tumor sample for the purpose of determining appropriate treatment.

Many cancer researchers believe that cutting-edge advances in genomics will pave the way for personalized or “precision” cancer medicine for all patients in the near future. A new study by researchers at the Dana-Farber Cancer Institute, however, suggest that not all doctors are ready to embrace tests that look for hundreds of genomic changes in a patient’s tumor sample, while others plan to offer this type of cancer genomic tumor testing to most of their patients. The study findings were published recently in the Journal of Clinical Oncology [1], along with an accompanying editorial. [2]

The wide variation in attitudes was in part determined by physicians’ “genomic confidence.” Physicians who had a lot of confidence in their ability to use and explain genomic findings were more likely to want to prescribe the test and consider using test results when making treatment recommendations. Other physicians had lower levels of genomic confidence and were more reluctant to offer such testing. These findings are particularly interesting because the survey was carried out at the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC), which has a comprehensive research program. The DF/BWCC research program allows all consenting patients to have genomic tumor testing, which is capable of finding gene mutations and other DNA alternations that drive a patient’s cancer. In some cases, the genomic tumor profiles identify “druggable” targets that may allow doctors to use specific drugs known to be effective against particular gene mutations or alterations.

The researchers were perplexed by another key study survey finding: 42 percent of responding oncologists approved of telling patients about genomic tumor test results even when their significance for the patient’s outlook and treatment is uncertain. This issue comes with the growing use of predictive multiplex genomic testing, which can identify tens or hundreds of gene mutations simultaneously and often detects rare DNA variants that may or may not be relevant to the treatment of an individual’s cancer.

“Some oncologists said we shouldn’t return these results to the patient, and others say ‘of course we should give them to the patient’,” said Stacy W. Gray, M.D., AM, of Dana-Farber, first author of the report. “I think the fact that we found so much variation in physicians’ confidence about their ability to use genetic data at a tertiary care, National Cancer Institute-designated Comprehensive Cancer Center makes us pause and wonder about how confident physicians in the community are about dealing with this,” she said. “It begs the question at a national level, how are we going to make sure that this technology for cancer care is adequately delivered?”

The study survey was conducted in 2011 and early 2012 as a baseline assessment of physicians’ attitudes prior to the rollout of the genomic tumor testing project referred to as “Profile” (which formerly utilized a technology platform called “OncoMap“) at DF/BWCC.

For purposes of the study, a total of 160 Dana-Farber adult cancer physicians – including medical oncologists (43%), surgeons (29%), and radiation oncologists (19%) – participated in the survey. They were asked about their current use of multiplex tumor genomic testing, their attitudes about multiplex testing, and their confidence in the ability to understand and use genomic data. The survey did not include a direct test of the physicians’ knowledge.

Among the many intriguing findings of this study, a wide variability in interest in multiplex tumor genomic testing was identified—25% of respondents anticipated testing more than 90% of their patients, whereas 17% of respondents anticipated testing 10% or less. Beliefs related to the potential value of multiplex tumor genomic testing were largely positive; most expressed belief that this form of testing would increase treatment (73%) and research options (90%) for patients, as well as both physician (80%) and patient satisfaction (80%).

Despite the foregoing, less than 50% of the physicians planned to view the multiplex tumor genomic testing results routinely. Moreover, the majority of respondents planned only to “rarely” or “sometimes” use the clinically relevant results (58%), called “Tier 1” by the study authors, and potentially actionable results (88%), called “Tier 2,” to assist them in the treatment of patients. However, the respondents more often indicated that results of multiplex tumor genomic tests should be shared with patients, particularly findings revealing the presence of a Tier 1 (clinically relevant) genomic variant—87% believed that these findings should be discussed—versus a Tier 2 (potentially actionable) genomic variant (50%), or a Tier 3 (uncertain significance) genomic variant (40%). A substantial minority (39%) also disagreed with a Dana-Farber Cancer Institute policy prohibiting the disclosure of Tier 3 genomic variants to patients.

Interestingly, despite limited exposure to routine genomic tests for a large portion of the respondents, the stated “genomic confidence” of participating physicians was quite high. The majority of participants reported that they were “somewhat” or “very” confident in their (i) knowledge of genomics (78%), (ii) ability to explain genomics (86%), and (iii) ability to use genomic results to guide treatment (74%); however, a substantial minority of the Dana-Farber physicians (28%) reported genomic confidence of “not very” or “not at all confident.”

Based upon the study survey findings, Dr. Gray and her colleagues conclude that there is “little consensus” on how physicians plan to use multiplex tumor genomic testing for personalized cancer care, and they suggest the need for evidence-based guidelines to help doctors determine when testing is indicated.

“I think one of the strengths of this study is that its information comes from an institution where ‘precision cancer medicine’ is available to everyone,” commented Barrett Rollins, M.D., Ph.D., Dana-Farber’s Chief Scientific Officer and a co-author of the paper. “It highlights the fact there’s a lot of work to be done before this can be considered a standard approach in oncology.”

The senior author of the study is Jane Weeks, M.D., MSc, of Dana-Farber; additional authors include Angel Cronin, MS, of Dana-Farber and Katherine Hicks-Courant, BA, of the University of Massachusetts Medical School.

The research was supported by the Dana-Farber Cancer Institute. Dr. Gray also receives support from the American Cancer Society (120529-MRSG-11-006-01-CPPB) and the National Human Genome Research Institute (U01HG006492)

Pursuant to a new phase of Profile, initiated by Dana-Farber in 2013, a more advanced technology platform (called “OncoPanel“) utilizes “massively parallel” or “next-generation” sequencing to read the genetic code of approximately 300 genes in each patient’s tumor sample. “Massively parallel” refers to the technology’s capacity for sequencing large numbers of genes simultaneously. The 300 genes evaluated in connection with the OncoPanel were chosen because they have been implicated in a variety of cancers.

In addition to the complete DNA sequencing of more than 300 genomic regions to detect known and unknown cancer-related mutations, the OncoPanel technology can also examine those regions for gains and losses of DNA sequences and rearrangements of DNA on chromosomes. The results are entered into a database for research purposes, but, if a patient agrees, the clinically important findings can also be returned to their doctor for use in the clinic.

The OncoPanel advanced sequencing platform is an important update to Dana-Farber’s original OncoMap platform. OncoPanel can detect not only commonly known gene mutations, but also other critical types of cancer-related DNA alterations not previously identified. In contrast, OncoMap was limited to screening for known cancer-related gene mutations. The OncoPanel testing is done at the Center for Advanced Molecular Diagnostics, a CLIA-certified laboratory operated by the Department of Pathology at Brigham and Women’s Hospital.

References:

1./ Gray SW, et al. Original Reports – Health Services and Outcomes: Physicians’ Attitudes About Multiplex Tumor Genomic Testing. J. Clin. Oncol., published online before print on March 24, 2014, doi:10.1200/JCO.2013.52.4298.

2./ Hall MJ. Conflicted Confidence: Academic Oncologists’ Views on Multiplex Tumor Genomic Testing. J. Clin. Oncol. Editorial, published online before print March 24, 2014, doi:10.1200/JCO.2013.54.8016

 

To Fight Cancer, Know The Enemy

An Op-Ed entitled “To Fight Cancer, Know the Enemy” was published in The New York Times on August 6, 2009.  The author of the Op-Ed was James D. Watson, Ph.D.  James Watson co-discovered the DNA double helix structure; a discovery for which he received the 1962 Nobel Prize for Physiology or Medicine. In the article, Watson states his belief that beating cancer is now a realistic ambition, and he makes several suggestions designed to ensure that victory.

On August 6, 2009, an Op-Ed entitled To Fight Cancer, Know the Enemy was published in The New York Times (NYT).  The author of the article was James D. Watson, Ph.D. James Watson co-discovered the DNA double helix structure; a discovery for which he received the 1962 Nobel Prize for Physiology or Medicine.  Dr. Watson is the Chancellor Emeritus of Cold Spring Harbor Laboratory, and is generally considered the father of molecular biology. Throughout most of his career, James Watson’s novel scientific ideas generated great controversy among, and resistance from, many members of the scientific community.  The suggestions posed by James Watson in his August 6th NYT Op-Ed are likely no exception.

Watson begins the Op-Ed by suggesting an ambitious, yet optimistic, goal in the area of cancer research:

“The National Cancer Institute, which has overseen American efforts on researching and combating cancers since 1971, should take on an ambitious new goal for the next decade:  the development of new drugs that will provide lifelong cures for many, if not all, major cancers.  Beating cancer now is a realistic ambition because, at long last, we largely know its true genetic and chemical characteristics. …”

James D. Watson, Ph.D. is the Chancellor Emeritus of the world-renowned Cold Spring Harbor Laboratory. Dr. Watson co-discovered DNA's double helix structure; a discovery for which he received the 1962 Nobel Prize for Physiology or Medicine. In an Op-Ed published in the New York Times on August 6, 2009, Dr. Watson states: "...Beating cancer now is a realistic ambition because, at long last, we largely know its true genetic and chemical characteristics."

Despite President Nixon’s declaration of  war on cancer in 1971, Watson states that the goal of “beating cancer” was not possible prior to the year 2000, because researchers did not possess the necessary scientific understanding of cancer molecular biology. Extensive details about specific cancers only became known after the 2003 completion of the Human Genome Project, says Watson. Researchers have identified most of the major cellular pathways through which cancer-inducing signals move through cells, and Watson notes that 20 or so signal-blocking drugs are in human clinical testing. By way of example, Watson highlights the breast cancer drug Herceptin, which is used to fight an aggressive form of breast cancer. Herceptin was approved initially by the U.S. Food & Drug Administration (FDA) in 1998, and today represents the standard of care in treating so-called “HER-2 positive” breast cancer.

With this scientific background, Dr. Watson outlines several suggested changes to the current U.S. cancer research paradigm. He believes that the various changes listed below will give the nation a fighting chance to win the war on cancer.

Change FDA Regulations To Allow Combination Testing of New Cancer Drugs Which Are Ineffective As Monotherapies.

Noting the lack of new cancer drugs that lead to lifelong cures, Watson explains that there are many types of cancer-causing “genetic drivers” within a single cancer cell. Although an analysis of several cancer genetic drivers may allow a doctor to prescribe more personalized chemotherapy treatments for the patient, Watson believes that use of drugs against one genetic cancer driver would simply lead to the emergence of increasingly destructive second and third drivers due to the inherent genetic instability of cancer cells.  Accordingly, Watson concludes that most anticancer drugs will not reach their full potential unless they are given in combination to shut down multiple cancer genetic drivers within a cancer cell simultaneously.

Dr. Watson, however, is quick to note that current FDA regulations effectively prohibit combination testing of new cancer drugs that, when administered alone, prove ineffective.  Thus, Watson concludes that current FDA regulations must be amended to allow combination testing of new cancer drugs that prove ineffective as monotherapies.

Better Understand The Chemical (Rather Than Genetic) Makeup of Cancer Cells

Dr. Watson believes that researchers should shift the current focus of cancer research away from decoding the genetic characteristics of cancer, and obtain a better understanding of the chemical reactions that occur within cancer cells. This suggestion, Watson explains, is based upon a 1924 discovery made by the German biochemist (and 1931 Nobel Laureate) Otto Warburg.  During experimentation, Warburg observed that cancer cells, irrespective of whether they grow in the presence or absence of oxygen, produce large amounts of lactic acid. Approximately one year ago, the significance of Warburg’s observation was revealed, says Watson. The metabolism of all proliferating cells (including cancer cells) is largely directed toward the synthesis of cellular building blocks from the breakdown of glucose. Based upon this recent discovery, Dr. Watson concludes that glucose breakdown runs faster in growing cells then in differentiated cells (i.e., cells that stop growing and perform specialized functions within the body).

The turbocharged breakdown of glucose in growing cells is attributable to growth-promoting signal molecules that effectively turn up the levels of transporter proteins which move glucose molecules into the cell, explains Watson. With this important discovery in hand, Watson suggests that researchers determine whether new drugs that specifically inhibit the key enzymes involved in the breakdown of glucose can produce an anticancer effect. Because this determination requires a better understanding of the chemical makeup of cancer cells, Watson believes that biochemists (rather than molecular biologists) will again move to the forefront of cancer research.

NCI Should Fund Smaller Biotechnology Companies & Increase Its Funding to Major Research-Oriented Cancer Centers

The next issue addressed by Dr. Watson relates to the lack of funding available to small biotechnology companies, which are generally engaged in highly innovative research. In the past, the requisite funding of these companies was provided by venture capitalists (VCs), Watson notes.  The level of VC funding required by small biotech companies is not currently available due to the severe U.S. economic downturn. To resolve this critical capital funding issue, Watson suggests that the National Cancer Institute (NCI) fund small biotech companies. This action, Watson believes, will allow the biotech companies to move drug discoveries from the laboratory into human clinical testing on an accelerated basis. In tandem with funding small biotech companies, Dr. Watson also requests NCI to increase its funding to major research-oriented cancer centers that engage in “low probability-high payoff” research projects, which are generally turned down by large pharmaceutical and biotech companies.

President Obama Should Appoint A Strong Leader To The Directorship of NCI

In 1971, the U.S. Congress provided the president, rather than the head of the National Institutes of Health, with the authority to appoint the NCI director.  Watson characterizes NCI in his Op-Ed as “an outpost of the White House” that has “… become a largely rudderless ship in dire need of a bold captain who will settle only for total victory.”  To resolve this issue, Dr. Watson advises President Barack Obama to appoint a strong leader, from among the nation’s best cancer researchers, to the directorship of NCI.  As part of this new leadership structure, Watson also recommends that NCI recruit a seasoned pharmaceutical developer who can radically increase the speed of anticancer drug development and human clinical testing.

Application Of Sun Tzu’s Strategies On The Art Of War To Cancer Research

A statue of the iconic Chinese military leader Sun Tzu. Sun Tzu wrote the earliest -- and still the most revered -- military treatise in the world. This 6th century BC masterpiece is best known to most of us as "The Art of War."

At the conclusion of his Op-Ed, Watson acknowledges that his views will provoke rebuttals from prominent scientists who believe that it is not the right time to wage war on cancer. Moreover, Watson anticipates that many scientists will recommend that, until victory is more certain, the U.S. should not expend large sums of money on cancer research. Watson admits that money alone will not win the war on cancer, but he emphasizes that victory over cancer will not come ” from biding our time.” As part of the Op-Ed title, Watson uses the phrase “know the enemy;” a phrase commonly attributed to the ancient Chinese military leader Sun Tzu. Sun Tzu wrote the earliest — and still the most revered — military treatise in the world.  This 6th century BC masterpiece is best known to most of us as The Art of War.  The clever use of the phrase “know the enemy” by Dr. Watson may suggest that the enemy is indeed cancer, and perhaps, ourselves as represented by the current U.S. cancer research paradigm.

In chapter III of The Art of War, entitled Attack by Stratagem, Sun Tzu describes the dual knowledge that one must possess to achieve ultimate victory in war:

“…If you know the enemy and know yourself, you need not fear the result of a hundred battles. If you know yourself but not the enemy, for every victory gained you will also suffer a defeat. If you know neither the enemy nor yourself, you will succumb in every battle. …”

To follow the advice of James Watson is to better know ourselves and the formidable enemy known as “cancer.” Will Watson’s advice allow us to achieve ultimate victory in the war on cancer? Perhaps. Only time (and appropriate research funding) will tell.

Source: To Fight Cancer, Know The Enemy, by James D. Watson, Op-Ed, The New York Times, August 6, 2009.