Randy Gascoyne, MD

New York—For those who are tired of hearing that genomic sequencing will soon transform cancer therapy, the wait may be over.

The first trickle has begun, and it will likely become a flood of radical change in the treatment of malignancy, particularly hematologic malignancies. This prediction is based on two factors: the speed at which sequencing is now being performed, and confidence that identifying and hitting molecular targets with new drugs represents a critical revolution in medicine.

In hematologic malignancies particularly, designing therapy for molecular subsets of specific cancer types is under way, according to Randy D. Gascoyne, MD, from the BC Cancer Agency Centre for Lymphoid Cancer in Vancouver, British Columbia, Canada. Speaking at the 17th International Congress on Hematologic Malignancies, Dr. Gascoyne described an example from work at his own center in diffuse large B-cell lymphoma (DLBCL): Just two years after a published description of a DLBCL mutation, targeted inhibitors are reaching clinical development.

If, as expected, any of these inhibitors prove viable, “we are going to be able to pick off those cases with this mutation and deliver a very targeted and selective intervention,” Dr. Gascoyne said. He insisted this is no longer a futuristic vision, but just one example in a wave of advances that is expected to accelerate in a relatively short period and eventually dominate hematologic cancer therapy.

Using a baseball analogy, Dr. Gascoyne indicated that most molecular targets identified through genomic sequencing will likely be “base hits.” Although there have been home runs, such as the BRAF V600E mutation, which was found in essentially 100% of hairy cell leukemias, and triples, such as the MYD88 mutation, which has been found in about 90% of Waldenstrom’s macroglobulinemia cases, many targets will be found in limited subsets of patients. The DLBCL mutation identified at Dr. Gascoyne’s center was found in just 22% of germinal center B-cell (GBC) DLBCL.

The identification of small subsets of B-cell lymphomas with different pathogenetic mutations is consistent with the development of B cells, which modify their DNA in germinal centers to develop effective antibodies in response to a vast array of antigens. The differences in the risk for malignant transformation from these somatic hypermutations and recombinations make it important to “dissect cancer into molecular and clinically significant subtypes based on cell of origin expression,” Dr. Gascoyne explained.

The gain-of-function somatic DLBCL mutation identified in an effort led by the University of British Columbia is known as EZH2Y641 and promotes proliferation through its ability to increase trimethylation (Blood 2011;117:2451-2459, PMID: 21190999). In the original publication, it was shown that knockdown of EZH2Y641 in GCB cell lines resulted in cell cycle arrest. The potential of an EZH2 inhibitor was immediately obvious and investigators moved quickly.

Lymphoma stain.

“In the last four months, three published studies have described inhibitors of EZH2,” Dr. Gascoyne said. “The mutation was discovered in 2010, and we are now poised to bring targeted agents forward for this particular molecular target.”

Other examples are plentiful. In a study that used RNA sequencing analyses to compare DLBCL and Burkitt’s lymphoma (BL), a mutation in the transcription factor TCF3 emerged as a key pathogenetic event in 38% of sporadic BL cases (Nature 2012;490:116-120, PMID: 22885699). While data from this study, with which Dr. Gascoyne was also affiliated, may be applied to identify new therapeutic targets, this and other unique mutations may change how cancers are classified. For example, in intermediate and largely unclassifiable B-cell lymphomas, “it is entirely possible that we can bring some resolution to these ‘gray zone’ cases by having an understanding of the distinct recurrent mutations,” Dr. Gascoyne said.

The rapidly growing list of targeted therapies confirms that interrupting specific molecular processes can improve outcomes in cancer, but the genomic analyses that uncover a specific molecular mechanism within a cancer type offer an opportunity to create therapies with a far greater specificity of action. The impact is difficult to over-emphasize, according to Dr. Gascoyne, who suggested the parallel might be the discovery of the microscope.

“Suffice it to say that the introduction of this technology will revolutionize medicine,” Dr. Gascoyne said. Although this kind of observation has been made for years, Dr. Gascoyne explained that it no longer involves speculation. The major change has been the speed of genomic analysis. He noted that it took 15 years to complete the Human Genome Project at a cost measured in billions of dollars. Due to improvements in technology over the past several years, current machines can now sequence a complete genome in less than a day at a cost of under $1,000.

“I think we will be able to sequence all of the major lymphoma types at least before the end of next year,” said Dr. Gascoyne, who noted an intense competition among centers to generate clinically useful data. Genomic studies will reveal more about the origins of hematologic malignancies even as they identify important prognostic markers and new targets of therapy. Assays to evaluate molecular events also have the potential to determine whether therapy is effective.

“Are patients going to want to be sequenced? I can tell you that I would want to be sequenced, particularly now that we can do it so well,” Dr. Gascoyne said.

Based on the development of targeted therapies to use against specific mutations, “I think the genomic insights are beginning to penetrate practice in terms of DLBCL,” Dr. Gascoyne said. He indicated that one of the immediate limitations will be the development of assays to readily and efficiently identify mutations against which targeted therapies can be applied. However, he expects all of these steps to proceed rapidly from this point.

“The status of mutations in hematologic malignancies is already starting to inform treatment decisions,” Dr. Gascoyne said. Based on the speed of current advances, Dr. Gascoyne said it “will revolutionize medicine” even in the near term, suggesting that information on molecular subtypes of given cancers will grow exponentially in the coming decade.

Laura Pasqualucci, MD, an associate professor of clinical pathology and cell biology at the Institute for Cancer Genetics at Columbia University in New York City, offered a similar but more cautious perspective. She agreed that the momentum in the understanding of the genetic basis of DLBCL, as well as other hematologic malignancies, has been accelerating rapidly, at least partly as a result of improvement in sequencing technologies. However, she cautioned that the complexity of the next steps should not be underestimated.

“DLBCL is a heterogeneous disease and is likely due to the disruption of multiple different pathways and genetic abnormalities, as opposed to a single aberration. Thus, one of the challenges we will be facing now, in the ‘post-genomic’ era, is understanding which ones are the alterations—or the combinations of alterations—that drive the success or failure of existing treatments,” Dr. Pasqualucci said.

Even after these aberrations are identified, Dr. Pasqualucci noted there are other potential obstacles, such as identifying and characterizing mechanisms underlying the development of secondary resistance. However, even if all this “takes some time to sort out,” she remains impressed with the progress at which “improved knowledge is being translated into the clinical arena.”

Dr. Gascoyne has served as an advisor or consultant for Roche Canada, Abbott Laboratories and Genentech. Dr. Pasqualucci reported no relevant conflicts of interest.