The study, published April 12, 2018 in the New England Journal of Medicine, was led by researchers at the Center for Cancer Research at the National Cancer Institute and represents many years of study to better understand the various gene mutations and gene expressions found in lymphoma patients. That information may help explain why treatment works in some patients and fails in others. The research also moves the field closer to a system of classifying cancers by their unique molecular signatures rather than the generic type of cancer or the organs in which tumors arise. “The way we have done it traditionally is to group people together based on some type of criteria, such as how cancers looks under a microscope,” says Louis M. Staudt, MD, PhD, the lead author of the study who works for the Center for Cancer Research of the National Cancer Institute in Bethesda, Maryland. “Our tools are so much sharper now, and they are becoming increasingly available. Treatment options can be informed by new science now.”
A Wide Variety of Treatment Responses Within the Same Diagnosis
In the study, researchers identified genetic subtypes of a type of lymphoma called diffuse large B-cell (DLBCL). This is the most common type of lymphoma, and although it’s aggressive, many patients are treated effectively. But doctors have long been perplexed by why treatment — a combination of chemotherapy and a monoclonal antibody called Rituxan (rituximab) — works in some patients and not others. Studies show that there are two different subtypes of DLBCL cancer that have different patterns of gene expressions, dubbed activated B-cell-like and germinal center B-cell-like. The patients with activated B-cell-like disease have a much lower rate of survival compared with germinal center B-cell-like: 40 percent compared with 75 percent average survival. But even patients with germinal center B-cell-like disease can experience relapse of the cancer, Dr. Staudt says. The study was aimed at trying to explain the widely varying outcomes. “The motivation was, gee, if we could do gene expression and study mutations and other gene abnormalities, maybe we could define more clearly a subset of patients who will respond better to the therapies,” he says.
Parsing out the Subtle Variations in Tumor Types
Researchers evaluated tumor samples from 574 patients with DLBCL, analyzing gene alterations and gene expression. They identified four major genetic subtypes, each characterized by specific genetic signatures. Patients with the subtypes dubbed BN2 and EZB tended to respond effectively to treatment while patients with subtypes MCD and N1 did not. The study showed that some of the subtypes occurred in both activated B-cell-like and germinal center B-cell-like subgroups. That means that a patient could have a “bad” subtype of disease, such as activated B-cell-like, yet still have a “good” genetic subtype, such as BN2, suggesting that treatment would have a better chance of working. Guidelines containing the new molecular information could help physicians select chemotherapy and rituximab for patients with responsive subtypes while guiding other patients to clinical trials that may help them. Moreover, the growing understanding of DLBCL genetics will also steer researchers toward treatments based on the genetic mutations that could make treatment even more effective. For example, a study published in July 2015 in the journal Nature Medicine showed that patients with activated B-cell-like DLBCL had better outcomes when treated with the drug Imbruvica (ibrutinib), a targeted therapy, compared with patients with germinal center B-cell-like disease. Targeted therapies address the biological underpinnings of the disease to fix the flaw and cripple cancer growth. These therapies are sometimes more tolerable than chemotherapy, which is a systemic treatment that causes a wide range of side effects. “We’re getting to the point of finding these subsets of patients where we have interesting treatment options becoming available,” says Staudt. “The idea is to do this for all patients — to pick off subsets one at a time: This drug for this subset and another drug for another subset. That may be the new way we classify lymphoma.”
Should All Lymphoma Patients Have Their Tumors Typed?
The study also raises the question of whether all lymphoma patients should undergo testing to identify the unique genetic characteristics of the tumor. That’s something individual patients should discuss with their oncologist, says Staudt. “We’re still in a very rapid development phase in cancer research,” Staudt says. “There aren’t drugs for every mutation. You can get this test and the best option for you may be to still get chemotherapy.” But the research is moving very fast toward classifying tumor subtypes and finding precision therapies that address those subtypes, he says. “We first have to understand. If we don’t understand, we can’t be rational about how we approach treatment. We are working on this as hard as we possibly can and as fast as we possibly can.”
