A Look at Germline Predisposition to Hematologic Malignancies
At a Glance
Section titled “At a Glance”| Metadata | Details |
|---|---|
| Publication Date | 2022-05-20 |
| Journal | Oncology Times |
| Authors | Catlin Nalley |
Abstract
Section titled “Abstract”FigureColleague Conversations offers insights into hematology/oncology from two different perspectives: a seasoned hematologist/oncologist and a clinician earlier in their career. In this installment, HemOnc Times sat down with Lucy A. Godley, MD, PhD, and Gina Keiffer, MD, to discuss germline predisposition to hematologic malignancies. They delve into our growing understanding of this area, including current and future research endeavors, and examine how germline predisposition intersects with disparities in cancer care.Lucy A. Godley, MD, PhD: Lucy A. Godley, MD, PhDGodley is the Hospira Foundation Professor of Medicine and Human Genetics at The University of Chicago Medicine, and Keiffer is in Internal Medicine, Hematology, and Oncology at Jefferson Health in New Jersey. How has the understanding of germline predisposition to hematologic malignancies evolved in recent years? Godley: “When I was training as a fellow, I was taught that germline predisposition to blood cancers was exceedingly rare; if you met one of these families in your whole career, you were lucky, but I felt like I was seeing them all the time. When I became an attending physician, I was able to send the testing on whatever patient I wanted to, and I started diagnosing patients and families with a frequency that was much more common than once in my whole career. I diagnosed two families with germline RUNX1 mutations within the first 6 months that I was attending, and that really made me feel like the germline predisposition was much more common than what people had been thinking. “Our work and the work by many groups across the world have really changed people’s ideas. And it may be that each individual disorder is relatively unusual, or rare, but there are so many different disorders that, in totality, the phenomenon becomes very common. I think that’s the part that people kind of missed. The other thing is that people have a lot of bias about germline predisposition. There’s a teaching that if you have inherited a risk factor you will present young for your disease, and that is sometimes true, but our most common germline predisposition disorder to myeloid malignancies presents in an average age. So even someone in their 60s, 70s, or 80s can have an inherited risk to that disorder. And that really challenges people’s assumptions about germline predisposition. “So, I think there’s been a real seismic shift in our understanding in recent years in terms of how common inherited risk to hematologic cancers is, and all the different cellular pathways involved in the mechanism by which these inherited mutations cause disease, and if they have inherited risk, how they’ll present.” Keiffer: “I agree with everything Lucy said and it’s interesting, even though I’ve not been in practice as long, my experience in training is not all that different from what Lucy described. Certainly, in medical school, I was taught that if you see these remember it because that’ll be the one, and I think a couple of things have contributed to the shift we’re seeing recently. Number one is, like Lucy was saying, the recognition of so many genes being involved. There are so many different genes that have been identified that figuring out how those genes may participate in similar pathways and lead to a similar phenotype in a patient has taken more time.Gina Keiffer, MD: Gina Keiffer, MD“[Also], now that we’re doing NGS, or next-generation sequencing, more routinely in the care of patients with blood cancers we’re finding mutations more often. And, even though we wouldn’t necessarily use that as a means to rule out an inherited hematologic malignancy, I think it’s raising the possibility of an inherited disorder in people’s minds when they might not otherwise have thought about it.” Are there any current studies that are particularly promising? What are the potential implications? Godley: “Collectively, I would say the first question people have raised is, how common are these disorders? There are many studies coming out now showing how common these disorders are—anywhere from 5-25 percent of patients, depending on what that population is, might have germline predisposition. So, this is incredibly common. “The next phase of study is, how does that knowledge affect the way you treat the patient? I’m not aware of any clinical trials yet that use the genetic information, but I think we’re within a year or two of seeing those kinds of trials coming on board so that patients’ treatments may in the future be different depending on their inherited risk. “The last kind of study I can think of that people are working on is, how many genes are there? The genes we know of today are the tip of an iceberg. How big is that iceberg? How many more genes are there that are conferring inherited risk that we don’t even know about right now?” Keiffer: “Just to piggyback off that, I think there’s some barriers to identifying these conditions and one of them may be that providers are saying to themselves, ‘Well, it’s not worth looking for it because maybe I wouldn’t do anything differently.’ And so, the phase of study that’s desperately needed is around how can we best manage these patients so that the information we’re identifying more and more often has some real clinical impact.” Together, you started a virtual tumor board that focuses on bringing together oncologists, genetic counselors, and others with a vested interest in germline predisposition to hematopoietic malignancies. Could you tell me more about this endeavor and why it is important? Keiffer: “This tumor board was really born out of some conversations that started at our institution after Dr. Godley came and gave a wonderful Grand Rounds about inherited risk of hematologic cancers, and at least from speaking with you, Lucy, something you’ve been hoping to do for a long time. “The hope was to create a forum where experts and non-experts could come and discuss patients both from a standpoint of raising interesting points about how a patient presented or an interesting patient history that might lead to future scientific endeavors, but also from a point of getting advice from colleagues. “And so, we held our first meeting just last week and I have to say I think it was a great success. We had participants from both coasts of the United States, Canada, and Europe. We presented a couple of cases and people were able to give input and guidance. Our hope is that this will be a place where people can bring cases and also will serve as a springboard to asking new questions.” Godley: “Already, the virtual tumor board has almost had a second meeting. Just a few hours after the tumor board, I saw a patient in clinic that I had never seen before. This is an adult patient who probably has Shwachman-Diamond syndrome, and that’s typically diagnosed in a pediatric age group. So, we quickly connected a few of us from the tumor board and asked each other what to do and how to move forward. Those conversations are continuing into this week because we want to give the patient the best care, but we need the expertise of our pediatrics colleagues who care for these patients much more frequently. “So, I’m very excited that Gina was able to organize this because I think so many of us are going to benefit. Our group has followed these disorders for many years, but yet still, I had never cared for a patient with Shwachman-Diamond before. We can all learn from each other, and it’s a great way to exchange ideas.” Keiffer: “One of the things that’s been abundantly clear about this forum is that there was very much an unmet need that this is hoping to fill. The feedback I’ve gotten from the people who we’ve reached out to and the number of new people that keep getting referred to me to participate in this has been very exciting and very overwhelming. There was great recognition that we needed a place to discuss these patients so we can do the best for them that we can.” How does germline predisposition to cancer, specifically in hematologic malignancies, impact the field of disparities? Godley: “There are two different ways that germline predisposition impacts the field of disparities. The first one is the idea that there are DNA variations that are more common in certain populations, and those DNA variations may give the people in those populations a higher, or even lower, risk of certain kinds of cancers. We’ve known for a long time, for example, that acute lymphoblastic leukemia is more common in Hispanics. And now, there’s a lot of science going into what are the actual DNA variations that are conferring that risk that explain at least part of that observation. “Another aspect is the institutional and structural racism that has gone on sadly in the field of medicine, like many aspects of our society. Patients from underrepresented groups tend not to get the same care as other groups. I see that both because I practice medicine on the south side of Chicago where we have a large African-American population, but also because I speak Spanish fluently and I have a large Spanish-speaking population. And many of these patients don’t get the same histories taken from them. Their family histories are not discussed with them to the same degree and I think, sadly, they’re often not evaluated in the same way and then eventually not treated the same way. So, I think there are many different ways in which DNA variation and access to care play out relative to underrepresented groups.” Keiffer: “One of the other issues that comes up is that this testing, outside of research protocols, is not necessarily always covered by insurance. The degree of insurance coverage can vary and, for patients who are uninsured or underinsured, even getting access to this type of testing can be very disparate. So, the access issue begets more problems because then we can’t have as complete a set of information. We’re not even able to ask the same questions that we might be able to ask with other patients.” Godley: “Gina, I think this is a very good point that you’re bringing up, and it’s very true. I have a colleague at Cook County who has tried to refer several of his patients to me, but there’s a huge barrier to that access and I really have not been able to consult on his patients in the same way that I can from other centers, even in the city of Chicago. So, I think you’re making a really important point.” Looking forward, how do you think our understanding of this area will continue to grow and what is the potential impact for clinical care in the future? Keiffer: “Knowledge begets knowledge and the more we know about what causes these conditions the more questions we are able to ask, including ‘Now what can we do about it?’ And so that’s [the] piece of designing clinical trials looking to answer questions for patients with this set of mutations; if we treat them this way, are we able to prevent blood cancers from developing down the road? Or are we ultimately able to help people live longer? “Because they can sometimes be rare individual disorders, the numbers are small so we need to be able to include as many patients as we possibly can in order to start answering those questions. But one of the biggest implications that I see is many patients with blood cancers will at some point need a bone marrow transplant as part of their therapy, and typically we turn to family donors in that situation. But of course, if you have a family member who has the same inherited condition that you do, the implications of using them as a donor are huge. So, ultimately, we’d like to be able to say [that] this set of patients with this set of disorders should be monitored this way and treated this way and, ultimately, we can or cannot turn to family members as a safe donor for them.” Godley: “I think, ultimately, all oncologists would like to put themselves out of business. And so, if we know who in the population is really at risk for cancer, can we give them some sort of preventive strategy as they go through their lives to minimize the risk of developing cancer or identify cancer so early that we can care for them very simply? Ultimately, that’s what I would like to do—really intercept the process to prevent developing cancer in the first place. That’s a very long-term goal, but if we can make strides in that direction, it would be great.” Catlin Nalley is a contributing writer. OncTimes Talk Podcast Listen to this interview on our podcast, OncTimes Talk. Available at: https://bit.ly/3KCO5mb