Dr. John Leonard (Host): Welcome to Weill Cornell
Medicine CancerCast, conversations about new developments in medicine, cancer
care and research. I'm your host, Dr. John Leonard. And today, on the podcast,
we will be talking about the link between our inherited genetics and cancer.
This is a really important topic and one that has changed dramatically over
recent years, something that had very little relevance to actual care of our
patients for the vast majority of people, and now is very important for an
increasing number of patients with cancer and other disorders.  

So, it's great to have our guest for this episode, Dr. Ravi
Sharaf. Dr. Sharaf is a gastroenterologist and health services researcher, and
cares for patients with hereditary or inherited cancer syndromes. Dr. Sharaf
serves as the Director of Clinical Cancer Genetics at Weill Cornell Medicine
and is an Associate Professor of Medicine. His research focuses on optimizing
the delivery of genomic medicine, studying cancer prevention strategies and
tailoring cancer prevention to individual risk. His research is funded by the
National Cancer Institute and the Patient-Centered Outcomes Research Institute
or PCORI.  

I'm really looking forward to a great discussion. We're
going to talk about the intersection of genetics and cancer, especially about
the genes we inherit from our parents or pass to our children, how that
connects to our cancer risk and how we should approach screening, prevention and
treatment of cancer. So, Ravi, thank you so much for joining us today. It's
great to have you.  

Ravi Sharaf, MD: Thanks
for having me. It's great to be here. 

Dr. John Leonard (Host): So,
this is the area that you've chosen to work in. And we're really fortunate to
have you here at Weill Cornell and NewYork-Presbyterian because, in many ways,
this is a relatively newer and perhaps not as widely known or widely available
aspect of cancer care, and primary care in some ways, that is really growing.
So, I want to start by asking you how you found yourself working in this area.
What about this area led you to focus your career and your expertise in cancer
genetics?  

Ravi Sharaf, MD: Like many things, I think it's a
combination of luck and mentorship and hard work. When I was in college, I had
a biochemistry mentor actually who took me under his wing, Dr. Namboodiri, who
was my first exposure to molecular genetics. Dr. Namboodiri guided me to the
NIH, where I ended up in Francis Collins' lab. At that point, he was lead of
the Human Genome Research Institute, the Human Genome Project. Our study was
looking at the inherited predisposition to type 2 diabetes. So, I could kind of
see the future and kind of the nascent beginnings of precision medicine. And I
thought it was really cool to be honest, and I knew it was something that I
wanted to be involved in regardless of where my clinical interests landed.  

Dr. John Leonard (Host): I'd like to start with just
some basic background on genetics. And I'm sure many people listening they
think about some of their high school biology classes and big A, little A and
some of the other things around how things are inherited. But really, I think
one of the aspects that's very important is differentiating the genetics in the
tumor cells, which kind of by definition have a number of different mutations
versus what are the inherited genetics of the person, that, maybe in some ways
is the soil for the seed of cancer. So, can you get into a little bit of the
differences and how you think about it from the standpoint of a patient and
their cancer risk as a person or as a whole body as opposed to what's happening
in a specific tumor cell?  

Ravi Sharaf, MD: That's a great question. Cancer is
common. We know that 40% of people in the US are going to be affected at some
point in their lifetime. We also know that all cancer is genetic. There's
always an interplay between environment and genetic risk factors in the
development of malignancy. About 80% of cancers are what we call sporadic, and
it's exactly what I just said. It's this interplay between environment and
genetics. Our focus is on the 10%, maybe even 20% of malignancy that is driven
by single monogenic changes, single gene changes that are inherited, that come
from mom or dad.  

One way to think about it is, broadly, there are genes that
affect cell growth and there are genes that are fundamental to DNA repair. And
we're usually born with two functional copies of these genes. What happens when
you have a hereditary cancer syndrome is that you're born with only one
functional working copy, so that's strike one.  

During the course of one's life, mutations happen in cells,
and a mutation might occur in the other copy of these genes that control cell
growth or DNA repair. So, in someone with an inherited cancer syndrome where
you already are starting on strike one, that second mutation that occurs during
an individual's life is strike two. And then, there's a series of events, that
eventually lead to strike three, which is carcinogenesis. So, you're basically
starting a little bit ahead in the cancer development process if you do have an
inherited mutation. That is the distinction between these "germline
mutations," which are inherited. And the somatic, which are present only
in the cancer cells, but not necessarily in every cell in the body. And the
somatic changes cannot be passed on to the next generation.  

Dr. John Leonard (Host): So, there are people that
won't get cancer. There are people that will get cancer and have one of these
predispositions. There are also people that will get cancer and don't have
these predispositions. And then, there are people that have a predisposition
but won't get cancer. So four different buckets of people with different
scenarios based on their risk and whether or not they actually get cancer. I
know that there are many types of cancer, many types of mutations, et cetera.
But at a very high level, what are the factors that might lead someone with a
mutation to get or not get cancer, or the fact that somebody might get a cancer
despite having none of these risk factors?  

Ravi Sharaf, MD: I think genetics plays a role,
whether it is single gene predisposition, and that means a single mutated gene
that confers an elevated risk of a single cancer or a spectrum of cancers. Risk
is not fate, it's not predestination, it's risk.  

Environmental risk factors unequivocally play a role,
whether you have an inherited mutation or whether you don't. So, I think that's
where all the realms of basic primary care and primary prevention come in.
Lifestyle factors, weight, tobacco use, alcohol use, diet, exercise, these are
things that whether you do have an inherited predisposition or not, that
unequivocally affect cancer risk. And then, there is the element of
capriciousness here as well. Things can happen, where one exerts whatever
control they can exert over their own risk factors and cancer still develops.  

Dr. John Leonard (Host): So, let's get a little
granular into the more specific and relatively common scenarios. Patients who
are diagnosed always ask the question, "Why did I get this?" And
people are worried about getting cancer because it's a scary thing. Which
cancers are more strongly associated with some sort of inherited connection?  

Ravi Sharaf, MD: Genetics move so, so quickly. Every
year, there is an evolutionary, if not, a revolutionary change. We now know
10-20% of solid tumor are going to have either an underlying single gene
predisposition or association and, increasingly even hematologic malignancies,
so leukemia, lymphoma, the percentages of finding an underlying gene mutation
are in the similar ballpark, so 10-20%. So, I do think this is relevant to all
malignancies. Some centers as such are offering universal germline testing,
testing for inherited cancer for every incident of cancer, for every new
diagnosis. That is something that we're trying to move towards as well.  

Dr. John Leonard (Host): I guess it's an example of
kind of shining the light on more areas, right? At one point, you could only
shine the light in a specific area or identify a specific number of patients
where this was at least relevant to an extent you could find something. And
now, the light beam gets broader and broader, you find more and more things. So
as you think about the mutations that we know about being relevant, what are a
few of the common ones that people would be interested in knowing about from
the standpoint of if you are worried about breast cancer, this is a mutation
that is commonly relevant as an example?  

Ravi Sharaf, MD: The ones that are most common in
patients’ psyche and I think in physician psyche, are two syndromes. And so,
one is hereditary breast and ovarian cancer, which is BRCA1 and 2 related in the
majority of cases. And the other syndrome, which tends to be a hereditary
gastrointestinal cancer syndrome, is Lynch syndrome, which is caused somewhat
simplistically, I'll say, by five genes that are mutated. These are not rare
conditions. And so when you combine the prevalence, it's about 1% of the US
population that's going to be a carrier. Though the overwhelming majority of
people do not know they're affected.  

When we think about cancer predisposition genes, these
single genes that are involved, I like to think of it as a hub and spoke. So if
you have a mutated gene, whether that's BRCA1 or 2, or a Lynch syndrome gene as
the hub, the spokes lead to multiple cancer predispositions. And so, it can be
for BRCA1 and 2 breast cancer, ovarian cancer, pancreatic cancer, prostate
cancer amongst many others. So, there is in terms of risk and in terms of
appropriate clinical a needed multidisciplinary spectrum that needs to occur
downstream. For Lynch syndrome, same idea, but slightly different cancer
predispositions. And so again, if you're starting with the Lynch syndrome
genes, MSH1, MLH2, et cetera, then what you find is inherited predisposition to
colorectal cancer, to pancreatic cancer, ovarian cancer, uterine cancer, et
cetera. And so, our management is guided by the cancers that are predisposed.  

Dr. John Leonard (Host): So, I'd like to get into the
kind of issues around being practical with all this. you've very clearly stated
that this is relative to a high number of patients and increasing percentage of
patients. But for patients who are worried about cancer or have cancer, kind of
operationalizing this is the key point. So, it seems to me like the major
things that people need to focus on are their family history and then, if to
get tested, how to test, et cetera. Why is it important for people to know
their family history and what do they need to know? How far back do they need
to get into this? And maybe an example or so of how just the family history
might change the approach for an individual patient in how they're screened or
managed.  

Ravi Sharaf, MD: Family history is the ultimate
phenotype, we say. it's the ultimate evidence of disease manifestation in a
family. When we look at family history, we tend to look at a three-generation
pedigree. if the patient is a proband, we will do a look at their children, the
generation above the patient, the parents, and then the grandparents as well,
trying to cull information about cancer incidence and the age of onset. And by
doing so, you can look for patterns, patterns that meet established clinical
criteria for who might be at risk of harboring one of these mutations.  

What's really interesting, and this is actually why I love
genetics, because it just changes so quickly and the data just keeps evolving,
a family history is good, but the sensitivity is 50%. And so, what that means
is about 50% of people who carry one of these mutations are not going to have a
family history. What you see increasingly is this movement towards two things.
One is universal testing of incident cancers. So, for people who are affected,
colorectal, breast, ovarian, pancreas, whatever it is, the recommendation to do
genetic testing to look for a hereditary predisposition, knowing that family
history may or may not be contributory. And two, because family history can be
helpful but isn't always, it's a coin flip, this movement towards population
level screening. So, you'll see this actually, the US is a bit behind in this,
but in the UK and Israel, there are movements, certainly in select populations,
towards testing everybody, acknowledging the limitations of family history.  

That being said, I think, family history is a low-hanging
fruit and so I think, for a patient, for an individual, to the extent one can
know about this, because families are families. And some people talk about this
stuff, some people don't and that's fine. Seeing what is going on just makes
sense and it's basically what types of cancer there are, the ages of onset.
What I'm going to say is very general and isn't always applicable, but
generally speaking, the more malignancies there are, the earlier ages of onset.
That's what's been tied historically to clinical criteria, which suggest the
presence or the need for further evaluation like genetic testing.  

Dr. John Leonard (Host): You've given a perspective
or a range of perspectives that everyone should get genetic testing or that
some people are at least exploring that or pursuing that. And in some ways, It's
an easy recommendation. It's harder to implement. But from the standpoint of
the patient, it's easy. There's no decision to make, you go. You get it done.
You go through the process. If I'm an individual patient and I haven't had
genetic testing yet, and maybe that's never been offered to me, how would you
advise somebody? The idea that if I have multiple people in my family with
cancer and/or they happen at younger ages, I should probably be more likely to
seek that out if my doctor hadn't suggested it. The extent of taking a family
history and then acting upon it and really going through the process that your
team does, which is clearly a value. Most people are busy and not necessarily
doing that. So from the patient perspective, what should ring a bell to say,
Yes, if no one's mentioned this to you for whatever reason, you really should
pursue this"?  

Ravi Sharaf, MD: The easiest thing to do is probably
to have a conversation with one's primary care physician, to say, "Hey,
this is something that might be of concern to me. What do you think? What's
your opinion? Is this something that merits genetic testing?" For some
people who want to speak directly to us, we always are happy to talk through
things as well. So, that's probably the most direct way of pursuing it.  

What's interesting in this field, and this is something that
I have to say as well, is a lot of our patients actually already come to us
with genetic testing data, whether it is 23andMe or Ancestry or something like
that, because people have this inherent curiosity or desire to know. The only
caveat with those types of studies is just to truly understand what they mean
and what they do and don't test for, so expectations are managed. Because I
think the direct-to-consumer companies, you want to make sure that what you
think you're getting is what you're getting in terms of a proper risk
assessment.  

Dr. John Leonard (Host): So, I'm a patient, I've
decided I want this done. I go to my primary care doctor, I say, "I want
this done. I need that." People are used to getting, you know, their
vitamin D checked or their PSA checked or whatever. What are the nuts and bolts
of this happening? What are the ranges of ways you can do this well? I mean, it
strikes me that there's the direct-to-consumer where you probably go to a website
and follow a process all the way to the other end where you go somewhere to a
specialized group like yours and meet with a counselor and go through a lot of
discussion and then do this, and then have a very involved process. So, what's
the spectrum? What are your recommendations generally as to who should follow
what path, recognizing that it's probably challenging and maybe unnecessary for
every single person to go through an extensive process as a screening test?  

Ravi Sharaf, MD: I agree with that, that not everybody
would need an extensive evaluation. I think like with anything in medicine,
there is a spectrum of care delivery options and they each have their pros and
cons. And somewhere in that spectrum is where people are going to land to
figure out what might be most appropriate. What I will say is, at least from a
physician-centered implementation. There are two delivery paradigms. And so,
one is called mainstreaming, which is the conduct of genetic counseling,
genetic testing by "non-genetics-trained" physicians or clinicians.
And so, people that don't have genetics training, but might have additional
specialized, focused training in counseling and testing. And the evidence to
support that, actually, there's a lot and it works. And it's a good way to open
up genetic testing in multiple disciplines to the population. There are some
people who are going to want to see us specifically, and that's fine too. I
think the entire care paradigm is changing. Especially, you know, we've been
talking about this movement towards population level screening, just from a
pure feasibility standpoint then, you have to be practical here. And so, what
tends to happen in practice is patients are often tested initially by a primary
care physician or their gynecologist or another provider, and that's perfectly
fine. And then, we end up seeing those that end up having a mutation for
further management.  

Stepping back about the direct-to-consumer approach, that's
completely appropriate as well. I think it honestly comes down to your preference.
Some people now in the internet age feel completely comfortable, like they do
ordering from Amazon, ordering a saliva kit or a blood kit from a company, and
that's fine. The couple things that people should be thinking about when it
comes to genetic testing, which is distinct from other laboratory tests, from
getting a CBC or getting your electrolytes checked, is the potential insurance
implications. So, there are potential implications for life insurance and for
long-term care insurance and for disability insurance. So, that is something
that we talk about during our visits, just to make sure that a process of
informed consent occurs. It is a bit more involved than other routine medical
testing we do.  

Dr. John Leonard (Host): What are the types of
results that someone might get? I would presume there's a range of findings
from nothing identified or very little relevant identified to something of
major concern, to something in the middle. What are a couple of examples on
that spectrum that someone might receive as a result? And then, maybe we'll get
into what one might do about those things as a follow-up.  

Ravi Sharaf, MD: What we tell folks is whatever you
see, don't worry. We'll talk through things when results come back. And
patients are often seeing these results before we are, because of transparency,
because of the direct release of results. When one does genetic testing for
cancer predisposition, what usually happens is a gene panel is sent because
each gene that we test for has the potential to increase risk for so many
cancers, you know, that hub and spoke model. We generally test for multiple
genes, 20, 30, 40, 80, 100 when we are looking at cancer predisposition. Results
can come back in one of three ways. They can be negative. Negative for us means
normal. They can be positive, which means that there's a mutation that
increases cancer risk, does not mean that the individual has cancer. And then,
we deal with it, we mitigate risk, we make a plan.  

A third option is something called a variant of unknown
significance, which is exactly what it sounds. These are functionally normal or
results that sit right next to normal, but that we can't put a definitive,
normal stamp on because we need a little bit more population level data.
People's genes don't change, but our understanding does. And so, part of this
is semantics. As we get more data on a variant of unknown significance, 90 to
95% end up getting downgraded to normal. So, those are the scope of results
that patients can get after testing and we follow people longitudinally
accordingly.  

Dr. John Leonard (Host): Is the approach any
different if you're a patient with cancer? So if I have a cancer and I myself
get screened, I mean, you already know I have cancer, is it you're looking for
other mutations? Are you looking to help my children? Is it going to change how
you manage my current cancer? Is it all the above?  

Ravi Sharaf, MD: It is all of the above. From the
personal sphere, it certainly can affect therapeutic options for the incident
cancer. After that cancer is treated, it can certainly affect future cancer
screening, specifically the modality, the organ screened and the frequency. And
then for the other sphere, it's this familial sphere I should say. So, it's
this cascading notion, this cascade testing effect. And so if a person is
affected with hereditary cancer, getting back to your, mention about high
school biology, it does come back to the Punnett square. The majority of these
genes are inherited in an autosomal dominant fashion. So, that means, it
doesn't matter your sex at birth. Male, female does not make a difference.
People still have a 50% chance of passing it on to their children. Their
siblings have a 50% chance of having the same mutation. And in the majority of
settings, this isn't universal, this came from mom or dad. There's a personal
effect, a personal sphere, and then there's a familial sphere that is also of
relevance here.  

Dr. John Leonard (Host): Tell us a little bit about
the genetic counseling process because I can imagine a patient gets a result
and maybe they go to their primary doctor, maybe they Google it. It seems to me
like the process of having an expert in this area, and I know your team is very
steeped in this. How does that add value? What are the key ways how that can
help somebody navigate this?  

Ravi Sharaf, MD: I think it is important. These
conditions are much more common than we historically thought, though there
aren't that many people who have the in-depth expertise, and experience with managing
them. And I think that is important. It certainly can provide perspective and
reassurance for appropriate management from a clinical standpoint for
appropriate psychosocial support, that's a big aspect here as well, and
appropriate familial management. And those are things that I think we do excel
at, and I think people who are in this field are particularly good at. So, you
know, it's a knowledge of what is the next step. It often is knowledge of not
making inappropriate steps of appropriate care, not underscreening, but not
over screening, because that's very important. You don't want to advise someone
towards an unnecessary surgery. You want to be intelligent about what we know,
what the results show in the context of what we actually know. And I think
patients do appreciate that because there's often a shock when a mutation comes
back.  

And really, after an in-depth discussion of what this really
means, given what we know and what we don't know more importantly as well, I
think people do come out feeling reassured. And then we can also provide a perspective
on longitudinal care because things change. And so as there are new
discoveries, whether it comes down to cancer risk associated with a gene or
novel mechanisms of cancer screening, we can make sure that affected patients
are the first to know.  

Dr. John Leonard (Host): I want to finish by just
getting your quick take on the key areas of research in this area. It sounds
like it's very much a moving target. Things are evolving and therefore research
is a very important part of this. What are the key areas where you and others
are doing research on how to move this field forward?  

Ravi Sharaf, MD: I think it’s so exciting because
there's so much happening in this field. And the spheres we think about are
basic science, which tends to be lab-based research. There's translational,
which is bridging the basic science to the clinical, which is the third sphere.  

I have to say we have experts who are doing this in all
facets at Cornell. And so, it makes it a really neat place to work and to
interface with people across the spectrum. So, on a basic science standpoint,
it's looking at mechanisms of carcinogenesis, modifiers of carcinogenesis. That's
what you were talking about earlier, really understanding genotype, phenotype
relationships. And so, that's with specific mutations, what are the exact
cancers that are predisposed to within a gene and why. It's not just
personalization by gene, it's personalization by mutation. So, that's what's
going on in that realm.  

From the translational aspect, there are vaccines that are
being trialed now at Cornell and at other institutions for Lynch syndrome, for
hereditary breast and ovarian cancer to target the specific molecular
fingerprint that those associated tumors show. And it's just fascinating work
that I think is going to be revolutionary.  

And then for the stuff that I do, we are interested in the
clinical management. So, how do you recognize individuals who have a
predisposition at the population level? What are the evidence-based effective mechanisms
to prevent cancer? From a societal perspective, kind of thinking about public
policy, what's cost effective, you know, in terms of money spent and outcomes?
And then, we also look at health policy and shaping health policy.  

So, a lot of medicine and healthcare systems and physicians,
there are quality metrics, diagnostic quality metrics, therapeutic quality
metrics that are reportable. And so, we're actively working with large
organizations like the National Committee for Quality Assurance, the NCQA, with
CMS, the, Centers for Medicare and Medicaid Services, to establish metrics for
providers to help encourage appropriate diagnosis and management in field. So,
it's a broad spectrum of stuff, each of which is important fundamentally to
patient care.  

Dr. John Leonard (Host): Well, thank you so much.
This has been a great discussion and you've highlighted the key aspects of this
important field as well as the opportunities available for patients,
particularly if they pursue this line of care and evaluation at a center like
yours that really is focused on really the multiple dimensions and aspects of
this particular field. So, thank you very much.  

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That's it for CancerCast, conversations about new developments in medicine,
cancer care and research. I'm Dr. John Leonard. Thanks for tuning in.  

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