Personalizing Ovarian Cancer: Knowing your Genetics – Beth Karlan, MD | UCLA OBGYN


Welcome to today’s webinar from UCLA.
I am Dr. Beth Carlin, the Director of Cancer Population Genetics at the
Johnson Comprehensive Cancer Institute and Director of Women’s Health Research
in the Department of Obstetrics and Gynecology. I’m a gynecologic oncologist,
and in honor of gynecologic cancer awareness month, we’re bringing you
lectures about those cancers that affect women’s reproductive organs. Today, I’m
going to talk to you about “Personalizing Ovarian Cancer: Knowing your genetics can
improve your survival.” As we go through the information today, please feel free
to ask questions on Twitter using #UCLAMDChat or comment directly
in the YouTube chat window. The objectives for today are to provide you
with an update on our understanding of ovarian cancer’s origin, to review what’s
different about hereditary ovarian cancer, to discuss the importance of
genetic testing and selecting the best treatment to improve the outcomes, to
highlight the importance of cascade genetic testing for relatives to
identify carriers and prevent cancer, and to discuss targeted therapies for
ovarian cancer, such as PARP inhibitors. So let’s get started. Unfortunately, we’ve
not been very successful at curing ovarian cancer. We’ve been able to
improve how long women live but not the overall cure rate. As you see here, ovarian
cancer remains the deadliest gynecologic malignancy, and over these last decades,
the slope of this line of survival going from 1980 to the current time is really
barely, barely rising. We need to do better, and I think that’s what we
have today to really make some progress in those areas. One of the most important
things that’s come out in recent years is that ovarian cancer is not one disease. The National Academy of Medicine brought
together a group of experts to understand and talk about how we can
really incrementally begin to increase the survival and the outcomes for
ovarian cancer, and the overarching confusion from this meeting was that
it’s not one disease, there are multiple subtypes, and that we need research into
these specific subtypes so that we understand best how to treat, how to
prevent, and how to detect the disease earlier. We need to collaborate since
ovarian cancer is not a very common disease, and we need to make sure we get
this information to you so you can know what to do to make your survival the
best. This is just a diagram from that meeting telling you that ovarian cancer
is not one disease, and believe it or not, most ovarian cancers don’t even begin in
the ovary. The most common type of ovarian cancer, the high-grade serous
cancer–that makes up 80% and is the most deadly. Likely begins in the fallopian
tube next to the ovary. Clear cell and endometrial cancers, the next most common
types–likely begin in the uterus, in the endometrium that typically sheds with a
period, but if it goes the other way, it can become malignant,
and that leads most likely to clear cell. Endometroid carcinomas, low grade
serous cancers that are really a very uncommon subtype, making less than 5% of
ovarian cancers, may begin in the ovary, and the mucinous ovarian cancers, we
really don’t know. They may begin in the appendix or other areas of the GI tract.
So if we’re going to really improve survival for ovarian cancer, this basic
understanding is important for how do we prevent, how to be diagnosed early, and
how to retarget, and that’s really where I show you here all the different groups.
High-grade serous clear cell, endometriosis, low grade serous, again,
high grade serous, I’ve highlighted here. This is the most common that we think
about, often associated with BRCA 1 & 2, causes that fluid on the
abdomen, the ascites, you know, initially it was sensitive to chemotherapy and
then resistant, and has lots of genes associated with it, but when you look at
the molecular genetics, and we think about how we’re going to target these
cancers, how are we going to get women to live longer, they’re all different, and
this was such an important understanding for us to recognize, that these are
really different diseases we call ovarian cancer. But as I said earlier,
they probably most of them don’t even begin in the ovary, so understanding
these genetics can really now help us understand how to better take care of
you. This was a large study, and really gone beyond just the BRCA genes, but
there are similar genes in the same family as BRCA. They have lots of
different names, you know, RADs, MSH, PALB– all these different gene names. They also
have worked in concert to help your DNA, the genes that make you who you are, stay
normal. When one of these is altered, has a mutation, a break, it can’t do its job,
so the DNA accumulates these mutations, and to become a malignant cell, well,
almost 1 in 5 women with ovarian cancer will have one of these inherited genes
in their body that may have predisposed them to getting ovarian cancer. It’s very
important because depending on which gene it is, they may be associated with a
different cancer as well, and their family members may have inherited that.
Overall, although we think about these genes as common–as only in certain
families, 40% of the women with ovarian cancer who actually was found to have a
mutation had no one in their family who had any of these, had any other cancer until
they got it, so it’s very important, and the national guidelines now recommend
that 100%, every woman who has an invasive ovarian cancer should at least be
offered genetic counseling, and then if they would like to go on for genetic
testing–and this will be covered by healthcare insurers because it really
does inform how to best take care of you. Although in an earlier slide I told you
that it’s the high-grade serous cancers that most commonly have a BRCA mutation,
it’s not 100%. The way we look at the cancers under the microscope
and call them one type or another, again, has some interpretive value, so whether
you have a high-grade serous cancer an endometrial cancer, clear cell carcinoma–
all these different types–they still can be associated with these genetic
alterations, so no matter what type you have, it’s very, very important to have
the genetic testing done. And now we’re gonna go into why–why is this so
important, why am I keep going over this? Now first, let’s touch base with how do
you get the testing done. It’s really a test that’s either a blood test, a simple
blood test, or even from saliva. You just need some cells, since these inherited
mutations are in every cell of your body. So you discuss it with your doctor, you
have the counseling, and I think, if you have cancer, it’s very helpful because it
could inform your treatment, but what labs should you use? When should it be
done? Should everybody have it? So there are a number of labs out there–they
all do it the same way and have about the same cost, so I think it’s which lab
your doctor has the best communication with, in terms of the follow-up.
I think the testing should be done early on when you’re initially diagnosed so
that you can help–this can help, you know, what chemotherapy, and what treatments
should be done after the chemotherapy to keep you in remission–yes, all ovarian
cancer patients should be tested, and using one of these multi-gene panels,
because that will let you know if you have more than one mutation, but we’ll
also let you know what other genes may be at risk in your family. Now, if in the
past you had BRCA testing done, maybe 10 years ago, in recent years, we continue to
discover more genes associated with ovarian cancer, and these laboratories do
offer you update testing to test for the additional genes, which could also
influence your treatment, so that’s very important to discuss that with your
doctor as well, and it really will help not just you determine treatments, but
it will also help your family members know what they can do to be empowered to
not get cancer at all. Please discuss this with your doctor and with your
family member; it’s really very important. Now, if you have a BRCA mutation and you
have ovarian cancer, how is that different than someone who
doesn’t have one of these mutations? So, while you are at a greater risk of
getting the cancer–and you may have it today–actually, the data show you likely
will have a longer survival because you will be more sensitive to the
chemotherapy agents, the platinum-based chemotherapy that we prescribe. The way
your tumor spreads may be different, you may be more likely to have a liver
metastasis or spleen metastasis, but those two will respond very well to
treatment, and you can do well. And this new class of drugs that you’ve heard
about called PARP inhibitors–PARP is an acronym that stands for polyadenosine
ribose polymerase–it’s a mouthful, so let me continue to say PARP or that’s all
we’re gonna cover today– but these PARP inhibitors can help you
stay in remissions longer, help you live longer, and really many, many years, so
this is very important–an important reason to have the testing done. And of
course, it has other implications for other screenings. If you have ovarian
cancer and find out you have a BRCA mutation, you’re also at a very increased
risk for breast cancer. We don’t want to let lightning strike
twice, so having that additional screening with MRIs or considering other
ways to reduce your risk of breast cancer would also be important,
maybe intermission for 10 years or more. We don’t want to let something else
happen to you again. This is just what we call a survival curve, to just
demonstrate that these genetic mutation associated ovarian cancers, these women
live longer. So here in orange are the BRCA carriers that seem to live longer,
and here they are at five years, and over 60% are still doing well. Here, the other
cancers, the other mutations that we discussed earlier, and the gray is those
women who don’t have any mutations. Again, we’re doing better–5-year survivals
are over 40%. We still want to get–5 is not enough, 10 is not enough–we
really want to get to cure, but this is important information for you and also
about the next steps. Now, we’ve really been focusing in on inherited mutations–
those that can come from either your mother or your father–but make you who
you are. The mutation is only one typo and one gene of the 20,000 that make you
who you are, but it’s also possible for the cancer cells to acquire additional
mutations, and we call those somatic mutations–so it’s important whether it’s
germline in every cell, okay, where it’s in every cell of your body, or whether
it’s just in your tumor. Both cases will respond to PARP inhibitors, and it’s
important to have your tumor tested if you’re BRCA negative, meaning you have
a normal gene. The PARP inhibitors may still really benefit you, or other
treatments. If we do something called tumor molecular profiling–so that’s
different than what we spoke about earlier, that’s the blood test–this
or the saliva, to look for the inherited mutations–with tumor molecular profiling,
your doctor would ask the pathology specimen from your surgery to be sent to
a laboratory to look at all the genes that define that tumor,
that cancer–that’s not the genes that define you but just the cancer–to see
whether or not there’s an alteration in BRCA or in other genes where we may have
a targeted therapy, a new molecule that will stop that cancer by attacking that
gene alteration, and that’s something else, but again, a different process. After
surgery, your doctor can have the tumor specimen sent to a laboratory to have
the tumor molecular profiling done. This is another piece of good news that made
me very happy. This is a survival curve, again, of a
series of women who had a BRCA mutation or had BRCA in their tumors who, after
they went through their standard of care platinum and taxane chemotherapy,
were placed on a PARP inhibitor–this one called olaparib–and we’ll get
to more PARP inhibitors in just a moment– and here they are. When they published
these data, the women on olaparib here getting to five years, almost 70% of them
still doing well, still in remission, not having had a recurrence, and what’s
exciting about this as a scientist, you see, this curve begins to flatten out, and
when it gets to this plateau area, you don’t know how long it’s gonna go, so
this may be a hint maybe we’re finding a way to really get women to live a very,
very long time, maybe even be cured despite having advanced stage ovarian
cancer. Really something very exciting. Well, there’s been a lot of trials since
we’ve discovered the importance of PARP inhibitors. There’s currently three PARP
inhibitors that are FDA-approved for women with ovarian cancer. One’s called
olaparib, rucaparib, and niraparib. They are very similar in their
effectiveness. They have slightly different side effects, and depending on
you and how you’ve done with chemotherapy and other things, and you
can discuss with your physician which one of these is best for you, but they’re
all three very, very effective. So genetics are really helping to direct
how we take care of patients, helping us make great improvements and letting
women live longer and live better. Unfortunately–thank you for being here
with me today–but most women out there are not getting the genetic testing that
can really help them, and these data just show you that these are ovarian cancer
patients and breast cancers. Less than 1 in 5 are getting the recommended
insurance-covered guideline indicated genetic testing. Over here are the
ovarian cancer patients. In gray are those women that they even had a
discussion with their healthcare provider about the testing, and blue are
those that actually underwent the test– 10%. Remember, we said there should be a 100%. 10% of women with
ovarian cancer are getting the genetic testing. The rest of these are women who
had a history of breast cancer, even if they had a relative who had ovarian
cancer and then they themselves had breast cancer,
here we are. Less than 10% to getting tested. Here, they have a relative
with breast cancer and ovary cancer, and their breast cancers under age
50. Again, you can see here all these blue bars–the highest one is close to 20%.
Women with breast cancer under age 45–those are the ones still
under 20%, so we need to spread the word. We need to get women to understand, to
ask for this, and as I said, most insurers will cover it. Once you’re tested, please ask your family members to be tested as well. If
you find out you have a mutation, it’s 50% of your blood relatives who are in
your immediate family will have this gene as well, and they can take action to
prevent cancer. Angelina Jolie, I think many people know about, because she
really helped popularize this idea of genetic testing, but knowledge is power.
Don’t be afraid look into it. Angelina knew her mom had carried a BRCA
mutation because she had both breast and ovarian cancer, had been
tested, and when she tested positive, she took preventative actions to prevent
getting cancer herself. So if you identify a mutation, it’s valuable
information. You have tailored health management for yourself, risk
reducing interventions such as surgeries, enhanced screening for early detection,
family planning and relief those carriers who find that they don’t have a
mutation–these are just some of the tests you can have. Again, for breast
cancer, you would add breast MR–magnetic resonance imaging–to your mammography.
You consider prophylactic surgeries for ovarian cancer, you could have perhaps
risk reducing surgery there or other screenings. If you’re a man–again, half of
the carriers will be men–you’re at increased risk of prostate cancer, so
having PSA screenings, increased risk of pancreas cancer in some families, as well
as melanoma. I just want to take one moment to talk about risk reducing salpingo-oophorectomy–removing the tubes and ovaries to reduce your risk of
ovarian cancer. So these are if you’re healthy but know you have a BRCA
mutation. There are actions you can take so you don’t get ovarian cancer. For
BRCA1 mutation carriers, we recommend you have the surgery by age 35 to 44, BRCA2
mutation carriers between 40 and 45–this will significantly reduce your risk of
ovarian or tubal cancers. A bit of a fringe benefit, you also reduce your risk
of breast cancer by about half, and even if you do this at a younger age, you can
take hormone replacement therapy after the removal of the tubes and ovaries, and
it will not increase your breast cancer risk, so that is very helpful. It was
really the study of these specimens from the women who underwent this
prophylactic surgery that really launched all our understanding of
ovarian cancer as perhaps beginning in the fallopian tube versus the uterus–
really change the paradigm of how we think about these cancers, and just for
these high risk serous tumors, the most common ones, we now understand that they
likely begin at the end of the fallopian tube, the conduit that takes the egg to
the uterus to meet the sperm, but it’s actually those cells in the fallopian
tube that become malignant and then shed and implant on the ovary or metastasize
elsewhere, and this data now is so strong that our national professional
organizations–both the American College of OBGYN and the Society of Gynecologic
Oncology–recommend that we discuss prophylactically removing the fallopian
tubes, whenever we do a hysterectomy or other type of surgeries. So we’ve gone
over a lot of material today. Some of the key takeaways I’d like you to remember:
Ovarian cancer is not one disease. When we think about prevention or think about
early detection, we think about treatment. We need to think about what type of
ovarian cancer you have. If you have ovarian cancer and joining us today, and
you don’t know which type you have, please discuss this with your doctor. Get
genetic testing. It has importance for you, for your treatment, and for your
loved ones. Tumor molecular profiling may allow you to participate in other
clinical trials or may make other treatments available to you to improve
your outcome. PARP inhibitors can extend survival,
maintain quality of life, especially for those with these genetic mutations, and
please remember to discuss this information with your family because
cascade testing really can save lives by allowing people to be empowered by this
knowledge and take actions to prevent cancer. So, thank you for joining us, thank
you for your attention. I’d be happy to answer any questions. Please join us on
Twitter using the hashtag #UCLAMDChat or comment on the YouTube chat window,
and we’ll speak with you in a moment. Thank you very much. I’ve just been given two questions, so I
will start with those. This woman asks, “I’m healthy, but my grandmother died from
ovarian cancer. Should I be tested?” So when you meet with your doctor and
discuss this family history, as I said, men are just as likely to carry a BRCA
mutation as a woman, so if your paternal grandmother or your maternal–but I think
it’s important to remember to ask for both sides of your family history–
but if you have a grandmother who died from ovarian cancer, you should discuss
that risk with your health care provider. if you are of Jewish Eastern European
heritage, that population has a much higher frequency–10 times higher than
the general US population–risk of carrying a BRCA gene, and the current
recommendations are that you should have genetic testing. We have a very exciting
study ongoing at UCLA called BFOR. It’s the BRCA Founder Outreach study, and BFOR
provides you with access to BRCA testing for men and women over the age of 25 who
have at least one grandparent of Jewish heritage. To access this study, you can do
it online on your smartphone or on your laptop by going to BFORstudy.com.
You’ll see a series of videos. It’ll get you to have informed consent
about the BFOR study, and you can then go to have your blood drawn, and a
genetics expert will then go over the results with you and also communicate
with your primary care physician. I think it’s a great opportunity and something
you should avail yourself of. The other question is from someone
who currently has ovarian cancer, who’s fortunate to have been in
remission for many years, and she’s asking if
cancer comes back, are there any new treatments? So, yes, yes, and yes. It is an
exciting time to be a physician and to be a scientist. There are new discoveries
all the time. I just spoke about the PARP inhibitors. Now, that may not have been
available when you were initially treated, but there are many other new
treatments available, and they may even be good clinical trials that can help
you really stay at the cutting edge to have the longest survival possible. If
there are other questions, we’ll look into it
over the next coming weeks, and thank you again for joining us for this
important webinar.

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