Dr. Lyndsay Harris, Clinical Trials for Breast
Cancer
August 31, 2008
Welcome to Yale Cancer Center Answers with doctors Ed Chu and Ken Miller. I am BruceBarber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Dr. Miller is a medical oncologist specializing in pain and palliative care and he also serves as Director of the Connecticut Challenge Survivorship Clinic. If you would like to join the discussion, you can contact the doctors directly. The address is canceranswers@yale.edu and the phone number is 1-888-234-4YCC. This evening Ed Chu is joined by Lyndsay Harris, Director of the Yale Cancer Center breast cancer program and co-director of the Yale New Haven Breast Center. Dr. Harris is an expert in the treatment of breast cancer and focuses research on identifying the subtypes of the disease.
Chu
How common is breast cancer here in the United States?
Harris
Breast cancer is extremely common in North America and in fact, is
the most common solid tumor in women. The incidence is about
1 in 200,000 per year; although it has been decreasing over the
years.
Chu
Are there any racial or ethnic differences in terms of the
incidence of breast cancer?
Harris
Yes, breast cancer is more common in white women, however, in
African American women, it is more likely to lead to death so it is
a much more serious disease in that group of women.
Chu
Actually, in getting ready for the show this evening, I went on the
American Cancer Society website and to bring things closer to home,
here in the State of Connecticut there will be an estimated 2500
cases of breast cancer diagnosed in the year 2008.
Harris
Right.
Chu
So it is a pretty significant major public health problem. A
very common misconception, Lyndsay, is that if there is no family
history of breast cancer then a woman does not have to worry about
the possibility that she, or one of her loved ones, may develop
breast cancers. Is this fact or fiction?
Harris
It is a fiction, in fact, the risk of breast cancer is about one in
eight if a woman lives through the age of 85. In fact, the vast
majority of women do not have a strong family history; probably at
least 80% to 90% of women who are diagnosed with breast cancer do
not have a strong family history.
Chu
What are some of the other risk factors that one needs to think
about?
Harris
Breast cancer is most likely related to hormonal exposure in life.
We know
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that certain things like estrogen replacement therapy over a long
period of time, or having exposure to estrogen either early on in
life with early menstrual cycles, or later with frequent menstrual
cycles with a late menopause are all risk factors for breast cancer
that suggest hormone exposure is the strongest risk factor.
Another interesting fact that has recently been reported in the
news is that since the decline of estrogen replacement therapy in
the last five years or so, there has been a decline in the
incidence of breast cancer, which is quite striking. There
was a report in the New England Journal recently indicating that
the decrease in hormonal replacement may partially explain the
reduction in the incidence of breast cancer.
Chu
And what about the role of diet?
Harris
Well, it is a complicated question because we do not have really
good information on whether fat in the diet is related to breast
cancer risk. There is some evidence that fat in the diet is
associated with risk, however, it is controversial and not all
studies are equivalent or show a similar effect.
Chu
There has been very positive news recently that, as you say, the
incidence, but in particular mortality of the breast cancer has
been dropping. Many folks have attributed that to the focus on
early detection screening. Can you tell us a little bit about
that?
Harris
It is actually equally encouraging that the mortality from breast
cancer has started to decline over the last decade, even before
this recent observation with the reduction in the incidence over
the new cases and that appears to be due to two different
things. One is the screening for breast cancer and earlier
detection. The second is better therapies for women who are
diagnosed with breast cancer and those are mainly systemic therapy
such as chemotherapy and hormonal therapy.
Chu
We will focus, I guess, on the therapy part later on in the talk,
but focusing on this issue of screening early detection, for an
average risk women, when should screening for the possibility of
breast cancer begin?
Harris
The recommendation is that at the age of 40 a woman starts having
annual mammograms. There is some controversy, but many
agencies recommend starting with the baseline screening mammogram
at the age of 35.
Chu
And again, these are women who do not have a family history of
breast cancer. Say for instance someone has a first-degree relative
that had breast cancer in the past, would screening start earlier
in that setting?
Harris
It depends a little bit on how strong the family history is.
A first-degree
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relative, in other words a sister or mother, who was diagnosed over the age of 50 only slightly increases the risk of developing breast cancer in that person, whereas having a first-degree relative less than 50 increases your risk more substantially for women. With a very strong family history such as someone carrying one of the genetic predispositions, we recommend starting screening 10 years before the first person in the family developed their breast cancer; in other words if that first person in the family was 40, you should start screening at 30.
Chu
Great, so these predisposition familial syndromes you just
mentioned, could you explain exactly what that is?
Harris
There are certain genes that we know predispose women to breast
cancer and these are, what we call, dominant change. You only
need one of them to be abnormal in order to stromatically increase
your risk. The BRCA-1 and BRCA-2 genes are two of them, p53
is another and P10. There are several that have been identified
that predispose to breast cancer. Those particular genes give
you a risk of somewhere between 20% and 40% likelihood of
developing breast cancer in your lifetime, which is much higher
than the average women in the population.
Chu
An important point to emphasize to our listeners out there is that
if in fact one carries one of those genetic mutations that does not
necessarily mean they are going to 100% develop breast cancer.
Harris
Correct, and in fact there are many options for prevention and
screening that are now available to prevent that from happening as
well.
Chu
One issue that has come up recently is the traditional mammography
approach versus using MRI. What are your thoughts on that?
Harris
MRI is, on the one hand, a wonderful tool and is very helpful for
screening high-risk women; in fact, it has been approved by various
insurance companies for screening women with a genetic mutation
such as BRCA-1 or BRCA-2, but the use of MRI in women with average
risk is at this point not recommended.
Chu
How often should women be screened? You mentioned you should
typically start at the age of 40, but what are the general
recommendations for follow-up screening efforts?
Harris
Well, it is controversial and some agencies recommend annual
whereas others
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recommend every other year for a 40-year-old woman. I would say to speak with your surgeon and understand what their particular approach is, because there is some variation depending on the person, but in general we recommend annual screening after the age of 40.
Chu
I would imagine the same would hold for a woman who has had a prior
history of breast cancer, where they are worried about the risk of
breast cancer occurring on the other side, and those women should
get annual mammogram screening as well?
Harris
Yes, for women who have been diagnosed with breast cancer, annual
mammograms are absolutely essential and in some cases, MRIs are
used in women who have difficulty with mammograms where they are
not that helpful. They are not that sensitive because of the
denseness of the breast tissue.
Chu
Typically, if a woman has had a screening mammogram and there are
some abnormalities seen, what would be the next step that
individual should take?
Harris
The mammography community is very sophisticated and typically a
woman should receive her information from her screening mammogram
the same day, this is part of legislation, and if there is any
abnormality it should be followed up either with a 6-month
mammogram, or if there is a higher degree of suspicion, they would
recommend that it be biopsied.
Chu
And typically who would do the biopsy?
Harris
Radiology departments now do biopsies in the mammographic screening
facility with something called a core biopsy used as the most
common approach for those areas and they are easy to biopsy using
that approach. If the mass is not detected that way but is
felt as a lump, then the surgeon will typically do the biopsy.
Chu
So, once a diagnosis of cancer has been made, then what is the next
step for that woman?
Harris
Well, once the diagnosis has been made definitely, there are a
number of different things to be considered for a particular woman.
The treatment of breast cancer is really multidisciplinary, meaning
that there are several different specialties involved in the
treatment even at the very beginning. These include the
medical oncologist, radiation oncologist, and the surgeon working
as a team to decide what the most appropriate approach for that
particular patient is.
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Chu
Great, maybe we can pick that up at the other side of the
break. At this time, we would like to remind you to e-mail
your questions to
canceranswers@yale.edu, or call 1-888-234-4YCC. At this
time, we are going to take a short break for a medical
minute. Please stay tuned to learn more information about the
treatment of breast cancer with our special guest expert, Dr.
Lyndsay Harris from the Yale Cancer Center.
Chu
Welcome back to Yale Cancer Center Answers. This is Dr. Ed
Chu and I am here in the studio with my close colleague and friend,
Dr. Lyndsay Harris, discussing the latest treatment options for
women with breast cancer. Before the break we were talking
about the multidisciplinary approach to women with breast
cancer. For those listeners who did not catch it, if a woman
is diagnosed with breast cancer and coming here to our center at
Yale, the different disciplines would all be working together to
figure out what the best treatment option for that individual
patient is.
Harris
Right, and the different disciplines that are so essential for
helping a woman with the diagnosis of breast cancer are the breast
cancer surgeon, the medical oncologist, and the radiation
oncologist. These specialties are all experts in their own
field and all of these treatments are often offered to a woman with
the diagnosis of breast cancer.
Chu
Also part of that team is the pathologist, the radiologist and some
other folks as well.
Harris
Absolutely. The treatment team is those that I mentioned and
the team that helps with understanding the type of breast cancer
and the extent of the breast cancer which includes the pathologist,
radiologist and our genetics counselors. Our genetics program is
also integrally involved all the way from the
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beginning of the diagnosis of breast cancer to help us make the best recommendations for treatment.
Chu
On a very simplistic level, we tend to think that breast cancer is
just one disease, but what you, and many of your colleagues around
the country, have now found is many different diseases within the
umbrella of breast cancer.
Harris
That is right, Ed. Although we know the most common type of
breast cancer is ductal carcinoma, within the ductal type there are
multiple different molecular subtypes that behave very differently
from one another and it is critical to know those differences when
you are beginning to treat a patient in order to offer her the best
type of therapy.
Chu
So this molecular profile of a tumor really can help pinpoint a
treatment that will work as opposed to a treatment that might just
provide side effects and toxicities and really have no benefit at
all.
Harris
Yes. That is exactly right and these molecular subtypes are
now recognized and are part of standard of care in order to decide
if a woman's tumor has the HER-2 receptor, for example, and she
should be receiving herceptin or the estrogen receptor, and she
should receive hormonal therapy, and there are new entities that we
think are more sensitive to chemotherapy. There are many
important features from the pathology that are critical for us to
make the best recommendation for treatment.
Chu
It really is remarkable, the advances that we have seen in the
treatment of breast cancer, because this has happened over the
last, say, 4 to 6 years.
Harris
Yes. Certainly within my career, I have seen the development
of understanding of the molecular biology of breast cancer and now
within the last 5 years or so, we have had changes in the way we
treat patients based on those molecular features of the breast
cancer.
Chu
We would like to talk about this concept of individualized,
personalized medicine, but there is probably no other disease
besides breast cancer that highlights what we can really do if we
have a better understanding of what is going on in the tumor
itself.
Harris
I agree completely and fortunately for women with this diagnosis of
breast cancer, scientists have really led the field in terms of
understanding the molecular biology of the disease and being able
to subdivide the tumors into different types for the benefits of
patients specifically.
Chu
Your own research has focused on trying to get a better
understanding of this
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HER-2 new gene protein. Can you tell our listeners what your research has focused on?
Harris
The breast cancer subtype that is dominated by the HER-2 gene is
something we have been starting for many years in our group, and we
and many others have found that this particular type of breast
cancer has a worse prognosis without treatment, but given specific
therapies, the prognosis is actually just as good as those less
aggressive types of breast cancer. We have looked
specifically at which therapies are best and in some cases women
benefit a lot from therapies such as herceptin or chemotherapies,
and in other cases they do not. So, we are focusing our
efforts on trying to define which molecular features predict. Who
is going to benefit the most from herceptin and who is potentially
not going to have this much benefit and maybe should try a
different medication.
Chu
You are very actively involved in helping to lead our efforts here
at the Yale Cancer Center to develop new clinical trials, which
incorporate a lot of this state-of-the-art science. Can you
tell our listeners out there what some of the interesting trials
that you and your group are leading here at Yale are?
Harris
Our goal is to take the next step to try to improve on the standard
therapies that exist. We do this by adding new drugs to the
standard therapy such as herceptin in order to overcome resistance
to those drugs. For example, Dr. Abu-Khalaf in our group has
a trial with herceptin and rapamycin. There is a recent
report from a meeting suggesting that combination is highly active
in women who are resistant to herceptin, and we now have this
available as part of a clinical trial. In addition, we are
looking at new approaches in early stage breast cancer by adding
new medications to herceptin or changing the way that we deliver it
in order to optimize therapy for HER-2 positive patients.
Chu
Not a new drug, but a new drug to breast cancer, is an agent called
Avastin which has received a great deal of attention and is
standard of care now, but I know that your group also is very
interested in incorporating Avastin in some of your clinical
trials.
Harris
That is right and Gina Chung leads our efforts looking at the
activity of Avastin and other angiogenic drugs. This class of
drug actually acts not so much by targeting the breast cancer tumor
itself, but the surrounding blood vessels that allow it to grow and
so there are a number of different drugs now with Avastin being the
first one that has been approved that can essentially starve the
tumors ability to develop its blood supply and can be added to
therapies to improve the outcome. For example, Avastin was just
approved by
the FDA for women with advanced breast cancer to be used in
addition to paclitaxel.
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Chu
It is interesting, as you know my own area of interest is
colorectal cancer where Avastin was first approved. This drug
is quite remarkable and in addition to inhibiting the tumor blood
vessels if you will, it also seems to enhance the normal blood flow
delivery of chemotherapy to the tumor which then makes the
chemotherapy work that much better. I wonder if that may also be
happening in breast cancer?
Harris
That is a great point, there are other ways that Avastin is
working. We do not entirely understand exactly how it
benefits patients but what we are trying to do in our program, and
Dr. Chung is leading this effort, is to offer Avastin to early
stage patients which would not otherwise be available and to try
and determine if the blood flow to the tumor is improving by doing
an MRI before and after the dose of Avastin.
Chu
All of your research interest is in tying to understand why
minority women, particularly African American women, may not have
the same level of benefit to treatment as their Caucasian
counterparts. Can you tell us a little bit more about
that?
Harris
The difference between outcomes from breast cancer in African
American and white women is really quite striking and has been seen
in multiple studies now. The reasons for it are still a bit
unclear. It appears that African American women are just as likely
to be screened for breast cancer, although some of the studies
suggest that the follow-up screening may not be as likely and so
that is an area of active research, trying to understand how to
improve that. In addition, we know now from our molecular
biology studies that tumors that arise in young African American
women are likely to be more aggressive. This triple negative, or
basal cell type of tumor, is much more common in those women and
partially as a result of that, the prognosis may not be as
good.
Chu
So they are less responsive to the traditional chemotherapy and the
newer therapies?
Harris
Suffice it to say they are not able to benefit from hormonal
therapy or herceptin. It may be that they are more sensitive to
chemotherapy, however, it is unclear exactly what subgroup is more
sensitive to chemotherapy. That is the area of active research, to
determine whether it is simply not receiving adequate therapy that
leads to a worse prognosis or whether there are some breast cancers
in African American women that are more resistant to therapy.
Chu
Your group is also very keen on trying to identify some newer
agents that
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really have not yet been used in the community. Can you tell us a little bit more about some of the newer agents that your group is working on?
Harris
We have as our goal to try and improve the outcomes of women with
breast cancer and we know that while there are many active drugs,
there are still breast cancers that do not respond to the standard
therapies. So for the HER-2 tumors, for example, there are a
number of drugs that do appear to work in women who do not benefit
from herceptin, or they become resistant. The HDAC inhibitors are
one class that is being actively evaluated in our group. In
addition, the triple negative breast cancers that do not have
either ER or HER-2 appear to be more sensitive to certain types of
drugs such as PARP inhibitors. We have a study that combines PARP
inhibitor with chemotherapy, which is about to open here at
Yale.
Chu
What was remarkable about this class of agents was that probably a
year ago at last year's ASCA meeting there was a very early
preliminary phase I study looking at a PARP inhibitor. It was from
Europe and it had unbelievable activity in women who had these BRCA
genetic alterations. I guess the thinking would be that for
women with breast cancer, these PARP inhibitors really should be
quite active, in particular for those who have either BRCA 1 or
BRCA 2 mutations.
Harris
That is right and in fact, there is a close relationship between
this triple-negative type of breast cancer and the BRCA mutations.
Women who have BRCA mutation often develop these triple negative
basal tumors but there may actually be a type of breast cancer that
is not associated with family history that behaves in a very
similar way.
Chu
Lyndsay if anyone out there would like to get more information
about any of the clinical trials that you or your group are doing,
do have a number or a website that they can go to?
Harris
Yes, the best place is to dial 1-888-234-4YCC or to go on to Yale
Cancer Answers website.
Chu
The other website would be www.yalecancercenter.org
where there is a complete listing of all of the clinical trials and
a particular focus on the breast cancer team with you leading the
way. We are ending our evening discussion, any last minute
words of advice for those out there?
Harris
I just want to emphasize that it is an incredibly hopeful time in
the treatment of breast cancer and cancer in general. There
are so many new developments, new treatments, that are making a
huge impact that are improving outcomes
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for patients. I would remind patients to please seek as much information as you can when you are diagnosed and make sure that you are getting the best therapy that is right for you personally. Seek the resources that are needed and make sure that you have a multidisciplinary team of doctors helping you make decisions about how to be treated for your breast cancer.
Chu
That is terrific advice and I want to thank you for joining me this
evening on Yale Cancer Centers Answers.
Harris
It is a pleasure Ed, thank you so much.
Chu
Until next week, this is Dr. Ed Chu from the Yale Cancer Center
wishing you a safe and healthy week.
If you have questions, comments, or would like to subscribe to our podcast, go to www.yalecancercenter.org where you will also find transcripts of past broadcasts in written form. Next week, we look at the latest information on skin cancer with Dr. David Leffell. I am Bruce Barber, and you are listening to the WNPR Health Forum from Connecticut Public Radio.
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