Dr. Maysa Abu-Khalaf and Dr. Gina Chung, Clinical
Trials for Breast Cancer
October 26, 2008
Welcome to Yale Cancer Center Answers with Dr. Ed Chu and Dr. Ken Miller. I am Bruce Barber. 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 the 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 Dr. Chu and Dr. Miller are joined by Dr. Maysa Abu-Khalaf and Gina Chung. Drs. Abu-Khalaf and Chung are Assistant Professors of Medical Oncology and leaders of several clinical trials for breast cancer at Yale Cancer Center.
Chu
How common is breast cancer in the United States?
Abu-Khalaf
Breast cancer is very common. About 1 in 8 women are expected
to have breast cancer during their lifetime. It is the most
common cancer in women, and therefore, it is very important for
patients to be screened.
Miller
About how many thousands of women will be diagnosed with
cancer?
Abu-Khalaf
About 200,000 women will be diagnosed in the US every year with
breast cancer.
Miller
In terms of cancer related deaths, is it also a significant
problem?
Chung
It is. It is the second most common cause of cancer related
deaths in US women, second behind lung cancer. As Dr. Abu-Khalaf
said, it is a very, very common and prevalent disease.
Miller
I want to ask you about screening. We have a lot of woman
listening to this show right now, what message do you want to get
across to them about what the optimum screening is?
Abu-Khalaf
The recommended screening for patients is that at age 40 they start
having a yearly mammogram. For women who are at a higher risk for
breast cancer, those that have a strong family history with
first-degree relatives or carry genetic mutations, it starts as
early as 25 years of age, or 5 to 10 years before the first-degree
relative developed breast cancer. The reason we recommend screening
is because it improves survival. If it is detected earlier rather
than later, there is a higher chance of cure.
Chu
There has been some discussion, or controversy, as to whether or
not mammography is the ideal imaging technique. Are there are
any other imaging modalities that may be better than mammography,
or is mammography still the gold standard?
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Chung
In this day and age we really do need to still emphasize that the
primary screening modality for breast cancer remains
mammography. There are other exciting and newer modalities,
for example MRIs of the breast, which are a very important tool as
well. But at this point, it is still reserved for
certain circumstances. For example, perhaps in patients, as Maysa
mentioned, with genetic mutations such as the BRCA gene. It still
should be done in conjunction with mammograms, so it is not a
replacement for mammograms and that is really important to
emphasize. It has strengths, but it also has weaknesses. Although
it may be more sensitive at detecting certain lesions compared to
mammograms, it does have a higher false positive rate, so that
needs to be taken into consideration as well.
Chu
On the low tech side of things, how about breast self-exam and exam
by doctors, how often should those be done?
Abu-Khalaf
That is controversial as well. However, for the most part we
do recommend breast self-examinations for adult women and certainly
a clinical examination should be performed regularly as well. For
adult women and premenopausal women we recommend that self-exams be
performed shortly after the menstrual period.
Chu
Both of you have mentioned BRCA-1, the genetic mutations that have
been linked to breast cancer, and obviously for women there is a
lot of anxiety about whether or not genetic testing should be
done. In what setting would one think about doing genetic
testing for breast cancer?
Abu-Khalaf
It is very important to know that most cancers are not due to
genetic mutations; about 5% to 10% of breast cancers are due to
genetic mutations. Red flags that make us think about
testing, or at least counseling, are younger patients, younger than
40 or 45 years of age, that have multiple family members, including
first-degree relatives, family history of ovarian cancer and breast
cancer, or men in the family that have had breast cancer. Sometimes
just young age by itself is a red flag that there might be
something more. At Yale-New Haven Hospital, when we see
patients in our clinics and suspect that there might be a genetic
mutation with a strong family history or young age, we refer our
patients for genetic counseling. When they meet with members of the
genetic team they discuss their risk factors, their family history,
and then after that discussion it is decided whether there is
really a need for testing.
Miller
Gina, when you see a new patient who is diagnosed with breast
cancer, let's say it is early stage breast cancer, what are the
factors that you look at for that patient as you start to think
about what you are going to do for her?
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Chung
It is a good question. The approach is multi-pronged.
We look at the specific features of that patient's tumor first,
very important is stage, and that is a measurement of how big the
tumor is and how far the tumor may have spread in the body.
That is one very important factor in prognosis, which obviously has
implications in treatment for the patient. In addition, there
are certain biologic features of the tumor that are very important
in prognosis and treatment as well. For example, in breast
cancer, we routinely test the status of the estrogen receptor, or
the ER status, as well as the progesterone receptor or PR, and the
HER2/neu protein, These things are all very important because we
have treatments targeted directly at these proteins, for example,
tamoxifen for ER positive disease and Herceptin for HER2/neu
positive disease. It is also very important to remember that
the patient is a person and we look at the functionality, the age,
and other medical problems that the patient has before we come up
with an overall treatment plan.
Chu
For early stage breast cancer it really is a team-based approach,
right? Maysa, can you help us go through that in terms of what
disciplines are involved other than medical oncology in coming up
with a treatment plan?
Abu-Khalaf
The physicians that are usually involved from the start are the
medical oncologist, the surgical oncologist, and the radiation
oncologist. In the past few years there has been a lot of emphasis
on a multi-disciplinary approach where we often meet with the
patient on the same day and then as a team we discuss what our
thoughts are about treatment options. Then we discuss the new
cases, especially at our Breast Cancer Tumor Board where we have
our colleagues from radiology and pathology and other members of
the medical oncology, surgical oncology, and radiation oncology
come up with a plan. Then we meet again with the patient and we
discuss the recommendations, and of course, we take into account
what the patient's wishes are.
Miller
I want to ask a couple of truth or myth questions. Gina, is this
truth or myth, that all patients with breast cancer need
chemotherapy after surgery?
Chung
I would say that is a myth.
Miller
We thought so, but why?
Chung
Well, again, going back to what I said earlier, it is very
important to look at an individual patient's tumor characteristics,
and the patient as a person. For some patient's breast cancer, for
example let's say a stage 1, small, less than 1 cm breast cancer,
we have been giving chemotherapy over the last 10, 15, 20 years,
more and more for patients with early stage breast cancer, there
are clearly a subset of patients with good enough
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prognosis for alternative treatments in the form of hormonal
therapies like tamoxifen, where I think chemotherapy would have
very little to add.
Miller
Maysa, truth or myth, mastectomy is better than lumpectomy and
radiation?
Abu-Khalaf
Myth.
Miller
All right.
Abu-Khalaf
A lot of the patients come in and their first inclination is "I
want the breast removed," thinking that's going to improve their
survival. There has been extensive data that breast conservation
surgery, with a partial mastectomy, or what we call a lumpectomy,
with the addition of radiation therapy has similar survival.
Often our treatment is focused on the local recurrences, or what we
call recurrences in the breast, and radiation therapy helps with
that as well. Most of the time as a medical oncologist, our
discussions are also about reducing recurrences that are distant.
These are more serious recurrences and the mastectomy would not
necessarily help with that, and that's why we talk about
chemotherapy and hormonal therapy to try to reduce the risk of the
cancer coming back outside the breast and the lymph nodes, such as
in organs like the lung or the liver, and the mastectomy would not
necessarily help with that.
Chu
Is it always the case that if the breast cancer is localized to the
breast, or has not spread to other tissues in the body, that
surgery is always done, or are there any instances in which one
might consider giving chemotherapy, hormonal therapy, or a
combination plus or minus radiation therapy beforehand?
Abu-Khalaf
What you are talking about is what we call preoperative
chemotherapy, or hormonal therapy. The standard has been that
when we are able to remove the cancer, we remove it and then we
follow it up with radiation therapy when needed, and then we talk
about chemotherapy and hormonal therapy. However, there are
cases where the cancer, although localized to the breasts or lymph
nodes, is large and the surgeon might have difficulty removing the
whole cancer without leaving anything behind. There are also
cases where the cancer is large enough and where the surgeon might
not be able to remove it and preserve the breast, so there are
instances were a mastectomy might have been the only alternative,
but now, with giving chemotherapy upfront, we might shrink it and
be able to preserve the breast and do only a lumpectomy
instead.
Miller
We have an email question regarding this. This is from
Phyllis who lives in Middletown, and she says, "I was found to
have breast cancer and the doctor is recommending that I
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receive chemotherapy before surgery. Do I need to worry
about leaving the cancer there in the meantime?"
Chu
Gina, your thoughts
Chung
I can understand the hesitancy and unease of certain patients, but
we think that delivering what we call systemic therapy, usually in
the form of chemotherapy but sometimes with hormonal therapy and
other drugs, is actually a plus in breast cancer. Breast
cancer is a disease that we think of as often being found localized
in the breast, but can potentially, what we call, micrometastasize,
very early on. That is, minute cancer cells may actually break off
and travel through the blood and the lymph stream and spread out
quite early on in the growth of the breast cancer. Thus, delivering
drugs that can actually target and kill these microscopic cells, as
well as the bulk of the tumor in the palpable tumor let's say, is
actually a good thing. It is certainly not something that is
addressed when you go to surgery first, and the reality is when you
give, for example, combination chemotherapy first before surgery,
the vast majority of patients actually have a good response, and
shrinkage of the tumor. It is really not a question of is it going
to shrink or not, but how much is it going to shrink? A minority of
patients, perhaps about 20% to 30% of patients, will have what we
call a pathologic complete response.
Miller
You are listening to the Yale Cancer Center Answers. We are
here discussing the latest in treatment and clinical trials for
breast cancer with Dr. Maysa Abu-Khalaf and Dr. Gina
Chung.
Over a 170,000 Americans will be diagnosed with lung cancer this year and more than 85% of these diagnoses are related to smoking. The important thing to understand is that quitting, even after decades of use, can significantly reduce your risk of developing lung cancer. Now, everyday, patients with lung cancer are surviving thanks to increased access to advanced therapies and specialized care, and new treatment options are giving lung cancer survivors new hope. Clinical trials are currently underway at Federally designated Comprehensive Cancer Centers like the one at Yale to test innovative new treatments for lung cancer, and patients enrolled in these trials are given access to medicines not yet approved by the Food & Drug Administration. This has been a medical minute, and you will find more information at yalecancercenter.org. You are listening to the WNPR Health Forum from Connecticut Public Radio.
Miller
Welcome back to Yale Cancer Center Answers. This is Dr. Ken
Miller and I am joined
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by my co-host Dr. Ed Chu, and also our guests Dr. Maysa Abu-Khalaf
and Dr. Gina
Chung from the Yale Cancer Center. Let's focus on some of
the work that you are doing which I think is very, very
exciting. Gina, you are working on research now on giving
preoperative hormonal therapy. Can you tell us about
that?
Chung
We have known, and alluded to earlier, that in patients who have
estrogen receptor positive breast cancer, which represents about
60% to 75% of breast cancers, those patients often have a very good
response, and sometimes a better response with hormonal therapy
such as tamoxifen or aromatase inhibitors than even chemotherapy.
Thus the question was, and we already talked about chemotherapy
shrinking breast tumors before surgery, but can we actually get a
better response, or at least an additive response, by adding
hormonal therapy? Our clinical trial is recruiting patients who
have ER positive breast cancer, in this case they must be
postmenopausal because the hormonal therapy of choice is something
called letrozole which is an aromatase inhibitor that is effective
in postmenopausal women. In addition, we will be combining
this drug with a drug called Avastin, or bevacizumab. This is
a monoclonal antibody therapy that is targeted against a protein
that we think is very important in angiogenesis called VEGF, and
the combination is felt to be more effective than individual drugs
on its own. So patients will be getting the two drugs in
combination for approximately four months before surgery with the
goal of shrinking the tumor prior to surgery.
Chu
And one of the nice things about this combination, I take it, it is
that there are relatively fewer side effects than compared to
traditional chemotherapy.
Chung
Yes, absolutely, and one of the hopes to underline is that if
patients have very good responses and good long-term outcomes,
perhaps there are patients we can tease out who can avoid
chemotherapy that may have otherwise received it. And yes, the
hormonal therapy, and Avastin in general, have much more tolerable
side effects, the most common being things like hot flashes
for the hormonal therapy that are not too bad, no hair loss,
etc.
Chu
Gina, you have also been very focused on trying to target this
process of angiogenesis that you just mentioned, can you tell our
listeners out there why this process of angiogenesis is so
important and why you are focused on trying to inhibit that
process?
Chung
Cancer growth, including breast cancer, is obviously a very
complicated process and there are many, many things that are very
important in the development, growth and spread of cancer.
One of the things that has really come to light recently is this
process of angiogenesis, which is the formation of blood vessels in
and around tumors. There are
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many hypotheses as to why this is important, and of course, if it
is really important the next question is, how can we stave this
process so that we can take advantage of it as a treatment
modality. When we look at tumors, we can actually see more blood
vessels around it, and it may be that these blood vessels are
serving to bring in more nutrients and oxygen to help the tumor
grow, but perhaps also what we can do is give treatments that can
take advantage of that, so treatments are delivered to the tumor
better. This is a very exciting field and there are certainly
many, many drugs currently available, Avastin being one of them,
but there are others in development targeting this very important
pathway.
Miller
Maysa, I know you have done some very interesting work related to
Herceptin, which is a target therapy. Tell us a little bit
about that, and what are you working on now?
Abu-Khalaf
Herceptin is a very important drug. As Dr. Chung talked
about, in the past having an expression of HER2 protein on breast
cancer cells led to a worse prognosis, so patients had worse
outcomes. Then the drug which targets these proteins and
blocks the pathway that causes the worse prognosis in breast
cancer, led to improved survival, and this was initially evaluated
in patients with advanced breast cancer. Most recently, there has
been a lot of data that supports giving it upfront for early stage
breast cancer. However, we know that a small percent of
patients are resistant to Herceptin upfront, and a lot more become
resistant later during treatment. Given the importance of this
drug, and this pathway, we have decided to look at other drugs that
might reverse the resistance to Herceptin. We have a drug called
rapamycin, which comes under the category of an mTOR inhibitor, and
this is a drug that's been studied in organ transplant extensively.
More recently, it has been found to have effects on cancer biology,
so what we are trying to look at in clinical trials is whether we
can reverse the resistance of Herceptin. One method to do this is
to evaluate whether this mTOR inhibitor called rapamycin can do
so.
Chu
What is really remarkable, as we learn more and more about the
biology of cancers in general, but specifically breast cancer, is
that breast tumors have an amazing way of adapting once we give a
certain treatment. There are so many different ways for the breast
tumor to continue to grow even in their presence. This is one
interesting approach to try to target the ability, or inhibit the
ability, of the breast cancer to overcome our treatments.
Chung
Yes, I think the major advances in breast cancer have come from
our understanding that not all breast cancers are the same.
Even within the subtypes like HER2 positive, or ER, PR positive
cancers, there is variation in how these tumors respond and how
they find ways to overcome, or become resistant to, the available
drugs. It is very important that we use these novel drugs that we
have to try to overcome this resistance.
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Miller
What other new agents are you working on right now, Maysa?
Abu-Khalaf
We have another clinical trial that we will be opening up soon
looking at a drug called vorinostat. It is one of the groups
that are called HDAC inhibitors, and again, we are using this with
a drug called capecitabine that has been proven to have effects in
advanced breast cancer. What we are doing is looking at different
schedules of capecitabine, or Xeloda, in combination with
vorinostat with the hope that we will find synergy and improve
efficacy in treatment of these patients.
Miller
Question for both of you, we have talked a lot about targeted
therapies, is there anything new or different in terms of using
chemotherapy for women with metastatic breast cancer? Any advances
that you have found to be exciting?
Abu-Khalaf
You mean chemotherapy targeted therapy?
Miller
Chemotherapy or combining chemotherapy and target it.
Chung
There is actually a number of them and there are always many
ongoing clinical trials looking at novel therapies in metastatic
breast cancer, as well as novel combinations and novel
chemotherapies as well. For example, a drug called
ixabepalone, which falls under a category called epothilones, is a
chemotherapy and has been recently approved for use in combination
with capecitabine in metastatic breast cancer. There are a
number of other combinations, for example, taxanes and taxol with
Avastin, the antiangiogenesis targeted agent, and that's been
approved for metastatic breast cancer recently as well. There
are very interesting drugs that are being approved and many others
that are being studied currently.
Chu
I think an important point to emphasize is that the treatment of
advanced breast cancer really has evolved and matured over the last
few years, such that I think it's fair to say that women with
metastatic breast cancer really are dealing with a chronic disease,
and perhaps colorectal cancer is next in line. There are so many
treatment options available, first line, second line, third line,
fourth line, chemotherapy, biologic agents and targeted agents,
that certainly since Ken and I were in training, back in the dark
ages, things have moved over the last 10 or 15 years. It's really
amazing, the advances that we have seen, wouldn't you say?
Abu-Khalaf
It's a very exciting time and we have a lot more novel drugs on the
way, so even with what we have right now, we have a lot more to
offer to patients. There are a lot of choices, and often it's
confusing for patients to have so many choices, but I always
tell
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my patients it's a good thing to have all these options.
Miller
Just as a final question, and a very broad one, if you see a new
patient with breast cancer, and they ask you if it's a curable
disease, what's your answer?
Abu-Khalaf
Yes, it is definitely a curable disease. That's why we encourage
screening because the earlier the diagnosis, the higher the cure
rate.
Chu
Great, Maysa and Gina, it's been great having you on the show
and we look forward to having you back and telling us what advances
have been made on the clinical trials front. You have been
listening to Yale Cancer Center Answers. We would like to
thank our guests, Drs. Maysa Abu-Khalaf and Gina Chung for joining
us this evening. Until next time, I am Ed Chu from the Yale
Cancer Center wishing you a safe and healthy week.
If you have questions for the doctors or would like to share your comments, go to yalecancercenter.org where you can also subscribe to our podcast and find written transcripts of past programs. Next week you will meet Dr. Otis Brawley, Chief Medical Officer for the American Cancer Society. I am Bruce Barber and you are listening to the WNPR Health Forum from Connecticut Public Radio.