A New Way to Tackle Triple-Negative Breast Cancer?
Kathy D. Miller, MD, Carlos L. Arteaga, MD
Jan 03, 2013
Introductions
Kathy D. Miller, MD: Hello. I am
Kathy Miller, Associate Professor of Medicine at the Indiana University
School of Medicine in Indianapolis. This is Medscape Oncology Insights,
coming to you from the 2012 San Antonio Breast Cancer Symposium. Joining
me today is Dr. Carlos Arteaga, Associate Director for Clinical
Research and Director of the Breast Cancer Program at the Vanderbilt
Ingram Cancer Center at Vanderbilt University in Nashville. Welcome,
Carlos.
Carlos L. Arteaga, MD: How are you?
Cleaning Up the Micrometastases
Dr. Miller: Thank you for taking the
time to come. I am looking forward to talking with you about your
profiling work on the genetic diversity found in triple-negative breast
cancer. This was started by your group and Jennifer Pietenpol, but the
work you are presenting here takes it to another level, looking at
whether metastasis is best predicted by the primary or residual disease.
Tell me how you did that study.
[1]
Dr. Arteaga: We speculated that
patients with residual tumors after neoadjuvant chemotherapy are
drug-resistant and may harbor targetable alterations that mirror what is
happening in their micrometastases. The standard of care is
observation, but we know that these patients tend to have a bad
prognosis. We should probably treat them with something, but we don't
know what. They have completed neoadjuvant chemotherapy, and they have
residual disease (which is a harbinger of high odds of recurrence), so
we speculated that we should be able to find targetable lesions in that
residual disease that may mirror what is happening in the
micrometastasis. If so, we could be in a position to institute early
adjuvant trials with targeted therapies to clean up that micrometastatic
compartment and potentially change the natural history of recurrence of
disease, curing some patients.
Dr. Miller: This is an idea that we
have talked about a lot -- that one of the benefits of neoadjuvant
therapy is allowing us to know how well that therapy works, specifically
for a particular woman and her tumor. We have tended to focus on the
successes; the patients who have a pathologic complete response do
really well. That has always left us with this problem, that the
patients who don't have a pathologic complete response -- particularly
if they have aggressive disease histology -- have a very high risk for
recurrence, and we don't have a clue clinically what to do about them.
Could this give us a way to find therapies for those patients?
Getting an Early Jump on Residual Disease
Dr. Arteaga: That is precisely the
purpose of this type of investigation. We still have to prove to
ourselves and to everybody else that when those metastatic recurrences
occur, they mirror the postchemotherapy residual disease better than the
primary disease. I think that we are going to find that the metastatic
recurrence, molecularly and by subtyping, resembles more that residual
tumor.
We are at a point, at least in academic centers that have access to
all these technologies, that we should be able to study these tumors in
some depth. We already have examples that stem cell signatures are
selected by chemotherapy.
There was a beautiful study from the MD Anderson Cancer Center
[2]
showing that in HER2-positive tumors after neoadjuvant chemotherapy, if
HER2 status went from positive to negative, those tumors didn't do
well. It suggested the possibility that this therapy had selected a
HER2-negative compartment that would not benefit from adjuvant
trastuzumab, if in fact it was reflective of the micrometastases in
those patients.
Dr. Miller: I have seen some of the
data from your work, which is a major tour de force with a large number
of samples -- not just paired samples, but a triplet of samples.
Dr. Arteaga: We don't have those data
yet. What we showed today was just the profiling of the
postchemotherapy residual cancer in the breast. In some cases, we have
the metastatic recurrences, and in many patients, we have the
pretreatment tumors. We have to complete the triplet and the analysis of
the triplets. That's in progress.
No Tumor Stays the Same
Dr. Miller: You would expect the postchemotherapy residual disease to look different from the primary disease in some ways.
Dr. Arteaga: It's always going to look different.
Dr. Miller: Is it going to look
different because something actually changed in the tumor, or because
there was tumor heterogeneity and the proportion of those different
populations has shifted?
Dr. Arteaga: Both of those hypotheses
can coexist; they are not mutually exclusive. Probably, both things are
going on. There is tumor heterogeneity, and in addition, it's possible
that for cells that don't die; the 4 months of therapeutic pressure may
change them. So, both things could be going on.
Dr. Miller: Would it affect how you would proceed with that patient after her surgery?
Dr. Arteaga: We have to do more
studies to confirm and to get more data that those metastatic
recurrences share targetable alterations with the posttreatment residual
disease. It would be interesting to know whether we are dealing with
selection as a function of the heterogeneity or selection as a function
of changing our tumor cell autonomous mechanisms, but that would be
academic. If we can confirm that they are targetable lesions that are
mirrored in the micrometastatic compartment and in the residual disease,
we probably have enough evidence to act upon some of these therapeutic
targets -- in randomized studies, of course.
Dr. Miller: Let me ask you about the
complexity, because you are likely to find not just 1 or 2 potential
targets, but a lot of alterations. Do you have any sense from the data
so far how wide that complexity might be? How big a number of different
therapies are we going to need?
Dr. Arteaga: That is a very good
question. We screen for only 182 oncogenes and tumor suppressors. We
found that there was not a single prominent lesion, except for p53
mutations, which as you know are not targetable. But 30%-40% of tumors
had
MCL1, which is a targetable antiapoptotic gene and Myc gene
amplification. There were other lesions in the PI3 kinase pathway,
alterations in different genes in the pathway.
We could be at a point eventually where we can lump types of
alterations in a network and say, "Okay, I see alterations in the
RAS/RAF/MAP kinase pathway; should I treat these patients with a Myc
inhibitor, or a group of alterations in the PI3 kinase pathway, PI3
kinase, P10, AKT, et cetera, and lump them?" This is going to require
collaboration -- multi-institutional studies that would allow us to
start exploratory studies where we already have very deep information
about the tumors we are treating.
Are Randomized Trials Possible?
Dr. Miller: I am going to ask you
about the practicalities of those studies, because it's an intriguing
idea to take advantage of what you learn about an individual patient's
tumor. It has this alteration, so I will treat the patient with a drug
targeting that alteration, but not all of those patients will have
recurrence. Some of them live long, happy lives in that setting,
although they are a high-risk group. With the complexity of the disease
and the number of different mutations, how does that become a randomized
study to find out whether those therapies had an impact?
Dr. Arteaga: I am not sure that it
will be difficult in the following sense. We are not treating the
patients who have a pathologic complete response, because we cannot
generate data from them; there is no tissue to study. Some of these
alterations are going to be associated with a very early recurrence.
For example, in our study, patients who have Myc gene amplification
recurred very quickly. So I bet that you can put studies together; it
will be multi-institutional studies where you group patients of the same
genotype and do a randomized study. It will be a difficult discussion,
but you can think of a 2:1 randomization of experimental therapy vs
observation, and based on the natural history that we see in these
recurrences, we may get an answer pretty soon as to whether we are
making an impact. It won't be easy, but at least in these trials we have
molecular information before we deploy it, and that's probably a
departure from what we have done up to now.
Alter Neoadjuvant Therapy to Match the Tumor
Dr. Miller: Are there other ways in
which this information could be helpful? Could you use that information
to alter the patient's neoadjuvant therapy at the beginning instead of
waiting until she has had standard therapy?
Dr. Arteaga: Absolutely. If those
lesions are present in the primary tumor and they have not been
eliminated by treatment, suggesting that they are associated with a
drug-resistant population, you could deploy your experimental treatment
in combination with chemotherapy up front. Of course, that would be
another potential benefit of this exercise.
Dr. Miller: Carlos, you have given us
a great view of the future. It's a complicated one, but one that has
great potential to benefit our patients. We look forward to catching up
with your work as it progresses.
Dr. Arteaga: Thank you.
Dr. Miller: Thank you for joining us,
and thank you to our audience for joining us for this edition of
Medscape Oncology Insights. This is Kathy Miller, signing off from the
2012 San Antonio Breast Cancer Symposium.
FROM MEDSCAPE, SHARING ONLY!
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COMMENT:
This research is an important one as it may open the door to knowledge to genetic pattern of resistant Breast cancers. It will answer a critical question about what to do with residual cancers?
This question is a major one particularly when you give up front all the chemotherapy in Neoadjuvant setting and you still have a residual mass that the surgeon eventually removes. Current recommendation is to proceed with Radiation and no further chemotherapy (Aromatase inhibitor or Tamoxifen in ER positive patient) and basically observe where the chips fall. (in triple negative patients).
By gaining insight into the nature of the residual disease, one may suggest additional intervention to offer to women with partial response after neoadjuvant chemotherapy.
Another important aspect discussed during the discussion is no notion of gene profile of the metastatic disease as it compares to the original presentation Vs the residual disease. This flow of progression in the profile of the gene will be even more important because it will bring out the variation in gene profile with the genetic intervention.
suppose:
A would be the gene profile at presentation
B gene profile in the residual disease after neoadjuvant therapy
C gene profile at Metastasis
difference between A and B
--------------------------------
could be induced by treatment but indeed could be a tumor evolution or both meaning evolution as affected or shaped by Chemotherapy intervention. The nature of the chemotherapy becomes critical. What agents were actually used. We can even detect the pattern of changes imposed by which chemotherapy.
Difference between B and C
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will tell us the true evolution of tumor,
it will point to evanescent effect of chemotherapy, and therefore which gene changes are temporary, due to chemotherapy or fixed.
It will point to important genes that actually drive metastatic progression
Difference in A and C
--------------------------
will point to what gene where not affected by chemotherapy and establish refractoriness and persist despite intervention. It may point to the soul of the cancer. if And C are completely different. True evolution of cancer will be learned.
This exhaustive comparative evaluation point to the fragmentary nature of the study by DR Arteaga SINCE IT FOCUSED B ONLY. It is a necessary step but clearly limited. It also point to the importance of the interpretation of the results obtained or to be obtained at each step!
They are onto something for sure. and 180 genes being looked at. that is impressive, and call for careful interpretation of results. HOW THESE GENES WERE SELECTED FOR SCREENING AGAIN?
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Follow-up at SAN ANTONIO
Researcher from Vanderbilt, namely Justin M Balko submitted a report where they examined tissue from 81 women who had undergone Neoadjuvant chemotherapy, in their study, they examined 450 genes as opposed to the 180 reported earlier.
90% of of all patient had at least 1 aberration in 5 signal pathways
1- PI3K/MTOR (therefore opening the door to Afinitor and related agents)
2. DNA repair (May be PARP will have a role here)
3. Ras/MAP kinase (Anti Myc /MEK inhibitor)
4. Cell cycle division (May be the Histone Deacetylase transferase inhibitor)
5. Growth Factor (Interferon and Interleukins)
Most common Mutations were in
-P53 (role of Vitamin D can be discussed here)
- MCL-1(found in 56% of tissue) and Myc, found in 36% (Histone deacyltransferase inhibitors here but also role of anti-actin/anti-Microtubule/anti-calmodulin )
The finding of prominent MCL-1, a Bcl-2 member goes directly to basic resistance to chemotherapy and actually could be reactive or an expression of primary refractoriness to chemotherapy.
JAK-2 was found in 11% (JAK2 inhitors could be tried)
The corollary question is whetehr to give the target therapy in maintenance setting or at time of progression.
