A New Way to Tackle Triple-Negative Breast Cancer?
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?
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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.
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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
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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
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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.
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.
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