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Is There a Role for TNBC Subtyping?

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Tuesday, Aug 30, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
Now, we’ll move on. We have a lightning round toward the end here on a few other topics we want to talk about. We’ll talk briefly about triple-negative breast cancer. I think the first thing I’d like to ask people is, do you think there’s going to be a role for subtyping triple-negative breast cancer going forward? And we’ll do it informally, but is there going to be a role for a formal subtyping to put people in trials for this particular type, say an AR-positive subtype? Or is it an immune-modulatory subtype? What do you think?

Carlos L. Arteaga, MD: I think we’re there. We’re doing it now, at least in my institution and our consortia we’re a part of. We are selecting patients with triple-negative breast cancer—that are androgen-receptor (AR)-positive—by immunohistochemistry for allocation into trials with enzalutamide plus something else versus cisplatin plus something else. So, I think that’s happening. Would that happen to other subtypes? Well, we don’t have any data yet, but eventually we may.

Adam M. Brufsky, MD, PhD: Just going to the AR-positive subtype for a minute. I started getting into this because I have a patient who’s undergoing a sex change and developed an ER-positive/AR-positive breast cancer. As we started looking into this—and testosterone in AR in non–triple-negative breast cancer actually involutes the breast—why are we doing inhibitors? Why are we not doing stimulators?

Carlos L. Arteaga, MD: That’s a very important question. There is a concern by people that study these receptors in tumors that are estrogen-deprived—ER-positive tumors that are on an aromatase inhibitor, and they are also AR-positive, which aren’t the majority of them—the addition of enzalutamide may be deleterious. I think we need some more mechanistic signs there in order to define whether we should deploy an anti-androgen just widely to any tumor that is AR-positive.

Sunil Verma, MD, MSEd, FRCPC: I guess the data that we have to date on ER-receptor inhibitors in triple-negative breast cancer is really phase II data, and we’re not sure if it’s more of a prognostic marker or a therapeutic marker, that these patients would have done well anyway if they have AR-positive disease, whether this is actually true treatment evaluation. So, we await the randomized data. But, there’s no doubt in our mind that we do need to start stratifying these patients. And the role of immunotherapy, probably at the present time, seems to be the strongest, and it’s relative terms, compared to other breast cancer subtypes. At least the data that we have seen that the mutational load, the type of triple-negative breast cancer that we’re seeing, it’s more likely the type that’s going to respond to immunotherapies compared to some other breast cancers.

Adam M. Brufsky, MD, PhD: I want to just finish with the AR. So, Joyce, you’ve done a lot of work with this, and what’s your thought of where you think this is going in the AR-positive triple-negative subtype?

Joyce A. O’Shaughnessy, MD: I think there’s a small percentage of the AR-positive triple-negatives, they’re very strongly AR-positive and more slowly proliferative. And if you looked, this new diagnostic PREDICT AR that’s RT-PCR–based (real-time polymerase chain reaction), etc, does look to be more predictive than just IHC (immunohistochemistry), so that’s helpful. But if you look at the correlation between the PREDICT AR-positive and the strongly AR-positive, it’s really skewed towards very strongly AR-positive. It does pick up some more weakly AR-positives by the IHC, so that might be helpful, but there’s a pretty good correlation.

I actually am impressed with the data as a predictive marker, and there is definitely a prognostic thing there, as well. But, I think that in the enzalutamide phase II, in this heavily pretreated group of patients, getting up around 40% to 50%, the clinical benefit rate was pretty impressive in these PREDICT AR-positive patients. But, then there’s this other group that are more weakly AR-positive; it won’t be all about AR in those patients. And are these the PIK3CA-mutant triple-negatives? Carlos has some interesting data on that. I think that’s an intriguing possibility. I think AR is very important; it’s one of those targets both in triple-negative and in HER2-positive—and even more complexly in ER-positive—that we need to go after pretty vigorously because we are going to figure out how to really utilize it.

But, I actually think that the phase III trial of enzalutamide will start in the first-line metastatic setting. So, we’ll get phase III data, but it’ll be awhile. It’s not a very common patient population. I personally would like to see a trial fairly quickly in, strongly predict AR-positive patients in, the no-path CR, for example. I’d like us to move a little faster in this regard.

Adam M. Brufsky, MD, PhD: Before we get to immunotherapy, which I think is the “topic A” in this field right now that we all have a lot to say about, I just want to ask one quick question. Should we be using BRCA status and/or HRD status, homologous recombination deficiency status, to determine who gets platinums? Should we be using that or not?

Sunil Verma, MD, MSEd, FRCPC: We have the TNT trial that was reported last year showing that patients who had BRCA-associated metastatic breast cancer received, in this case, carboplatin. Whereas in taxane, the carboplatin arm had a much stronger PFS and much higher response rates. So, yes, I think it does influence the treatment decision and BRCA status. BRCA-positive patients in the metastatic setting should preferentially get platinums over taxane. The question in the adjuvant setting, “Should that make a difference?”, is not as clear because the German group did not show the additional DFS (disease-free survival) advantage in the neoadjuvant platinum setting that we have seen in the overall patient population in the BRCA-positive patient population. So, that’s kind of surprising. And I think it may well be that chemotherapy may be more effective in BRCA-positive triple-negative patients with anthracyclines and taxanes.

Adam M. Brufsky, MD, PhD: Yes, I’m up in the air in my practice on this right now. I don’t know about you guys. Do you use it, Kim?

Kimberly L. Blackwell, MD: For node-positive triple-negative, I’m routinely incorporating a platinum in the neoadjuvant setting.

Adam M. Brufsky, MD, PhD: With or without BRCA?

Kimberly L. Blackwell, MD: With or without.

Adam M. Brufsky, MD, PhD: BRCA? Good. Carlos?

Carlos L. Arteaga, MD: No. We are, but something we’re doing, actually, is that we are, at my institution, now reflexing androgen-receptor immunohistochemistry in patients with newly diagnosed triple-negative disease. We have a couple of situations where, when encumbered by those data, we decided not to do neoadjuvant chemotherapy. This is a patient that had a relatively small tumor, so neoadjuvant therapy may not have been indicated on her. There are an increasing number of papers that show that these luminal AR-positive triple-negative patients, they just don’t care about chemotherapy after a number of observations. I know this is not a standard of care, but sometimes biology can tell us a little bit about something we can do in unique situations.

Kimberly L. Blackwell, MD: But you’re still offering those LAR (luminal androgen receptor) triple-negative patients adjuvant chemotherapy or some chemotherapy? I just want to be clear because I don’t think we have enough data.

Adam M. Brufsky, MD, PhD: For that, no.

Carlos L. Arteaga, MD: No. In this case, we thought that it was; we have a large trial we just completed where we compared cisplatin/Taxol plus/minus everolimus. There’s was no difference between both arms. Overall, path CR rate was about 40%, and it was very clear the AR-positives, luminal AR subtypes didn’t respond.

Joyce A. O’Shaughnessy, MD: Interesting. I just want to make a comment about carboplatin—and we await the NSABP (National Surgical Adjuvant Breast Project) adjuvant with the AC (Adriamycin and cyclophosphamide), followed by paclitaxel plus/minus—to add on to a standard. I had been using a lot of carboplatin, initially based on the path CR rate, but I was sobered a bit by Dr. Sikov’s 3-year disease-free survival data and digging into the supplemental tables and seeing the actual number of events and such. Unfortunately, there’s just not a hint on the backbone of a standard ACT (AC + Taxol/Taxotere) that we’re doing anything from a disease-free survival perspective. Although, if somebody’s got a BRCA, then I do really think very, very carefully about it.

Kimberly L. Blackwell, MD: GeparSixto’s long-term outcome on the backbone of a weekly taxane schedule, I just don’t think we have a definitive answer.

Joyce A. O’Shaughnessy, MD: No, no.

Sunil Verma, MD, MSEd, FRCPC: But, I think at least they are both consistent to show that there is a higher PCR rate. To your point, if you want to obtain local control in a high disease burden, then it makes perfect sense to be able to incorporate the platinums. Whether it’s going to translate into better disease-free survival for all these patients still is debatable.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
Now, we’ll move on. We have a lightning round toward the end here on a few other topics we want to talk about. We’ll talk briefly about triple-negative breast cancer. I think the first thing I’d like to ask people is, do you think there’s going to be a role for subtyping triple-negative breast cancer going forward? And we’ll do it informally, but is there going to be a role for a formal subtyping to put people in trials for this particular type, say an AR-positive subtype? Or is it an immune-modulatory subtype? What do you think?

Carlos L. Arteaga, MD: I think we’re there. We’re doing it now, at least in my institution and our consortia we’re a part of. We are selecting patients with triple-negative breast cancer—that are androgen-receptor (AR)-positive—by immunohistochemistry for allocation into trials with enzalutamide plus something else versus cisplatin plus something else. So, I think that’s happening. Would that happen to other subtypes? Well, we don’t have any data yet, but eventually we may.

Adam M. Brufsky, MD, PhD: Just going to the AR-positive subtype for a minute. I started getting into this because I have a patient who’s undergoing a sex change and developed an ER-positive/AR-positive breast cancer. As we started looking into this—and testosterone in AR in non–triple-negative breast cancer actually involutes the breast—why are we doing inhibitors? Why are we not doing stimulators?

Carlos L. Arteaga, MD: That’s a very important question. There is a concern by people that study these receptors in tumors that are estrogen-deprived—ER-positive tumors that are on an aromatase inhibitor, and they are also AR-positive, which aren’t the majority of them—the addition of enzalutamide may be deleterious. I think we need some more mechanistic signs there in order to define whether we should deploy an anti-androgen just widely to any tumor that is AR-positive.

Sunil Verma, MD, MSEd, FRCPC: I guess the data that we have to date on ER-receptor inhibitors in triple-negative breast cancer is really phase II data, and we’re not sure if it’s more of a prognostic marker or a therapeutic marker, that these patients would have done well anyway if they have AR-positive disease, whether this is actually true treatment evaluation. So, we await the randomized data. But, there’s no doubt in our mind that we do need to start stratifying these patients. And the role of immunotherapy, probably at the present time, seems to be the strongest, and it’s relative terms, compared to other breast cancer subtypes. At least the data that we have seen that the mutational load, the type of triple-negative breast cancer that we’re seeing, it’s more likely the type that’s going to respond to immunotherapies compared to some other breast cancers.

Adam M. Brufsky, MD, PhD: I want to just finish with the AR. So, Joyce, you’ve done a lot of work with this, and what’s your thought of where you think this is going in the AR-positive triple-negative subtype?

Joyce A. O’Shaughnessy, MD: I think there’s a small percentage of the AR-positive triple-negatives, they’re very strongly AR-positive and more slowly proliferative. And if you looked, this new diagnostic PREDICT AR that’s RT-PCR–based (real-time polymerase chain reaction), etc, does look to be more predictive than just IHC (immunohistochemistry), so that’s helpful. But if you look at the correlation between the PREDICT AR-positive and the strongly AR-positive, it’s really skewed towards very strongly AR-positive. It does pick up some more weakly AR-positives by the IHC, so that might be helpful, but there’s a pretty good correlation.

I actually am impressed with the data as a predictive marker, and there is definitely a prognostic thing there, as well. But, I think that in the enzalutamide phase II, in this heavily pretreated group of patients, getting up around 40% to 50%, the clinical benefit rate was pretty impressive in these PREDICT AR-positive patients. But, then there’s this other group that are more weakly AR-positive; it won’t be all about AR in those patients. And are these the PIK3CA-mutant triple-negatives? Carlos has some interesting data on that. I think that’s an intriguing possibility. I think AR is very important; it’s one of those targets both in triple-negative and in HER2-positive—and even more complexly in ER-positive—that we need to go after pretty vigorously because we are going to figure out how to really utilize it.

But, I actually think that the phase III trial of enzalutamide will start in the first-line metastatic setting. So, we’ll get phase III data, but it’ll be awhile. It’s not a very common patient population. I personally would like to see a trial fairly quickly in, strongly predict AR-positive patients in, the no-path CR, for example. I’d like us to move a little faster in this regard.

Adam M. Brufsky, MD, PhD: Before we get to immunotherapy, which I think is the “topic A” in this field right now that we all have a lot to say about, I just want to ask one quick question. Should we be using BRCA status and/or HRD status, homologous recombination deficiency status, to determine who gets platinums? Should we be using that or not?

Sunil Verma, MD, MSEd, FRCPC: We have the TNT trial that was reported last year showing that patients who had BRCA-associated metastatic breast cancer received, in this case, carboplatin. Whereas in taxane, the carboplatin arm had a much stronger PFS and much higher response rates. So, yes, I think it does influence the treatment decision and BRCA status. BRCA-positive patients in the metastatic setting should preferentially get platinums over taxane. The question in the adjuvant setting, “Should that make a difference?”, is not as clear because the German group did not show the additional DFS (disease-free survival) advantage in the neoadjuvant platinum setting that we have seen in the overall patient population in the BRCA-positive patient population. So, that’s kind of surprising. And I think it may well be that chemotherapy may be more effective in BRCA-positive triple-negative patients with anthracyclines and taxanes.

Adam M. Brufsky, MD, PhD: Yes, I’m up in the air in my practice on this right now. I don’t know about you guys. Do you use it, Kim?

Kimberly L. Blackwell, MD: For node-positive triple-negative, I’m routinely incorporating a platinum in the neoadjuvant setting.

Adam M. Brufsky, MD, PhD: With or without BRCA?

Kimberly L. Blackwell, MD: With or without.

Adam M. Brufsky, MD, PhD: BRCA? Good. Carlos?

Carlos L. Arteaga, MD: No. We are, but something we’re doing, actually, is that we are, at my institution, now reflexing androgen-receptor immunohistochemistry in patients with newly diagnosed triple-negative disease. We have a couple of situations where, when encumbered by those data, we decided not to do neoadjuvant chemotherapy. This is a patient that had a relatively small tumor, so neoadjuvant therapy may not have been indicated on her. There are an increasing number of papers that show that these luminal AR-positive triple-negative patients, they just don’t care about chemotherapy after a number of observations. I know this is not a standard of care, but sometimes biology can tell us a little bit about something we can do in unique situations.

Kimberly L. Blackwell, MD: But you’re still offering those LAR (luminal androgen receptor) triple-negative patients adjuvant chemotherapy or some chemotherapy? I just want to be clear because I don’t think we have enough data.

Adam M. Brufsky, MD, PhD: For that, no.

Carlos L. Arteaga, MD: No. In this case, we thought that it was; we have a large trial we just completed where we compared cisplatin/Taxol plus/minus everolimus. There’s was no difference between both arms. Overall, path CR rate was about 40%, and it was very clear the AR-positives, luminal AR subtypes didn’t respond.

Joyce A. O’Shaughnessy, MD: Interesting. I just want to make a comment about carboplatin—and we await the NSABP (National Surgical Adjuvant Breast Project) adjuvant with the AC (Adriamycin and cyclophosphamide), followed by paclitaxel plus/minus—to add on to a standard. I had been using a lot of carboplatin, initially based on the path CR rate, but I was sobered a bit by Dr. Sikov’s 3-year disease-free survival data and digging into the supplemental tables and seeing the actual number of events and such. Unfortunately, there’s just not a hint on the backbone of a standard ACT (AC + Taxol/Taxotere) that we’re doing anything from a disease-free survival perspective. Although, if somebody’s got a BRCA, then I do really think very, very carefully about it.

Kimberly L. Blackwell, MD: GeparSixto’s long-term outcome on the backbone of a weekly taxane schedule, I just don’t think we have a definitive answer.

Joyce A. O’Shaughnessy, MD: No, no.

Sunil Verma, MD, MSEd, FRCPC: But, I think at least they are both consistent to show that there is a higher PCR rate. To your point, if you want to obtain local control in a high disease burden, then it makes perfect sense to be able to incorporate the platinums. Whether it’s going to translate into better disease-free survival for all these patients still is debatable.

Transcript Edited for Clarity
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