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Neoadjuvant Therapy in TNBC

Panelists: Aditya Bardia, MD, MPH, Massachusetts General Hospital Center; Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center; Joyce OShaughnessy, MD, Baylor University Medical Center Texas Oncology; Tiffany Traina, MD, Memorial Sloan Kettering Cancer Center
Published: Friday, Mar 09, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: Let’s go on now to the preoperative setting, the neoadjuvant setting for triple-negative breast cancer. Do we have a standard of care there?

Tiffany Traina, MD: I think it’s a great question. I’ve just seen the evolution in the past few years of the trend towards much more preoperative therapy for our patients with triple-negative breast cancer. I think we used to really reserve preoperative therapy for somebody who needed to get to surgery and have downstaging a chance of breast conservation. But really the bar has been lowered. I know in our institution, a tumor as small as 1.5 cm, even in the setting of node-negative disease, we would favor preoperative chemotherapy. And I think that’s for a couple of reasons.

It’s a rich opportunity for research and tissue acquisition and trying to understand the underlying biology of the cancer. But for the patient’s benefit, I think we are able to better risk stratify. What we’re aiming for and hoping for is that that disease melts away at the time of surgery, and it’s incredibly satisfying when a patient has a pathologic complete response. And that’s equated, I think, with better outcomes in terms of survival for TNBC. But when a patient fails to have a pathologic complete response, we know that’s a higher-risk situation and then creates an opportunity to look for clinical trials or, as we’ll talk about I think in a bit, other standard therapies that can be utilized. So, we are doing much more preoperative chemotherapy. It helps to risk stratify our patients, creates research opportunities for them. And because these patients still are high-risk, I would say in terms of a go-to backbone regimen, we still favor an anthracycline and taxane-based regimen. And a controversy lies in where do we place the platinum, and is it mandatory in any way to incorporate a platinum? I think this is where there is more art of medicine and some remaining controversies.

Joyce A. O’Shaughnessy, MD: What do you do with the platinum preoperatively?

Tiffany Traina, MD: So, I actually flip the order a little bit from the what the clinical trials have shown. The Alliance trial of backbone anthracycline/taxane with carboplatin began with a taxane and platinum and then finished up with 4 cycles of AC (Adriamycin/cyclophosphamide). I tend to flip that order. I start with my 4 cycles of AC. In that time, I’m getting my genetic test results back. I’m also getting a sense of how chemotherapy-sensitive, in general, this tumor is. And many of these women who have an association with BRCA1 perhaps are already working towards mastectomy. I know I’m not going to gain necessarily the breast conservation advantage to preoperative therapy or to adding in the platinum. And so, it’s an ongoing conversation as I’m getting more information from treatment response. To your point about the BRCA mutation carriers, the subset data from GeparSixto were sobering. The patients who had germline BRCA mutations were the ones who did not derive the benefit from platinum.

Joyce A. O’Shaughnessy, MD: On a disease-free survival basis, yes.

Tiffany Traina, MD: Exactly. And so, as you said before so eloquently, we’re doing the best that we can with the information that we have today, and these are hard conversations. Adding in the platinum comes with increased toxicity, a need for dose modifications, often treatment delays, and that’s concerning, too, in the curative setting.

Joyce A. O’Shaughnessy, MD: Yes, and the thing about the GeparSixto was the nonstandard weekly liposomal doxorubicin; no cyclophosphamide, no alkylator. So, it was a nonstandard regimen but it was a bit interesting.

Claudine Isaacs, MD: I think as Tiffany said as well, the issue with adding it is the added toxicity, the myelosuppression, the issues in terms of dose reductions. And some of the trials had different ways that they gave the taxane and the platinum. In practice, I tend not to give it like it was given in the Alliance trial, although we participated in that trial. Because I find it very hard to give an AUC of 5 or an AUC of 6. You really end up running into trouble, so I tend to give weekly Taxol, or weekly paclitaxel, with weekly carboplatin with an AUC of 2. And I find that easier to get in. I still feel like we’re getting dose density because we’re giving the weekly therapy. And so, that’s what I’ve converted to in the group of patients when I’m giving them a platinum. The issue about GeparSixto, it was sobering. And I think the bottom line is that we actually think that BRCA1 and BRCA2 carriers probably get greater benefit from chemotherapy. So, some of them might not need the platinum because they get such significant benefit from the chemotherapy, the standard backbone.

Joyce A. O’Shaughnessy, MD: Yes, yes.

Aditya Bardia, MD, MPH: I think that’s a great point because tumors that are BRCA-deficient are, in general, more sensitive to DNA-damaging agents. And if we look at anthracyclines, it’s a topoisomerase I inhibitor. So, it’s also a DNA-damaging agent, and maybe with the use of an anthracycline, you really don’t need that much platinum because anthracycline could fill in that role as a DNA-damaging agent. And sometimes, I think we think of platinums as the only agent that should be used in BRCA-mutant cancers, but I think anthracyclines also have a role. In the early breast cancer setting, BRCA-mutant tumors, maybe the question should be, should you use platinum instead of an anthracycline rather than platinum in addition to an anthracycline? I think that’s an open question at this time.

Joyce A. O’Shaughnessy, MD: An important question. I would like to actually mention a trial that I guess probably is not as well-known as much because it wasn’t a phase III trial. It was a preoperative phase II trial, but it was published in Clinical Cancer Research just in 2016 by Priyanka Sharma who looked at preoperative docetaxel at 75 mg with carboplatin AUC of 6, just the 2 agents preoperatively in triple-negative breast cancer, 6 cycles, had a pathological CR rate that was about 60%. It was the same as we had seen in the GeparSixto and in the CALGB with the 4 doses, adding a platinum in there. There’s another paper in submission or in press that looks at the 3-year disease-free survival outcome of those patients who had the path CR versus not. It’s just as you’d expect. It was excellent path CR for the patients with disease-free survival, very, very reassuring. Would I actually use that in my practice, the preoperative to get an understanding of the disease and the chemotherapy sensitivity if I have that, what you mentioned, the old T1 N0? We do want to still use the preoperative. But do they really need the anthracycline, to your point, or is it an either/or, etc? I’ll give the docetaxel and carboplatin up front and then go to surgery, knowing I could always give the AC out back if necessary for the small cancers that you think, “Wow, I’m not sure we need 4 drugs with this small but otherwise what looks to be highly proliferative chemotherapy-sensitive agent.” But what do you do with the platinum in your practice, Aditya?

Aditya Bardia, MD, MPH: I do what was said earlier by Tiffany and Claudine, that we actually start with AC. And after AC, if you’re seeing an excellent response, maybe you don’t need other agents and you can add taxane. But in a patient who does not give a good response to AC, that’s a discussion. We don’t know whether the addition of platinum would necessarily be helpful, but we know that this is a patient that is not going to do well. And that is a patient who I would consider the addition of a platinum, especially if they are young because toxicity is an issue. It’s very difficult to give the anthracycline plus platinum with a taxane in someone who is 60 or 65 years old, and I think that is a challenge.

Joyce A. O’Shaughnessy, MD: Like all of us, I struggle when trying to individualize. But where I’ve been coming down to lately is for those with substantial risk, node-positive disease or T3 disease, etc, I’ve been erring on the side of adding in the platinum. Initially, I was doing most of the AC up front but I’ve been impressed with the weekly paclitaxel/carboplatin. And, of course, the GeparSixto was excellent. A disease-free survival advantage, again, nonstandard regimen, no alkylator in there, but the liposomal doxorubicin with weekly paclitaxel plus/minus the carboplatin/bevacizumab was in there, too. But plus or minus the carboplatin not only had the big improvement in path CR rate but also had a disease-free survival, a distant disease-free survival that was just updated at ESMO, stat sig (statistical significance) there.

The other thing on that point is that though not stat sig, on the BrighTNess trial with the veliparib preoperatively—where the veliparib did not add to the carboplatin but carboplatin itself added quite a lot on path CR 20+% to a weekly paclitaxel followed by AC versus weekly paclitaxel with carboplatin every 3 weeks followed by AC—is that if you look at the point, just the estimates now, when they read out the path CR data, they took a look at disease-free survival. It’s about 50% less in terms of disease-free survival events, 8% versus 13-plus% in favor of adding the platinum, not stat sig. But the CALGB was also in-trending toward the platinum on the disease-free survival but not, again, stat sig. So, I’m just putting that all together for the higher-risk patient, but the lower-risk patient, I either don’t or I start with the AC and see how they’re doing clinically, etc, knowing I can always bring in the platinum out back, too, again. You can always do that as well, but for higher-risk, I’ve been leaning towards it.

Transcript Edited for Clarity 

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Transcript: 

Joyce A. O’Shaughnessy, MD: Let’s go on now to the preoperative setting, the neoadjuvant setting for triple-negative breast cancer. Do we have a standard of care there?

Tiffany Traina, MD: I think it’s a great question. I’ve just seen the evolution in the past few years of the trend towards much more preoperative therapy for our patients with triple-negative breast cancer. I think we used to really reserve preoperative therapy for somebody who needed to get to surgery and have downstaging a chance of breast conservation. But really the bar has been lowered. I know in our institution, a tumor as small as 1.5 cm, even in the setting of node-negative disease, we would favor preoperative chemotherapy. And I think that’s for a couple of reasons.

It’s a rich opportunity for research and tissue acquisition and trying to understand the underlying biology of the cancer. But for the patient’s benefit, I think we are able to better risk stratify. What we’re aiming for and hoping for is that that disease melts away at the time of surgery, and it’s incredibly satisfying when a patient has a pathologic complete response. And that’s equated, I think, with better outcomes in terms of survival for TNBC. But when a patient fails to have a pathologic complete response, we know that’s a higher-risk situation and then creates an opportunity to look for clinical trials or, as we’ll talk about I think in a bit, other standard therapies that can be utilized. So, we are doing much more preoperative chemotherapy. It helps to risk stratify our patients, creates research opportunities for them. And because these patients still are high-risk, I would say in terms of a go-to backbone regimen, we still favor an anthracycline and taxane-based regimen. And a controversy lies in where do we place the platinum, and is it mandatory in any way to incorporate a platinum? I think this is where there is more art of medicine and some remaining controversies.

Joyce A. O’Shaughnessy, MD: What do you do with the platinum preoperatively?

Tiffany Traina, MD: So, I actually flip the order a little bit from the what the clinical trials have shown. The Alliance trial of backbone anthracycline/taxane with carboplatin began with a taxane and platinum and then finished up with 4 cycles of AC (Adriamycin/cyclophosphamide). I tend to flip that order. I start with my 4 cycles of AC. In that time, I’m getting my genetic test results back. I’m also getting a sense of how chemotherapy-sensitive, in general, this tumor is. And many of these women who have an association with BRCA1 perhaps are already working towards mastectomy. I know I’m not going to gain necessarily the breast conservation advantage to preoperative therapy or to adding in the platinum. And so, it’s an ongoing conversation as I’m getting more information from treatment response. To your point about the BRCA mutation carriers, the subset data from GeparSixto were sobering. The patients who had germline BRCA mutations were the ones who did not derive the benefit from platinum.

Joyce A. O’Shaughnessy, MD: On a disease-free survival basis, yes.

Tiffany Traina, MD: Exactly. And so, as you said before so eloquently, we’re doing the best that we can with the information that we have today, and these are hard conversations. Adding in the platinum comes with increased toxicity, a need for dose modifications, often treatment delays, and that’s concerning, too, in the curative setting.

Joyce A. O’Shaughnessy, MD: Yes, and the thing about the GeparSixto was the nonstandard weekly liposomal doxorubicin; no cyclophosphamide, no alkylator. So, it was a nonstandard regimen but it was a bit interesting.

Claudine Isaacs, MD: I think as Tiffany said as well, the issue with adding it is the added toxicity, the myelosuppression, the issues in terms of dose reductions. And some of the trials had different ways that they gave the taxane and the platinum. In practice, I tend not to give it like it was given in the Alliance trial, although we participated in that trial. Because I find it very hard to give an AUC of 5 or an AUC of 6. You really end up running into trouble, so I tend to give weekly Taxol, or weekly paclitaxel, with weekly carboplatin with an AUC of 2. And I find that easier to get in. I still feel like we’re getting dose density because we’re giving the weekly therapy. And so, that’s what I’ve converted to in the group of patients when I’m giving them a platinum. The issue about GeparSixto, it was sobering. And I think the bottom line is that we actually think that BRCA1 and BRCA2 carriers probably get greater benefit from chemotherapy. So, some of them might not need the platinum because they get such significant benefit from the chemotherapy, the standard backbone.

Joyce A. O’Shaughnessy, MD: Yes, yes.

Aditya Bardia, MD, MPH: I think that’s a great point because tumors that are BRCA-deficient are, in general, more sensitive to DNA-damaging agents. And if we look at anthracyclines, it’s a topoisomerase I inhibitor. So, it’s also a DNA-damaging agent, and maybe with the use of an anthracycline, you really don’t need that much platinum because anthracycline could fill in that role as a DNA-damaging agent. And sometimes, I think we think of platinums as the only agent that should be used in BRCA-mutant cancers, but I think anthracyclines also have a role. In the early breast cancer setting, BRCA-mutant tumors, maybe the question should be, should you use platinum instead of an anthracycline rather than platinum in addition to an anthracycline? I think that’s an open question at this time.

Joyce A. O’Shaughnessy, MD: An important question. I would like to actually mention a trial that I guess probably is not as well-known as much because it wasn’t a phase III trial. It was a preoperative phase II trial, but it was published in Clinical Cancer Research just in 2016 by Priyanka Sharma who looked at preoperative docetaxel at 75 mg with carboplatin AUC of 6, just the 2 agents preoperatively in triple-negative breast cancer, 6 cycles, had a pathological CR rate that was about 60%. It was the same as we had seen in the GeparSixto and in the CALGB with the 4 doses, adding a platinum in there. There’s another paper in submission or in press that looks at the 3-year disease-free survival outcome of those patients who had the path CR versus not. It’s just as you’d expect. It was excellent path CR for the patients with disease-free survival, very, very reassuring. Would I actually use that in my practice, the preoperative to get an understanding of the disease and the chemotherapy sensitivity if I have that, what you mentioned, the old T1 N0? We do want to still use the preoperative. But do they really need the anthracycline, to your point, or is it an either/or, etc? I’ll give the docetaxel and carboplatin up front and then go to surgery, knowing I could always give the AC out back if necessary for the small cancers that you think, “Wow, I’m not sure we need 4 drugs with this small but otherwise what looks to be highly proliferative chemotherapy-sensitive agent.” But what do you do with the platinum in your practice, Aditya?

Aditya Bardia, MD, MPH: I do what was said earlier by Tiffany and Claudine, that we actually start with AC. And after AC, if you’re seeing an excellent response, maybe you don’t need other agents and you can add taxane. But in a patient who does not give a good response to AC, that’s a discussion. We don’t know whether the addition of platinum would necessarily be helpful, but we know that this is a patient that is not going to do well. And that is a patient who I would consider the addition of a platinum, especially if they are young because toxicity is an issue. It’s very difficult to give the anthracycline plus platinum with a taxane in someone who is 60 or 65 years old, and I think that is a challenge.

Joyce A. O’Shaughnessy, MD: Like all of us, I struggle when trying to individualize. But where I’ve been coming down to lately is for those with substantial risk, node-positive disease or T3 disease, etc, I’ve been erring on the side of adding in the platinum. Initially, I was doing most of the AC up front but I’ve been impressed with the weekly paclitaxel/carboplatin. And, of course, the GeparSixto was excellent. A disease-free survival advantage, again, nonstandard regimen, no alkylator in there, but the liposomal doxorubicin with weekly paclitaxel plus/minus the carboplatin/bevacizumab was in there, too. But plus or minus the carboplatin not only had the big improvement in path CR rate but also had a disease-free survival, a distant disease-free survival that was just updated at ESMO, stat sig (statistical significance) there.

The other thing on that point is that though not stat sig, on the BrighTNess trial with the veliparib preoperatively—where the veliparib did not add to the carboplatin but carboplatin itself added quite a lot on path CR 20+% to a weekly paclitaxel followed by AC versus weekly paclitaxel with carboplatin every 3 weeks followed by AC—is that if you look at the point, just the estimates now, when they read out the path CR data, they took a look at disease-free survival. It’s about 50% less in terms of disease-free survival events, 8% versus 13-plus% in favor of adding the platinum, not stat sig. But the CALGB was also in-trending toward the platinum on the disease-free survival but not, again, stat sig. So, I’m just putting that all together for the higher-risk patient, but the lower-risk patient, I either don’t or I start with the AC and see how they’re doing clinically, etc, knowing I can always bring in the platinum out back, too, again. You can always do that as well, but for higher-risk, I’ve been leaning towards it.

Transcript Edited for Clarity 
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