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Approach to Neoadjuvant Therapy for Triple-Negative Breast Cancer

Panelists: Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Erika P. Hamilton, MD, Sarah Cannon Research Institute; Sara A. Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Joyce A. OShaughnessy, MD, Baylor University Medical Center; Debu Tripathy, MD, The University of Texas MD Anderson Cancer Center
Published: Thursday, Aug 22, 2019



Transcript:

Joyce A. O’Shaughnessy, MD:
Let’s switch gears and talk about triple-negative breast cancer. One of the somewhat controversial areas is, how do we approach the neoadjuvant setting? Does one size fit all? Sometimes we have smaller cancers, we’ve got larger cancers, we’ve got difference in grade, etc. Sara, give us some thoughts on this.

Sara A. Hurvitz, MD: Well you know I’m from the West Coast. We like to be a little controversial every now and again. You know what I like to do. I actually have translated what we have done in HER2-positive disease now. Learn from the response in the patient’s body. Learn from what happens after neoadjuvant therapy. Use that in order to guide our approach to whether a patient needs more therapy or less therapy. My preference for the last several years has been to utilize the taxane-based platinum doublet—docetaxel, carboplatin, the Priyanka Sharma, University of Kansas Medical Center regimen—if you will.

Follow the patient exceedingly closely who has triple-negative breast cancer for response or growth. If there isn’t a good response with physical exam—ultrasound, mammogram sequentially every 2 cycles—then certainly switch then to dose-dense AC [Adriamycin, cyclophosphamide]. But if there is a good response, and I would say the majority of my cases have great responses, take them after 6 cycles to surgery. If they have a pathologic complete response, we can omit further chemotherapy and feel fairly comfortable about that, especially with her recent data that has been presented here at ASCO [American Society of Clinical Oncology].

If, on the other hand, there’s residual disease or not a good response, we have dose-dense AC. The CREATE-X study has told us we should use capecitabine. I think it’s careful dose de-escalation of therapy to try and protect those patients from serious toxicity if their tumor won’t respond to something that’s not an anthracycline.

Joyce A. O’Shaughnessy, MD: Yeah, so Priyanka Sharma had published in Clinical Cancer Research in 2018 a 3-year invasive disease-free survival [DFS] update on her single-arm trial of the 6 cycles of docetaxel, carboplatin, and had shown a pathologic CR [complete response] rate of 55%, regardless of BRCA status—both in wild-type and BRCA mutant. The patients who achieved a path CR had a 90% 3-year invasive disease-free survival. But at this conference, she had taken it to the next step, right?

Sara A. Hurvitz, MD: Right. It was a 100-patient randomized prospectively designed trial rather than retrospective, which was the first one. She did actually an even more dose escalation in the anthracycline arm. Using the anthracycline regimen, it was actually paclitaxel, carboplatin weekly for the 12 weeks, followed by dose-dense AC for 4 cycles versus 6 cycles of the regimen that I use. The total path CR rates were very similar—55% for the anthracycline, about 52% for the taxane platinum. If you include RCB, residual cancer burden, 0 or 1—so path CR and near path CR—they’re exactly equivalent at 67%. Promising intriguing data that I think, again, if you’re watching your patients closely, you’re not out to lunch when they’re getting their therapy and seeing them after surgery. You’re keeping a close eye on them. I feel that this is something that should be at least offered to patients. Not every patient will choose to take this type of strategy.

Joyce A. O’Shaughnessy, MD: I have been very impressed, because we need a prospective phase III trial of course.

Sara A. Hurvitz, MD: Of course.

Joyce A. O’Shaughnessy, MD: But 4 drugs versus 2 drugs is quite intriguing. Bu, I was speaking about this the other day, and Sara Tolaney, MD, MPH, brought to my attention some presentation from ESMO [European Society for Medical Oncology] last year from the German Breast Group [GBG]. It isn’t published yet, so we don’t have it—it’s not really widely available. But the GBG went back and looked at about 2000 patients who had had a path CR with a variety of different regimens over a variety of different trials to see how well they did over time and also to look at whether clinical parameters—T size, nodal status—made a difference in terms of the recurrence risk. Interestingly, and I guess not too surprisingly, if you were a T3, T4, and the higher number of nodes you had, even though you were a path CR, you didn’t do quite as well in terms of your recurrence risk, if you were node negative or T1, T2.

In the T1s or early T2s, I’ve been doing a clinically node-negative approach. I’ve been using the Priyanka Sharma regimen. I like to give people preoperative therapy even if they have small tumors because of that possibility of avoiding the anthracycline. But in the larger bulkier tumors, that GBG data are interesting to me. I’m going to give that some good thoughts, you know?

There was another study from ASCO that was also asking this question of the need for anthracycline preoperatively.

Erika P. Hamilton, MD: Yeah, another study out of China; 132 patients, which was small, but it was dose-dense epirubicin-cytoxan followed by a taxane or taxane in combination with carboplatin, again given in a dose-dense fashion.

They showed really dramatic results, about a 16% improvement in 3-year disease-free survival, and about a 6% improvement in overall survival. For a small study, that’s pretty impressive. It suggests that not only can we omit the anthracycline, but we actually could be doing our patients a favor by adding carboplatin instead.

Joyce A. O’Shaughnessy, MD: It’s a very important question, the anthracycline versus the carboplatin, whether they really are cross-resistant or whether they really add to disease-free survival in particular. So intriguing and hopefully will set us up for the next round of randomized trials.

Just a brief point for me, everybody, because I think this is such a controversial area. If you do have a patient who is quite high risk, and/or BRCA, BRCA germline, is anybody adding carboplatin to an ACT [Adriamycin, cyclophosphamide, Taxol] backbone, for example, or do you see how they do with AC first and then decide? Or bring it in afterwards along with capecitabine, etc? So, Sara, what do you do?

Sara A. Hurvitz, MD: Well, I think I’ve already given away my hands that I like to start with a taxane and platinum. I do think that the data are compelling. They’re not entirely consistent. Different studies have shown improvements in DFS and path CR rate. Other studies haven’t confirmed them. They’re different trial designs, and many of them are small studies. The point I would make is, we really need biomarker data. You know, the study looking at Topo 2 [Topoisomerase II]-normal breast cancer indicating anthracycline really didn’t appear to benefit patients without Topo 2. We need more large studies that are going to interrogate these sorts of important biomarker questions so that we can help hone in on what we should be doing, as we’re getting to with the HER2 story.

Aditya Bardia, MD, MPH: I agree. It’s complicated. In general, we’ve been using ACT. I guess that’s the difference between the East Coast and West Coast.

Sara A. Hurvitz, MD: I totally agree.

Aditya Bardia, MD, MPH: But it is an important question in terms of the role of platinums; that’s very provocative. One factor to consider would be the tolerability and the number of patients who required a dose reduction with ACT and how well they were able to tolerate DCN [decorin], whether tolerability accounted for some of the improvement in disease-free survival. Regarding BRCA mutations, anthracyclines also work well in BRCA-mutant tumors. It is a DNA-damaging agent.

In the ovarian literature, we can see that anthracyclines have shown remarkable activity in tumors that have BRCA mutations. So, I feel very comfortable with the use of ACT in patients who have germline BRCA mutations. But if we are going to replace anthracycline, then I think platinum would be the best agent. For BRCA mutations, for me, it’s not about the addition of platinum; it’s whether we can replace the anthracyclines with platinum.

Joyce A. O’Shaughnessy, MD: In a higher-risk patient, I’ll see how it goes with up-front dose-dense AC, and if they’re clinical CR, I will just go on usually to dose-dense paclitaxel, and then go from there afterwards. This is because I can combine carboplatin no problem with the 6 months of capecitabine, if somebody has a lot of residual disease and I feel like I don’t want to leave anything off the table for this patient. But if they have a small amount of residual disease, I would of course go on to capecitabine. But I tend to use the AC response. If somebody is not responding that well, I will add the carboplatin to the paclitaxel just because many of the studies have shown some increment in path CR with the addition of the carboplatin, though we don’t have solid data but what that’s going to do with DFS, you know? So that’s for me. I take up a similar approach in BRCA-positive patients because of the GBG showing really. For the patients with BRCA, that’s where platinum did not make a difference in the path CR rate or in the progression-free survival. This is because, like you said, the anthracycline-based chemotherapy was so effective for those patients. How about you, Debu?

Debu Tripathy, MD: I’m generally not using platinum all the time. I do it in patients that are not responding, just like you do. I think the point you made about long-term outcome is important. But also, it’s been noted in multiple trials that when you do use platinum, you end up attenuating the dose of taxane. We know that taxanes are an important part of the treatment. So I think it remains to be seen. We do have randomized trials now in the adjuvant setting. I think the story is still out.

Joyce A. O’Shaughnessy, MD: How about you, Erika?

Erika P. Hamilton, MD: I do something very similar to Debu. I don’t routinely do it one way or the other. I do a little bit of both depending on who the patient is. In very high risk, and also to very young people, I tend to maybe add the platinum more and for patients that aren’t responding as well.

Joyce A. O’Shaughnessy, MD: That’s good, great.

Transcript Edited for Clarity

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Transcript:

Joyce A. O’Shaughnessy, MD:
Let’s switch gears and talk about triple-negative breast cancer. One of the somewhat controversial areas is, how do we approach the neoadjuvant setting? Does one size fit all? Sometimes we have smaller cancers, we’ve got larger cancers, we’ve got difference in grade, etc. Sara, give us some thoughts on this.

Sara A. Hurvitz, MD: Well you know I’m from the West Coast. We like to be a little controversial every now and again. You know what I like to do. I actually have translated what we have done in HER2-positive disease now. Learn from the response in the patient’s body. Learn from what happens after neoadjuvant therapy. Use that in order to guide our approach to whether a patient needs more therapy or less therapy. My preference for the last several years has been to utilize the taxane-based platinum doublet—docetaxel, carboplatin, the Priyanka Sharma, University of Kansas Medical Center regimen—if you will.

Follow the patient exceedingly closely who has triple-negative breast cancer for response or growth. If there isn’t a good response with physical exam—ultrasound, mammogram sequentially every 2 cycles—then certainly switch then to dose-dense AC [Adriamycin, cyclophosphamide]. But if there is a good response, and I would say the majority of my cases have great responses, take them after 6 cycles to surgery. If they have a pathologic complete response, we can omit further chemotherapy and feel fairly comfortable about that, especially with her recent data that has been presented here at ASCO [American Society of Clinical Oncology].

If, on the other hand, there’s residual disease or not a good response, we have dose-dense AC. The CREATE-X study has told us we should use capecitabine. I think it’s careful dose de-escalation of therapy to try and protect those patients from serious toxicity if their tumor won’t respond to something that’s not an anthracycline.

Joyce A. O’Shaughnessy, MD: Yeah, so Priyanka Sharma had published in Clinical Cancer Research in 2018 a 3-year invasive disease-free survival [DFS] update on her single-arm trial of the 6 cycles of docetaxel, carboplatin, and had shown a pathologic CR [complete response] rate of 55%, regardless of BRCA status—both in wild-type and BRCA mutant. The patients who achieved a path CR had a 90% 3-year invasive disease-free survival. But at this conference, she had taken it to the next step, right?

Sara A. Hurvitz, MD: Right. It was a 100-patient randomized prospectively designed trial rather than retrospective, which was the first one. She did actually an even more dose escalation in the anthracycline arm. Using the anthracycline regimen, it was actually paclitaxel, carboplatin weekly for the 12 weeks, followed by dose-dense AC for 4 cycles versus 6 cycles of the regimen that I use. The total path CR rates were very similar—55% for the anthracycline, about 52% for the taxane platinum. If you include RCB, residual cancer burden, 0 or 1—so path CR and near path CR—they’re exactly equivalent at 67%. Promising intriguing data that I think, again, if you’re watching your patients closely, you’re not out to lunch when they’re getting their therapy and seeing them after surgery. You’re keeping a close eye on them. I feel that this is something that should be at least offered to patients. Not every patient will choose to take this type of strategy.

Joyce A. O’Shaughnessy, MD: I have been very impressed, because we need a prospective phase III trial of course.

Sara A. Hurvitz, MD: Of course.

Joyce A. O’Shaughnessy, MD: But 4 drugs versus 2 drugs is quite intriguing. Bu, I was speaking about this the other day, and Sara Tolaney, MD, MPH, brought to my attention some presentation from ESMO [European Society for Medical Oncology] last year from the German Breast Group [GBG]. It isn’t published yet, so we don’t have it—it’s not really widely available. But the GBG went back and looked at about 2000 patients who had had a path CR with a variety of different regimens over a variety of different trials to see how well they did over time and also to look at whether clinical parameters—T size, nodal status—made a difference in terms of the recurrence risk. Interestingly, and I guess not too surprisingly, if you were a T3, T4, and the higher number of nodes you had, even though you were a path CR, you didn’t do quite as well in terms of your recurrence risk, if you were node negative or T1, T2.

In the T1s or early T2s, I’ve been doing a clinically node-negative approach. I’ve been using the Priyanka Sharma regimen. I like to give people preoperative therapy even if they have small tumors because of that possibility of avoiding the anthracycline. But in the larger bulkier tumors, that GBG data are interesting to me. I’m going to give that some good thoughts, you know?

There was another study from ASCO that was also asking this question of the need for anthracycline preoperatively.

Erika P. Hamilton, MD: Yeah, another study out of China; 132 patients, which was small, but it was dose-dense epirubicin-cytoxan followed by a taxane or taxane in combination with carboplatin, again given in a dose-dense fashion.

They showed really dramatic results, about a 16% improvement in 3-year disease-free survival, and about a 6% improvement in overall survival. For a small study, that’s pretty impressive. It suggests that not only can we omit the anthracycline, but we actually could be doing our patients a favor by adding carboplatin instead.

Joyce A. O’Shaughnessy, MD: It’s a very important question, the anthracycline versus the carboplatin, whether they really are cross-resistant or whether they really add to disease-free survival in particular. So intriguing and hopefully will set us up for the next round of randomized trials.

Just a brief point for me, everybody, because I think this is such a controversial area. If you do have a patient who is quite high risk, and/or BRCA, BRCA germline, is anybody adding carboplatin to an ACT [Adriamycin, cyclophosphamide, Taxol] backbone, for example, or do you see how they do with AC first and then decide? Or bring it in afterwards along with capecitabine, etc? So, Sara, what do you do?

Sara A. Hurvitz, MD: Well, I think I’ve already given away my hands that I like to start with a taxane and platinum. I do think that the data are compelling. They’re not entirely consistent. Different studies have shown improvements in DFS and path CR rate. Other studies haven’t confirmed them. They’re different trial designs, and many of them are small studies. The point I would make is, we really need biomarker data. You know, the study looking at Topo 2 [Topoisomerase II]-normal breast cancer indicating anthracycline really didn’t appear to benefit patients without Topo 2. We need more large studies that are going to interrogate these sorts of important biomarker questions so that we can help hone in on what we should be doing, as we’re getting to with the HER2 story.

Aditya Bardia, MD, MPH: I agree. It’s complicated. In general, we’ve been using ACT. I guess that’s the difference between the East Coast and West Coast.

Sara A. Hurvitz, MD: I totally agree.

Aditya Bardia, MD, MPH: But it is an important question in terms of the role of platinums; that’s very provocative. One factor to consider would be the tolerability and the number of patients who required a dose reduction with ACT and how well they were able to tolerate DCN [decorin], whether tolerability accounted for some of the improvement in disease-free survival. Regarding BRCA mutations, anthracyclines also work well in BRCA-mutant tumors. It is a DNA-damaging agent.

In the ovarian literature, we can see that anthracyclines have shown remarkable activity in tumors that have BRCA mutations. So, I feel very comfortable with the use of ACT in patients who have germline BRCA mutations. But if we are going to replace anthracycline, then I think platinum would be the best agent. For BRCA mutations, for me, it’s not about the addition of platinum; it’s whether we can replace the anthracyclines with platinum.

Joyce A. O’Shaughnessy, MD: In a higher-risk patient, I’ll see how it goes with up-front dose-dense AC, and if they’re clinical CR, I will just go on usually to dose-dense paclitaxel, and then go from there afterwards. This is because I can combine carboplatin no problem with the 6 months of capecitabine, if somebody has a lot of residual disease and I feel like I don’t want to leave anything off the table for this patient. But if they have a small amount of residual disease, I would of course go on to capecitabine. But I tend to use the AC response. If somebody is not responding that well, I will add the carboplatin to the paclitaxel just because many of the studies have shown some increment in path CR with the addition of the carboplatin, though we don’t have solid data but what that’s going to do with DFS, you know? So that’s for me. I take up a similar approach in BRCA-positive patients because of the GBG showing really. For the patients with BRCA, that’s where platinum did not make a difference in the path CR rate or in the progression-free survival. This is because, like you said, the anthracycline-based chemotherapy was so effective for those patients. How about you, Debu?

Debu Tripathy, MD: I’m generally not using platinum all the time. I do it in patients that are not responding, just like you do. I think the point you made about long-term outcome is important. But also, it’s been noted in multiple trials that when you do use platinum, you end up attenuating the dose of taxane. We know that taxanes are an important part of the treatment. So I think it remains to be seen. We do have randomized trials now in the adjuvant setting. I think the story is still out.

Joyce A. O’Shaughnessy, MD: How about you, Erika?

Erika P. Hamilton, MD: I do something very similar to Debu. I don’t routinely do it one way or the other. I do a little bit of both depending on who the patient is. In very high risk, and also to very young people, I tend to maybe add the platinum more and for patients that aren’t responding as well.

Joyce A. O’Shaughnessy, MD: That’s good, great.

Transcript Edited for Clarity
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