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Chemotherapy for Metastatic Breast Cancer in 2017

Panelists: Mark Pegram, MD, Stanford Cancer Institute; Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center
Published Online: Wednesday, Apr 19, 2017



Transcript:

Mark Pegram, MD:
The treatment of advanced breast cancer, historically, has relied largely on the use of sequential single-agent chemotherapies. This is for patients who either are steroid receptor-negative and HER2-negative or patients who have had prior endocrine therapy who then need to move on to chemotherapy, having become endocrine-resistant. And for the HER2 population, chemotherapy is usually used in combination with anti-HER2 agents.

For a brief time, perhaps in the 90s and early 2000s, there was some enthusiasm for combinations of chemotherapy in advanced breast cancer, and there were regimens even approved by regulators along these lines. For example, the docetaxel/capecitabine combination is an approved regimen. Gemcitabine in combination with paclitaxel is an approved regimen. But by-and-large, the combination use has fallen by the wayside, except in cases of severe symptomatic disease burden where it may be appropriate to use combinations. But otherwise, sequential single agents are as effective and less toxic than the combinations. So, we’re looking at sequential single-agent use of chemotherapy, one after another—often trying to change from one class of chemotherapeutic to another—trying to avoid the cross-resistance mechanisms within the particular class.

Joyce O’Shaughnessy, MD: Chemotherapy is still a very important mainstay of our treatment for metastatic breast cancer patients across all the various subtypes of breast cancer, and I think it will stay there in the future. Chemotherapy really is targeted itself. We’re going to learn more and more as time goes on that certain chemotherapy agents are going to be best for certain subtypes of breast cancer. For example, do you know that there can be a very small percentage, about 10%, of first-line only, triple-negative breast cancer patients who go into a complete response with mainly cisplatin, or carboplatin to a lesser extent, and will stay there indefinitely? It has been published by Steven Isakoff in JCO, but we all have patients in our practice where we’ve been just utilizing the platinum-based regimen in triple-negative breast cancer. But it’s a first-line phenomenon. It doesn’t happen in second-line, and it’s because the cisplatin is targeting a defect. It’s a targeted agent—in some triple-negative breast cancers, targeting the inability of some of them to repair double-strand breaks. So, it’s just the perfect selective agent.

Well, what about some of these breast cancers that are highly invasive, for example? They are using their microtubules for metastasis and for a highly invasive nature. Maybe those aren’t going to respond that well to platinum-based agents, DNA-damaging agents. So, let’s utilize antimicrotubule agents for those patients. And what about cancers that are all about proliferation when you are blocking the estrogen receptor, for example, and now you have utilized a serial number of options against the estrogen receptor in ER-positive breast cancer, you’ve been really inhibiting that PI3 kinase pathway perhaps with everolimus, and now the cancer is resistant and you’ve got bone-liver metastasis and ER-positive disease that’s highly proliferative?

Capecitabine is an antiproliferative agent, really an S-phase agent. It’s very, very, very good. But, again, it’s focused on cell proliferation of those cells. So, our chemotherapies are targeted. We haven’t really studied them in such a way as to understand which subsets of breast cancer they’re best suited for. But in practice here, you figure out over time which of the various subtypes of breast cancer respond to which different chemotherapy agents.

An example of why we’ll always need chemotherapy—in addition to the fact that sometimes, like with cisplatin in first-line triple-negative breast cancer, it will cure a very, very small percentage of those patients—is that, in some situations, such as HER2-positive breast cancer, HER2-amplified disease, you really need the chemotherapy in addition to the inhibitors of HER2 in order to really get very massive cytoreduction.

Certainly, the targeted agents, such as trastuzumab or pertuzumab, and the combination are definitely effective. But they really dial down to survival signal and, to some extent, the proliferation of the cancer. But to really cause that strong apoptotic stimulus and reduce that tumor burden, you need chemotherapy. And the chemotherapy—such as platinum-based agents, etc—will try to repair their DNA, and then the anti-HER2–targeted agents will stop the repair of the DNA, for example. So, there are synergies between the chemotherapy in some of our targeted agents—not all, but some of them—and we will never want to give up on those synergies.

Transcript Edited for Clarity
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Transcript:

Mark Pegram, MD:
The treatment of advanced breast cancer, historically, has relied largely on the use of sequential single-agent chemotherapies. This is for patients who either are steroid receptor-negative and HER2-negative or patients who have had prior endocrine therapy who then need to move on to chemotherapy, having become endocrine-resistant. And for the HER2 population, chemotherapy is usually used in combination with anti-HER2 agents.

For a brief time, perhaps in the 90s and early 2000s, there was some enthusiasm for combinations of chemotherapy in advanced breast cancer, and there were regimens even approved by regulators along these lines. For example, the docetaxel/capecitabine combination is an approved regimen. Gemcitabine in combination with paclitaxel is an approved regimen. But by-and-large, the combination use has fallen by the wayside, except in cases of severe symptomatic disease burden where it may be appropriate to use combinations. But otherwise, sequential single agents are as effective and less toxic than the combinations. So, we’re looking at sequential single-agent use of chemotherapy, one after another—often trying to change from one class of chemotherapeutic to another—trying to avoid the cross-resistance mechanisms within the particular class.

Joyce O’Shaughnessy, MD: Chemotherapy is still a very important mainstay of our treatment for metastatic breast cancer patients across all the various subtypes of breast cancer, and I think it will stay there in the future. Chemotherapy really is targeted itself. We’re going to learn more and more as time goes on that certain chemotherapy agents are going to be best for certain subtypes of breast cancer. For example, do you know that there can be a very small percentage, about 10%, of first-line only, triple-negative breast cancer patients who go into a complete response with mainly cisplatin, or carboplatin to a lesser extent, and will stay there indefinitely? It has been published by Steven Isakoff in JCO, but we all have patients in our practice where we’ve been just utilizing the platinum-based regimen in triple-negative breast cancer. But it’s a first-line phenomenon. It doesn’t happen in second-line, and it’s because the cisplatin is targeting a defect. It’s a targeted agent—in some triple-negative breast cancers, targeting the inability of some of them to repair double-strand breaks. So, it’s just the perfect selective agent.

Well, what about some of these breast cancers that are highly invasive, for example? They are using their microtubules for metastasis and for a highly invasive nature. Maybe those aren’t going to respond that well to platinum-based agents, DNA-damaging agents. So, let’s utilize antimicrotubule agents for those patients. And what about cancers that are all about proliferation when you are blocking the estrogen receptor, for example, and now you have utilized a serial number of options against the estrogen receptor in ER-positive breast cancer, you’ve been really inhibiting that PI3 kinase pathway perhaps with everolimus, and now the cancer is resistant and you’ve got bone-liver metastasis and ER-positive disease that’s highly proliferative?

Capecitabine is an antiproliferative agent, really an S-phase agent. It’s very, very, very good. But, again, it’s focused on cell proliferation of those cells. So, our chemotherapies are targeted. We haven’t really studied them in such a way as to understand which subsets of breast cancer they’re best suited for. But in practice here, you figure out over time which of the various subtypes of breast cancer respond to which different chemotherapy agents.

An example of why we’ll always need chemotherapy—in addition to the fact that sometimes, like with cisplatin in first-line triple-negative breast cancer, it will cure a very, very small percentage of those patients—is that, in some situations, such as HER2-positive breast cancer, HER2-amplified disease, you really need the chemotherapy in addition to the inhibitors of HER2 in order to really get very massive cytoreduction.

Certainly, the targeted agents, such as trastuzumab or pertuzumab, and the combination are definitely effective. But they really dial down to survival signal and, to some extent, the proliferation of the cancer. But to really cause that strong apoptotic stimulus and reduce that tumor burden, you need chemotherapy. And the chemotherapy—such as platinum-based agents, etc—will try to repair their DNA, and then the anti-HER2–targeted agents will stop the repair of the DNA, for example. So, there are synergies between the chemotherapy in some of our targeted agents—not all, but some of them—and we will never want to give up on those synergies.

Transcript Edited for Clarity
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