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Evolution of Chemotherapy for Metastatic Breast Cancer

Panelists: Mark Pegram, MD, Stanford Cancer Institute; Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center
Published: Monday, May 01, 2017


Transcript:

Joyce O’Shaughnessy, MD:
I began practicing in the mid-1980s, and all we had in the mid-1980s, as far as chemotherapy for metastatic breast cancer, was doxorubicin and cyclophosphamide. We did have CMS. And then, we had vinblastine/mitomycin C. That’s all we had. You could also use an infusional 5-FU, which was used then. And the vinblastine/mitomycin C was a limited clinical utility—very limited and very myelosuppressive. So, we had very, very limited options.

Now, we have a much larger number of chemotherapy options. Truthfully, only a few of them have really been demonstrated at the highest level to prolong survival, but they certainly can get prolonged progression-free survival. I remember so distinctly when the taxane, paclitaxel, was the first, right around 1990 or so. It was just an amazingly non–cross-resistant agent after doxorubicin. It really revolutionized metastatic disease and gave patients durable responses and improvement in survival. It was very, very impressive. Docetaxel came out very soon thereafter. And with these agents, patients had this deep clinical response, complete responses, that would last sometimes for years. And they could, on the paclitaxel, keep getting it. With docetaxel, you’d have to stop after about 6 to 7 cycles because of anasarca.

And then, in 1998, capecitabine was approved by the FDA. And lo and behold, it was approved specifically because it’s non–cross-resistant with the anthracyclines and the taxanes. If those patients were having about a 13-month survival after an anthracycline/taxane, now continuous infusions by the view was also useful there. But it was very, very cumbersome for patients to have to get continuous infusions of 5-FU, so capecitabine was another big, big step forward there.

The next agents that came out were the epothilones, and the one that has been FDA-approved is ixabepilone. And ixabepilone as a single agent had limited development. It did have a response rate of about 18% in patients who would have an anthracycline, a taxane, and capecitabine, so it does have a response rate. No improvement in overall survival, but it still was a non–cross-resistant agent to some extent. But when you put it together with capecitabine in patients who have more heavy tumor burden after an anthracycline and a taxane, particularly those patients who are refractory—primary refractory or a rapid recurrence after neoadjuvant or adjuvant anthracycline/taxane—the combination of the ixabepilone and capecitabine was clearly better than capecitabine alone and led to approval of that combination. So, that became useful for patients with—I call it, “severe disease”—more refractory disease.

Most recently was the eribulin that became available to us via phase III trials. And that one was different because it was the only one we had seen that could really improve survival of late-line metastatic breast cancer patients. It was sufficiently non–cross-resistant with all the other microtubule agents—the taxanes and the epothilones—because it works differently against the microtubules. And it’s basically that you could get very rapid responses and pull the chestnuts out of the fire when patients had extensive liver disease or lung disease, and prolong survival in those patients.

So, we had a very good evolution over time, and there’s more to come. I think the topoisomerase 1 inhibitors, some of the antibody drug conjugates that are utilizing FM38, such as TROP 1 sacituzumab, are going to be exciting agents. There has been very good progress. But the key, I think, has been that what has been brought to the armamentarium has been non–cross-resistant with what we already had.

Mark Pegram, MD: More and more as patients are doing better and better with advanced disease. We’re seeing situations where patients are using many different treatment approaches during the lifetime of their cancer. And consequently, we’re seeing more and more lines of therapies being utilized in the modern era compared to times past. Plus, we have more agents to choose from with better activity.

Patients are living longer with advanced disease. Our goal is for it to become a chronic disease like other medical illnesses—diabetes, heart disease—and try to manage it for as long as possible with the least amount of side effects. So, the landscape has really changed. And sadly, we have patients that have really run out of opportunities for chemotherapies because we’ve actually run through them all. In those patients, we’re considering participation in clinical trials frequently. So, it is a big problem. We need more and better therapies because patients are doing well for much longer periods of time. But that’s another challenge for the field to come up with newer and better treatments for those patients to do even better.

It’s really exciting to be in the clinic now because of all of the clinical research opportunities and so many new treatment approaches. But many of them are still based on the backbone of chemotherapy. For instance, let’s take the excitement and the enthusiasm about immuno-oncology and treatment with the checkpoint inhibitor antibodies, which are very promising and already FDA-approved for other disease states like non–small cell lung cancer, melanoma, etc. These are now being tested in metastatic breast cancer in triple-negative disease, but with a chemotherapy backbone, usually a taxane. And consequently, we still have to be mindful of all the principles of chemotherapy and worry about the toxicities. But it holds great promise, that in combination with chemotherapy, these antibodies that augment cytotoxic T-cell immunity against cancers might be a huge benefit. So, even in clinical research, we’re often looking at a chemotherapy backbone. The same is true for new human-engineered HER2 antibodies. Those are in the salvage setting in phase III trials right now, and those are using a chemotherapy backbone head-to-head against trastuzumab for an FDA registration attempt.

Transcript Edited for Clarity
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Transcript:

Joyce O’Shaughnessy, MD:
I began practicing in the mid-1980s, and all we had in the mid-1980s, as far as chemotherapy for metastatic breast cancer, was doxorubicin and cyclophosphamide. We did have CMS. And then, we had vinblastine/mitomycin C. That’s all we had. You could also use an infusional 5-FU, which was used then. And the vinblastine/mitomycin C was a limited clinical utility—very limited and very myelosuppressive. So, we had very, very limited options.

Now, we have a much larger number of chemotherapy options. Truthfully, only a few of them have really been demonstrated at the highest level to prolong survival, but they certainly can get prolonged progression-free survival. I remember so distinctly when the taxane, paclitaxel, was the first, right around 1990 or so. It was just an amazingly non–cross-resistant agent after doxorubicin. It really revolutionized metastatic disease and gave patients durable responses and improvement in survival. It was very, very impressive. Docetaxel came out very soon thereafter. And with these agents, patients had this deep clinical response, complete responses, that would last sometimes for years. And they could, on the paclitaxel, keep getting it. With docetaxel, you’d have to stop after about 6 to 7 cycles because of anasarca.

And then, in 1998, capecitabine was approved by the FDA. And lo and behold, it was approved specifically because it’s non–cross-resistant with the anthracyclines and the taxanes. If those patients were having about a 13-month survival after an anthracycline/taxane, now continuous infusions by the view was also useful there. But it was very, very cumbersome for patients to have to get continuous infusions of 5-FU, so capecitabine was another big, big step forward there.

The next agents that came out were the epothilones, and the one that has been FDA-approved is ixabepilone. And ixabepilone as a single agent had limited development. It did have a response rate of about 18% in patients who would have an anthracycline, a taxane, and capecitabine, so it does have a response rate. No improvement in overall survival, but it still was a non–cross-resistant agent to some extent. But when you put it together with capecitabine in patients who have more heavy tumor burden after an anthracycline and a taxane, particularly those patients who are refractory—primary refractory or a rapid recurrence after neoadjuvant or adjuvant anthracycline/taxane—the combination of the ixabepilone and capecitabine was clearly better than capecitabine alone and led to approval of that combination. So, that became useful for patients with—I call it, “severe disease”—more refractory disease.

Most recently was the eribulin that became available to us via phase III trials. And that one was different because it was the only one we had seen that could really improve survival of late-line metastatic breast cancer patients. It was sufficiently non–cross-resistant with all the other microtubule agents—the taxanes and the epothilones—because it works differently against the microtubules. And it’s basically that you could get very rapid responses and pull the chestnuts out of the fire when patients had extensive liver disease or lung disease, and prolong survival in those patients.

So, we had a very good evolution over time, and there’s more to come. I think the topoisomerase 1 inhibitors, some of the antibody drug conjugates that are utilizing FM38, such as TROP 1 sacituzumab, are going to be exciting agents. There has been very good progress. But the key, I think, has been that what has been brought to the armamentarium has been non–cross-resistant with what we already had.

Mark Pegram, MD: More and more as patients are doing better and better with advanced disease. We’re seeing situations where patients are using many different treatment approaches during the lifetime of their cancer. And consequently, we’re seeing more and more lines of therapies being utilized in the modern era compared to times past. Plus, we have more agents to choose from with better activity.

Patients are living longer with advanced disease. Our goal is for it to become a chronic disease like other medical illnesses—diabetes, heart disease—and try to manage it for as long as possible with the least amount of side effects. So, the landscape has really changed. And sadly, we have patients that have really run out of opportunities for chemotherapies because we’ve actually run through them all. In those patients, we’re considering participation in clinical trials frequently. So, it is a big problem. We need more and better therapies because patients are doing well for much longer periods of time. But that’s another challenge for the field to come up with newer and better treatments for those patients to do even better.

It’s really exciting to be in the clinic now because of all of the clinical research opportunities and so many new treatment approaches. But many of them are still based on the backbone of chemotherapy. For instance, let’s take the excitement and the enthusiasm about immuno-oncology and treatment with the checkpoint inhibitor antibodies, which are very promising and already FDA-approved for other disease states like non–small cell lung cancer, melanoma, etc. These are now being tested in metastatic breast cancer in triple-negative disease, but with a chemotherapy backbone, usually a taxane. And consequently, we still have to be mindful of all the principles of chemotherapy and worry about the toxicities. But it holds great promise, that in combination with chemotherapy, these antibodies that augment cytotoxic T-cell immunity against cancers might be a huge benefit. So, even in clinical research, we’re often looking at a chemotherapy backbone. The same is true for new human-engineered HER2 antibodies. Those are in the salvage setting in phase III trials right now, and those are using a chemotherapy backbone head-to-head against trastuzumab for an FDA registration attempt.

Transcript Edited for Clarity
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