Targeting Angiogenesis with Chemotherapy for Advanced Breast Cancer - Episode 5
Transcript:Joyce O’Shaughnessy, MD: Chemotherapy really is a targeted agent therapy. We think of it as more broad based, a little bit more like a sledge hammer than targeted. But truly, they’re targeted. They go after very specific enzymes that have to do with cell replication, mitosis, and as well as metastases. So, these really are targeted. And the mechanism of the batch, and I think increasingly, will be matched up with the biology of the various subtypes of breast cancer. And particularly, I will say some of the DNA repair deficits or capability is going to help us sort out over time, as we get more good diagnostics to help us understand in this cancer right now, is it homologous or combination deficient or isn’t it at this moment, for example? So, the mechanisms are very different. The taxanes certainly are antimitotic, as well as cytoplasmic microtubules. They also have anti-metastatic affects, clearly, and they inhibit a microtubule depolymerization, of course. But it’s really microtubule targeted—both the mitotic spindle and cytoplasmic microtubules.
The antimetabolites, such as capecitabine/methotrexate, for example, are really about S-phase. Those are proliferating—not as helpful for your mesenchymal breast cancers that are more invasive and metastatic at that time, and more resistant, if you will. The epothilones are also similar in that they prevent depolymerization, but they bind differently to the microtubule than the taxanes do, and they can be effective even when cells are resistant to the taxanes because of certain tubulin mutations or upregulation of PGP that extrudes the taxanes from the cell. The epothilones, ixabepilone, can be useful. But, again, the mechanism is the same as the taxanes; it just overcomes some of the resistance mechanisms to the taxanes.
And then, lastly, there are agents that prevent polymerization, such as eribulin, and the other vinca alkaloids, such as vinorelbine. Vinorelbine hasn’t been as extensively studied late-line. We actually don’t have data on the extent of its non—cross-resistance in patients who have had an anticyclone taxane and capecitabine, for example. But in the setting, we do have eribulin, which—coming in after cells have become refractory to a taxane and refractory to capecitabine and in stopping the polymerization of the microtubules—is highly antimitotic, highly antiproliferative, as well as, interestingly, highly anti-invasive.
We can see this when we look at the CT scans. We’ll have this diffuse liver infiltration, and the liver enzymes will be really markedly elevated. That’s very, very serious because you really can’t safely give a lot of chemotherapy. If patients with liver function tests are very abnormal, they will not clear it. But eribulin within 1 or 2 cycles, you can get very dramatic reductions in the liver function tests and improvement on the CT scans very, very quickly because of the anti-mesenchymal properties. It just stops it from infiltrating them and proliferating. So, it’s very highly non—cross-resistant. Interesting, the mechanisms of resistance to taxanes probably set the cells up for benefit to go after those microtubules in a different way than a taxane.
Mark Pegram, MD: I think the mechanism of action of chemotherapy is really interesting, and I do think it is important, especially if you’re trying to avoid drug resistance. And so, it’s typical in my practice to try to switch from one mechanism to a completely different mechanism when that opportunity arises, hoping to avoid overlapping cross-resistant resistance pathways. So, I think it is important. We need to be mindful of this. It’s common practice in the clinic to think about the class of chemotherapeutic, the mechanism of chemotherapy, and to switch from one to maybe a completely different class when possible. It’s not always possible, but I’m often mindful of that. It does weigh in on my treatment decisions and I think about it a lot.
Joyce O’Shaughnessy, MD: Today, I think it’s probably fair to say that most of us utilize the NCCN guidelines and the big phase III clinical trials that are out there in terms of choosing and recommending a sequence of chemotherapy, whether it be single agents or combinations. I don’t think we’re really factoring in the mechanism of action or subtype of breast cancer now as much as we will be in the future. We’re limited. We really want to have level 1 evidence; we’re going to obviously favor agents that will improve survival, for example. We will favor, earlier on in metastatic breast cancer, agents that have less toxicity so that you can then prolong the duration of the treatment, because then the patient will stay in disease control for a longer period of time.
We’re favoring agents mainly based on what we know works when somebody’s already had an anthracycline. The taxanes work well, for example. What works after somebody’s had anthracycline and taxes? Well, capecitabine works, ixabepilone works, eribulin works, etc. Where’s our biggest body of evidence? That’s really what we’re mainly utilizing these days. However, like some of the alkylating agents, such as cisplatin, for example, or even utilizing some doxorubicin in the metastatic setting, these agents tend to be effective for breast cancers, typically triple-negative breast cancers.
We don’t know so much about some of the highly genomically unstable luminal B, ER-positive breast cancers. That hasn’t been studied well there. But in ER-negative disease, particularly triple-negative disease, there’s a group of these that are very, very, very highly proliferative, with KI67s of 80% to 90%, that are really in types of disease that would render them quite sensitive to platinum-based agents, such mediastinal lymph nodes, thoracic lymph nodes, parenchymal lung, etc. And we don’t have that same high level of evidence that platinum-based agents are superior to other choices, such as a taxane. They’re in that setting. And so, we’re not thinking as much about the mechanism there. I think that should evolve over time. We just need better diagnostic tools to help us understand, what kind of breast cancer? What is the subtype right now? What are the DNA repair deficits that we can exploit right now? I really think that’s where we’re going.
Transcript Edited for Clarity