Adam M. Brufsky, MD, PhD: I want to focus on something George said about the paradigm shift: We had that huge paradigm shift when Bernard Fisher and everybody else—not only Bernie, but a lot of people—said breast cancer is a systemic disease. That was the big shift; that was the first huge shift.

What about a shift that would say, “What are our cytotoxic agents? What are they really doing?” Yeah, they are debulking the cancer. We get it, but the question we always asked was more of a philosophical 1, which is to say, “We debulked the cancer. Where is it going? When we kill cells off, and they apoptose, where do they go? Who gets rid of the garbage? How does a body react to it?” This gets into the immune system business.

There has been a crazy paradigm that has been floating around for a while, saying that what chemotherapy may be doing in some cases is manipulating the host tumor microenvironment in combination with treating the cancer. Have you guys ever thought of that or even considered it as something? I know it is crazy; I am just bringing that up as something out there.

George W. Sledge Jr., MD: It is absolutely sensible. I read somewhere that basically every cell in your body is touched by a macrophage every day of your life.

Adam M. Brufsky, MD, PhD: Right.

George W. Sledge Jr., MD: If those big eaters see something abnormal, if they see some funny set of antigens since these are antigen-presenting cells, then they are going to do something to that cell. It is absolutely likely.

Of course, I said that chemotherapy is an efficient inducer of apoptosis, but if you look at what chemotherapy actually does, it does a lot of things. In killing cancer cells, it is releasing lots of antigens that are probably activating the immune system. Many chemotherapy agents are antiangiogenic in preclinical model systems and indeed in some clinical model systems. Rather than saying that we are just pounding cancer cells, when we give chemotherapy, we are doing several things at once.

Lee S. Schwartzberg, MD, FACP: It is interesting. We would all agree that we do cure breast cancer, but we cure it only in the micrometastatic situation for now.

Adam M. Brufsky, MD, PhD: Right.

Lee S. Schwartzberg, MD, FACP: We would agree on that. I believe that is true, and that is what adjuvant therapy does, but we do not know exactly how it does it. Is it a volume issue? Is it immune stimulation in a more intact immune system?

We now have some early clues from checkpoint inhibitors: They work better the earlier you use them. We are less dependent on our not-so-great biomarkers right now, like PD-L1 in the neoadjuvant setting, than we are in the first-line setting or in the late-line setting in metastatic cancer. We are going to make progress, and we may still use chemotherapy, particularly in the early stages to increase cure rate. It is going to be hard to cure metastatic cancer without chemotherapy, which is probably benefiting because it is not discrete in terms of 1 single target. It is difficult to cure with 1 target.

Adam M. Brufsky, MD, PhD: Otherwise, I still remember something important that I am always going to remember, George. This must have been in 2003 or 2004. We were probably talking about how there was some trial. I am trying to remember what it was. I was doing something with Gemzar [gemcitabine], and I was at a meeting with you. We were talking about it, and I will always remember this. You said, “Gemzar [gemcitabine] is a targeted agent. Chemotherapy is targeted therapy.” It is a more general target; it is not a specific 1. I always remember that.

I want to comment on the thing that I am interested in. What is going to make me turned on about this is that this is the exact thing that we are seeing in the neoadjuvant checkpoint trials: If you are PD-L1 positive, you benefit from chemotherapy regardless of whether you get the checkpoint inhibitor. Your pCR [pathologic complete response] rate is higher, but if you are PD-L1 negative, the absence of checkpoint inhibitor—what is that telling us?

George W. Sledge Jr., MD: Similarly, if you are in the adjuvant setting, you have a large number of TILs [tumor-infiltrating lymphocytes], and you have triple-negative breast cancer, then you have a higher cure rate in the absence of checkpoint inhibitors with just chemotherapy.

Adam M. Brufsky, MD, PhD: Right, right.

George W. Sledge Jr., MD: It tells us that we have always been giving immunotherapy. We just called it chemotherapy.

Adam M. Brufsky, MD, PhD: That is right. These are the things that the generation beyond you guys and I may be thinking about. I agree. This is going to be a long-term project, but it is cool that we are starting to see this when people are talking about signatures of response and survival even in metastatic disease and involving the immune system. It is getting interesting.

Transcript Edited for Clarity