Julie R. Gralow, MD

Question

What is the difference between long-lasting remission and a “cure,” in your opinion?

Answer

That’s a hot topic. We’ve been talking a lot about how to define cure. The definition of cure in breast cancer would be that you live out your life without a recurrence. Even with early-stage patients, when they are all done with their treatments, we aim for the best chance of cure and the majority of our patients will be cured, meaning they won’t relapse. But we can’t tell any single one of them that we’re sure that they have been cured. That gets to the whole question of what is cure, because we can even have relapses 15 years or 20 years later. In metastatic breast cancer, which means it has come back someplace beyond the breast and the locoregional lymph node area, I do believe that we are getting some cures, particularly with what we call oligometastatic disease with just a few sites of occurrence where we can maybe add some locoregional therapy. The issue of long-term disease-free survival or remission, whatever you want to call it — at what point can you call it cure? Just like in the early-stage setting, you really can’t say with 100% certainty that you’ve gotten a cure until you’ve lived out your lifespan and died of something else. I have patients in my own panel who are 15 or even 20 years out now from having liver mets, brain mets, lung mets and we treated it aggressively locally as well as with total body therapy, and many years later, the tumor hasn’t come back. I suspect that those patients are cured, but I can’t tell them that. I say to a lot of these patients, I suspect that we might have gotten it all, I’m hoping you’re cured, but let’s work out a plan for how we are going to follow you now.

Question

What is the best strategy for communicating the nature of metastatic disease to patients?

Answer

What I say to a patient when I’m confirming that they have metastatic disease — usually they know there is at least some suspicion — I would say at this point we would consider it treatable but the expectation is not a cure any longer. I emphasize that we do have a lot of treatments for metastatic disease, it’s highly treatable in most cases, but we are not aiming for cure. I like to say, “let’s talk about things, do you like statistics, generalities, how do you like to talk about it?” And I let them ask what they want to ask in the terms they want to ask it. I don’t always throw numbers at them. That first visit is an emotional one, but I try to be honest about the fact that the goal is not cure while also being hopeful and making sure that the patient knows that there are a lot of other goals that we can achieve. We talk about how we are aiming for improved quality of life, symptom control, and prolonged life. We focus on those things and weighing the benefit of quality of life with quantity of life. I want the patient to tell me if the treatment is worth living another 3 months, 6 months, a year, whatever it might be. We don’t need to be negative at every visit, but we need to be honest and not set false expectations.

I do tell my patients about other patients who have lived a long time because I think it’s important to know that it can happen, even if the odds would say it’s not the most likely thing. At our institution, we also have a peer-to-peer network of patients who have agreed to talk to other patients, at least a one-time phone call or a meeting in the infusion room, which enables patients with metastatic disease to talk to other patients with metastatic disease. For some of my patients, I refer them to an essay written by evolutionary biologist Stephen Jay Gould from Harvard in the 1990s when he was diagnosed with peritoneal mesothelioma called, “The Median Isn’t the Message.”¹ He talks about how the survival curve for most cancers is bell-shaped, there are some people alive on the tail of the curve after many years, and there is nothing in the studies to predict which patients will die. He turned around his mindset to consider that even though the odds are not good, some patients are still alive years later. He actually wrote the piece many years after his diagnosis, so we know he was one who outlived the average survival expectation for his disease. Also, often most of our statistics are from studies that are old now — in order to have 5-year survival, the study had to have been done 5 years ago. Look at all the drugs that have been approved in a 5-year time. If you live long enough, a new drug might be approved that’s effective against your cancer or a new trial may open up.

Question

What is the current role of immunotherapy in metastatic breast cancer?

Answer

It is a really exciting new era for us in the treatment of breast cancer with the recent U.S. Food and Drug Administration (FDA) approval of the programmed death-ligand 1 (PD-L1)-directed antibody atezolizumab in combination with chemotherapy for first-line metastatic TNBC. The FDA approval was based on the IMpassion130 data (ClinicalTrials.gov Identifier: NCT02425891), wherein an overall survival benefit of 9.5 months was demonstrated with the addition of atezolizumab to chemotherapy, in this case nab-paclitaxel, in the first-line setting in a subset of metastatic TNBC patients. In this study, about 40% of patients had tumors that were positive for the biomarker PD-L1 and it was the PD-L1–positive subset who derived that notable survival benefit. Although this was an informal survival analysis, it represents a particularly remarkable finding given that we had not previously seen a clinically meaningful improvement in survival for metastatic TNBC with prior strategies. So, this really is the hallmark of a promising new era. It is incredibly encouraging to see durable responses that translate into survival benefit for some patients.

We have some data in HER2-positive and HR-positive breast cancers as well, but really the most robust data we have to date is in the TNBC setting. There are huge numbers of studies underway because we need to make immunotherapy relevant for the majority population and not a minority population. So, it is a very exciting time whereby rational combinations with chemotherapy, biologic agents, targeted therapies and local modalities such as radiation are currently underway.

Question

What are some of the most promising trials in metastatic breast cancer that are under way?

Answer

We’re dividing breast cancer into different subsets now and I think that’s important. The old days of just enrolling 500 patients with breast cancer and testing a drug is long past us. For example, we are finding with the new phosphoinositide 3-kinase (PI3K) inhibitors that we’ve had a couple of positive trials but the drugs were toxic. But, now we have some excitement with some less toxic PI3K inhibitors and they seem to only work in patients with PI3K mutations. I don’t think they will be a homerun in the majority of patients, but in the small subset of patients with PI3K mutations that might be an exciting new drug. A lot of our newer trials are really interesting in narrower subsets.

I’m fascinated by the PARP inhibitors. We now have 2 PARP inhibitors, olaparib and talazoparib, approved in metastatic breast cancer in patient with BRCA1 or BRCA2 mutations, but the concept of whether there is benefit with other germline or somatic mutations in DNA repair genes is interesting. We’re finding that you can have somatic mutations in BRCA1/2, meaning the patients didn’t inherit it but they can be acquired as part of the tumor development. And then we have other DNA repair genes that can be associated with somatic or germline mutations. We have some studies that we are about to start to see if we can broaden the PARP inhibitors. In breast, now that I’m doing genomic profiling in most of my metastatic patients at least at some point, I have a whole panel of patients who have acquired BRCA mutations. So, I think we’re going to explore the somatic DNA repair genes, we’re going to explore many more inherited but less common DNA repair genes. We’re also looking for a signal in triple-negative in that don’t necessarily have mutations in these specific DNA repair genes, but have a problem with their DNA repair more broadly and have a “BRCA-ness,” or homologous repair deficiency. There are studies going on with homologous repair deficiency in triple-negative breast cancer.

I also like the idea that we’re looking at antibody drug conjugates beyond ado-trastuzumab emtansine (T-DM1) because I think it’s a cool technology. We’re looking to have sacituzumab govitecan approved in triple-negative breast cancer. In San Antonio last December there were several other antibody-drug conjugates with different targets and differing payloads of chemotherapy agents, and I’m excited about exploiting that possibility as well.

Question

Should all breast cancer patients really get genetic testing, in your opinion?

Answer

There was a presentation at San Antonio of 20 academic and community cancer centers where they took 1000 consecutive patients with breast cancer and did an 80-gene panel.2 They showed that about half of the patients met the National Comprehensive Cancer Network (NCCN) criteria for BRCA germline testing as it now stands and half didn’t. There was no statistical difference — across the board, about 9% had mutations in one of the 80 genes that was in this panel. Although there was no statistical difference whether you did or did not meet NCCN criteria, all of the BRCA1 and most of the BRCA2 mutations were in the group that met NCCN criteria. So, the point is that these NCCN criteria and other similar criteria were formulated in an era when we were looking for BRCA1 or BRCA2 families and so a lot of these other genes have weaker penetration and may be associated with other cancers besides breast and ovarian, and now that we’re doing multigene testing, the guidelines become outdated. The guidelines really do no better job of picking who might have a mutation. You could argue that BRCA1/2 mutations have the highest risk, we know the most about them, and they have the most actionable results, but in looking at what the other genes are, there are either guidelines being written or being discussed about how to manage these patients with other mutations, too. I’ve also found patients with BRCA germline mutations that weren’t picked up until I did next-generation sequencing.