If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live.
—Larry Norton, MD
Since 1990, we have seen an approximate 35% reduction in breast cancer mortality among women in the United States. Three protagonists can share this clinical success story: prevention, early detection, and better therapies. To shed light on the current state of breast cancer research and therapy, The ASCO Post spoke with internationally regarded breast cancer expert and ASCO past president Larry Norton, MD, Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center in New York.
Reinvention of Clinical Trials
Please tell the readers what has been the most significant advance in breast cancer treatment over the course of your career?
This may surprise some, but I believe the most significant advance has been the development of clinical trial methodology. Innovative scientific ideas come along frequently, but they still have to be tested. Not everything logical is true, but everything that is true should be confirmed. And the major leap forward in that confirmation process was the emergence of the randomized controlled prospective trial. Over the past few decades, we’ve seen many good ideas sorted out by rigorous trials, which ultimately developed into active therapies.
This is particularly relevant to this time in history, because we’re seeing a potential reinvention of clinical trials due to the advent of precision medicine: that is, defining a particular target, developing an intervention to hit that target, and then examining the results. Seeing responses in this setting is the most important step in the development of active therapeutics. However, it is a first step, and we then need to see how durable the response is, determine the optimal time in which to give the drug, learn how to use it in combination, and then compare the drug with other approaches. That said, we are currently ruminating over the best way to use molecularly targeted therapies in clinical trials to answer those vital questions quicker and more accurately.
This critical evaluation process is important, because we’ve had times in medical oncology in which a dramatic response was seen as the endpoint, stifling further critique. For example, autologous bone marrow transplant with high-dose chemotherapy produced dramatic responses in breast tumor shrinkage. Investigators judged this a huge clinical win, which in effect created a consensus among the oncology community that further confirmatory randomized trials were not needed. It took us 10 years to discover that bone marrow transplant with high-dose chemotherapy was no better than standard chemotherapy, which was also less toxic.
This episode offers an important cautionary lesson that shouldn’t be forgotten. Clearly, with the advent of molecularly targeted therapies, our opportunities are greater than ever, but we have to think very long about how we’re going to test these new therapies in trials that ensure their benefit before bringing them into the clinic.
Dissecting Resistance Pathways
Chemoresistance has been a persistent problem in breast cancer. Are we making headway in this area?
Drug resistance is a major problem throughout all medical disciplines where drugs are delivered. In cancer, it’s especially difficult because we’re treating a disease that comprises the host’s own cells. And evolution has taught these cells how to survive in a noxious environment of toxins. Drug resistance develops from a wide variety of cellular mechanisms, and one of the great powers of the modern molecular revolution is being able to dissect those resistance pathways and find ways to diagnose and prevent them.
This is one of the most exciting areas we’re investigating in molecular therapeutics. We’re seeing a lot of the newer agents being developed as initial therapies. For instance, we have many effective hormone therapies for breast cancer; the next step is to combine a hormone therapy with a promising drug de novo, which might overcome potential mechanisms of resistance. This approach is meritorious, but what might be more important in the long run is to treat a patient with a drug and if a resistance mechanism emerges, have another drug in place that will halt the resistance mechanism in its tracks.
Both of these approaches tie into my leading argument about clinical trial methodology, which, if properly designed, can be used to find the mechanisms of drug resistance and then develop drugs specially engineered to “turn off” those mechanisms. I think that’s the kind of clinical trial we’ll see more of in the future.
Immunotherapy is emerging as one of the most promising therapeutic opportunities in several cancers. Please discuss the future role of immunotherapy in breast cancer.
Immunotherapy is part of the molecular revolution we’re talking about, because what made it possible is the discovery of particular mechanisms by which our cells can avoid attacking their host, in particular the CTLA-4 (cytotoxic T-lymphocyte antigen 4) mechanism, which has opened up this exciting area of molecularly targeted therapies. What truly makes this interesting is that this process exists at the interface of the cancer cell and a host’s white blood cell, which is an important topic for future development; it is not the cell itself but the cell’s relationship with other cells. Nobody ever died of breast cancer cells; you die of tumors, which are complex organs involving cancer cells, white blood cells, and host tissues such as fibroblasts. And those cells in the tumor environment have a functional relationship, and the communication among those cells is a valuable target—I think that is the core of immunotherapy in cancer.
We’re currently doing a trial at Memorial Sloan Kettering in which we use cryoablation, radiotherapy, and other techniques, such as introducing DNA into the cancer cell to make it secrete its own immunostimulatory components, which are all methods to make the cancer cell a better target for the immune response. Then, if you combine that method with drugs that inhibit the checkpoint blockade for preventing cellular self-against-self attack, you’ve opened the door for promising immune therapies.
Targeting Both Growth and Migration
The metastatic process remains, to a certain extent, still a mystery. Are we getting closer to a full understanding of the process? And can you please bring our readers up to speed on your fascinating work on tumor self-seeding.
Cancer is basically two things: growth and migration. Over the decades, we’ve gotten much better at treating the growth abnormalities with chemotherapy. We’re seeing targeted therapies such mTOR inhibiters and anti-CDK4/6 drugs, which are effective at perturbing the abnormal cell division of cancer, but we’ve lagged behind in attacking the other component of cancer—the ability of cancer cells to migrate. And evidence suggests that cell migration may be key to the malignant process, because when migratory cells return to their original primary site, they bring white blood cells and blood vessels, which are tools to reinvigorate the malignant process.
To that end, there is tremendous interest in developing antimigratory drugs, which is a better term then antimetastatic. I think that moving forward this will be one of the most important areas of research in modern medical science. If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live. In other words, if we can inhibit the circulating cancer cells from lodging and forming tumors, it doesn’t matter how many cancer cells are in the blood, because the patient will never get sick.
We’re also making headway in a very novel technique, which is a trap that can actually capture circulating cancer cells. The immediate application is to capture the cells for study, hopefully to lead us to better molecular targets. However, it may have therapeutic value in being able to rid the body of cancer cells before they have the opportunity to root in an organ and form tumors.
Please share a closing thought or two about the state of breast cancer research and care from your perspective as Director of the MSKCC Evelyn H. Lauder Breast Center.
We have never had a period like this in all the history of cancer research and treatment. Compared to just a few decades ago, our growing knowledge of cancer biology is nothing short of incredible, but we have challenges ahead. For one, funding for research is very tight, and it’s a problem that we all wrestle with, one that ASCO has taken a lead on. I also think that the business model used to develop early ideas needs to be reinvented.
The brilliant MIT economist Andrew Lo has written extensively about this. He’s also organized a yearly meeting in Boston that is attempting to find better ways to finance drug trials. I have great confidence that if the oncology community partners with innovators such as Andrew Lo and others, we will generate the creative juices needed to reinvigorate the clinical trial process and bring these novel ideas to fruition. ■
Disclosure: Dr. Norton reported no potential conflicts of interest.