The next 10 years are expected to usher in unprecedented advances in oncology, including molecularly driven diagnostic and therapeutic developments, whole genome sequencing that results in true precision-based medicine, survivorship care plans that address long-term quality of life concerns, and team-based, cross-disciplinary approaches to research. However, continued reductions in research funding due to the Federal sequester threaten to slow and even halt momentum just as the ability to detect and define cancer based on its panomic characteristics, rather than on tumor site alone, so it can be more effectively treated is reaching a turning point.
The ASCO Post recently spoke with José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, about the progress being made in the treatment of both early-stage and metastatic disease, the care of long-term survivors, new approaches to research, and the roadblocks and opportunities that lie ahead.
Precision-Based Medicine and Immunology
How will cancer therapies change over the next decade?
We will see advances in treatment on multiple fronts. There are two areas that I predict will have the biggest advances. One is that our capacity to interrogate tumors is going to improve, so the whole genome mutational landscape of every tumor will make every tumor different. We will, therefore, be able to develop therapies that are much more effective and that will be determined on a tumor-by-tumor basis.
Breast cancer is going to split into at least 20 to 25 diseases, and the same applies to colon, lung, and ovarian cancers, so we are going to have a fermentation of the tumor subtypes. Knowing the mutational landscape of every tumor will allow us to predict the clinical behavior of that tumor. Further, it will allow us to deliver on the promise of precision-based medicine in which we will be able to define the best cocktail of therapies for a particular tumor. That is one prediction.
The second big advance is the total revolution that is happening on the immunology front, especially with immune therapies such as PD-1 and PD-L1, but also with genetically engineered T-cells modified with a chimeric antigen receptor (CAR).
So, precision-based medicine and immunology are going to be the two major fronts for advances in cancer care over the next few years.
Screening and Prevention
Will some types of cancer become preventable over the next decade?
That is an area where we need to make more progress. Prevention is going to be key, but we don’t understand well, with some exceptions, what are the determinants of cancer and how to prevent them from happening. I think once we have plasma-based DNA assays that can be routinely employed as screening tools, we can envision a situation in which we can begin to identify whether something is cooking. But at this point, it is very difficult for us to identify whether a tumor is developing or advancing, and if we can’t identify these processes, it is very difficult to prevent their occurrence.
Gene Sequencing and Targeted Treatments
Will whole genome sequencing be routinely incorporated into clinical care?
Yes, it will become routine across the country. The cost of sequencing tumors will drop dramatically and the results from the testing will determine therapy. This year at MSKCC we are going to sequence 15,000 tumors in metastatic diseases.
Will greater progress be made in more effective therapies for difficult to treat cancers like lung and pancreatic?
Oh, yes, there is no question. The key issue in pancreas and lung cancers is finding a way to target the KRAS gene mutation. But I’m hopeful. There are a number of initiatives in very good labs around the country that are beginning to identify ways to target KRAS. In lung cancer we have therapies that target the epidermal growth factor receptor and the ALK gene, among others. In pancreas cancer it is going to be tougher to solve the problem because the science is more complex and the stroma also plays a big role in the disease, but there are very exciting data coming along. At MSKCC, we have decided to establish a pancreatic carcinoma center and we are committed to finding solutions for this difficult cancer.
Will it actually be possible to cure more cancers vs converting them into chronic illnesses?
We don’t know. There are a proportion of melanoma patients treated with immune therapies who have not relapsed. Are these patients cured? We will need to follow them over a longer period of time to answer that question. There are some HER2-positive breast cancer patients who have metastatic disease, and the disease doesn’t come back after treatment. I think now, however, the realistic endpoint in patients with metastatic disease is to improve survival. But down the line, the next stop after survival is cure, and we could be just a few cells away from accomplishing cure in metastatic disease.
For early-stage cancers, for example, patients with HER2-positive disease, we are curing over 90% of patients. Who would have thought that would be possible a few years ago? So in a disease that was lethal not that long ago, over 90% of patients are now cured. It is in metastatic disease where we still have challenges.
Quality of Life in Survivors
With more people surviving cancer, how will survivorship care plans and surveillance need to be improved to ensure survivors’ long-term quality of life?
This is a big question. All the cancer centers will need to work on improving survivorship plans. At MSKCC, we are creating a survivorship center where a number of issues will be addressed. Point number one is the well being of survivors. Second is determining who should take care of these patients down the line. We [oncologists] are going to be very, very busy taking care of new patients. More importantly, we want the patients who are survivors to be transferred back to where they belong for health care, which is back to their communities and back to the primary care setting.
At MSKCC, we will soon be performing bone marrow transplants on an outpatient basis, and we are building a hotel to house these patients while they recover from their transplant. We need to determine how to physically condition these patients through diet and exercise programs so they are in good shape and able to tolerate the treatment.
Then, very importantly, we need to address survivorship issues and to identify long-term sequelae. These are patients who are at risk of developing secondary tumors. What do we do about that? Addressing the question of how to maintain quality of life in long-term survivorship will be an area of tremendous importance, and we need to bring scientific methodology to the problem to make progress.
Team Science and Intellectual Curiosity
Will the concept of a team-based, cross-disciplinary approach to research lead to faster development of new treatments?
There is no question that the idea of a team of scientists working together is important, but at the same time, the power of the individual mind is equally important. There are going to be major discoveries made because one astute clinician/researcher is going to find something is different in his or her research and pursue it.
For example, in a small study at MSKCC, patients with advanced bladder cancer were treated with everolimus (Afinitor), and using conventional criteria, it was a negative study.1 There was one person who had a very good response from the drug, three others had minor responses, and the majority of patients did not respond at all. But in the one patient with the very good response, the tumor disappeared and never recurred. The lead investigator, David B. Solit, MD, [of MSKCC’s Human Oncology and Pathogenesis Program] questioned why has this one patient had responded so well to everolimus. With the help of a team of investigators, Dr. Solit sequenced the whole tumor and found that it had a TSC1 mutation, which is known to be involved in the mTOR signaling pathway. Everolimus works by inhibiting the pathway. Dr. Solit went back over his records and found that every patient in the trial who had a minor response had a TSC1 deletion. We have since opened up a bladder cancer trial in which any patient whose tumor possesses a TSC1 mutation is being offered everolimus.
So, yes, there are certainly advantages to the team-science approach, but it will not be able to substitute the intellectual curiosity and the drive of one smart investigator who will be relentless in the pursuit of identifying why a patient may be responding to therapy. Research needs both approaches. We need team science and we need very smart individuals to be fully engaged and freethinkers, so they can be daring and push investigations on their own.
Challenges and Opportunities
What impediments to advances in oncology do you see over the next decade?
There are multiple threats to continued progress. I think the biggest threat of all is the lack of federal support for research. It is very worrisome. Are we going to be able to attract the best and the brightest people to medicine and to oncology? Will young, smart college graduates be interested in pursuing a career in science if there is uncertainty about support and funding for research, or will they look to other careers because they don’t see a future in biomedical research?
The other major threat is are we going to have proper reimbursement for all the complex care that we are delivering? So we need to find a way in which we can deliver care that is affordable, but we also need to make sure that this care is reimbursed.
The challenges are there and we need to look into finding solutions for them, but the most important message here is that despite any threats we have, we are perhaps at a turning point in our fight against cancer. This is a very exciting time to be involved in treating and researching cancer. This is the moment for which we have been waiting so very long.
When people come to me with concerns, I remind them that, yes, there are always problems to overcome, but we were never, ever, so close to making a big impact in cancer as we are today. This is perhaps the most exciting time ever to be in the field of oncology. ■
José Baselga, MD, PhD, is Physician-in-Chief at Memorial Sloan-Kettering Cancer Center in New York, New York.
1. Iyer G, Hanrahan AJ, Milowsky MI, et al: Genome sequencing identifies a basis for everolimus sensitivity. Science. August. 23, 2012 (early release online).
The panomics of cancer include the networks of molecular pathways and characteristics of tumor microenvironment that interact to drive the development of each individual’s cancer, response to treatment, and long-term toxicities. ■