Angelo Di Leo, MD, PhD
Head of Sandro Pitigliani Medical Oncology Unit
Department of Oncology
Hospital of Prato, Istituto Toscani Tumori
Q: Tell us about yourself as a scientist and how you became interested in breast cancer research. Did you ever seriously consider another kind of career than that of the sciences?
A: I started with an interest in cancer as a student in high school, where I was fascinated by the biology of the tumor cell and decided then that I wanted to become a doctor. Because of my mother, I became very interested in breast cancer. In the second year of medical school, she became a breast cancer patient at the very young age of 46. Since I was still living with my family, I had the opportunity to see exactly what breast cancer is and began to understand how it impacts people.
I was also interested because I realized then that breast cancer is a disease where there are many things that doctors can actually do to try and help patients. At the time in 1984, there was clearly room for improvement in clinical care. Patients were all receiving chemotherapy, as part of standard practice, but chemotherapy causes many side effects. Since I was already fascinated by tumor cell biology, I started to study with more interest the biology of breast cancer cells - how they proliferate or spread to other parts of the body. When I was completing medical school, there was no doubt that I was going to become a breast cancer specialist. After a few years, I decided to move to Brussels, where Martine Piccart, MD, PhD, a fellow BCRF grantee, was starting her studies in the breast cancer field at Institut Jules Bordet. So I had the opportunity to work with her and started training in breast cancer.
As a result, I am a fully committed medical oncologist and breast cancer oncologist.
Q: Briefly describe your BCRF-funded research project. What are some laboratory and/or clinical experiences that inspired your work? What are your primary goals for this research?
A: The starting point of our BCRF research is that the biology of metastatic breast cancer is different from the biology of primary breast cancer. A woman whose breast cancer returns ("relapses" or "metastasizes") a few years later will have a different form of the disease than the one she had when her primary breast cancer was discovered. It is, therefore, extremely important to look at the biological characteristics of the metastatic breast tumors if you want to personalize or tailor the treatment of metastatic disease or to make substantial progress in the field of metastatic breast cancer treatment.
Now, with the help of technology, we have the potential to isolate circulating tumor cells (CTCs) from the blood of metastatic breast cancer patients and to study these cells. This is a very important advance because CTCs are thought to cause breast cancer relapse and spread. And CTCs are extremely rare - estimated at one CTC per billion normal blood cells. If we can actually isolate the CTCs from the blood, not only can we spare the patient from undergoing the biopsy of her metastatic tumor, which is a quite aggressive procedure, we can also investigate the biology of the origin of metastatic breast cancer. With the BCRF grant, we aim to find specific biomarkers from CTCs which ultimately can be used to help develop targeted therapy for treating metastatic breast cancer and will help lead to individualized therapies for patients.
Another branch of our studies focuses on a completely different aspect of metastatic breast cancer. Unfortunately, the way we are predicting the risk of disease relapse is still not very precise, because we sometimes tend to over-estimate this risk. As a consequence, some patients are receiving more treatment than they need and are being exposed to unnecessary side effects. In collaboration with a team at Memorial Sloan-Kettering Cancer Center (MSKCC) - specifically Monica Fornier, MD, Clifford Hudis, MD, Patrick Morris, MD, and Larry Norton, MD - our centers have been collecting blood samples from patients immediately following their tumor removal to identify specific metabolites, or small molecules, that are produced by tumors. Theoretically, after the primary tumor has been removed, there should be very few metabolites detected. The presence of these metabolites would therefore suggest that there are still tumor cells in the patient and, perhaps, additional interventions or closer monitoring may be necessary. This method can be used to help predict the risk of relapse more precisely than markers, such as tumor size, the involvement of the axillary nodes, or the hormone receptor status, used in current practice.
The technology we are using is called metabolomics, and it actually seems to be able to detect signals produced by metastatic lesions, even tiny micrometastatic ones that cannot be found by any standard radiology or even sophisticated imaging equipment. The reason why we collect blood after breast cancer surgery is because the blood collected before surgery still contains the metabolites that are produced by the primary tumor.
This metabolomics technology looks really very promising, and collecting just a few milliliters of blood for a sample is not as invasive, as a biopsy for instance. Our findings show that if you look at the metabolites of early breast cancer patients, you can make a more specific estimate of the risk of disease relapse than using traditional factors. If our findings are confirmed in a large set of patients, which is exactly what we are doing now with MSKCC, it means that in the future we might have a more specific, more precise estimate of risk of disease relapse. This would translate into a less intensive treatment after breast cancer surgery for some patients.
We have recently completed the first part of the work and together with the MSKCC team just finalized a manuscript which will be submitted to scientific journals.
Q: Are there specific scientific developments and/or technologies that have made your work possible? What additional advances can help to enhance your progress?
A: The isolation of the circulating tumor cells was something that ten years ago was absolutely impossible. Now thanks to new technology, we can do this almost routinely.
In detecting metabolites in the peripheral blood, once again thanks to advances in the field of nuclear resonance magnetics, we can now identify small metabolites that ten years ago could not be identified. Technology is absolutely central in our research once we have clearly defined what the clinical problems are. This area is something that technology cannot help. Once you have identified your primary questions, the technology can be helpful to isolate the CTCs and the metabolites and to identify micro-metastases that otherwise cannot be identified.
Continuing to make advances in all areas is important. A specific one is developing a more sophisticated way to analyze DNA. When we isolate a CTC, we isolate also its DNA to analyze it. Now, with the technology of new next generation sequencing, we have a more specific, more detailed picture of the DNA of the tumor cell. And this is absolutely key if we want to create more targeted treatment for metastatic breast cancer patients.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: I think in the next ten years without doubt we are going to have more and more personalized treatment. When I started 25 years ago, breast cancer was considered a single disease. Fifteen years ago, we started to understand that breast cancer is not one disease but at least four. A couple of years ago, we reached the conclusion that we are actually speaking about ten diseases.
I am convinced that in the next ten years, we will speak about several different types of breast cancer or very tiny subgroups of breast cancers that are characterized by the presence of key alterations or by key biomarkers. New technologies are helping us understand that there are specific DNA changes that occur only in one or two percent of the breast cancer population. So, we should treat this one or two percent of patients in a very specific, targeted way. This phenomenon has many implications for us in the clinical research field. One is that we will need to collaborate more and more. Let's say you see two thousand breast cancer patients a year at your cancer center. If you are studying a new drug that is estimated to work on only 2% of the population, you will have perhaps only 30 or 40 patients per year who are good candidates for this particular drug. Unfortunately, with this limited number, you cannot draw any definitive conclusions.
What we will need to do is to join forces internationally, across clinical trials groups and across the oceans. We need to pool together all of our results in order to demonstrate the activity of this new drug so that if it works, there will be enough statistical support to help pass regulations and become available to patients. In April, we had a very interesting meeting with Drs. Norton and Hudis and many other investigators from Europe and the US at which we discussed exactly this issue of reinforcing international collaboration. This is definitely in the future. There is no way that we will continue to run trials where we assume all patients have the same type of breast cancer. Even the pharmaceutical companies are starting to understand this. So in ten years, we will see more tailored approaches towards breast cancer.
Q: How close are we to preventing and curing all forms of breast cancer?
A: This is a really difficult question to answer because I am pretty sure that we are making progress on a daily basis; however, estimating the day on which our world will be breast cancer free is very difficult. We can now cure most cases of primary breast cancer. It is more difficult to treat metastatic disease. But, I am ready to say that the next ten years, we will dramatically improve treatment for patients with metastatic breast cancer.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: BCRF has impacted breast cancer research in three ways. One, the financial help allows us to pursue research that is completely independent of any pressure that could potentially come from the pharmaceutical industry. BCRF enables pure, independent research by investigators who are focused on curing breast cancer.
Another way BCRF has dramatically improved my laboratory's work is by putting us in contact with an extensive network of outstanding breast cancer scientists from all over the world. This connection, established through the annual retreat that we have in New York, has facilitated collaborations and is instrumental to improving the way we do research.
Last but not least, I work in Italy, a country where there is not as much support for breast cancer research as there is in other countries, especially in the US. When our local authorities realized that our research is funded by such a prestigious organization as BCRF, we got very positive feedback. They started to improve the financial support to our center for breast cancer research because they realize that our research is at the international level. The way that BCRF has improved our progress in breast cancer research is multi-fold, and it depends not only on the financial support but also the many other things that follow when we become part of this wonderful network.