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Investigating Breast Cancer: Dr. Luca Gianni

Focusing on early treatment
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In this important and engaging conversation, Dr. Luca Gianni remains grateful to his mentor – Dr. Gianni Bonadonna – who brought him into the National Institute for the Study and Treatment of Cancer in Milan, Italy some 40 years ago. Based on what he learned there, Dr. Gianni has since delivered numerous breakthroughs in cancer research.

One involved finding ways to introduce therapies – to treat tumors before a main treatment – particularly in women with locally advanced or inflammatory HER2-positive breast cancer.

Now he is taking that same mindset – focus on early treatment – to drive his research in an important different direction: To help identify triple negative breast cancer patients most likely to benefit from checkpoint inhibitor therapy before beginning the treatment and those who will do well with chemotherapy alone. Not only would this help find patients with greater likelihood for an improved outcome, of course, but it also could help reduce the extreme costs and toxicity side effects for patients unlikely to benefit.

Dr. Gianni is Director of the Department of Medical Oncology and the head of the Project of Development of New Drugs and Innovative Therapies in Solid Tumors at the San Raffaele Scientific Institute in Milan. He is also Cofounder and President of the Michelangelo Foundation, a non-profit organization designed to advance research in oncology, and chairman of the Michelangelo Breast Cancer Study Group. Dr. Gianni has received several grants and research support, and was awarded the “Gianni Bonadonna Award and Fellowship” by the American Society of Clinical Oncology in 2011 – an award named after his mentor. He also has been a BCRF Investigator since 2018.


Read the transcript below:

Chris Riback: I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.

You likely know the expression, Pay It Forward. It’s an important concept for any kind of social awareness, but it can carry special meaning as well in the breast cancer world, particularly in research.

That’s because so much of today’s important breakthroughs are built not only on yesterday’s participation of other patients, but, of course, the work of other researchers. 

It’s a sentiment Dr. Luca Gianni not only knows well, but also puts into practice every day.

As you’ll hear, in this important and engaging conversation, Dr. Gianni remains grateful to his mentor – Dr. Gianni Bonadonna – who brought him into the National Institute for the Study and Treatment of Cancer in Milan, Italy some 40 years ago. Based on what he learned there, Dr. Gianni has since delivered numerous breakthroughs in cancer research.

One involved finding ways to introduce therapies – to treat tumors before a main treatment – particularly in women with locally advanced or inflammatory HER2-positive breast cancer.

Now he is taking that same mindset – focus on early treatment – to drive his research in an important different direction: To help identify triple negative breast cancer patients most likely to benefit from checkpoint inhibitor therapy before beginning the treatment and those who will do well with chemotherapy alone. Not only would this help find patients with greater likelihood for an improved outcome, of course, but it also could help reduce the extreme costs and toxicity side effects for patients unlikely to benefit.

More about Dr. Gianni: He is Director of the Department of Medical Oncology and the head of the Project of Development of New Drugs and Innovative Therapies in Solid Tumors at the San Raffaele Scientific Institute in Milan. He is also Cofounder and President of the Michelangelo Foundation, a non-profit organization designed to advance research in oncology, and chairman of the Michelangelo Breast Cancer Study Group. Dr. Gianni has received several grants and research support, and was awarded the “Gianni Bonadonna Award and Fellowship” by the American Society of Clinical Oncology in 2011 – yes, an award named after his mentor. He also has been a BCRF Investigator since 2018.

I connected with Dr. Gianni in his lab in Italy, which left me envious of course that the conversation occurred, as you’ll hear, via computer, rather than in person – say, in a local Milan cafe… Well, we can’t have everything

Chris Riback:    Dr. Gianni, thanks for joining me. I appreciate your time. I'd like to start this conversation with history. After all, you're in Italy, a country rich with incredible his story. You're also cofounder and president, among other things of the Michelangelo Foundation. That certainly feels to me like a nod towards history, so I assume you have no problem with history, correct?

Dr. Luca Gianni: Well, I have little problems with history, but the name of the Michelangelo Foundation was not because of Michelangelo. It was a much less emphatic reason for that. The first meeting of the foundation was in a hotel that was the Michelangelo Hotel, so we picked that up.

Chris Riback: Okay, well but I would think perhaps the Michelangelo Hotel was named with the historical nod.

Dr. Luca Gianni: Absolutely.

Chris Riback:    Somewhere.

Dr. Luca Gianni: Absolutely.

Chris Riback: It's a good thing, I guess, that you did not have that meeting in a hotel with a silly name, and then ended up with a foundation with a silly name. At least you were in a hotel with a very-

Dr. Luca Gianni: Maybe we would have reverted it to the Michelangelo for some odd reason.

Chris Riback:    I'm sure that you would have. The history though that I really want to ask you about, of course, is your own. Specifically, much of your early career work helped identify neoadjuvant therapies, particularly in women with locally advanced or inflammatory HER2-positive breast cancer. I want to really understand that, because what I'm believing, and we'll get into this, and you'll correct me if I'm wrong, is that so much of your early work helped inform the work that you subsequently did and that you are doing now. So just to begin, what are neoadjuvant therapies, and why were those discoveries so significant?

Dr. Luca Gianni: Well, it is a very difficult question, especially to explain. A neoadjuvant in simple words is applying drugs before the application of surgery, rather than as an adjuvant after the surgery. In principle, it's a simple swap of timelines, so you start with one of the ingredients of the ideal type of therapeutic approach instead of the combination or one which has seen for many years as the surgical approach.

Dr. Luca Gianni: The history goes that a time ago, it was very frequent to observe women with very advanced breast cancer at first diagnosis, and so advanced that the surgeon couldn't apply a clean type of surgery. By clean surgery, you mean a surgery where the margins were free of tumor cells. So those were the years when the first effect chemotherapeutic combinations were made available. The idea was, "Okay, let's try with effective drugs first and see if we can shrink the tumor to a size where the surgeon can kick in and do his job at his best. So that the origin of the neoadjuvant approach.

Chris Riback: Is there something about your mindset, your thinking, your scientific approach that had you focus on the period before the surgery? As we get into the work that you are doing, in terms of the scoring and your immune-based gene score work, and we'll talk about that in a moment, but it was feeling to me, in looking at your history and looking at the work that you do, that a lot of your focus is on, "How do we address things early, or as early as possible? How do we work in advance of some other event?" Am I interpreting your approach correctly?

Dr. Luca Gianni: You have a correct interpretation. What is my real drive is to try and apply what we have, at this best, in controlled conditions. If I apply the drugs before surgery, I can investigate and see what happens with drugs, and eventually change the drugs if the results are not as satisfactory as I want them to be for the benefit like the patient. While if I apply the drugs after the surgery, I basically am treating a condition where I am considering risk. The risk is not certainty. It is not something that they can measure. I can approach an estimate of risk, and if I apply the wrong type of drugs, I will know it only when there will be a relapse, and I don't want a relapse. If I apply them early, when I can measure "What did they do?" I can optimize the type of approach and the treatment.

Chris Riback: So let's talk about one of those conditions. It's one of the most challenging conditions, obviously, within the breast cancer world, and that's triple negative breast cancer. Not all triple negative breast cancer cases are responsive to immunotherapy, are they? The belief is that one factor impacting the ability to generate responsiveness is a lack of a biomarker to predict response to those therapies. Is that right? Talk to me about the challenges around potentially the lack of responsiveness to immunotherapy among some if not many triple negative breast cancer cases.

Dr. Luca Gianni: Okay. The topic is extremely complex, because immunotherapy has different possibilities of being the right answer according to many different thing, many variables, as we call them. First of all, we shouldn't be distracted by the relatively minor type of results with immunotherapy in metastatic breast cancer. We are now having a good feeling that, indeed, in metastatic disease, there are a number of down-regulation of immune systems that are not present at first diagnosis. If you speak about immunotherapy of triple negative breast cancer, recently there was a clear cut demonstration that in the neoadjuvant setting, the application of immunotherapy with chemotherapy affords potentially an outstanding rate of responses that have never been witnessed before.

Dr. Luca Gianni: So that tells us two things. Number one is that we should apply these drugs as early as possible. Number two, that maybe neoadjuvant, that is application before surgery, is better than adjuvant treatment. Why is that so? We think, and there are experiments going this direction, that if you apply immunotherapy as we have it with chemotherapy, in the presence of large burden of tumor, you have a higher chance of achieving kind of a vaccination against the tumor, and so the results tended to be much longer lasting than if you apply the same drugs after surgery when the tumor is almost nil or actually nil.

Chris Riback: What is the process? And I think this starts to get among the work that you're doing. What is our process for identifying which cases, which individuals are receptive to that vaccine, that prework that you've just described versus the ones that aren't, so that it's not being done ... randomly is not the right word, but so that it's being done with as much science and predictability as possible?

Dr. Luca Gianni: Okay. We have approached the problem in different ways. One way is that of designing specific particles so we use immunotherapy with chemotherapy prospectively as neoadjuvant and test for immune particles. That is one aspect. The other one is a different type of approach. In the past, when there was only chemotherapy around, we were already focusing our attention on immunology and in the value of the immune system in modulating the response of chemotherapy. We define and derived it from data available in literature that the expression of six genes associated with immune response was strongly associated with the probability of long-term survival without progression or relapse. We applied that to our patients, both in the adjuvant and in the neoadjuvant studies, and we observed that it worked. So our first approach is, okay, if it works, we needed to validate this finding, and if we validated this finding, we already have one major tool in our hands, because we will be able to identify those patients who are at very good chance of being cured by chemotherapy only.

Chris Riback: Is this the immune-based gene score, or is that-

Dr. Luca Gianni: Exactly.

Chris Riback: Yes.

Dr. Luca Gianni: This is an immune-based gene score. That will allow us to focus our attention on the remaining cases that they're not the type of probability, and try to modulate the immune response into these patients.

Chris Riback: My understanding is the benefits of this opportunity of the work that you're doing could be considered actually in two directions. One is positive direction, identifying the cases that perhaps have a higher probability of success, but then also in terms of managing the down-side risk, managing wasted cost, but even more significantly probably, saving people from having to deal with the toxicity when the process likely won't work for them anyhow. Is that right? Is it right to look at this bi-directionally?

Dr. Luca Gianni: You got it perfectly right. The point is that any additional drug is an addition of a potential source of toxicity. Drugs are very good, but drugs can be very toxic, so if I can avoid drugs, because they are not needed, that is a very important type of information. The other thing is that there are cases where I do need those drugs, and I want to know that positively, rather than giving the drug to 100% of the cases who come to my office, and causing many of them just the toxicity, and a lot of patients have no effect whatsoever, because they progress. I wanted to discriminate the effect of the drugs that they get. This is even more important in current oncology where many new drugs are so expensive that really challenge the financial possibilities of individuals.

Chris Riback: Yes, doing that prework, it could be very, very helpful on a number of fronts as you're identifying. How would you characterize where you are on this work? Are you where you thought you would be, where you would hope to be? Is there any aspect of it that you're finding particularly challenging, and you wish maybe you had Michelangelo around to help you think through the problem? How would you characterize where you are on your work?

Dr. Luca Gianni: Well, we are at mid-way, as it often happens. We have very good initial findings, and what we have done is to use a very good sample collections that we have done during the years in a couple of our trials. We have conducted in the past years, as the Michelangelo Group, two large trials of neoadjuvant approach, and we have now selected more than 350 patients with triple negative breast cancer, in whom we have available the tissue of the original diagnosis of the tissue, during the treatment, and whatever it was left at surgery. In addition to that, we have blood from them, so we started recently to perform a series of assays and tests to explore several aspects of the tumor and interpret the results, and apply our immune score in these patients. This is not immediate, but we now have the possibility of using this tool, which is very important.

Dr. Luca Gianni: To give you an example, since the collection of samples and the analysis of the trial have already been completed, we basically have the possibility of linking the immunoscore or the findings already to the results, to the intermediate results measured at surgery, and to the longer-term results, measured with continuous follow up. So although we have just started with these assays, we have the privilege of counting on the completed clinical trial done, and so we interpreted the results in a faster way than if we started today the collection of tumor.

Chris Riback: Earlier in this conversation, you indicated that one thing that you don't like, and nobody likes of course, is recurrence. Am I understanding you correctly that part of this work, or maybe it's adjacent work that you're doing, also can help identify various factors linked to the risk of recurrence?

Dr. Luca Gianni: Yes. Yes, this is exactly the point, because you know, we have a positive part, as you already said, which is identifying those who do not need anything more, because they already have a very high probability of being cured. On the other hand, we have the possibility of identifying those cases who unfortunately didn't reach that level, and do need more, and so apply to them more therapeutic opportunities that currently we have available, and do something that is more focused and more optimized for their needs.

Chris Riback: Dr. Gianni, what is it like doing this work in Italy? What is the culture there around breast cancer? Here in the United States, of course, it's obviously a very big deal, a very high level of awareness, maybe not about every medical detail, but certainly about the disease generally, the seriousness of it. Because it's affected so many people, there's a certain openness about discussion. Is that the case in Italy? What's the public consciousness like there around breast cancer?

Dr. Luca Gianni: Well, the consciousness is very deep. I would say that especially in the northern part of Italy, the approach is not very far and very different that in the United States. Also, in terms of awareness of the problem and adherence to the criteria for screening and so on and so forth. As it happens also in the United States where you have less privileged subgroups of population, also in Italy, we have groups of people who do not fully understand the relevance of screening and the importance of early diagnosis of breast cancer. But in general, the type of approach is not very far.

Dr. Luca Gianni: You have also to consider that we were very lucky. In Italy, we grew in terms of oncology under the guidance of giants of oncology such as Gianni Bonadonna, and for the surgical part, such as Umberto Veronesi. They were able to reach not only the doctors, but also the lay people, and make them understand how important it is to have an early diagnosis. So I think that Italy is, in this respect, a country where it's easy to work with the type of objectives that we have within Michelangelo and within my group.

Chris Riback: You just mentioned him. It's impossible to have a conversation with you without asking about the influence of Gianni Bonadonna on you. Now you come from a family of doctors. Your parents, I understand, were both doctors. So was it always going to be medicine of some sort for you, and then the work that you did with Bonadonna moved you towards research? Or were your parent pushing you towards the arts and literature and you rebelled against them and went into science instead?

Dr. Luca Gianni: No, my father was a prominent doctor in Italy, but he didn't want me to be a doctor. I decided to be a doctor, and my interest has always been in internal medicine and actually liver diseases. When I met Gianni Bonadonna, I met him by chance. Gianni Bonadonna had been working with my father when my father was senior staff at the University of Milan. So when he came back, Gianni Bonadonna came back from the United States, called up my father and said, "Well, I need young people to work in my new division, and would like to know, do you know anybody?" So my father said, "My son is here and he's an internist," and he asked me to go and speak with Gianni Bonadonna.

Dr. Luca Gianni: I went to Gianni and I said, "I'm not interested in oncology." Those were times when oncology patient had very terrible prognosis in front of them. They were late in making diagnosis, had no drugs and so on. "The only interest," I said to Gianni Bonadonna, "to come and work in oncology is if I had a chance to go in the United States and do research." So he said, "Well, I'd like people that do not sit on their back to make a career, so come on and I will send you to United States and do research." So that was my entrance door into the oncology field and into my acquaintance with Gianni Bonadonna.

Chris Riback: And then I read where, in 2011, the American Society of Clinical Oncology awarded you the Gianni Bonadonna Award and Fellowship. Given your relationship, and you know, I don't if he is still alive. I don't know, and if he did pass away, I don't know when that was, but that must have been extremely meaningful to you to win the award in his name.

Dr. Luca Gianni: Absolutely. It was absolutely incredible for me, and you know, Gianni had been really hit hard by a vascular hemorrhage, a cerebral hemorrhage, and so I took over all of his work and went on. Until then, I was working in oncology and new drug development, not in the breast field. So when they awarded me the Gianni Bonadonna prize, it was very emotional for me. Gianni Bonadonna was still alive then. He was as moved as I was when it was given to me. Gianni passed away in 2015, and we decided in Michelangelo to create a new nonprofit foundation dedicated to him. So now we have a Gianni Bonadonna Foundation just for innovating new drugs, doing something different from the Michelangelo, but it is something that we really care a lot about.

Chris Riback: That's a tremendous legacy. That's wonderful. To close out, BCRF, what role has BCRF played in your research?

Dr. Luca Gianni: BCRF is playing a key role. You know, we have been very good in making clinical trials and running clinical trials in a very resolute, innovative, and very reliable way, but we were missing the opportunity to run translation research. We had collected plenty of samples, but we had no possibility to go on with that beyond any given point. Breast Cancer Research Foundation is just looking to our deficit and saying, "We like it, and we support you," and does so in such a simplified way that our life is much easier than with any grant application that I ever had. So I am particularly grateful to Breast Cancer Research Foundation for this straight forward approach and support of all our science.

Chris Riback: Finally, a look to the future. I read a piece on you that starts, "According to Luca Gianni, everyone has a wish list of career milestones that feeds their dreams and ambitions." You have accomplished so much. What is the next career milestone that would feed your dreams and ambitions?

Dr. Luca Gianni: Well. Frankly, I would love to leave this intent and intenseness into people that they know that they can do something and accomplish something. Young people must be supported. You know, the future is with them, so my next goal is to maintain a tradition. I was supported by Gianni Bonadonna and others like him. I could name Larry Norton. I could name Gabriel Hortobagyi and plenty of friends that I met during my career. I think that I was an extremely lucky man, very fortunate to make these meetings and encounters. I would like to create the opportunities for other young and talented people to get the same good luck and support in their career. So that's my real goal for the future.

Chris Riback: Dr. Gianni, thank you. Thank you for your time, and thank you, of course, for the work that you have done and are doing.

Dr. Luca Gianni: Thank you very much for this chat. It was very pleasant.

Chris Riback: That was my conversation with Dr. Gianni. My thanks to Dr. Gianni for joining and you for listening. To learn more about breast cancer research or to subscribe to our podcast, go to bcrf.org/podcast.

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