Tumor profiling, DNA sequencing, and other tools have helped revolutionize cancer care—bringing us closer to a world where all care is personalized. Breast cancer researchers led the charge to establish the importance of a patient’s tumor makeup, so that today, breast tumors are routinely analyzed for key drivers of the disease (estrogen, progesterone, and HER2 receptors) that can guide treatment.
Breast cancer researchers are continuing to find ways to personalize treatment for this disease. One leader in the field is BCRF investigator Fabrice André, MD, PhD, whose focus is two-fold: identifying new mutations and targets to treat metastatic breast cancer and proving the utility of personalized strategies by making high-tech analyses actionable and useful for oncologists and patients.
Recently, at the San Antonio Breast Cancer Symposium—the world’s largest conference dedicated to the disease—Dr. André received the 2021 AACR Outstanding Investigator Award, which recognizes scientists who have made significant contributions to the field before the age of 50. There, he also presented exciting results from his team’s phase II SAFIR02-BREAST trial.
BCRF’s Margaret Flowers, PhD spoke with Dr. André about his research, results from this trial, and where personalized medicine is going next. Watch their video above or read an edited version of their conversation below.
Tell us about yourself and the research you do.
Thank you, Margaret. My name is Fabrice André. I'm a medical oncologist by training, and I work at the Institut Gustave-Roussy in Paris, France. My work is about personalized medicine. What does that mean? It means that we are trying to find the right treatment for each patient thanks to molecular analysis. Our research focus is to identify, in each patient, what marker will define specific sensitivity to specific therapy (or specific toxicity to therapy and outcome) with the aim to have a comprehensive analysis of the biology of [someone’s] cancer to decide on the right treatment.
That's exciting. Your award presentation at SABCS focused on how this molecular characterization (or tumor profiling) and precision medicine have evolved. When we talk about molecular characterization and tumor profiling, what do we mean by that? And how should we be thinking about precision/personalized medicine in 2022 and beyond?
Let's start from the beginning. What is a cancer? A cancer is growing because some mutation in the DNA occurs. When we analyze these mutations in many different cancers, we can see that [one] cancer does not have the same mutation as another one. This is the pillar and the rationale to think that we should analyze each patient’s molecular profile to give [them] the right treatments.
Now, if we look into prospective and daily application in patients with breast cancer, we have two important applications of this concept now: the analysis of HER2—that is a protein overexpressed by a cancer cell—and the expression of estrogen receptor, or what we call hormone receptor. These two molecular analyses are done in daily practice and define whether a patient should receive endocrine therapy, chemotherapy, and trastuzumab/Herceptin]. That was the starting point of precision medicine in patients with breast cancer. In the last five years, new markers have arrived. For example, now we are determining BRCA [and PI3Kα] mutations. … These two genes are associated with sensitivity to two newer therapies: PARP inhibitors and PI3K kinase inhibitors.
So, what is happening next is [we’re] trying to model the biology of cancer in each patient. And for this, we need two different [avenues of] research. First, we need research on technologies. Because we need new technologies to analyze the molecule—the molecular profiling of each cancer—to make a kind of ID card of the cancer. And we need new method of analysis, like artificial intelligence. The aim in the future is for each patient to have a kind of virtual cancer, or avatar of cancer, where we can analyze all the different molecules. And we can say, 'Oh, this molecule is abnormal, and it's specifically this molecule we need to target.' New technologies are coming, and our research group is going to take advantage of these new technologies to better characterize cancer and identify therapeutic targets in each patient.
When we think about the technologies we have available to us that allow scientists to identify mutations in individual tumors, not all of those mutations may be informative to that patient’s treatment. Mutations happen all the time. And, as you mentioned, once you have a key mutation in breast cancer, many other mutations may happen. But they might not be driving mutations, or they might not be targetable by drugs. So how does the field go about identifying the mutations that really have clinical implications and that are valuable to precision medicine and treatment decisions? You presented results at SABCS on the SAFIR02-BREAST trial, where you looked at different categories of mutations and found that not all of them really informed the right treatment for patients.
You perfectly described the problem. The DNA of cancer contains important information to understand why cancer is growing. Nevertheless, we have a problem because we don't have the tools to interpret the DNA alteration and to really identify the right mutation. What did we do to address this question? We did a prospective clinical trial. The name is SAFIR02. SAFIR01 was the feasibility study. SAFIR02 aimed at addressing two questions. The first question is: Is it useful for a patient with metastatic breast cancer to have determination of DNA mutation (what we call sequencing)? And the second question was: What should be the tool to interpret these results? It's important to say that these clinical trials were supported by the Breast Cancer Research Foundation. It was a very large trial in France with 1,462 patients over seven years. It was a huge effort.
What are the results? The results [showed] that it is useful for patients with metastatic breast cancer to receive DNA sequencing. This is clear. Nevertheless, when we perform a sequencing of DNA, we need to interpret the results with some specific tools that colleagues have developed, including colleagues at Memorial Sloan Kettering Cancer Center or in Europe at ESMO, and these tools are telling the doctor and the patient, what is the expected benefit of hitting the gene that is mutated. And this is extremely important. Why? Because currently, most of the sequencing effort—most of the genomic report—do not interpret this mutation and do not report with a ranking system. And this SAFIR02 trial clearly showed that you need to rank the level of evidence of each mutation if you want to get a benefit from the sequencing. We think—but of course we are biased because it's our trial—that this is an important trial, because in terms of concept, it’s telling everyone that any patient in the world should receive a sequencing of DNA. But it's also telling what characteristics of the mutation are useful for the oncologist and the patient. Not all mutations should be taken into account. And what we are showing here is the utility of these informatics tools to classify the mutation.
What I'm hearing is that we're at a place now where it is important for patients with metastatic breast cancer to have their tumor profiled. And that the information from that can direct the right treatment to that patient. If there is a targeted treatment that pertains to a specific mutation. Reports that come from tumor profiling don't necessarily categorize these and say, 'This is important. This isn't important.' And that doesn't necessarily add more information, and it may, in fact, add more confusion. So, the tool that you used in the in the SAFIR02-Breast study was, as you said, a bioinformatics tool that looked at evidence that was available for the different mutations and kind of set them in different tiers. And your study showed that only those that are in the highest tiers were informative for treatment. Is that correct?
Exactly, and this is important because it means that when a mutation is lower tier, there is absolutely no evidence [to consider] the existence of this mutation in the decision. It's the first trial that is … proving the utility of what we call a kind of clinical decision support system. We know that between the technology and the doctor, there is nothing in between. This is why precision medicine is so difficult. What this trial is showing is that between the technology (DNA sequencing) and the oncologist and patient, we need something between that explained to the oncologist and the patient which mutation they should take into account and which they should not take into account. This a system to support and to inform the decision to administer therapy.
This really is an important finding. Where are we in terms of being able to bring this into real-time management of breast cancer? How far off is this in terms of being part of care and being able to identify mutations and connect those with specific treatments?
Let's think globally. What are the three tools we need to have precision medicine in 2022? First, we need DNA sequencing. We need machines and infrastructure that allow [us to] analyze the DNA of cancer. Theoretically, this is not so expensive, because the cost of the sequencing now has dramatically decreased. … Second, we need these tools to interpret the mutation, and these tools are available. It's open access. For example, the OncoKB from Memorial Sloan Kettering is perfectly available. And this tool is meant to allow interpretation of the sequencing. And then what we need are the drugs. Because it's totally useless to tell a patient, 'Look, this mutation is important for the growth of your cancer. But, oh, we don't have the drugs available.' This is the worst situation. Theoretically, we have everything in countries where there is reimbursement to put in place this precision medicine. It's much more difficult in some countries, or some social situations, where sequencing is not affordable, or the drugs are not reimbursed. But theoretically, the three tools are: sequencing, interpretation of sequencing, and drugs are available.
Right now, what are the questions? There are two. First, how can we add new drugs that are driven by genomics? And this is the field of clinical trials trying to validate the efficacy of some drugs matched to genomic activation. And the second question in the field of precision medicine is how do we go beyond the DNA sequencing? DNA sequencing is the analysis of DNA of the cancer. Where we are going now is the other issue of proteins, but also more and more aiming to grow the cancer ex vivo [outside the body] and analyze what molecules are involved in cancer progression ex vivo. And what are the sensitivities of this ex vivo cancer to the existing panel of drugs? This is the next step of precision medicine: moving beyond genomics to what we call living system. We grow the cancer of the patient outside [the body], and we understand from this ex vivo cancer which molecule we should target in each patient. Some clinical trials have already started on this question.
It's so exciting to realize the progress we've made. The pace of technology is dizzying. What I also hear is that we still have a lot of work to do. And that's why research continues to be so incredibly important. Fabrice, before I let you go—and I thank you for acknowledging BCRF support in this SAFIR02 study—could you tell our audience just a little bit about how BCRF has impacted the work that you're doing and your own career.
My God, I don't have words that are strong enough to thank BCRF. First, BCRF is acting globally. This is extremely important for people to know because research is global. There are extremely good researchers [all over]. So what BCRF is funding is excellence of research globally. … For me, it has totally changed the way I do research, because first, it allowed me to structure a team. And we all know that if there is no group of people, we cannot do research. It has allowed me to create a group of people with whom we can have long-term projects. Second, BCRF, of course, has an evaluation every year, but is also committed for the long term. And as we all know, research does not deliver in six months or one year. It's very important that BCRF supports [investigators and scientific programs] long term. We just discussed this clinical trial. [It took] seven years of effort to finally answer a question that will impact the patient. … And then the last point is the fact that the research supported by BCRF is diverse. It means one year, I can fund some experimental biology, if I need a year to focus on that. But the year after, pending good evaluation by BCRF's Scientific Advisory Board, I can switch to a clinical trial. That's important because it's the continuum of research. You can start from experimental biology, and you make a discovery. And when you want to move to clinical trial, BCRF will support you. It's a unique modality of funding. Because usually funding is what we call one-shot funding: I fund you for two years for a very specific project. Having an organization that supports you long term allows you to put in place a vision—and that is what we need in cancer research.
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