Thank you, everybody. I thank you for giving us the last end of this meeting to talk about something that I'm passionate about, which is new treatments for ovarian cancer. So I don't have a lot of slides. I just have 10 slides. I'm going to get this done in seven minutes to respect everybody's time. All right. So as you know, there are three hallmarks of cancer. Dr. Doug Hanahan was at UCSF when he wrote this paper with Dr. Weinberg. And the top three that we're using on the right side is number one, immune destruction, number two, genomic instability, and number three, inducing angiogenesis. So I'm going to talk about the middle one, which is genomic instability. As you know, Dr. Vallejo was at Duke and Dr. Van Lee is at UNC. These three professors won the Nobel Prize for understanding the DNA repair mechanism and the toolbox for repairing cells when we went and visited with Dr. Modric at Duke. And he basically said, it's very simple. You basically have 3 million different gene mutations or cell divisions every day in your life. And you're going to have errors that happen. And these mistakes happen and ourselves have this special way to repair these mistakes. And this safeguard for this genetic information that nature provides for us could also be a crutch for us to understand cancer treatments and better development of drugs. So here it is. So when a cancer cell or normal cell undergoes division or natural division, you get DNA breaks. And these double-stranded breaks get broken. And the cells are really smart. They have these enzymes called PARP enzymes. They're basically repair trucks that go along the single-stranded DNA. And they basically repair that truck or the DNA railroad that's broken. And this repair truck that I tell my patients about is the PARP enzyme. And these enzymes now can be broken down. So basically, you can put a boot on the repair trucks of these cancer cells, enzymes. And that DNA, because the truck cannot repair that single-stranded DNA, will undergo a double-stranded break. And it will lead to cell death. And these scientists that are cancer biologists at UCSF and others basically show that this PARP enzyme is vulnerable and can be inhibited. And that's how we got drugs now. I'm not going to bore you with the drugs. But man, that's three New England Journal of Medicine papers researched by Nobel Prize laureates from Duke and UNC. What did it get us? Take a look at this. In the upfront treatment of patients with advanced ovarian cancer with BRCA, about 400 patients, all these patients have BRCA gene. Look at that magnitude of benefit. That hazard ratio is 0.28. I don't think we've ever, in my career, have seen magnitude of benefits this big. IP therapy, the advent of Taxol. We brought Taxanes into the medical oncology world. None of it has been able to show this magnitude of benefit. Even anti-vascular drugs, we were not able to see this benefit. And we sure didn't expect it right here, because these are BRCA patients. We've always thought BRCA patients are going to respond really well to platinum-based chemo drugs. But man, by adding norepirib, I mean by adding olaparib here, you're able to improve the progression-free survival from 14 months to now beyond 48 months or even 60 months now, as you follow these patients longer. So that's in BRCA patients. What if you don't have BRCA? What if you're not in that 10%, 20% group that have that germline or somatic mutation? Here's another New England Journal of Medicine paper that Dr. Martine put together on over 700 patients with stage 3 cancer. Now these patients were different. How are they different? Because most of them had neoadjuvant chemotherapy. Almost a fourth of them, more than a fourth, had actually stage 4 cancers. So these were much more difficult to treat and poor prognostic tumors. Even in this heavily difficult-to-treat group of patients that had even neoadjuvant, didn't even have upfront surgery on a significant portion of them, norepirib or the other PARP inhibitor is able to bring that progression-free survival from 10 months to 22 months. So a doubling of the PFS with a hazard ratio of 0.4, right? So clearly, even in all comers, you're able to improve the progression-free survival in these patients with advanced stage ovarian cancer, not just the BRCA. Clearly the patients with BRCA, HRD, and had significantly more benefit compared to the patients with HR-proficient types. You can combine this now by giving, Dr. Ray Cricard showed this, by combining elaporant and bevacizumab in over 800 patients, you're able to push that progression-free survival to even now to 37 months. So from 17 months to 37 months of PFS. So these are huge breakthroughs for us. So we put together a flow sheet to simplify this. And this we put into a commentary in 2020 on the three decisions that we have to make. And this is the last minute of my talk, okay? What do you do with upfront ovarian cancer? These are three decisions. The first is, do you take this patient to surgery? Just like our tumor board today, 50% of the time, we gave them chemo first. The other half, man, go debulk them. So that's the first decision you got to make. Do we give them treatment with chemo first, neoadjuvant on the bottom here, or do we give them primary surgery? The second decision is, do you add Bev? We generally do Bev based on Icon 7, Stage 4, pleural fusion, massive amount of ascites, give these patients Bev. If it's a patient with Stage 3, optimally debulk, maybe you don't give Bev for the subgroup. So let's go with this top group here that you didn't give Bev. And then decision three would be, hey, let's see what their BRCA status is. If they're BRCA mutated, give them Olaparib based on Solo 1. If they're HRD positive, then give them Meraparib. You can bring that PFS from 10 to 22 months. Uh-oh, what if you did give them Bev? Then you can actually combine it with Olaparib, right? Because that combination, based on the Paola study, is effective. And if you did use Bev, but you don't want to give them Olaparib, you can also just stay alone because adding Olaparib does not help the patients with HRD proficient disease. Man, look at our drugs. Check this out. All that yellow on top are all the PARP inhibitors. The second row of yellow are our antivascular drug. The third row, man, these are all our immunotherapies for uterine cancers, for all comers. Immunotherapies combined with antivascular therapy with Lembima. Now we have Tivdac. We may even get Simipumab, even though they think they pulled it from the FDA. But for the last seven years, every three to four months, we got a new indication or a new drug. We've never seen this before, right? Prior to 2014, for eight years, we had no new drugs. And now we got a new drug every three months. Thank you very much. I want to also thank our Vietnam colleagues. When I went to visit the National Museum and the War Museum in Vietnam, I saw this picture. And this is Dr. Van Le's boss and my boss when I was at UCSF. It was in the National Museum where in the Ho Chi Minh City Department of Health and UCSF, we helped them establish one of the first medical school curriculums that we were able to. And here is Dr. Washington, you know, signing the creed for the first medical school. And I always have great memories of all the grapefruits in Vietnam. I became a master monk for half a day. And also I was able to visit these cool Cu Chi tunnels. Thank you so much for having me. Appreciate it.

ovarian cancer

genomic instability

DNA repair mechanisms

PARP inhibitors

BRCA gene mutations