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Genetics & Ovarian Cancer
Genetics & Ovarian Cancer
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me, thank you for letting me speak on a topic of my choice. And as Linda knows, we do a lot of work in our genetics clinic here at UCSF. And I wanted to tie it to ovarian cancer and just talk a little bit about kind of some state of the art and the importance of genetics in ovarian cancer. Now I have to figure out how to advance my slide. Here we go. In 2014, a decade ago, I was chairing the clinical practice committee of the Society of Gynecologic Oncology. And at that time, a lot of information was coming out regarding genetics and ovarian cancer. And we put out a clinical practice statement at that point, which has been adopted at ASCO by NCCN, pretty much acknowledged that people who are diagnosed with epithelial ovarian fallopian tube and peritoneal cancer should have genetic testing, should have genetic counseling, even without a family history. So back in the day, we used to say that if you have a positive family history, this prompted our workup, but the paradigm change was that people with ovarian cancer should have a genetic assessment. So what I wanted to talk about today was genetic testing options relevant to the treatment of ovarian cancer and how information about genomics can influence ovarian cancer treatment. In the NCCN guidelines for ovarian, tubal, and peritoneal cancer, there is a recommendation on essentially page one that says patients should have genetic evaluation and that genetic evaluation can be part of a familial assessment, but it can also include germline and somatic BRCA one and two assessment. And if that's not positive, also an assessment on homologous recombination deficiency. And the reason for that is the role that this information has on treating with PARP inhibitors, which I'll talk about a little bit more. From data that came out of University of Washington, they looked at patients with ovarian cancer and they screened them for germline mutations. So this was testing to look and see whether the tumors carried mutations that could be inherited in the germline so that the idea was, if we look at patients with ovarian cancer and get genetic testing, who has a genetic predisposition. And in this series of 360 patients who were screened with or without a family history, regardless of age, they found that 11% of patients with ovarian cancer had a germline BRCA one or two mutation, 6% had BRCA two, and 6% had other genes. And this included patients without a family history and patients who are both older and younger. So as we used to think about a fraction of ovarian cancer patients being hereditary, we now understand the hereditary piece better, understanding that the tumors are actually associated with mutations in BRCA one, BRCA two, and a whole host of other genes, but most commonly BRCA one and BRCA two. Also, in addition to germline testing, looking to see what people carry in their germline in all of the cells in their body, there also have been tests looking at ovarian cancer and somatic testing, or looking at the tumor itself, looking for mutations. And in the Cancer Genome Atlas Project, the sequencing of ovarian carcinomas, specifically high-grade serous carcinomas of the ovary, were able to identify not only a mutation in the tumor in P53, but also 21% of the tumors had mutations in BRCA one and BRCA two. And that fits along with the patients that have the germline changes are also going to manifest these changes in the tumor. So the P53 mutations are somatic. If we look in the germline for these patients, most of the time people don't carry a germline P53 variant, but a quarter of patients may carry BRCA one and BRCA two, or some of the other genes that I showed you in the pie chart in the slide before. So how we think about that then is that for patients with ovarian cancer, we want to recommend germline genetic testing or somatic tumor genetic testing to look for the presence of BRCA one, BRCA two, or other changes that suggest that the tumors may be responsive to a treatment of PARP inhibitors. So there's been a lot of information that has been accumulated about maintenance therapy in ovarian cancer, either looking at PARP inhibitors, including olaparib, neraparib, or ocaparib, to some degree looking at bevacizumab, which can be combined with the PARP inhibitors, and really thinking about how PARP inhibitors can be used to improve ovarian cancer outcomes. PARP inhibitors are involved in DNA repair. So what they're involved is in the breakage of DNA to repair that, the PARP inhibitor is engaged in these double strand breaks. So in a normal cell, the having a PARP inhibitor doesn't cause a major problem because there's a separate pathway, homologous recombination, where the cell can fix itself. In a tumor that's missing BRCA one or BRCA two, or one of the other homologous recombination genes, if there's a double strand break, the PARP can fix part of it. But if you inhibit PARP, then you have a double damage, which is that with the PARP inhibitor and the damaged BRCA gene, the cell cannot fix itself and undergoes cell death. So in the different clinical trials, looking at the different PARP inhibitors, there's been a whole series of PARP inhibitor versus placebo after first-line treatment in ovarian cancer, and including first-line treatment with chemotherapy and PARP inhibitor, in the case of oliparib and the Velia study. Fairly consistently, we can see that adding a PARP inhibitor can improve the hazard ratio for survival, which is this outcome here in the line that I have highlighted in particular, patients with BRCA mutations in their tumors or variants in their germline that are pathogenic have a significant benefit so that the hazard ratio for survival is really quite dramatically improved. SOLO1 was the clinical trial looking at using oliparib versus placebo in patients with stage three and stage four ovarian cancer, and all of these patients had either a germline or a somatic variant in BRCA1 or 2 that was pathogenic. So patients were treated with this oral medication for up to two years. The patients were followed for three and a half years, and at three years, you can see the significant difference in the survival curves for progression-free survival when you used a PARP inhibitor versus placebo. So the difference between the progression-free survival was 60% versus 27%, and thinking about statistics, this hazard ratio was 0.3, which is a 70% decrease or improvement in progression-free survival at three years. Some people have said, well, if you stop the treatment, does that benefit still maintain? And there is longer-term follow-up from this patient population that received treatment. So remember, after two years, they stopped the treatment, but when you look at the survival curves following the patients for up to five years, the immediate amount of time for treatment was two years, but even at five years, which is out here, you can see a significant difference of patients who were treated with Olaparib who have BRCA1, BRCA2, and advanced ovarian cancer. Their survival was 56 months compared to 13.8 months. This hazard ratio is still pretty much the same in terms of progression-free survival over this long period of time. So the importance of understanding the genetics is that it does make a difference in terms of treatment options if we know that someone can benefit from the PARP inhibitor therapy. Some studies suggest that you can treat everybody, but if we wanted to really look at the patient population that benefits the most, it's really the patients who have this genetic inheritance, and it's been demonstrated with the longest follow-up. In context, and I want to kind of wrap up this short discussion, where we understand genetics is also that we have germline variants and we have gene variants in the tumors, somatic mutations. In our sequencing of tumors, we're understanding more and more. We know that certain genes are present and are important in high-grade serous carcinoma. We know that other genes like BRAF or KRAS are important in low-grade serous carcinoma. We know that some genes are important in endometrioid tumors, clear cell tumors, mucinous tumors. And I don't think that you need to think about all the different genes in this slide, but it's really helping to broaden the landscape and why it's important that we classify the tumors into the histologic types that the pathologists can tell us about. And for us, where we have the technology, the molecular types, because they really can help us think about treatment planning. We know that there are challenges to genetic testing globally. So, you know, starting off at the top, it's understanding, you know, the role of genetics. So the education, which I'm hoping to help Billy you in on today, the indication, so really focusing on those who are at highest risk. What we do here in San Francisco is that we can talk about mainstreaming, testing everybody and the system of how to do it. But we do know that certain patients and certain families may have the most benefit. So if you have resource limitations on who to test, you could test everybody with ovarian cancer. You can also look at people who still have strong family history or young patients, prior history of breast cancer at a young age, a triple negative breast cancer. It's important that we are able to teach the patients. So the genetic counselors are still a really important part of our challenge to getting all of the information out there. And we certainly acknowledge the financial limitations of, you know, these tests are less expensive than they used to be, but they're still expensive and can be limited if your resources are limited. But this is a place of potential collaboration with pharmaceutical industries, doing research projects, and really trying to think about government support in national health systems. So to conclude, I wanted to mention that genetic testing options include germline, which affects patients because it can affect the patient, the cancers that they have, but also their family members. So somebody with the germline pathogenic variant, their first degree relatives, their family members should also be considered. Somatic testing only affects the tumor in that patient, but what we know about genomics and ovarian cancer treatment is that it can affect therapy, and PARP inhibitors are a significant area where we've shown benefit in research that PARP inhibitors for patients who have genetic risk can really benefit from treatment. And as we understand the landscape of targeted therapies, thinking about immunotherapies for patients with mismatched repair, defects in their tumors, and other targets for treatment are going to be important in the future. This is my email, just so that you have that for contact information. And this is my team. We're in San Francisco, and that's a picture of the warehouses on the Bay. So thank you for letting me talk to you today. I appreciate the opportunity.
Video Summary
The video transcript discusses the importance of genetics in ovarian cancer treatment, emphasizing the role of genetic testing in identifying mutations like BRCA1 and BRCA2. The use of PARP inhibitors is highlighted as a significant advancement in improving outcomes for patients with specific genetic variations. The transcript also touches on the benefits of germline and somatic testing, as well as the challenges and importance of educating patients and accessing genetic testing. Overall, understanding the genetic makeup of tumors can guide personalized treatment plans and enhance therapeutic options for ovarian cancer patients.
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Lee-May Chen
July 2024
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education@igcs.org
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