Dr Rao: As an epidemiologist and pathologist， I can open with my thoughts on this important topic. As you said， ovarian cancer is deadly and scary， and usually when the cancer is diagnosed， it is in an advanced stage. My colleagues in gynecological oncology will agree with that. We do need tools for early detection and then for screening. From the epidemiological perspective， it is probably not cost effective to screen for ovarian cancer for a number of reasons. One reason is that the cancer incidence is fortunately not very high and unfortunately， trying to screen too many women may produce too many false positives and false negatives.

 

Either way， that would not be a good outcome. The other point to remember is that we don’t have specific biomarkers for this screening process. That limits our ability to specifically identify women with cancer risk. In terms of early detection， there have been advances and progress. There are biomarkers that have been tested which may show some benefit， but these would usually require huge clinical studies to validate and that still remains to be done. But in general， I think we are all looking forward to better approaches to ovarian cancer detection at an early stage so the oncologists can do their jobs.

 

Dr Dorigo: I agree with Professor Rao. We don’t have a screening method that allows us to check for ovarian cancer early enough. The goal of every screening method is that it can be applied to a population. We have done many studies over decades that have used pelvic ultrasound of the ovaries， pelvic exams and CA125 on a regular basis， and we have thought that this might allow us to detect ovarian cancer early on. Unfortunately， that has not been the case. There is a large UK study ongoing right now that may change our thinking about this. Although the data looks promising， it is not going to be what we are likely to be able to apply to the general population.

 

I want to make a comment on a couple of developments that are out there. Nowadays， there is the ability for us to detect cell-free DNA， at least in patients who have a large tumor burden. If we can downscale this and find cell-free DNA from early lesions in the fallopian tube that ultimately develop into ovarian cancer， we may be able to find a screening method at the DNA level. What we need to figure out is what molecules to look for， and that is not very easy because it comes down to the very early mutations and lesions in the fallopian tubes. I think we are going to get there， but it will take many years for us to identify a test for screening for ovarian cancer.

 

Secondly， I wanted to outline the new technologies in ultrasound. At Stanford， we have initiated a trial that looks at the ovaries， either benign lesions in normal ovaries or malignant lesions， with a different technology using microbubbles to achieve a better resolution of the ovary， and a more specific way of imaging the ovary. Ultrasound is not a very specific imaging technology. We can’t predict what masses are going to be benign versus malignant based on our current ultrasound findings. This study is actually adding a biomarker related to angiogenesis to the imaging that may provide more specificity.

Dr Rao: I would add one comment here about detection and screening. One of the things that is important for successful screening is to have defined at-risk populations. BRCAs are important tumor risk genes and have proven to be a good marker of ovarian cancer risk in certain populations. That has successfully reduced the incidence of mortality in those people who carry the genes for ovarian cancer， as well as breast cancer. I know Dr Wu has done some work on the BRCA mutations in Chinese women and wonder if he has a comment to make in that regard?

 

Dr Wu has said that in China， the BRCA mutation can be detected in the germ line in around 20% of cases， which is quite high. We will have to look into how we can use that information to guide the management of high-risk women， but it is a very important piece of data.

Dr Dorigo: Once we identify women who have a genetic predisposition for developing ovarian cancer， we do advise those women to undergo prophylactic surgery， which means removing the fallopian tubes and ovaries before the cancer can develop.

 

 

Dr Dorigo: This was the topic of the lecture I have given here. This has been the focus of my academic and research interest for a very long time. In general， we have seen some fantastic responses in patients with solid tumors， particularly melanoma， but also lung cancer， where we didn’t expect a response to immunotherapy using immune checkpoint inhibition. Those are the drugs that target PD-1 and PD-L1 mostly， and these are now in many clinical trials used alone or in combination. They have been approved for solid malignancies， but have not been approved for any particular gynecological malignancy， including ovarian cancer， except for those cancers that have a high degree of microsatellite instability. When we look at the response to immune checkpoint inhibition in gynecological cancer， it appears the response rate is around 15-20% overall. It is not as high as we have seen in other solid tumors. It is about what we see in patients undergoing standard chemotherapy in a platinum-resistant ovarian cancer.

 

What we do see is that a fair percentage of patients have stable disease. So we can induce a response from the immune system that at least keeps the tumor under control and potentially causing more symptoms and complications for the patient. I think that is encouraging. We need to better understand at what point in the treatment course for ovarian cancer， when immunotherapy is of greatest benefit. We are doing trials now where we have introduced the immune checkpoint inhibitors in first-line chemotherapy after surgery for ovarian cancer patients and we will see how this potentially relates to an increased progression-free survival， and maybe， even an overall survival.

 

Another point where these immunotherapies (checkpoint inhibitors or vaccines or cell-based therapy) can be useful is in a maintenance setting. At the completion of first-line treatment or second-line treatment， patients have a higher chance of recurrence. So can we prevent these recurrences by stimulating an anti-tumor immune response after completion of chemotherapy that prevents those recurrences? We still need to understand much more about immunotherapy. We still don’t know how to select the patients who are best candidates for this treatment.

 

Dr Rao: It is an exciting time.  There is no question that immunotherapy presents a new strategy for cancer treatment， management and control. As Professor Dorigo alluded to， not everyone will respond uniformly to treatment. Even though there is no doubt that the immune system is involved in the process， differences in phenotypes and even within the same tumor type between individuals， the tumor microenvironment and many other things need to be taken into account. But it is a very exciting time with these new strategies for tackling cancer.

Dr Dorigo: I am very familiar with those treatment strategies. PARP inhibition really capitalizes on the inability of the cell to repair DNA damage. In the United States， we now have three PARP inhibitors approved for the maintenance treatment mostly of patients with ovarian cancer after first recurrence. We do know that the PARP inhibitors can increase progression-free survival quite significantly. The efficacy is most pronounced in patients who have either germline or somatic BRCA mutations， but also in patients who have defects of homologous recombination repair. So there is a clear cohort of patients who do benefit from PARP inhibition， and we have treated many more patients with PARP inhibitors than immunotherapy.

 

As we said before， immunotherapy looks promising. We haven’t used it as a maintenance therapy. There is no data to suggest that it might be helpful. Biologically， there is a rationale to combining PARP inhibitors and immune checkpoint inhibition. It could be that under PARP inhibition， tumors continue to express neoepitopes. Increasing neoepitopes might increase the efficacy of immunotherapy， so combining those two might have an additive if not just synergistic effect. As always when combining two agents， one concern is predictable side effects. Can patients tolerate this type of treatment? Can they particularly tolerate this as a maintenance therapy? We will see what the clinical trials are going to show us and whether this is going to be a strategy that can potentially be better than the standard chemotherapy for the treatment of recurrent ovarian cancer. We need to be generating the right clinical data. The current studies have unpredictable outcomes， but biologically make sense.