It is a distinct pleasure to also be here today with Dr. Anna Fagotti. Dr. Fagotti is going to talk to us about disparities in endometrial cancer outcome. What more can we do? This has emerged as an area of active interest for many of us. Diversity, equity, inclusion, access, most importantly to clinical trials for diverse patient populations. And I think many of us, whether we are practicing in our local institutions or talking about clinical trials on a more broad level, clearly recognize the importance of a diverse patient population, not only for equity and access to these novel therapies, the treatments of tomorrow, today, but in parallel, because of the implications of understanding efficacy of these agents in diverse patients and being able to apply these treatment programs to patients after a successful clinical trial suggests benefit. And really, from our perspective, this is about understanding where does the opportunity lie? And that's in patient education, programs like Just Ask, making sure that collectively, as treating physicians, as team members within our institutions, we are making sure that patients are aware, they're educated about the potential benefits of clinical trials, they have the resources that are needed such that they can enroll and be treated on clinical studies with a shared goal of improving clinical outcomes. So thank you, Dr. Fregatti, for taking the time to present this data with us today. It is much appreciated. Actually, this is a different topic about disparities in endometrial cancer outcomes. This is the agenda. So we will discuss about the present and future of endometrial cancer worldwide, disparities in outcomes, and strategies to reduce these disparities. You all know that endometrial cancer is the sixth most commonly occurring cancer in women and the 15th most common cancer overall. And in 2020, there were more than 417,000 new cases of endometrial cancer and 97,370 deaths worldwide. And this is the distribution in the world about the incidence of cancer of corpus uteri. So you can see very easily that we can define different countries or continents with different incidence. So we have mainly an incidence higher than 20% in Northern America and Eastern Europe, where Poland is the most, the country with the highest incidence. Then we have another part of the world where the incidence is between 10% and 20%, which is actually Europe and Australia, with some exceptions, of course. Then we have another part from 5% to 10% of incidence, which is mainly Asia and South America and Central America. And then we have Africa with an incidence a little bit higher than 1%. And of course, on the other side, you will see the mortality rate, which is always quite low and corresponds more or less to the incidence of this disease. But in the past 30 years, we have assisted to a global increase in endometrial cancer incidence. And if you look at this map, you will see that in the dark red, you will see the places and the countries where we have seen the higher increase, which are mainly low-income and middle-income countries. And this can be explained with a faster-growing trend and the birth-court effect, which reflect the change in lifestyle and high prevalence of risk factors like, for example, obesity or inactivity levels in the younger generation. And indeed, we have also observed a higher trend of endometrial cancer increase in the Asian countries. And indeed, this has brought to the development of pan-Asian-adapted asthma clinical practice guidelines for diagnosis, treatment, and follow-up for endometrial cancer patients. Now, you see that these are the numbers in Asia, but it's quite interesting that, especially in China, we observe a higher rate of younger women being diagnosed with 40% of patients diagnosed before their menopause compared with less than 25 patients in the Western countries. But however, this is a trend that we have observed all over the world, and these are the data from the United States, where you see that we have assisted an increasing number of patients developing endometrial cancer before the age of 50, and this is across all races, more or less. So, what we should expect for the future? Now, we have, of course, an aging population all over the world, and with an aging population, we do expect a higher rate of cancer events all over the world, and with higher costs for the health community. But regarding 2040, you see that endometrial cancer is projected to be the third most prevalent cancer and the fourth leading cause of cancer death in women worldwide. And if you look at the United States only, we will have in 2040 more than 100,000 new cases, and the same will happen in Australia, where estimates suggest another increase of over 50% by 2040. And if we look at the numbers, these are the numbers where we started from in 2020, and you see the numbers, the projection for 2040, where we see an increase both in terms of incidence, but also in terms of mortality. So, the relationship or the ratio between mortality and incidence seems to be unchanged, although all the effects of these new treatments. And, of course, if this will be the trend, then if there are gaps, we do suppose that these gaps will increase in terms of outcomes. So, the second point is, what are the disparities in endometrial cancer outcomes? And, of course, we have already seen about the differences in terms of incidence across all countries all over the world, and the same will be in terms of prevalence. How many patients will live with cancer? What is the morbidity and mortality related to this disease and the quality of life of patients who will survive after endometrial cancer? Now, we have some data from the literature, as you can see here. You see that this is a comparison between white women and black women, and you see that although the incidence seems the same in the United States, if you look at that, that's exactly the difference. You see black women will die more frequently than white women for a uterine cancer, and this is represented across all stages, all situations in these patients. You see that white women will survive much more than black women, irrespectively from the stage of disease. But also, we must admit that data that we can keep from the literature are very, let's say, not satisfying enough. I mean, we are still sticking to the conceptualization of race, which is something that is declared by the patients, and it's not always analyzed in depth. Indeed, in this case, for example, you see that if we differentiate black women between those who are U.S. born, Haiti born, or Jamaica born, you see that they are not the same, and they have a different survival for all histology, especially for serous endometrial cancer. This might highlight the fact that there might be subgroups of women among black women who may require different treatment and surveillance based on characteristics other than race, or considering different groups within the race. So, what are the factors contributing to disparities? We have income, insurance type, educational level, and also tumor characteristics, and all of these factors may be either preventable or actionable. So, what about clinical inequalities in the spectrum of care of black women with high-risk endometrial cancer? And we can identify actually four points. First of all, early diagnosis with transvaginal ultrasound is impaired in black women, and this is due to the higher prevalence of fibroids and non-endometriotic cancer, which is not related to thickness of the endometrium itself. Then, the five evidence-based quality metrics that have been identified for endometrial cancer, such as surgical treatment within six weeks from diagnosis, the use of minimal invasive approach, the nodal assessment, and any kind of adjuvant treatment, both radiation treatment and chemotherapy, are less likely offered to black women than white women, and all these differences are statistically significant. Also, there are some studies that have demonstrated that post-operative complications and side effects adverse events are more frequently observed in black women, and the difference is again statistically significant. And finally, we observe more frequently treatment refusals in black women than in white women. But regarding treatment refusals, actually, we speak about adjuvant treatment, and we can speak about radiation therapy or chemotherapy, whereas there is no difference in terms of radiation therapy. So, black women are very keen to have this kind of treatment. They mainly refuse chemotherapy, and this difference is actually, across all histology, mediates only five percent around of the survival disparities between black and white women, whereas if we consider only serous cancer, then this difference grows up to seven percent. But however, treatment refusals among black women is only a small contributor to the disparity in terms of mortality of these patients. So, there is something more, and what is this more? It's marginalization. So, I have learned today that marginalization can be assessed through a very clear index, and considering especially three different indexes, which are residential disability, material deprivation, and ethnic concentration. And you see that the higher is the index, the higher is the quantile, and the lower is survival. This is very clear from this curve, so where the quantile is five, then the survival is low. So, in other words, it means that living in marginalized neighbors is associated with more limited survival in any patient population, irrespective from their ethnicity, and this is true even after adjusting for patient age, comorbidity, obesity, and disease factors like stage and histology. But let's go to the molecular classification. Now, this is the molecular classification from the TGCA, and you know what? Almost all women were white, and if you look at the rate of black women in this classification, this was only 14 percent, whereas all the other ethnicities were even less represented. So, of course, the prognostic value of molecular characterization in these minorities has been limited by a lack of data, and especially in all other validation studies, these studies do not report any data about patient ethnicity. But we do know something about differences in terms of molecular characteristics and ethnicity, as you can see here. So, we know since a long time that patients, black American or African patients, have a higher rate of p53 mutated patients with respect to tumors with respect to Asian or Caucasian, and on the other side, Caucasians have higher rate of p10, like Asians, and lower rate are found in black African Americans. This has been also confirmed in following studies, like, for example, this one, where we see very clearly, again, that there is a higher rate of p53 abnormal expression or mutation in black women with respect to white women, irrespective from the type of evaluation they say that is used, and there is also higher copy number values in black patients. And this is the last study that comes from the Memorial Sloan-Kettering. You see here around 1,800 patients that have been characterized and divided according to the race. You see on one side, the black women, on the other side, white women, and of course, we know there are differences in terms of histology. We have more serious cancer in the black population. We have more carcinosarcoma, and we have more mixed high-grade non-other specified tumor, and this is reflected in the molecular characteristics of the patients. As you can see here, most of these patients have actually p53 mutated tumors, and if you look at the poly mutation, there is only 1% with respect to 6%. And again, if we want to assess the tumor mutational burden, don't mind how you want to evaluate it. There is still a difference, a statistically significant difference between black women and white women with a higher, let's say, tumor mutational burden found in the white women. And this is another study showing exactly the same. So if we're looking to markers to immune checkpoint response, although we know they don't work so well, anyway, anyone we want to use, we will see here that across the histologies, there is still a higher rate in white women than in black women. I wouldn't go through each histology because these are low numbers, so we can't really rely on this difference regarding histologies. So what are still the gaps today from the literature? I would say that first of all, most of the studies are focused on black women in the United States. So all other races or ethnicities are less represented. All the data came from national databases, so they do not provide information enough. And then there is the fact that when you say race, I mean, we're still kept to what we think about race. So we don't know exactly whether they are black American or black African or Haiti or Jamaica. And this is also self-reported racial categories, so what the patient believed they belonged to. So I would say that at the end of this summary, I would say that we have mainly two big blocks. One is the biological factors, as we have seen right now. So some intrinsic differences in tumors in black or white women. But we also have some other factors that bring to disparities which are modifiable and are not biological. So I think that if we want to look and improve, and we will see how outcomes in disparities, we should work in these two different blocks. However, if we look at the data from the literature, we will find very few studies showing interventions to reduce any kind of disparities, regardless of the block we are discussing. So finally, the last chapter is about, I'm sorry, okay, the last chapter is how to reduce these disparities. And I would like to start from here. If we look at the map of the world today, we have almost half of the countries in the world where we have more than 30 percent of patients who are obese. And you know what's going on. In the next years, in the next 10 years, we will see that half of the world will have half of their overall population who will be obese. And you know that obesity is associated with endometrial cancer through different pathways. You see here the relative increase of estrogens, the increase of insulin. And so the two pathways that are related to this are chronic inflammation. So it's very clear that if we offer a lifestyle change to our patients, we can modify this kind, at least this risk factor. But it's quite sad to see that we had this abstract in ESGO a few months ago, which was from a group from Poland, actually, where we know endometrial cancer is very, the incidence is very high. They sent a survey to around 700 patients with endometrial cancer. And these patients were educated about the fact that lifestyle changes like intervention regarding exercising and diets could have led to a lower risk of having a relapse in their disease. But it's quite sad to see that 47 percent, they did the same as before. And actually, 39 percent of these patients did even less than before. So although there is a chance to reduce this risk factor, there is still a lack of education in patients that do accept changing their lifestyle because of their risk. Another option, and my colleagues have discussed it, is, of course, characterizing the tumor from the molecular point of view. But what does this mean? First of all, having the chance to identify at least the four molecular classes, and you know that some of this now can be done through immunochemistry, but there are temptatives in order to identify all these four classes thanks to simply some hematoxylin and deoxyinstated wall slide images. And this is something that could bring to a lower cost analysis and to identify the classes. So these are the results on more than 2,000 patients with endometrial cancer. These come from different trials, as you can see on your upper side. And we are comparing, actually, the true molecular classes coming from this population with the image-based molecular classes. So although not perfectly matching, you will see that the four classes are still very well represented. And if you look at the LC curves, you will see that they are quite satisfying. Of course, these need validation in larger prospective groups, but this is a tentative to give the possibility to everyone at least to characterize patients from this point of view. Now, the last point is trying to offer these patients, actually, a molecular-driven treatment and so include these patients into trials. But you know what? In this study on 156 patients who were interviewed about their willingness to participate into a clinical trial, the first response was yes, only in 35 percent of the world population, whereas 65 percent of them actually refused. They were unwilling to participate. Now, after an educational intervention, which was realized thanks to these kind of questionnaires, you see that there was a complete inversion of the trend. So patients willing to participate now were 82 percent, and only 18 refused. Now, if we look at the data from this study, you see that there will be an increase across all the classes, all the subpopulations. But if you look very well and deeply, you will see that this increase was mainly observed in white women and mainly observed in highly educated women. So we can identify some classes where the educational intervention must be much higher than in others because of these results. Now, I just want to show you that there is a consortium for enhancing minority participation into clinical trials. This was established in 2009 and involves five NCI designated comprehensive cancer centers. This project was aimed to increase the number of minorities or different ethnicity into clinical trials. And although there was some chance in some result, as you can see here, so an increase of about 10 percent of patients included on target therapies or enrolled in clinical trial, there is still much to do. And so here you see some initiatives, always in the United States, like the SISTER study, which is the first national randomized trial to focus on improving outcomes for black African-American women with endometrial cancer. And this is, again, focused on reducing the risk of marginalization, which is one of the main reasons not to include or having patients participating into clinical trials. But the last comment I would like to do in this situation is that probably what we should do in the future is asking two key opinion leaders working in the clinical trials or even the companies to have a predefined number of patients who belong into the minorities to be enrolled in the trial, just to be sure that the results that we achieve can be used and validated for everyone. So actually I would say that sometimes when we discuss which patients putting into the clinical trials, we are even constricted by the restricted number of patients that we have in our centers available for the trial. And so if we have a fixed number of these patients with minorities belonging to minorities, I think we could reach much better results. So in conclusion, I would say that endometrial cancer incidence is going to dramatically increase in the next future, that several factors may contribute to disparities in outcome of endometrial cancer cases. Lifestyle changes, inclusive policies, and precision medicine are urgently needed to reduce this gap and improve treatment outcomes. Thank you very much for your attention.

endometrial cancer

disparities

clinical trials

mortality rates

molecular differences

equitable treatment