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Sophia George, PhD, and Judith E. Hurley, MD, discuss the importance of the genetic association study, challenges faced with launching such an effort, the key findings from the research, and the clinical implications of the data in the Caribbean as well as the United States
In examining the proportion of patients in the Caribbean with breast or ovarian cancers who carry actionable pathogenic variants, a unique landscape of genetic mutations was uncovered across 7 island nations, according to Sophia George, PhD, and Judith E. Hurley, MD.
“We started off in the Bahamas, but we ended up in Haiti, Jamaica, Barbados, Trinidad and Tobago, Dominica, and the Cayman Islands,” Hurley said. “What we realized was that each island is very unique and very individual, even in the types of breast cancer and the genetic mutations that are found. This is important in the Caribbean, but it is also really important here, in the United States. When you emigrate to another country, you bring your genes with you; [approximately] 1 in 10 immigrants in the United States are from the Caribbean, so this is a big issue that needs to be recognized.”
In an interview with OncLive®, George, a research assistant professor at Sylvester Comprehensive Cancer Center of the University of Miami Health System, and Hurley, an oncologist at Jackson Memorial Hospital, discussed the importance of the genetic association study, challenges faced with launching such an effort, the key findings from the research, and the clinical implications of the data in the Caribbean as well as the United States.
Hurley: We both live and work in Miami, [which] is really, geographically, part of the Caribbean.It all started with a clinical observation that the Bahamian patients with breast cancer that I saw in my clinic at the University of Miami in the Jackson Memorial Hospital were very young. This led me to ask, 'Well, why is that?'
We discovered that Bahamian women had a very high incidence of inherited breast cancer. When we started to speak with other oncologists in the Caribbean, they said, 'The same thing that is happening in the Bahamas, is happening on my island. Why don't you come to my island?’ We basically [focused on] 7 islands in the Caribbean and spent many years accruing patients to the study.
George: For me, as a person from the Caribbean, clearly my interest was a bit self-serving. Also, at the time, I was studying hereditary ovarian cancer. I learned about the initial BRCA testing in the Bahamas through a colleague [who was also] in the Bahamas while I was there. This led to me reaching out to Dr Hurley, where I asked her about the other islands, and [she told me] that we were actually going to [look at] the others.
Hurley: The black woman that you are seeing in your practice with a new diagnosis of breast cancer could easily be from the Caribbean, and you do not even know it or have not [considered] it. [Also, perhaps] you do not realize that she [may have] a very high rate of inherited breast cancer. For example, we found that 24% of women in the Bahamas who had breast cancer had a deleterious mutation, which is the highest rate in the world. Before that, it was the Ashkenazi Jewish women, at 12%. This changed the way that Bahamian women are treated in the Bahamas and how they are screened. It should change the way that your patients who are Bahamian are screened for breast cancer.
George: The objective was really straightforward. [We wanted to identify] the prevalence of inherited breast cancer and ovarian cancer in the Caribbean. It really stemmed from observations in the clinic that young black woman from the Caribbean, at that point, were being diagnosed with triple-negative breast cancer, advanced stage [disease], and often with a family history, when probed. [Due to the fact that] we knew about what was happening in the Bahamas, we wanted to know [whether we would see] the same [thing across] all the islands. That is why we included different populations of Caribbean women in this particular study.
Hurley: We ended up gathering a lot of collateral information, like their fertility factors, family histories, how their breast cancer was diagnosed, and what stage their breast cancer was. Although our primary goal was to look at inherited risk, we collected a lot of other data that showed us that over 90% of the women in the Caribbean who were diagnosed with breast cancer were diagnosed because they felt the mass themselves.
[Knowing this] really changes the way that you need to deal with the epidemic of breast cancer in the Caribbean. Breast cancer is a leading cause of cancer death in Caribbean women. [About] 40 million people [reside] in the Caribbean, so you are talking about a population of [approximately] 20 million women; it is a significant population.
George: [Due to the fact] we were looking at germline DNA, we decided to collect saliva DNA from consenting study participants instead of blood because it was easier to manage, easier to transport, and also was more acceptable for the population. Initially, in the study, we looked at BRCA1 and BRCA2 [mutations] across the participants. As the study progressed, it became cheaper to do more panel testing. Initially, it was BRCA1/2 next-generation sequencing with multiplex ligation-dependent probe amplification; then, we included PALB2 and RAD51C. We then did the panel test in a larger cohort of women.
Hurley: The technology really evolved over the course of the study. When we first started, the BRCA1 and BRCA2 tests costed $3500 to test 1 person. By the time we were done, we could do 40 genes for $199. The improvement in technology over the course of this study did not change results that much. Once we went back, and panel tested everyone, we did not find a single Lynch mutation in over 1000 patients; that was kind of surprising. Presumably, there is Lynch syndrome in the Caribbean, but it does not appear to manifest as breast cancer. We were expecting to pick up a few [cases of] Lynch [syndrome] that we had not known about, but we did not.
Hurley: Although many countries in the Caribbean do not have tumor registries, the countries that do, [such as] Trinidad and Tobago and Jamaica, will show you that the average age of their patients is relatively young compared with the United States population. The average patient from the United States who has breast cancer is a white woman who is 62 years of age; in Trinidad, it is a 50-year-old black woman; and in Jamaica, it is a 49-year-old black woman. All very different pictures. Breast cancer is postmenopausal in the United States, and it is premenopausal in the Caribbean.
We also looked at the body mass index of our patients, which was high. We looked at parity, age of menopause and menarche, and other fertility factors. Interestingly, [when looking at] known people who were alive [over the course of the study], the grandmothers vs the mothers vs the daughters, [we saw that] family size markedly decreased and the age of first pregnancy markedly increased—all of this epidemiologically impacts breast cancer risk.
[We have seen] a transition from a third-world fertility pattern to a first-world fertility pattern during the course of our lives, which is fascinating. There has also been a major change in diet patterns during that exact same period of time. All these [factors] impact breast cancer risk, so it may be that as the Caribbean has gone from being a relatively third-world area to being a first-world area, [some good has come out of it] but also some bad, like an increased risk of breast cancer, which is impacting their survivorship and their health systems.
George: About 14% to 14.2% of participants who were on the study had a germline pathogenic mutation variant in BRCA1/2, PALB2, and, very rarely, in RAD51C, NBN, STK11, TP53, and CHEK2. One in 7 people who were in our study had a germline variant, [which] is very high. Secondly, the majority of people in the Caribbean are of African descent, but we also have a mixed population of Middle Eastern, European, Chinese, and Southeast Asian [individuals]. As a result, we also have a very mixed population that we saw play out in the types of mutations that we [observed].
We did not see the [same] mutations across the entire region. What we saw was that each country essentially had their own spectrum of mutations. This led to us believe that unlike with the Ashkenazi Jewish population where you have 3 [kinds] of mutations, for the purposes of doing genetic testing in a Caribbean population, you would want to offer panel testing across genes and for multiple genes—even the rare [ones].
Hurley: [To reiterate what Dr George said], each island has a very individual profile. We started at the Bahamas and were naïve enough to think that—back before panel testing was [accessible]—we could just get the mutations from the Bahamas and make a panel from that. [We felt] it would be cheaper than $3500, and [that we could] apply it across the Caribbean. [However], that was a complete failure because each island has different mutations.
Fortunately, technology rescued us: Broad panel testing became available and financially feasible. You could not extrapolate from 1 island to the other [to determine what] the mutations were going to be. You could not extrapolate what the frequency [of those mutations] was going to [to look like]; it was completely unique. For example, we saw a very high incidence of PALB2 in Barbados and Jamaica, but nowhere else. In Barbados, [the incidence of this mutation] was [approximately] 4.4%, while in Jamaica it was 2.2%. These are very high rates of PALB2; we do not see those kinds of rates in any population. In the Bahamas, 28% [of individuals] had a germline mutation vs 11.7% in Trinidad and Tobago, and [approximately] 17.4% in Barbados.
Each island was totally unique because of the mix of people who [live there]. At the beginning of the study, we used to ask people about their racial and ethnic background. We would [ask], ‘How do you describe yourself?’ Often, in the Bahamas, they would say, ‘It is a conch salad. You take a little of this, a little of that, and throw it all in. That is what I am.’
That is kind of what the Caribbean is. You have this very broad, diverse mixture of backgrounds with the [indigenous] population, Southeast Asia, China, Middle East, Northern Europe, Southern Europe, Western Africa, and a little bit Eastern Africa. A lot of different contributions [to make up an individual profile].