As Division Chief of Clinical Cancer Genetics at City of Hope, Dr. Jeffrey Weitzel leads a multidisciplinary clinical, research and training program that emphasizes translational research in genomic cancer risk assessment, chemoprevention, targeted therapy, clinical and psychosocial outcomes, genetic epidemiology and health services research in underserved minorities. For over a decade, he has had a particular interest in hereditary cancer in Latin America with a goal of increasing awareness of inherited risk and access to screening and prevention.
BCRF spoke with Dr. Weitzel about his work in the Latin community both in the U.S. and Latin America and asked him to comment on new discoveries that are helping us to understand the role of genetics in breast cancer risk in Latinas.
Dr. Weitzel, what is the landscape of breast cancer in Latinas? How do the incidence and mortality rates differ from non-Hispanic whites or other minority populations?
It’s well recognized that Latinas have a lower incidence of breast cancer compared to non-Hispanic whites. In spite of that, they are more likely to be diagnosed with advanced breast cancers and are more likely to die of their disease than the general population.
What do we know about role of genetics in breast cancer risk in Latinas?
Because Latinas are disproportionately underrepresented in research and disproportionately economically disadvantaged and uninsured, there is relatively little information about the spectrum of genetic mutations seen in this population. Currently, we only have information on the BRCA genes. Nobody as yet has looked at mutations in other breast cancer risk genes in the Latina population, but our group has started to do so. For example, we have identified several mutations in PALB2, a gene that was recently characterized as an intermediate breast cancer risk gene.
Dr. Weitzel, how did you come to be interested in breast cancer disparities in Latina populations?
Much of it has to do with taking care of the folks in our community. As you know, I’m a medical oncologist and geneticist in Los Angeles. Around 2000, Dr. Nancy Feldman, a friend and colleague from the Olive View LA County hospital, which serves a predominantly Latino population, told me about the number of young Latinas coming in with advanced breast cancer. At that time, Medicaid was not providing any coverage for genetic testing, so even those women with a family history of the disease were not getting genetic screening.
Our group helped to develop the science that integrates genetics into the care of women. Those studies defined the medical necessity and the need to know, especially with reference to mutations in the BRCA genes, which are the most commonly mutated genes in hereditary breast cancer in any population. Learning about the lack of screening in an apparently high risk population caused us to focus our attention on young Latinas with breast cancer.
How did your genetic screening program come about?
The first thing we did was survey the underserved/uninsured Latina community we had access to through the Olive View hospital to learn about their attitudes about prevention and what they understood about genetics and cancer. Our surveys revealed that 80 percent of the patients would be receptive to genetic testing and counseling.
Based on the survey we decided to test the uptake of genetic counseling and testing in an outreach project at the LA County hospital. In other words: if we build it [a genetic counseling and testing program], will they come? We provided trained genetic counselors and secured funding to pay for genetic testing for those with family histories. And they came. We had an 80 percent response rate, which is even better than what we see in our insured patients.
The next step was to determine whether the counseling and testing had the desired impact. In other words: if they come [to the clinic], will they learn and if they learn, will they do the right thing? We conducted a series of pre- and post-tests and showed that participants learned about cancer genetics, and we were able to document that those who tested positive for the BRCA1/2 mutation shared that risk information with their families so that prevention measures could be taken.
These studies represent a decade of progressive health services research, combining elements of behavioral and social sciences and genetic epidemiology. Health services research is the critical last step in translational research and is very hard to get funded.
It really takes the most prescient agencies, like BCRF, to have the vision and see why these studies need to be done. We are incredibly grateful for the support we’ve received from BCRF to continue to build on our earlier work.
What have been some of the most important findings from these genetic screening studies?
One of the main things we learned was that there were certain repeating mutations in the Latina patients, similar to what we see in the Jewish population. Five mutations accounted for over 50 percent of the positive cases in our screening studies. That discovery made us think about the ancestry of these patients. As Mexican descendants they shared ancestry with the indigenous people of Mexico (Amerindians) and Europeans, representing Spanish colonization, and Africans, reflecting the slave trade.
We studied anthropology and did haplotyping experiments, discovering that most of the recurring mutations could be traced back to Spain (likely coincident with Spanish colonization around 500 years ago), demonstrating the influence of world history on inherited risk of disease in distinct populations. This is probably due to the fact that these were agrarian people who didn’t migrate and thus certain genetic patterns are traceable to geographic areas. We found some mutations in clusters from unrelated families that were specific for Guatemala or El Salvador, for example.
We also found the same BRCA1 mutation, 185delAG that was previously believed to be specific to Ashkenazi Jews. This tells us that this mutation was present among Sephardic Jews and likely predates the separation of the Ashkenazi population, probably dating back to the second Jewish Diaspora, which occurred around 70 BCE.
Breast cancer incidence is lower in Latinas than in non-Latina whites, but Latinas tend to get breast cancer at a young age and more often have more aggressive types, such as TNBC. Can this observation be explained by your findings?
Our work has revealed that while the overall risk of breast cancer is lower in Latinas, the likelihood that an early onset breast cancer or a diagnosis of triple negative breast cancer is due to inherited predisposition is as high or higher in this group of women than any other population. Therefore, there is an enormous opportunity as well as responsibility to provide appropriate genetic counseling and screening to prevent breast cancer.
In your most recent work, you showed that less than half of the Mexican women with TNBC in your study who tested positive for BRCA had a family history of breast cancer. Similarly, a recent study in Ashkenazi Jews also indicated that family history was not a reliable screening criterion and risked missing BRCA mutation carriers without family histories. Do you think these findings support the need for population-wide genetic screening early in life?
There are limitations of family history that can lead to underestimates of risk. When considering family history, it’s important to factor in family structure. For instance, if a woman’s father did not have any sisters, there will be no information on paternal inheritance, and thus a whole generation of information on family risk is missing. In 2007, we reported that women with breast cancer whose fathers had no sisters (“limited structure”) were three times more likely to have a BRCA mutation than those with paternal aunts’ history. We also demonstrated that family structure should be taken into account with the BRCA mutation prediction models, lest they underestimate familial risk.
The second part of the equation in population-wide genetic screening is the controversy of withholding information on variants of uncertain significance, ambiguous findings for which little information is available at the time of testing. Some have argued that patients shouldn’t be told of these gene variants. However, who is responsible for tracking down that patient when the variant they carry is reclassified and determined to carry a specific risk that we can quantify?
In Ashkenazi Jews, where there are distinct founder mutations, I think population-wide screening in those without a family history makes sense, but beyond that I’m skeptical that population-wide genetic testing is appropriate or desirable. When you begin testing outside of a founder population, you bear the risk of increasing the burden of genetic information that is ambiguous. By testing someone with no family history and with adequate family structure, what is the benefit to them to be informed of uncertain risks based on genetic screening? As long as the gene panel is small and relevant, genetic screening is reasonable–in other words, when we can quantify the risk and there are evidence-based guidelines for risk management. The large gene panels of 20 or more genes are still too ambiguous. They may contain mutations in genes that we don’t yet understand.
What are some of the barriers to genetic screening in Latina populations and how is your research addressing these needs?
There are two major barriers in Mexico, Peru and Colombia: not enough trained genetic practitioners and lack of resources. While mammography is a covered benefit in Mexico, there are such limited resources for screening, that if all the women who are eligible to get mammograms did, the system would be overwhelmed. Genetic testing creates an even bigger burden. Consequently, while genetic testing has been commercially available in the US for nearly two decades, it is still not widely available in Mexico or other low and middle income countries.
Our BCRF support is helping us to provide both training and resources to clinics in Peru, Colombia and Mexico. We’re teaching the doctors in these countries how to do genetic medicine with on-site training at the City of Hope and in Latin America, with ongoing access to multidisciplinary genetic tumor boards to enable continuous quality improvement and ensure they acquire the skills necessary to do genetic cancer risk assessment well. They continue to enroll patients in our ongoing prospective registry studies. We provide them with an inexpensive assay, which we call HISPANEL, and once the patients are counseled on genetic risk, the doctors administer the genetic screen, at a cost of about $25 per patient. That pre-screen allows patients to make preventive decisions based on family history and genetic screening. We are using next generation technologies to provide complete sequencing for HISPANEL-negative cases that meet National Comprehensive Cancer Network criteria.
We’re creating a protocol that can be transferred to our Latin American partners on a screening platform that will be affordable for them locally, and ultimately suitable for other low resource settings. We also work with the advocates to help them understand the importance of genetic screening in directing the limited resources to those at most risk.
In a 2014 article, a group from USCF identified a genetic variant common in Latina women that seemed to be protective against breast cancer. Can you comment on these finding and the impact they may have on screening recommendations?
The study found a single nucleotide change in the DNA, called a SNP, in a Hispanic population. The people who had this particular SNP, which the authors believe could be traced back to an indigenous population, were protected from breast cancer. We are now working with the UCSF group to study the same SNP in Latina BRCA mutation carriers to see if it modifies the risk of breast cancer in a high risk population. The challenge is determining whether that one SNP is protective enough to be able to tell someone they don’t need screening. Once we learn more about how the gene where the SNP occurs influences risk the better we can apply that information to risk assessment and prevention.
What do you see as the priorities in ending breast cancer disparities in Latina populations around the world?
There have always been health disparities in the Latina community, but in my mind the genetic disparities have lasted longer than many. It’s a multi-level problem that requires a multi-level solution. We need training for the clinical workforce to assimilate the new technologies in genomic sequencing; we need genetic testing that is both pragmatic and economical and accessible to the general population, not just to patients who can afford it. Leveraging the genomic technologies and allowing them to be used responsibly by trained clinicians will help us to direct limited resources to those with highest risk. For women with high risk mutations, a salpingo oophorectomy (surgical removal of fallopian tubes and ovaries) is the most effective preventive surgery and costs a fraction of mastectomy and reconstruction. Studies have shown that salpingo- oophorectomy is not only cost-effective preventive strategy, but that it actually saves money per year of life saved, meaning that we can’t afford NOT to do this.
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