conTEXT for advancing science: 2021

Monday, June 21, 2021

Fostering Unrinary Microbiome Health in Older Adults to Reduce Urinary Tract Infections

Rebecca M. Goodwin

PhD Student, College of Nursing

April 20, 2021

An increasing focus on the health of older adults and inclusion of older adults in biomedical research is consistent with efforts by the National Institutes of Health to fund research across the lifespan.

Urinary tract infections (UTI) are common in older adults, but can be difficult to diagnose. One indicator of UTI in institutionalized older adults is behavioral changes (e.g., delirium), but it can be more difficult to identify those changes in people who already exhibited such behaviors related to other conditions (e.g., cognitive impairment/dementia).

Asymptomatic bacteriuria (ASB) may protect against urinary tract infection, and ASB is highly prevalent in institutional older women with incontinence (80%). However, further compounding the challenge of UTI diagnosis is that presence of ASB in the urinary tract can make urine dipstick tests for acute UTI show positive culture results. The positive test results can then lead to overuse of antibiotics.

Overuse of antibiotics can wreak havoc on an individual's microbiome by destroying beneficial or protective bacteria. In turn, this can increase the number of disease-causing (pathogenic) bacteria, and make those pathogenic bacteria increasingly resistant to antibiotics.

Microbiome research may be helpful in improving prevention, diagnosis, and treatment of acute and recurrent UTIs by helping to differentiate between harmful and helpful microbes in the urinary tract, also known as the urobiome.

As the population in the United States continues to age, urobiome research is increasingly important to improve the health and comfort of older adults by identifying novel ways to prevent and treat acute UTI. The research community should continue to consider ways to weave together innovative models and techniques for UTI prevention and treatment with traditional wisdom and therapies. For example, fermented foods and drinks have been touted as beneficial for the gut microbiome; they may also benefit the diversity and health of the urobiome. Additional research is also needed to explore alternative therapies to avoid overuse of antibiotics, such as bacteriophage therapy.

(Biggel et al., 2019; Godbole et al., 2020a, 2020b; Pannek, 2020; Sybesma et al., 2016; Thomas-White et al., 2018; Wainwright et al., 2010; Wolfe & Brubaker, 2019)

What is Precision Medicine?

As technology has advanced, the focus has moved from broad scoping treatments to treatments that are personalized for the individual patient. In patients with cancer, the potential of individualized treatment that is designed to target their disease has offered hope for more treatment options. In the not-too-distant future, clinician may have the ability to develop individualized treatment plans based on the genetic characteristics and identifiable targets. The clinician will be able to choose from a wide variety of treatment options to offer the best response.

Figure 1: The evolution of personalized treatment.

Note: Cancer treatments have evolved form broad topics based on signs and symptoms, treatment implementation based on evidence from clinical-trials. As technology advances, treatment algorithms will be based on individual genetic components rather than just disease state. From “Precision Medicine: Changing the way we think about healthcare”(Gameiro et al., 2018)

Cellular therapies

In 1979, the first successful transplant for leukemia of bone marrow stem cells from an unrelated donor (Rafei et al., 2019). Since that time, with the help of developments in clinical trials, genetic technology, and identification of cellular markers in cancer cells, many more cellular therapies have been developed. Engineered cellular therapies include tumor infiltrating lymphocytes (TIL), engineered T-cell receptors (TCR), cytotoxic T-cells (CTC), natural killer cells (NKC), and chimeric antigen receptor T-cell (CAR-T). Of these, only CAR-T therapies are FDA approved to treat some forms of B-cell malignancies.

The administration of CAR-T therapies has a cost in excess of ~$400,000. This limits availability of the treatment to patients with insurance that will cover the cost (Lyman et al., 2020). Other therapies are limited to clinical trials, but estimations are that the cost will be comparable to CAR-T therapies. The responses rates to CAR-T therapies clinical trials ranged from 4-25% achieving complete response (Grigor et al., 2019). Even though CAR-T is a promising therapy, there is more work to do to improve response rates.

CRISPR/Cas 9 Gene Editing

In 2020, for the first time in history two women, Dr. Emmanuella Charpentier and Dr. Jennifer Doudna, were jointly awarded the Nobel Prize in Chemistry for the discovery and development the CRISPR/Cas 9 technology. This “genetic scissor” allows scientist to insert genes of interest into target cells. https://www.nobelprize.org/prizes/chemistry/2020/press-release/

https://www.journals.elsevier.com/animal-gene/news/congratulations-charpentier-doudna-animal-gene

This technology is revolutionizing how we look at the world. Now, modifications that could take generations to breed, and be inserted directly into target cells in small labs that are accessible to many outside of large scientific research institutions. The uses also cross many disciples, not just healthcare. In produce, lettuce can be made heartier, more resistant to pathogens, with longer shelf-lives (Damerum et al., 2020).

Changing the face of cancer care

In oncology, CRISPR/Cas 9 technology has the potential to revolutionize precision medicine. It could be completely customizable to the individual patient. Cells could be targeted with for each individual patient. One of the most important aspects is that the use of this technology is much cheaper than current cellular therapies, can be upscaled more rapidly, and is highly customizable. https://www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treatment

Challenges

The use of CRISPR/Cas 9 technology is not without risk. The gene insertion is not 100% precise. Once initiated, the gene could be inserted into the wrong cell or at the wrong site, potentially creating other mutations. The efficacy of the treatment still needs to be determined, and if it follows the trend of other cellular therapies, response rates will initially be low. There are also many unknowns about potential side effects. First in human trials are ongoing right now. The scientific community is holding it’s collective breath at the promise gene editing to revolutionize cancer therapy.

References:

Damerum, A., Chapman, M. A., & Taylor, G. (2020). Innovative breeding technologies in lettuce for improved post-harvest quality. Postharvest Biology and Technology, 168, 111266. https://doi.org/10.1016/j.postharvbio.2020.111266

Gameiro, G. R., Sinkunas, V., Liguori, G. R., & Auler-Júnior, J. O. C. (2018). Precision Medicine: Changing the way we think about healthcare. Clinics (Sao Paulo, Brazil), 73, e723-e723. https://doi.org/10.6061/clinics/2017/e723

Grigor, E. J. M., Fergusson, D., Kekre, N., Montroy, J., Atkins, H., Seftel, M. D., Daugaard, M., Presseau, J., Thavorn, K., Hutton, B., Holt, R. A., & Lalu, M. M. (2019). Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis. Transfusion Medicine Reviews, 33(2), 98-110. https://doi.org/10.1016/j.tmrv.2019.01.005

Lyman, G. H., Nguyen, A., Snyder, S., Gitlin, M., & Chung, K. C. (2020). Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma. JAMA Network Open, 3(4), e202072. https://doi.org/10.1001/jamanetworkopen.2020.2072

Rafei, H., Mehta, R. S., & Rezvani, K. (2019). Editorial: Cellular Therapies in Cancer. Frontiers in Immunology, 10. https://doi.org/10.3389/fimmu.2019.02788

Universal germline genetic testing of individuals with cancer

Samantha Greenberg

PhD Student, College of Nursing

April 6th 2021

Rapid changes in genomics increase accessibility and affordability

The Human Genome Project kicked off in 1990, sparking a decade of revolutionary genetic science¹. During the discovery of ~22,000 genes, BRCA1 and BRCA2 were identified as two genes associated with hereditary breast cancer^2,3. Notably, pathogenic variants, or mutations, in these genes, put individuals at increased risk for breast and ovarian cancer among other cancer types⁴. The technology was costly, where sequencing of a genome cost over 10 million dollars. While BRCA testing was not millions of dollars, it was often over a thousand dollars out of pocket after insurance had paid their portion. Gene sequencing was then complemented by deletion/duplication analysis, and later usurped by next generation sequencing, sending the cost of testing plummeting⁵. As a result, comprehensive germline testing is recommended for individuals who had previous genetic testing prior to 2013, when the Supreme Court lifted restrictions on Myriad Genetics’ BRCA patent, and multi-gene panel testing became the new gold standard of care⁶.

As prices fall and growing evidence suggests individuals with germline pathogenic variants may be missed by current guidelines, there is a rising question: Should we stick to guidelines, or consider universal germline genetic testing in all individuals with cancer?

The argument for maintaining guidelines-based genetic testing

For decades, the National Comprehensive Cancer Network has been the leader in cancer treatment, prevention, and screening guidelines for the oncology community^7,8. Comprised of experts from designated comprehensive cancer centers by the National Cancer Institute, bi-annual panels review the newest literature and adjust guidelines based on evidence-based research. In the germline genetic testing realm, guidelines are set both by genetics committees, as well as individual cancer type panels that determine who benefits from germline genetic testing. Evolving alongside new research, these expert panels evaluate the cost and benefit of germline genetic testing in patients. As of now, guidelines are still based on personal and family history, though the past few years have brought new criteria. Specifically, individuals with somatic tumor testing that identifies a BRCA1/2 variant benefit from germline testing regardless of tumor type due to the high rate of concordance with germline mutations⁹.

The argument for the continuation of reliance on guidelines for germline testing in individuals with cancer is based on the potential downstream impact of widespread genetic testing. Genetic information is sensitive, and has previously been considered to need a ‘gatekeeper’. It is only in the last few years that direct-to-consumer comprehensive cancer genetic testing has become available without a formal visit with an ordering provider. Furthermore, concerns for psychosocial and familial impact of a mutation, or a variant of uncertain significance, may fuel some of the resistance to wider spread testing^10,11.

Why universal genetic testing is warranted

Though data guides decision making, it is the ancedotes that help frame the argument for universal genetic testing. Often an individual comes in with a history of breast cancer and a BRCA2 mutation they got through direct-to-consumer testing and no one had mentioned genetic testing in the previous 60 years of their life. This means we are missing people who could be undergoing preventative measures to reduce cancer mortality.

This is reflected in the literature. In individuals with prostate cancer, 37% of individuals with germline mutations did not meet clinical criteria¹². This is the same in breast cancer, where nearly half of patients with breast cancer and a mutation would have been missed by current testing guidelines¹³. Recently, guidelines expanded to recommend germline testing in all pancreatic adenocarcinoma after limited criteria missed germline mutations in only those with cancer and a known family history¹⁴. A study of individuals with solid tumors found that 192 patients (6.4% of the sample) had clinically actionable mutations that would have been missed by guidelines¹⁵. Furthermore, as somatic testing evolves, incidental findings that have allele frequencies aligned with inherited germline variants rather than tumor-specific markers are identified, sparking a need for oncologist education¹⁶. As testing costs continue to fall, the future seems inevitable: in the near future, we will offer germline testing to all individuals with cancer.

What needs to be figured out for widespread acceptance of universal genetic testing

Germline genetic testing is not a simple thing to be thrown into standard of practice. Patients benefit from pre-test education from a genetic counselor or their clinician to understand the personal, familial, and societal impact of their genetic test before they consent to testing¹⁷. Genetic counselor supply is a frequently highlighted topic¹⁸. If we drastically expand the population who needs genetic testing, will there be enough clinicians to provide this pre-test education? Do oncologists feel comfortable educating patients on potential outcomes? Research suggests the jury is out, and additional studies are needed to identify appropriate service delivery mechanisms if we test all patients¹⁹.

Furthermore, the ethics of universal genetic testing must be considered. Will billing insurance for 100 patients to undergo germline testing have a cost-benefit in preventing future cancers in two people with hereditary cancer risk? What is the threshold at which resource allocation is equitable and universal germline testing can help address disparities in cancer care? If germline testing is opt-out, how can we ensure appropriate education so that patients don’t receive information they are not interested in? And importantly, in communities where genetic research has previously been harmful, how do we rebuild trust to equitable access? As the oncology and genetics communities approach the inevitable shift of broader germline genetic testing in cancer patients, many questions are left to be answered. Inter-disciplinary collaborations across multiple stakeholders will be required to create a smooth transition to this next stage in precision and preventive oncology.

References

1. Collins FS, Morgan M, Patrinos A. The Human Genome Project: lessons from large-scale biology. Science. 2003;300(5617):286-290.

2. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66-71.

3. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789-792.

4. Risch HA, McLaughlin JR, Cole DE, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J. Natl. Cancer Inst. 2006;98(23):1694-1706.

5. Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nature reviews. Genetics. 2016;17(6):333-351.

6. Costello V. The Impact of Association for Molecular Pathology v. Myriad Genetics on Cancer Genetic Counseling Practice [M.S.]. Ann Arbor, Sarah Lawrence College; 2014.

7. Daly MB, Pilarski R, Berry M, et al. NCCN Guidelines (R) Insights Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017 Featured Updates to the NCCN Guidelines. J. Natl. Compr. Canc. Netw. 2017;15(1):9-19.

8. Daly MB. Prostate cancer genetic testing: NCCN familial high-risk assessment: breast/ovarian. The Canadian journal of urology. 2019;26(5 Suppl 2):29-30.

9. Daly MB, Pilarski R, Yurgelun MB, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020. J. Natl. Compr. Canc. Netw. 2020;18(4):380-391.

10. Alegre N, Perre PV, Bignon YJ, et al. Psychosocial and clinical factors of probands impacting intrafamilial disclosure and uptake of genetic testing among families with BRCA1/2 or MMR gene mutations. Psychooncology. 2019;28(8):1679-1686.

11. McLeavy L, Rahman B, Kristeleit R, et al. Mainstreamed genetic testing in ovarian cancer: patient experience of the testing process. Int. J. Gynecol. Cancer. 2020;30(2):221-226.

12. Nicolosi P, Ledet E, Yang S, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA oncology. 2019.

13. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;37(6):453-460.

14. Shindo K, Yu J, Suenaga M, et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J. Clin. Oncol. 2017;35(30):3382-3390.

15. Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. JAMA oncology. 2021;7(2):230-237.

16. Catenacci DV, Amico AL, Nielsen SM, et al. Tumor genome analysis includes germline genome: are we ready for surprises? Int. J. Cancer. 2015;136(7):1559-1567.

17. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J. Clin. Oncol. 2015;33(31):3660-3667.

18. Hoskovec JM, Bennett RL, Carey ME, et al. Projecting the Supply and Demand for Certified Genetic Counselors: a Workforce Study. J Genet Couns. 2018;27(1):16-20.

19. Stoll K, Kubendran S, Cohen SA. The past, present and future of service delivery in genetic counseling: Keeping up in the era of precision medicine. Am. J. Med. Genet. C Semin. Med. Genet. 2018;178(1):24-37.

conTEXT for advancing science