January/February 2018 - New Horizons in Genetic Testing by Advocates for Better Health

January/February 2018

New Horizons in Genetic Testing

In This Issue: • • • •

The Promises and Perils of Genetic Testing New TCMS Leadership Charles Bolles Bolles-Rogers Award Luminary of Twin Cities Medical Society

“Your patients will thank you for referring them to Dr. Crutchfield.”

A FAC E O F A M I N N E SOTA DE R M ATOL O GIST Recognized by physicians and nurses as one of the nation’s leading dermatologists, Charles E. Crutchfield III MD has received a significant list of honors including the Karis Humanitarian Award from the Mayo Clinic, 100 Most Influential Health Care Leaders in the State of Minnesota (Minnesota Medicine), and the First a Physician Award from the Minnesota Medical Association, for positively impacting both organized medicine and improving the lives of people in our community. He has a private practice in Eagan and is the team dermatologist for the Minnesota Twins, Wild, Vikings and Timberwolves. Dr. Crutchfield is a physician, teacher, author, inventor, entrepreneur, and philanthropist. He has several medical patents, has written a children’s book on sun protection, and writes a weekly newspaper health column. Dr. Crutchfield regularly gives back to the Twin Cities community including sponsoring academic scholarships, camps for children, sponsoring programs for children with dyslexia, mentoring under-represented students from the University of Minnesota, and establishing a Dermatology lectureship at the University of Minnesota. As a professor, he teaches students at both Carleton College and the University of Minnesota Medical School. He lives in Mendota Heights with his wife Laurie, three beautiful children and two hairless cats.

AES

THET I C

L OF APPROVA L SEA

CRUTCHFIELD DER MATOLOGY Experience counts. Quality matters. Mayo Clinic Medical School Graduate | University of Minnesota Dermatology Trained Top Doctor Minneapolis St. Paul Magazine | Best Doctors for Women Minnesota Monthly Magazine Team Dermatologist for the Minnesota Twins, Vikings, Timberwolves and Wild 1185 Town Centre Drive, Suite 101, Eagan | 651.209.3600 | www.CrutchfieldDermatology.com

CONTENTS VOLUME 20, NO. 1 JANUARY/FEBRUARY 2018

IN THIS ISSUE

Genetic Testing: Is it Good for Your Patients? Is it Good for You? By Charles G. Terzian, MD

PRESIDENT’S MESSAGE

Making 2018 the Best Year Yet By Thomas E. Kottke, MD

TCMS IN ACTION By Nancy K. Bauer, Interim CEO GENETIC TESTING

Page 32

•

Colleague Interview: A Conversation with Shari Baldinger, MS

•

Genetic Testing: Moving into the Mainstream of Medicine By David Tilstra, MD, MBA, and Emily Mayerhofer, MS, LCGC

•

SPONSORED CONTENT:

Progress Toward Effective, Individually Tailored Breast Cancer Therapies By Douglas Yee, MD, with Paul Mamula, PhD

Page 7

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Pharmacogenomics and Optimal Opiate Prescriptions: A Quick Guide By Gregory A. Plotnikoff, MD, MTS, FACP

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Revisiting Direct-to-Consumer Genetic Testing: What are the Ethical Issues? By Megan Allyse, PhD and Richard R. Sharp, PhD

January/February 2018

New Horizons in Genetic Testing

Environmental Health: Pipelines, Tar Sands Oil, and the Health of Minnesotans By Bruce D. Snyder, MD, FAAN Health Professionals for a Healthy Climate

Charles Bolles Bolles-Rogers Award/In Memoriam

Senior Physicians Association Career Opportunities

Page 5

LUMINARY OF TWIN CITIES MEDICINE

Robert James Gorlin, DDS MetroDoctors

The Journal of the Twin Cities Medical Society

In This Issue: • • • •

The Promises and Perils of Genetic Testing New TCMS Leadership Charles Bolles Bolles-Rogers Award Luminary of Twin Cities Medical Society

A deeper look into the opportunities for improved care with genetic testing — as well as its costs and fears. Articles begin on page 7. January/February 2018

Doctors MetroDoctors THE JOURNAL OF THE TWIN CITIES MEDICAL SOCIETY

Physician Co-editor Peter J. Dehnel, MD Physician Co-editor Thomas E. Kottke, MD Physician Co-editor Robert R. Neal, Jr., MD Physician Co-editor Marvin S. Segal, MD Physician Co-editor Richard R. Sturgeon, MD Physician Co-editor Charles G. Terzian, MD Medical Student Co-editor Mac Garrett Managing Editor Nancy K. Bauer TCMS INTERIM CEO Nancy K. Bauer Production Manager Sheila A. Hatcher Advertising Representative Erica Nelson Cover Design by Annie Krapek MetroDoctors (ISSN 1526-4262) is published bi-monthly by the Twin Cities Medical Society, 1300 Godward Street NE, Broadway Place West, Suite 2000, Minneapolis, MN 55413. Periodical postage paid at St. Paul, Minnesota. Postmaster: Send address changes to MetroDoctors, Twin Cities Medical Society, 1300 Godward Street NE, Broadway Place West, Suite 2000, Minneapolis, MN 55413. To promote its objectives and services, the Twin Cities Medical Society prints information in MetroDoctors regarding activities and interests of the society. Responsibility is not assumed for opinions expressed or implied in signed articles, and because of the freedom given to contributors, opinions may not necessarily reﬂect the ofﬁcial position of TCMS.

TCMS Ofﬁcers

President: Thomas E. Kottke, MD President-elect: Ryan Greiner, MD Secretary: Andrea Hillerud, MD Treasurer: Nicholas J. Meyer, MD Past President: Matthew A. Hunt, MD TCMS Executive Staff

Nancy K. Bauer, Interim CEO, and Managing Editor, MetroDoctors (612) 623-2893; nbauer@metrodoctors.com Karen Peterson, Executive Director, Honoring Choices Minnesota (612) 362-3704; kpeterson@metrodoctors.com Lynn Betzold, Program Coordinator, Honoring Choices Minnesota (612) 362-3703; lbetzold@metrodoctors.com Grace Higgins, Senior Project Coordinator, Physician Advocacy Network (612) 362-3706; ghiggins@metrodoctors.com Annie Krapek, Assistant Project Coordinator, Physician Advocacy Network (612) 362-3715; akrapek@metrodoctors.com Sadie Rubin, Executive Director, The Convenings (612) 362-3724; srubin@metrodoctors.com Katy Vanderwood, Project Coordinator, The Convenings (612) 623-2885; kvanderwood@metrodoctors.com

January/February Index to Advertisers Crutchﬁeld Dermatology.....................................

Send letters and other materials for consideration to MetroDoctors, Twin Cities Medical Society, 1300 Godward Street NE, Broadway Place West, Suite 2000, Minneapolis, MN 55413. E-mail: nbauer@metrodoctors.com. For advertising rates and space reservations, contact: Erica Nelson 4084 Jana Ave. NE St. Michael, MN 55376 phone: (763) 497-1778 fax: (763) 497-8810 e-mail: erica@pierreproductions.com

Inside Front Cover Entira Family Clinics .......................................30 Episcopal Homes of Minnesota ....................19 Fairview Health Services .................................30 Gislasen & Hunter, LLP ................................... 9 Health Equity Conference..............................24 HealthPartners....................................................31 HealthPartners...................................................... 6

MetroDoctors reserves the right to reject any article or advertising copy not in accordance with editorial policy. Advertisements published in MetroDoctors do not imply endorsement or sponsorship by TCMS. Non-members may subscribe to MetroDoctors at a cost of $15 per year or $3 per issue, if extra copies are available. For subscription information, contact Nancy Bauer at (612) 623-2893.

Lakeview Clinic .................................................31 Mankato Clinic .................................................... 2 M Health ........................... Outside Back Cover North 61 ..............................................................15 St. Cloud VA Medical Center ............................ Inside Back Cover U.S Army .............................................................27

January/February 2018

MetroDoctors

The Journal of the Twin Cities Medical Society

IN THIS ISSUE...

Genetic Testing: Is it Good for Your Patients? Is it Good for You?

adio and television advertising, AARP bulletins, articles in throwaway and peer reviewed journals, and now our edition of MetroDoctors addressing genetic testing. Is it for you? Is it for your family? Do you really want to have it done and know the answers? In the July/August 2016 edition of MetroDoctors we had a commentary written by Shari Baldinger about genetic testing. (Ms. Baldinger is also the Colleague Interview for this issue). I read her article with a heightened interest. Based on the knowledge of my family history, I decided to have some genetic testing done and encouraged my sisters to do so as well. Unfortunately, I tested positive for the BRCA1 genotype. Luckily, I was able to seek professional counseling for myself (guided by information from the article that I had read) and development determinations for my daughters. However, there are still many unanswered questions that I have about my results and undoubtedly you will have after reading this current edition. The editorial board has attempted to bring you a multitude of articles addressing this current healthcare conundrum. Our leadoff article by Dr. Tilstra and Ms. Mayerhofer conﬁrms that genetic testing has become an important diagnostic tool; however, they caution interpreting the results will remain a challenge. The article by Dr. Olson, et al. is a discussion about the various types of genetic testing currently available. The article further elaborates on the testing costs and the genetic determinations in drug responses (i.e. pharmacogenomics). This dovetails nicely into an article by Dr. Plotnikoff concerning pharmacogenomics and an individual’s response to opiates. Good information from a practical perspective when prescribing opiates; however, the majority of speciﬁc laboratory testing is not yet available to the practicing physician. We also see how individual breast cancer therapies are directed based on genetic markers in the article submitted by Drs. Yee and Marmula.

By Charles G. Terzian, MD Member, MetroDoctors Editorial Board

MetroDoctors

The Journal of the Twin Cities Medical Society

As mentioned earlier, the media and entrepreneurs are just addressing and/or capitalizing on the public’s craving for more knowledge about themselves. However, many people do not understand the costs involved with genetic testing, nor the psychological impact of the results of the tests. Dr. Dehnel’s article discusses the economic challenges and who is responsibile to pay for the testing. Are we as physicians obligated to recommend, order, or provide these options to our patients? When our patients present asking questions about genetic testing, what should we tell them? Drs. Sharp and Allyse help us in this regard suggesting that caution be used when speaking with our patients regarding genetic testing and its limitations. Is there a medical-legal responsibility if we withhold or do not advise the patient or their family to undergo genetic testing? This idea is explored in the article written by Ms. Branum, policy counsel for the MMA. Then, once we provide this testing and know the results, what are the potential psychological impacts that these results will have on our patients? Will that individual, based on test results, have a “gloom and doom” or alternatively a “cavalier attitude to preventative medicine” philosophy? A lot of food for thought as we explore this uncharted territory encompassed within the realm of human genetics. We hope we have brought this issue front and center for you and welcome your comments. It brings to mind the adage: you can pick your friends but you can’t pick your family. Finally and as always, Dr. Segal so eloquently re-acquaints us with a Luminary in Twin Cities Medicine — in this edition, it is Dr. Robert James Gorlin.

January/February 2018

President’s Message

Making 2018 the Best Year Yet THOMAS E. KOTTKE, MD

AS WE ALL LOOK FORWARD TO 2018, I am pleased and honored to assume the Presidency of

Twin Cities Medical Society (TCMS) and promote its vision of providing leadership for the health of our communities. Although Minnesota ranks at or near the top of all health and well-being indicators, great disparities are hidden in that grand mean. These disparities harm the health of the poor and excluded, and they reduce quality of life for us all. TCMS gives every physician the opportunity to address the threats to health, the disparities, and the social determinants that we all see when in the exam room but are much more effective when we address them in the community. Our focus on community health makes TCMS rather unique among medical societies. A flagship TCMS community health program is Honoring Choices Minnesota (HCM). Now in its 11th year, HCM helps individuals in the Twin Cities and statewide use advance care planning so that they receive the care that they want where and when they want it. This past year, the Minnesota Department of Health awarded HCM the resources to increase its statewide activities. Sporting the tag line, “Real families. Real choices. Real life.” and winning an Emmy® Award, The Convenings with Cathy Wurzer, hosts community forums that promote the discussion of end-of-life wishes. Initiating conversations in an entire community removes a barrier and creates a space for discussing a difficult topic. Tobacco and nicotine continue to be an unnecessary health and economic burden for Minnesotans that falls especially on communities of color. TCMS, through its Physicians Advocacy Network (PAN), is providing physician leadership in initiatives that support raising the age of tobacco sales to 21, making the hazards of e-cigarettes and vaping clear, and restricting where menthol-flavored tobacco products can be sold. The PAN has had significant success, but opposition is stiff and there is much work left to be done. Through a Physician Foundation grant, the Medical Directors of HCM and PAN have been providing consultations nationwide on how organizations similar to TCMS can spearhead public health and advocacy initiatives in their communities. Thirty-five years ago, Physicians Serving Physicians (PSP) began providing assistance to chemically dependent and alcoholic physicians and their families in Minnesota. Supporting PSP through a time of transition, TCMS has stepped in to manage the program so that the benefit to the health and well-being of physicians who are at risk or who are dealing with addiction challenges can continue. TCMS created its Environmental Health Task Force in response to the need for physicians to address the environmental determinants of health — clean air, safe drinking water, sufficient food, and secure shelter. The task force, by developing organizational partnerships across the metro and the state, brings the physicians’ voice to this conversation and empowers our members to become better stewards of the environment for the benefit of our patients. For all of these programs, I tip my hat to Sue Schettle, our CEO (resigned) for the past 16 years. None of them would have happened without her energy, vision, and constancy of purpose. Because of her, TCMS is nationallyrecognized as a model of physician-led community programs that promote health and well-being. What do I see for TCMS in the future? In addition to sustaining our current programming, in the next year I will be looking for resources so that TCMS can become more active in three areas: Assuring that everyone — particularly women, adolescents and LGBTQ — have access to the sexual health services that allow them to flourish; assuring that all infants have the best early childhood experience possible; and, reducing homelessness and housing insecurity. This is a big and bold agenda, but when we provide these services, we not only benefit the individuals who receive them, we ourselves benefit by being compassionate, and we increase community-wide prosperity. Please join me. Step down from the bleachers, come on to the playing field, join TCMS, be a leader, and help make Minnesota the best of the best for everyone. 4

January/February 2018

MetroDoctors

The Journal of the Twin Cities Medical Society

TCMS IN ACTION NANCY K. BAUER, INTERIM CEO

Happy New Year from the staff at TCMS. We look forward to another busy and rewarding year working on your behalf.

or Elizabeth Anderson at eanderson@ mnmed.org with any questions. You may also renew online at http://www. mnmed.org/renew.

New Ofﬁcers and Board Members

Physician Advocacy Network

The Annual Meeting of the TCMS Board will be held on January 15, at which time Matthew Hunt, MD will formally pass the President’s gavel to Thomas Kottke, MD. Joining Drs. Hunt and Kottke on the Executive Committee are: Drs. Ryan Greiner, President-Elect; Andrea Hillerud, Secretary; Nicholas Meyer, Treasurer; and Directors-at-Large, Rupa Austria, and medical student Jennifer Janssen. In addition, Drs. Kristen Helvig, Sarah Traxler and Jennifer Tessmer-Tuck (representing the MMA Policy Council) will be welcomed as incoming members on the Board of Directors.

It’s been a busy couple of months for our tobacco prevention advocates. Bloomington and Plymouth became the 3rd and 4th cities to raise the tobacco sales age to 21 in Minnesota with the support of TCMS’ Physician Advocacy Network. Doctors Tom Kottke, Bob Neal, Emily Borman-Shoap and Lisa Mattson all testiﬁed in support of the measures. Doctors Dick Patterson and Emily Bannister also spoke in support of successful ordinances to restrict the sale of ﬂavored tobacco in St. Louis Park and Robbinsdale, with Robbinsdale voting to increase cigar prices as well.

Welcome Katy Vanderwood

Serving as project coordinator, Katy Vanderwood is the newest member of The Convenings team. Katy is originally from London, England and is an accomplished singer songwriter in her (not-so-spare) time. Welcome Katy! 2018 Dues Renewal

If you haven’t already, please take the time to renew your 2018 membership dues. Only with your membership can MMA and TCMS work on your behalf to reduce the challenges of your practice and support efforts to improve the health of our communities. Contact me at nbauer@metrodoctors.com

MetroDoctors

Physician and community advocates celebrate Plymouth becoming the 4th city to pass Tobacco 21 in Minnesota.

Health Equity Month

TCMS is partnering with MMA, the American Academy of Pediatrics, Minnesota Academy of Medicine and others to raise awareness of health disparities. A number of activities are being planned throughout the month of January, culminating with a Health Equity Forum on January 24 with Commissioner Edward Ehlinger, MD and Brooke A. Cunningham, MD, Assistant Professor, Department of Family Medicine and Community Health at the University of

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Minnesota. (See related announcement on page 24.) TCMS Foundation Update

A meeting of the TCMSF Board of Directors was held in November, at which time nearly $25,000 in grants were distributed to community organizations working to improve access to care. Thank you for your ongoing donations to the TCMSF to support these funding opportunities. In addition, there are immediate openings on the TCMSF Board of Directors—one representing East Metro, one representing West Metro, and a Director-at-Large. Please contact me if you are interested at nbauer@metrodoctors.com. Charles Bolles Bolles-Rogers Award

Elie Gertner, MD, Internal Medicine/ Rheumatologist at Regions Hospital, was presented with the 2017 Charles Bolles Bolles-Rogers Award. Congratulations Dr. Gertner! (See related article on page 29.)

January/February 2018

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Genetic Testing

Colleague Interview: A Conversation with Shari Baldinger, MS

hari Baldinger, MS, is a certiﬁed genetic counselor who specializes in cancer risks assessment and cancer gene testing. She was involved in establishing the Minnesota Genetic Services Program at the University of Minnesota and in initiating genetic counseling services at Abbott Northwestern Hospital, Children’s Hospital, HCMC, United Hospital, Park Nicollet and Fairview Health Service. Since 2011, Ms. Baldinger is the Manager of Genetic Counseling Services for the Oncology service line at Allina Health, The Virginia Piper Cancer Institute. She received her B.A. from Washington University, St. Louis, MO; and a Master’s Degree in Genetics and Cell Biology from the University of Minnesota. She is certiﬁed by the American Board of Medical Genetics and the American Board of Genetic Counseling.

To give us an idea of the current state of genetic counseling, how much has the volume of your patient encounters increased in the past ﬁve years? The past one year?

that may extend to multiple relatives. Results now also impact surgical and systemic treatment options. We have eight dedicated cancer genetic counselors at Allina.

The number of requests for cancer genetic counseling services has grown in the last several years. With universal tumor screening for Lynch syndrome (the most common form of hereditary non-polyposis colon cancer associated with not only a high risk of colon cancer but also endometrial cancer, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin) that we began in 2012, we have started to identity the 2-3% of those with colon cancer and uterine cancer due to Lynch syndrome, many of which would not be identiﬁed by history alone. In fact, 1/300 people in the general population have a Lynch mutation and 95% of them are unaware. In that vein, we have also recently developed, but not yet operationalized, an EMR-based screening tool for primary care to identify those who may beneﬁt from genetic assessment for hereditary breast, ovarian and colon cancer. We also have developed a robust cancer screening tool used by our care coordinators on all newly diagnosed cancer patients. If any of the criteria are met, referral to genetics is undertaken. Approximately 40% of our newly diagnosed breast cancer patients meet current NCCN guidelines for such a referral — test results not only indicate the patient’s risk for metachronous cancer, (more than one cancer arising at different times) but also identify risks

What are the credentialing and/or training requirements for valid genetic counseling? Any negative “information” sources to avoid?

MetroDoctors

The Journal of the Twin Cities Medical Society

The state of Minnesota now requires that those providing genetic counseling need to be licensed as genetic counselors (or clinical geneticists). To obtain licensure, a genetic counselor must be board certified by either the American Board of Medical Genetics and Genomics or the American Board of Genetic Counseling. Given the complexity of new testing choices and the potential of getting results involving variants of unknown significance, test choice and, most importantly, test interpretation is best done in the context of formal genetic counseling. In fact, a recent Journal of Clinical Oncology article (2017) Kurian et al, showed that many patients with breast cancer are tested without ever seeing a genetic counselor. Half of average-risk patients with VUS (variant of unknown clinical significance) undergo BLM (bilateral mastectomy), suggesting a limited understanding of results that some surgeons share. These findings emphasize the need to address challenges in personalized communication about genetic testing. (Continued on page 8)

January/February 2018

Genetic Testing Colleague Interview (Continued from page 7)

Is the current population of Minnesota physicians sufficiently aware of the genetic counseling services available so that appropriate types of conditions and numbers of referrals can take place? We are working on EMR tools to help with patient identification before individuals get cancer. However, we published an article this year on women identified during their mammogram screening as in need of genetic counseling to address a possible heritable breast cancer risk based on self-reported history. Letters were sent to both the patient and primary care provider; only 8% of patients followed up with recommended consult. One main reason was lack of support/encouragement to do so by the primary care provider. We have a long way to go.

those who see perinatal patients and others that provide pediatric services, cardiac genetic services, neurogenetics, general genetics and other specialty services such as those for CF (cystic ﬁbrosis), NF1(neuroﬁbromatosis type1) etc.

Assuming that much of your counseling work is related to breast cancer, what other genetically related malignancies are amenable to your services? Colorectal? Pancreatic? Our counseling is not just related to breast cancer. We see patients who have all types of cancer, including colorectal and pancreatic as well as those who have family members with these types of cancer. We provide risk assessment, individualized management plans and help with genetic testing if indicated.

Are genetic testing and counseling covered beneﬁts? Assuming physicians are not informed, where do they ﬁnd appropriate/reliable information? Do the major metro health systems have referral sources in their networks? Is there a directory perhaps? Most of the major medical systems have access to genetic services. However, the Minnesota Genetic Counseling Association (Mygenepool.org) and the National Society of Genetic Counselors (Nsgc.org) are both sites where resources can be found. We also provide telehealth cancer genetic counseling services to 10 sites outside the metro area.

Are these referral sources adequate to meet demand — especially if the primary care givers improve/increase their sensitivity to referral? There were over 600 jobs for genetic counselors posted last year with only 300-400 new graduates. However, genetic counselors are one of the fastest growing health professions. According to a recent analysis of our workforce published on the nsgc.org website, we are expected to grow at 6-10% year over year for the next 10 years and, in ﬁve years’ time, there will be one genetic counselor for every 100,000 Americans. In recognition of these challenges, efforts are underway to develop alternative models of service delivery and optimize the EMR and other IT to assist with the genetic counseling process; but we also need to partner with other healthcare providers to both ensure patient access and to improve genetic literacy in health care. Regardless of the challenges we face, many patients can get in to see genetic counselors in a reasonable amount of time and many centers, including ours allow for STAT scheduling for patients, when necessary. There are several ways to receive genetic counseling services: in-person, via telephone or telehealth encounters.

Are your counseling services available for non-cancer genetic conditions? If so, what are they? While my team only provides cancer genetic services, there are 8

January/February 2018

Most payers pay for genetic counseling and genetic testing if the patient meets guidelines to do so. In cancer, this is often based on NCCN (National Comprehensive Cancer Network) guidelines. In fact some payers require genetic counseling before paying for testing to be sure the right tests are ordered and they are interpreted properly.

Are there any new clinical genetic knowledge breakthroughs on the near horizon? We are in the era of personalized medicine. In the near future all tumors will have their genomes analyzed for treatment targets, or reanalyzed to understand acquired resistance to drugs and choices of new drugs. With that information we can precisely define genetic drives for every patient and treat with a tailored regimen. The first FDA approved drug based on microsatellite instability and agnostic of tumor origin is currently being used, i.e. immune therapy. Such tumor evaluation will also alert some to an inherited risk. In fact, the American Society of Clinical Oncology recommends that patients should be educated before testing about the possibility that germ-line variants might be identified and that providers communicate the limitations and risks of receiving germ-line findings. Pharmacogenomics will likely be characterized prospectively on patients so when drugs are prescribed the EMR can guide physicians to avoid adverse reaction, maximize drug efficacy and select responsive patients upfront.

Are algorithms being used in the EMR so the physician is alerted to counseling necessity and payment issues? Our EMR tool (in process) will alert physicians regarding the need for referral based on history questions. I know EPIC is also working on a genomics module to help with patient identification and management once identified. There really are not any specific payment issues that would prompt an alert. Genetic counselors address those before testing is done.

MetroDoctors

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Please share any additional thoughts relating to genetic testing that would help to improve our readers’ understanding. From the American Society of Clinical Oncology 2015 guidelines: Providers with expertise in risk assessment should be involved in ordering and interpreting multi-gene panels that include genes of uncertain clinical utility and genes not suggested by the patient’s personal and/or family history. D. Hayes, MD, FASCO, PresidentElect noted: “Increasingly we will be the recipients of data that we did not anticipate, or perhaps, even seek to know. Accordingly we will be in the uncomfortable position of reacting to that data on the basis of an immature and incomplete understanding of what that data mean.” Genetic professionals can play a key role in minimizing the harm from misinterpretation. In addition we can serve as a resource to educate physicians about the power of genomics and how this can empower patients to minimize risk for disease. Physicians considering testing should prepare patients for the following possible outcomes of tests: • Positive: this may be a helpful result. Target for therapy or explanation for history and help target at-risk family members and avoid costly unnecessary screening in others. • Positive but a surprise result that is inconsistent with phenotype: does this mean the same to this family? For example, if a patient with ductal breast cancer and no family history of

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•

• •

lobular breast cancer or diffuse gastric cancer, tests positive for a CDH1 mutation, should they consider risk reducing gastrectomy, as is the guideline for those who truly face the recognized risk of such a mutation? Ambiguous results (VUS)-NOT ACTIONABLE: whether in well described or newly identified genes, physician should base management on personal and family history not on presence or absence of a variant of uncertain significance. Negative result: this is not good or bad news. It rarely rules out a heritable concern and is frequently UNINFORMATIVE. Normal results are of limited value unless a causal mutation has previously been found in an affected family member. Disappointing results: e.g. a mutation in a gene without much literature on risk. A patient with breast cancer could test positive for a mutation in a gene that would pose a reproductive risk if partner carried a mutation in the same gene, e.g. risk for autosomal recessive condition such as ataxia telangiectasia (a multisystem disorder characterized by progressive neurologic impairment, cerebellar ataxia, telangiectasia, immunodeficiency with susceptibility to infection and to malignancy in childhood), and a predisposition to malignancy or Fanconi anemia (also an inherited disorder associated with birth defects, bone marrow failure and solid tumors in childhood with some subtypes).

January/February 2018

Genetic Testing

Genetic Testing: Moving into the Mainstream of Medicine

enetic testing has been the subject of much hype and hope of pop culture since the discovery of DNA over half a century ago. The consequences of knowing our genetic code, often with a heavy dose of imagination, has been the subject of novels, movies, and plays. Genetic testing has been feared as a means of loss of control of our personal biology as shown in the 1997 ﬁlm Gattaca. It has also been welcomed as the means to reveal the secret of our biologic blueprint. Now that genetic testing is readily available at relatively low cost, what are the realities of genetic testing? Is it just a passing interest, the keeper of our biologic destiny or something in between? Genetic testing is integral to the current state of health care. Technology has introduced sequencing at mind-boggling speed; the detailed structure of chromosomes can be revealed in the matter of a few days. Despite technological advances, results of testing are complex and often challenging to interpret. Insurance coverage decisions are unpredictable, often lag behind current technology, and occasionally are misaligned with what seems to be medically indicated. Even with those limitations, genetic testing can also be the most rapid way to a diagnosis, clarify prognosis and aid in making treatment decisions. Genetic testing may predict risk of a patient developing a condition or the patient’s response to treatment. However, this information is typically a probability, not a certainty, of a patient developing a condition. For example, a female with By David Tilstra, MD, MBA, and Emily Mayerhofer, MS, LCGC

January/February 2018

a pathogenic BRCA gene alteration may have up to an 87% risk of developing breast cancer in her lifetime. In other words, there would be greater than a 13% chance that this individual would not develop breast cancer. Another limitation is that all possible mutations of a known condition cannot David Tilstra, MD MBA Emily Mayerhofer, MS, LCGC be detected through genetic testing. This is due to technical challenges of testing, limitations in (referred to as microdeletions or duplicacurrent knowledge of all the genes associtions) and is unable to analyze single genes. ated with the tested condition, or a host Karyotyping often takes up to two weeks of other possibilities. Without appropriate to complete. FISH analysis can rapidly pretest counseling or if the wrong test is detect targeted CNVs and are useful for ordered, genetic testing can reveal unexconfirming a highly suspected CNV or in pected or unwanted results. For example, rapidly determining trisomies on prenatal tests may reveal unexpected paternity or specimens. an unknown health condition. Chromosome microarrays (CMA) Although a complete review of all tests can detect much smaller CNVs, to about currently available is beyond the scope of 50,000 base pairs. CMA may be targeted this article, we will review several comor enriched for a specific purpose, such mon genetic tests including examples of as looking at a gene or region of interest. appropriate use, limitations, and potential Chromosomal microarray analyzes the pitfalls. We will start with tests that analyze genome for small deletions or duplicachromosomal structure. tions within the genetic material. CMA Changes in chromosome structure has become the genetic test of choice for or number are now referred to as copy evaluation of autism, intellectual disability, number variants (CNVs). CNVs can be multiple congenital anomalies, as well as determined by karyotyping, florescent many other indications. The leap from in-situ hybridization (FISH) or by chrokaryotyping to CMA is analogous to the mosomal microarrays (CMA). Karyotypleap from encephalograms to MRI. ing has been available for decades and is For single gene conditions, gene serelatively inexpensive. It excels at deterquencing determines the specific sequence mining the presence of extra or missing and order within a gene. Ideally, the conchromosomes and detecting chromosomal sequence of an alteration from “normal” rearrangements. It is limited in its ability is known and can be interpreted as causto detect small deletions or duplications ing a condition, determining prognosis or MetroDoctors

The Journal of the Twin Cities Medical Society

predicting a response to a specific treatment. Positive results are often very specific and useful. A negative test might also give specific results and may reduce the probability of developing a condition. As with many genetic tests, “variants of unknown significance” (VUS) can also be identified. Variants of unknown significance refer to changes (variations) within the gene that were identified, but the clinical significance remains uncertain. Depending on the context, these ambiguous results may be useful. A variant that was not inherited from a parent (new mutation) may be causal of the condition while a variant that has been in the family may just be normal variation (given the parent is unaffected). Variant reclassification is an ongoing effort and over time these changes are reclassified (as disease causing or benign alterations). However, the clinical significance of a VUS can be challenging to interpret and would be best supported by a genetics professional. Currently, the most common way of performing gene analysis is through a gene panel. Gene panels combine multiple related genes into a single test, utilizing next-generation sequencing to enable high throughput at a low cost. Gene panels might be designed for a specific purpose such as breast cancer mutation detection, or much larger panels such as intellectual disability or autism. Gene panels range in size from two genes to thousands of genes. Certainly, the more genes evaluated, the higher the possibility of finding a variant of unknown significance. Gene panels are a cost-effective approach to analyze the genes of concern, offer a more timely return of results, are more informative for patients and providers and can reduce the emotional rollercoaster of a diagnostic odyssey. Gene sequencing on a massive scale is done in two variations: whole exome sequencing and whole genome sequencing. These tests provide a robust, comprehensive genetic test to identify disease-causing alterations. Whole exome sequencing (WES) focuses only on the coding portion of the DNA sequence (called the exons), which is about 2% of the total sequence.

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WES is being used quite frequently for medically complex cases, especially if other testing has a low probability of finding a result, when multiple other genetic tests have failed to identify a specific etiology, or when turnaround time for results is especially important, etc. Whole genome sequencing (WGS) analyzes the entire genetic sequence of an individual, to include the non-coding sequence. The non-coding sequence is poorly understood and highly variable, limiting its clinical use. Limitations of large scale gene sequencing methodologies are not unique to WES or WGS and include many of the limitations addressed above. Despite the implication that whole implies, some mutations can still be missed. The genetic code is complex and is not simply analyzed or understood. It is estimated that WES in clinical situations finds a pathogenic mutation in 25-35% of cases. Outside of the clinic setting, direct to consumer (DTC) genetic tests are available through vendors such as “23andMe.” Such labs use a method called genotyping — determination of specific variants that a patient/consumer might have. Unlike gene sequencing, only a few well-known alterations in a gene might be evaluated, potentially missing less common variants in a gene of interest. In such testing, a common BRCA mutation might be discovered, but an equally pathogenic mutation next to it might not. In some DTC labs, the presence of a mutation could predict real disease, although we always recommend confirming results in a clinical lab. A “negative test” only indicates the absence of that specific sequence and cannot eliminate the risk that other sequence variants are carried by the patient that may contribute to disease or disease susceptibility. Genetic testing will continue to improve in speed and accuracy while costs will fall. As that change occurs, the increased access to genetic testing will also expand into new applications. Pharmacogenetics is emerging as an application for nearly the entire population. Sequencing tumors to reveal possible medication responses is becoming a reality with the potential to improve morbidity and mortality.

The Journal of the Twin Cities Medical Society

Researchers and ethicists are debating the utility of whole genome sequencing for broad populations. The future will require all physicians to be comfortable interpreting basic genetic test results. As discussed above, results of genetic testing need to be interpreted in the speciﬁc clinical context of an individual patient. Ordering the right test can be challenging, given the broad number of tests, labs and disorders. Ordering the wrong test can result in unnecessary expense, may pose psychological burden or harm to the patient and might give a false impression about the presence or absence of a condition. A genetic professional can help guide the patient and physician to a cost effective, accurate and informative test. So, what is the current state of genetic testing? We aren’t in the dystopia of Gattaca, but it is more than a passing amusement. Genetic testing can provide rapid and cost-effective information to guide management in thousands of conditions, with a precision that surpasses many other forms of testing. Interpreting results will remain challenging for many years. Despite certain limitations, genetic testing is emerging as a foundational tool in the medical toolbox. David Tilstra, MD, MBA, is a clinical geneticist who works at CentraCare Health in St. Cloud, Minnesota and is President of CentraCare Clinic. His clinical interests are in pediatric and adult genetic disorders. He can be reached at tilstrad@centracare.com or 320-654-3654. Emily Mayerhofer, MS, LCGC, is a licensed certiﬁed genetic counselor who works at CentraCare Health in St. Cloud, Minnesota. She sees a variety of patients ranging from prenatal cases to cancer, general genetics (infants to adult patients with concerns for a wide variety of genetic disorders), specialty genetics (including cardiovascular, Alzheimer’s or dementia disease, preconceptual, etc.). She can be reached at emily.mayerhofer@ centracare.com or 320-654-3654.

January/February 2018

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Navigating the Complex Landscape of Genetic Testing Genetics Professionals are a Key Resource Contributed by Doug Olson, MD; Virginia Kakacek, MD; and Pamala Pawloski, PharmD, FCCP

The genetic and molecular age is upon us and — like the advent of automobiles or cell phones — it’s changing lives forever. Advances in molecular biology have enabled truly personalized medicine. Our understanding of the molecular basis of disease has rapidly advanced. In 1943, we learned DNA plays a critical role in inheritance. Within 10 years, James Watson and Francis Crick defined the structure of DNA. In 1983, Kary Mullis improved the polymerase chain reaction technique, making it central to biochemistry and molecular biology. The first eukaryotic organism was sequenced in 1996. Seven years later, the Human Genome Project had sequenced the entire human genome and its three billion base pairs. Today, we can sequence millions of genes for pennies. In January 2017, Illumina announced plans to sequence anyone’s genome for just $100. These achievements make molecular medicine possible and inevitable. But navigating this landscape can be challenging for clinicians, patients and health plans. Types of Genetic Testing According to Concert Genetics, over 70,000 genetic testing products are available nationally, and 10 new products enter the market daily. The National Institutes of Health National Human Genome Research Institute defines many types of testing. • Diagnostic testing identifies genetic conditions or diseases. Results can affect care and treatment choices. (e.g., hemochromatosis) • Predictive and pre-symptomatic testing identifies genetic variations that increase the chance of developing specific 12

January/February 2018

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diseases. These provide information about a person’s risk and can inform lifestyle and care decisions. (e.g., cardiovascular Douglas A. risk genes) Olson, MD Carrier testing identifies people who carry genetic changes that can cause disease. Carriers usually show no signs but can pass on the variation to their children. (e.g., cystic fibrosis) Prenatal testing identifies fetuses with certain diseases during pregnancy. (e.g., Down’s syndrome) Pre-implantation testing occurs in conjunction with in vitro fertilization to determine if embryos carry genes that could cause disease. (e.g., Huntington’s disease) Newborn screening identifies diseases that cause problems with health and development in newborns. (e.g., errors of metabolism) Pharmacogenetic testing informs how medications are processed in a person’s body, which can affect prescribing. (e.g., genotyping for HIV anti-viral drugs) Research testing helps scientists learn how genes affect health and disease, and develop gene-based treatments. (e.g., personalized cancer therapy with targeted chemotherapies)

Pharmacogenomics Pharmacogenetics was ﬁrst used in the 1950s, when adverse drug reactions were attributed

Virginia L. Kakacek, MD

Pamala A. Pawlowski, PharmD, FCCP

to single-gene abnormalities. Pharmacogenomics studies genetic determinants of drug response variability across the human genome. It is a distinct healthcare discipline that increasingly applies to clinical practice. The goal is to direct pharmacotherapy to optimize drug-related patient outcomes by identifying genetic variants associated with drug-metabolizing enzymes and customizing therapeutic decisions accordingly. Pharmacogenomic testing occurs preemptively and at point-of-care. Preemptive involves testing all patients during medical encounters within a healthcare system. Actionable results are stored in patients’ medical records. Evidence-based clinical recommendations are provided when patients are prescribed medications for which they have related genetic mutations. Point-of-care testing is used with patients who may have signiﬁcant clinical impact and actionable genetic mutations. It’s used to cost-effectively improve the risk/beneﬁt ratio of pharmacotherapy and generate clinically-relevant results. Testing should change patient care. Ideally, it includes prescriber collaboration with a clinical pharmacy, genetic counselors, and laboratory staff to ensure adequate implementation, application and follow-up.

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Pharmacogenomics has demonstrated improved clinical outcomes for certain druggene pairs. Promising research is ongoing for others, but challenges exist. Many haven’t shown enough positive outcomes to be used regularly in clinical settings or covered by third-party payers. Additional mature, reliable clinical evidence indicating which tests impact health outcomes is critical. Other challenges include patient unwillingness to undergo testing; patient inability or unwillingness to pay for testing; lack of practitioner or laboratory reimbursement; and lack of structures and systems for storing and reporting results. Some patients will pay for testing. A survey demonstrated race and socioeconomic status didn’t impact patient interest in pharmacogenomic testing; although, respondents with a history of drug-related side effects and private insurance showed stronger interest.1 Regardless, it’s imperative patients and practitioners have current, reliable scientific evidence and resources on actionable druggene pairs to determine whether testing will change patient care. Pharmacogenetics research is evolving. More literature is becoming available on gene-drug pairs shown to reliably impact outcomes, which can assist with diagnosis and treatment. However, much is still unknown and many clinical trials are ongoing. For this reason, coverage and requirements vary among third-party payers. Cancer-related Genetic Testing Next-generation sequencing and targeted therapy is changing cancer care. Selecting targeted therapy for non-small cell lung cancer based on genetic testing results is routine. Patients with late-stage tumors and those in whom primary treatment fails are offered tumor sequencing in anticipation of targeted therapies being developed. Targeted cancer therapy offers great hope for treating advanced disease, but its unclear how to best and most efficiently use them before clinical trial results are mature. Cost of Genetic Testing Genetic testing costs can be difficult to define. The amount charged can depend more on the testing location, how it’s coded and billed, and whether it’s a covered benefit than on the actual test cost. The rapid evolution of easily-obtained blood testing for genetic testing means

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independent labs have proliferated. Many tests have shown positive outcomes confirmed by evidence-based standards, but not all. Insurance coverage often exists when there is clinical evidence of positive outcomes. Multiple approaches are used to ensure appropriate coverage, including coverage criteria and prior authorization. This ensures patients meet specific clinical and benefit criteria; that the most clinically-relevant and cost-effective test is requested; and that all appropriate information has been submitted. Prior authorization offers patients protection by ensuring their plans provide coverage; that tests are done at certified labs with appropriate follow-up; and that they meet coverage criteria. Many genetic testing labs are freestanding and evolve rapidly. Patients and providers may not know all testing approaches and options. Even if testing is covered and meets coverage criteria, payment isn’t guaranteed. Networks, fee schedules and deductibles affect payment. Labs outside the patient’s network don’t have to ensure coverage is authorized before testing. And labs aren’t held financially responsible if it isn’t covered; the patient is. Some benefit designs require patients to pay the first $5,000 or more outof-pocket for services. The cost for genetic testing can be over $20,000. Causing further confusion, labs may offer direct-to-consumer pricing for the same test at a lower cost, but without those protections. Contracted labs are obligated to ensure testing is approved, which protects patients from additional costs if coverage is denied. It’s important to steer patients to contracted labs within their plan networks whenever possible for these quality and cost reasons. Genetics Professionals as a Resource Genomic competence is in increasing demand due to the relative rarity of many genetic diseases, and complexity and variety of diagnostic laboratory techniques. Choosing between them depends on specific clinical situations and needs. In this environment, genetic professionals are a critical resource. At HealthPartners, we created an infrastructure to support our clinicians. Consultation with a lab-based genetic counselor automatically occurs whenever a genetic test is ordered. Tests that meet the physician and

The Journal of the Twin Cities Medical Society

patient’s clinical need are reviewed for accuracy. An appropriate sample is collected and sent to a reputable, contracted lab. Our labbased genetic counselor assists the clinician in choosing from the diagnostic options, and identifying the clinical need or diagnostic goal. If testing is needed, the clinician orders the most appropriate test. About 9% of orders require modification or are unnecessary. The lab may recommend against testing if proven clinical utility is limited. Conclusion Navigating the genomic testing and personalized medicine landscape requires a concerted effort. Many tests are relatively uncommon, and clinicians may not have the training or experience to select the best one for their need. An infrastructure with support from genetic professionals is key. Additionally, much of this testing is unproven and therefore unlikely to be a covered benefit. Patients must be fully informed of the proven and unproven health benefits, and the cost of proposed testing. We must give patients the information needed for optimal decision making. Staying focused on evidence-based medicine will help us support patients and clinicians in making these choices, and maximize health benefits while protecting patients from unnecessary expense. Douglas A. Olson, MD, is Assistant Medical Director of Clinical and Laboratory Medicine for HealthPartners Medical Group and Regions Hospital, as well as Medical Director of HealthPartners Central Lab. He specializes in Pathology, particularly the diagnostic aspects of infectious disease and diagnosis and staging of tumors. Virginia L. Kakacek, MD, is Associate Medical Director for Health Plan and Medical Management at HealthPartners. She has been a Family Medicine physician for more than 15 years and practices at Park Nicollet Clinics. Pamala A. Pawlowski, PharmD, FCCP, has been a clinical pharmacy researcher at HealthPartners Institute since 2008. Her areas of expertise include Oncology Clinical Pharmacy, Clinical Pharmacology and the application of pharmacogenomic testing methods to enhance treatment optimization. References 1. O’Daniel J, Lucas J, Deverka P, et al. Factors influencing uptake of pharmacogenetic testing in a diverse patient population. Public Health Genomics. 2010;13(1):48-54.

January/February 2018

Genetic Testing

Genetic Testing — Another Potential Cost Tsunami

n many ways in the world of genetic diagnostic testing, the situation is similar to one previously described by Charles Dickens in A Tale of Two Cities (1859): “It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to Heaven, we were all going direct the other way—in short, the period was so far like the present period, that some of its noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only.” On the one hand, during this past holiday season, you could give the gift of limited genetic testing to a friend or relative for the low cost of $49.95, primarily for ancestry tracing. Any person, with a simple saliva test, can have testing through 23andMe related to “genetic health risks,” “wellness,” “carrier status” and “traits” in addition to ancestry testing. An important side question here is what is the average consumer going to do with the information obtained? This will likely fall on the primary care physician to help interpret the results that are obtained. Are you fully equipped to have this kind of conversation when your patients bring in their printout of genetic results? By Peter Dehnel, MD

January/February 2018

On the other hand, there are well over 70,000 different specific genetic tests or panels of genetic tests available for any clinician to order if he or she so desires. The true clinical utility of this testing is often not well defined, and changes in treatment recommendations or improvements in health outcomes are not necessarily tied to the results that are obtained. These results often end up in the “nice to know” category, but there are few meaningful interventions available based on the results of this testing. The additional challenge with the testing available to clinicians is the price tag associated with this assessment. These specific tests, and especially the genetic panels, are more likely in the neighborhood of $5,000.00. A full “genetic workup,” depending on the clinical situation, can easily run over $10,000.00. A year ago, one University of Michigan study estimated that over $500 million is paid by taxpayers for genetic testing, much of which has little clinical utility.

This testing, in effect, allows the clinician to be very “fact rich, but wisdom poor.” You could argue that knowing a specific genetic anomaly will help to prevent further testing down the line, or that the diagnosis is now certain (e.g., a microdeletion or duplication on the short arm of chromosome #15), but there still is no specific intervention or treatment. Health insurance companies have recognized this situation for some time — expensive testing with little clinical utility — and have created a number of medical policies and claims processing procedures that work to limit coverage for the testing to situations where there is some proven clinical utility. For example, coverage of BRCA1 and BRCA2 is likely to be covered by insurers when there is a possible connection to breast cancer. On the other hand, a 70-test panel for breast cancer predisposition is not likely to get covered, simply because the outcome proof is not there — at least not yet. There are a handful of cancers and other serious medical conditions (e.g., thrombophilia) with reasonably helpful predictive genetic profiles. This number is still small compared with the total number of genetic tests purporting to be clinically helpful for predictive or intervention purposes. Testing Required for Treatment and/or Coverage Decisions

It is important to understand that genetic testing may be required to qualify some individuals for coverage of treatment for various serious, or potentially serious, medical conditions. For example, the PCSK9 inhibitors are seen as a signiﬁcant

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step forward in the management of hypercholesterolemia/dyslipidemia. The cost of these medications is about $14,000.00 per year. The guidelines for recommended use of these medications have changed from individuals who have either homozygous or heterozygous hypercholesterolemia, to those who are not responding adequately to statin therapy or who cannot tolerate

Morquio A (mucopolysaccharidosis IVA). Treatment costs for these conditions are as follows: SMA — $750,000.00 for the ﬁrst year, then $375,000.00 a year thereafter and it is an intrathecal infusion; Batten’s Disease is $700,000.00 per year for this intraventricular infusion; Morquio A is listed at $380,000.00 per year. These are all in the “enzyme replacement” category,

GET INVOLVED! My personal recommendation is that physicians need to get informed, empowered and engaged in the whole area of genetic testing, its role in local medical decision making, treatment recommendations and best patient care. them for some reason. A number of insurance companies still require genetic “proof ” that they are actually in the cohort of individuals who have a genetic cause of their hypercholesterolemia. A number of cancer therapies have genetic testing as a part of their pathway/ guideline recommendations, and those tests are almost always covered by insurers, reflecting the “Minnesota mandate” for cancer treatment coverage. If the genetic testing is included in the guideline recommendations of the National Comprehensive Cancer Network (NCCN) or other national oncology groups, it is very likely to get covered with little resistance from insurers. This testing is having more influence on which of the expanding portfolio of chemotherapy agents to use in the fight against cancer, including the sequence of agents used as first line treatment, which to use for relapsed or treatment-resistant cancers, which should be used for third line treatment, and so forth. There is an emerging class of diseases which have a genetic basis for which there are now some very expensive therapies which do require genetic testing to qualify for treatment. Diseases in this category include spinal muscular atrophy (SMA), Batten’s disease (ceroid lipofuscinosis) and MetroDoctors

and patients will have a lifelong need because the underlying genetic defect is not being corrected through the use of pharmaceuticals. Due to the high costs involved, additional genetic deﬁnition may be required to conﬁrm the qualifying diagnosis before treatment is approved. For example, some insurers have limited coverage for SMA to those patients with SMA type I, based on the initial clinical studies that were conducted to show the effectiveness of this treatment. True genetic replacement therapy is now on the horizon. The cost of these treatments is likely to be in the “millions” category, and how those costs are to be covered is yet to be decided. What Can You Do?

GET INVOLVED! My personal recommendation is that physicians need to get informed, empowered and engaged in the whole area of genetic testing, its role in local medical decision making, treatment recommendations and best patient care. Some entity or organization will be deciding how this plays out in our community and it would be great to have physicians like you playing more of an active role in these discussions and decisions.

The Journal of the Twin Cities Medical Society

My overall hope is that we land on the “best of times” and “spring of hope” side of this topic, to use Dickens’ words. Physicians can play an influential role if actively involved and our patients will benefit from our professional engagement. The cost tsunami can be seen on the horizon and the time to act is now. Peter Dehnel, MD, is a board certified pediatrician who has been in practice for 30 years. He’s been actively involved with Twin Cities Medical Society public health initiatives and organized activities, including involvement with the Honoring Choices Minnesota movement. Dr. Dehnel is the current Medical Director of the Physician Advocacy Network and leads physician education about alternative forms of tobacco use and encourages physician leadership in the form of advocacy. Dr. Dehnel has been involved with efforts to reduce tobacco’s impact on the lives of people for over 15 years with tenured involvement with city, county and state efforts to eliminate second hand smoke and include e-cigarettes in smoke-free ordinances.

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Genetic Testing

Psychological Perspective of Genetic Testing

enealogy and ancestry testing are popular hobbies. It’s not a surprise that people place more emphasis on family history and health information for relatives as the public has become more curious in learning more about themselves as well as future health risks. After all, despite having many fancy DNA tests, family history is the foundation of precision medicine and the key to accurately interpreting DNA test results. Recently, celebrities such as Angelina Jolie and Christina Applegate bravely shared their personal stories that brought them to consider genetic testing. Ms. Jolie had a family history of breast and ovarian cancer and hoped to learn information to define her cancer risk and protect her health. Ms. Applegate was diagnosed with breast cancer at a young age and potentially hoped to learn the underlying reason for the cancer. Two women. Two different stories. One commonality: A mutation in the BRCA1 gene, which is a common inherited risk factor that significantly increases the chance of developing breast and ovarian cancer over a lifetime (40-85% and 1668% respectively vs. 12% and 1.5% in the general population).1 Approximately 1:300 to 1:400 people have a mutation in either the BRCA1 or BRCA2 genes. When to Consider Testing Under recognition of individuals who would benefit from a genetic risk

By Joy Larsen Haidle, MS, LGC

January/February 2018

assessment, genetic testing, and/or personalized surveillance remains a problem that requires the healthcare community’s attention. The common criteria to consider DNA testing are listed below.2 • Early age of onset of cancer (breast or colon cancer less than 50 years). • Three people in one side of the family (mother’s or father’s) who have the same kind of cancer or cancer that may be in a pattern (breast/ ovary, colon/uterine/ovary, breast/ thyroid, breast/pancreatic, breast/ prostate). • Having an aggressive form of prostate cancer (Gleason 7 or higher) or metastatic prostate cancer. • Male breast cancer. • Ovarian or fallopian tube cancer. • Triple negative breast cancer <60 years. • 10 or more colon polyps over a lifetime. • Having a known mutation in the family. • Being of Ashkenazi Jewish descent with a personal or family history of breast, ovarian, prostate or pancreatic cancer. With the changes in DNA technology, patients who previously tested for BRCA1/2 and did not have mutations identiﬁed may wish to consider updating their genetic testing as many additional cancer predisposition genes have been identiﬁed whose results may be used to guide medical decisions.3-5 Adjusting to the News Learning about an inherited risk factor

can bring mixed reactions that usually change over time as people adjust to the news. Often the reactions are dependent on the initial goals for testing. Some people will be quite happy with the identification of an inherited risk factor as the cause of the cancers in the family has been defined, cancers risks can be estimated, and steps can be taken to either detect the cancer early or prevent it. This can be an empowering experience for families as individuals can begin to make decisions on data versus family lore. There is also a possibility a person will learn they did not inherit the mutation in the family and do not need to pursue heightened surveillance or risk reduction surgery. For others, the identification of an inherited risk factor may cause anxiety particularly if they did not feel that there was an action plan to address the results or they did not have sufficient pre-test counseling. It is helpful to remind people that the mutation was present since

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conception and may not have caused health problems for many years. A mutation in a cancer predisposition gene suggests that there is an increased chance of developing cancer over a lifetime, but it does not give a diagnosis of cancer. Some people live well into their later years and never developed a cancer despite being at increased risk. Taking time to discuss these concerns can help alleviate anxiety and may help them to realize that they are not alone in their fears. Learning that a genetic test result was negative can also be met with mixed reactions. Some people will be upset with negative test result, as the test did not answer their questions. While they may feel some relief with a negative test result, if the family history is quite strong, the negative test result does not mean that there is not an inherited risk factor. It means that we were not smart enough to find it and the test did not answer the question. Cancer risk estimates, surveillance recommendations and consideration for risk reduction would be based on the family history. In this scenario, people do not have access to a blood test to tell them not to worry. Relatives must be followed as if they are at increased risk until we can prove that they are not. At times, the negative test result is frustrating as people are in a position to make major decisions without solid data to guide them and at times express worry that their decision for surgery will be wrong or have less support because peers feel their decision is too aggressive without a mutation or not aggressive enough based on the family history. Others will find relief in the negative genetic test result, as despite not finding anything definitive, the cancer risks may no longer be as high as they had feared. People are quick to believe that the negative test results means the cancer in the family is not genetic; however, that may not be the case. If the family history is strong, it is worthwhile to have patients contact a genetic counselor in 2-3 years as the genetic tests will evolve over time MetroDoctors

and it may be reasonable to consider additional testing in the future in hopes to identify the risk factor. Fear for the Children and Grandchildren When an inherited risk factor is identified, a common concern is the risks to their children and grandchildren. Parental guilt is important to address. Talking through ways in which parents might share the information with their children is helpful and ensures that they have a good grasp on the information they are about to share. As a genetic counselor, I provide a letter with a brief summary of the gene found in the family and how the information might impact medical care. Encouraging people to share the letter along with a copy of their test results with family members is very important to help protect the health of relatives. Often the conversation focuses on the women in the family, but the men in the family should be included as they, too, have a chance to inherit the mutation. While their chance of developing cancer may be lower than their female relatives, they also have a chance of passing it to their offspring. Resources Genetic testing options and the technology are changing rapidly with 10 new genetic tests coming to market daily. Genetic counselors are a valuable resource to facilitate the risk assessment, ensure the best test is selected for the situation, and review the results in the context of the personal and family history and relevant literature. Resources are available at http://aboutgeneticcounselors. com to find a genetic counselor and to facilitate the discussion with patients regarding genetic testing and/or genetic counseling. Discussion DNA testing does not need to be a scary experience. Patients need to understand the goals of testing in addition to the risks, benefits, and limitations of testing

The Journal of the Twin Cities Medical Society

prior to having their blood drawn. Helping patients define these goals and level setting expectations are critical components of the pre- and post-test genetic counseling if we are to create an empowering experience. Joy Larsen Haidle, MS, LGC, is a past president of the National Society of Genetic Counselors and a genetic counselor at the North Memorial Health Cancer Center in Robbinsdale, MN. She is a board certified and licensed genetic counselor with more than 22 years of experience in counseling hereditary cancer genetics. She is also a Policy and Peer Review consultant for Blue Cross Blue Shield of Minnesota and an expert resource for other Minnesota Payers. Joy is a Clinical Preceptor in the Genetic, Cell Biology, and Development Department at the University of Minnesota. She has authored several practice guidelines and published articles on topics such as Lynch syndrome and juvenile polyposis. Joy has a special interest in public policy, appropriate utilization of genetic tests, and identifying individuals/families at increased cancer risk that might benefit from heightened surveillance or risk reduction. References: 1. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM et.al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017 Jun 20;317(23): 2402-2416. 2. Genetic/Familial High-Risk Assessment: Breast and Ovarian (Version 1.2018-October 3, 2017). National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/ PDF/genetics_screening.pdf. Accessed October 3, 2017. 3. Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC et.al. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA Oncol 2017 Sep 1;3(9):1190-1196. 4. LaDuca H, Stuenkel AJ, Dolinsky JS, Keiles S, Tandy S et.al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014 Nov;16(11):830-7. doi: 10.1038/ gim.2014.40. 5. Espenschied CR, LaDuca H, Li S, McFarland R, Gau CL, Hampel H. Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. J Clin Oncol. 2017 Aug 1;35(22):25682575. doi: 10.1200/JCO.2016.71.9260.

January/February 2018

Genetic Testing

Genetic Duty to Warn

ho knew genetics could be trendy? From Ancestry.com to 23andMe, Americans are flocking to consumer-directed genetic testing in hopes of gleaning insights into their past and future. For clinical geneticists, the human genome is all in a day’s work — but as genomics makes its way into the public consciousness and clinics of all shapes and sizes, legal questions abound. By definition, genomic information is both individual and familial — and indeed, some of the most common uses for genetic information are family planning and screening for inheritable diseases. But what does the law make of the dual nature of genomic information? All physicians have duties to their own patients — including a duty of confidentiality. But in the case of genetic information, where does that duty begin and end? Could a physician ever have a professional duty to warn a patient’s relatives about a genetic condition? The California Supreme Court was the first to formally identify a professional duty to warn. In 1969, Dr. Lawrence Moore began providing psychological counseling services to Prosenjit Poddar, a graduate student at the University of California-Berkeley. During these services, Poddar confided that he intended to kill his former love interest, Tatiana Tarasoff. Dr. Moore subsequently diagnosed Poddar with paranoid schizophrenia and

By Becca Branum, JD

January/February 2018

recommended that he be detained as a dangerous person. Tragically, this recommendation was not followed and in October of 1969, Poddar acted upon his threat and killed Tatiana Tarasoff. Tarasoff ’s family sued the Regents of the University of California and the Court found that Dr. Moore, despite his obligations relating to the privacy of Poddar’s information, also owed a duty to Ms. Tarasoff, famously stating that “protective privilege ends where the public peril begins.” Following Tarasoff v. Regents,1 many states statutorily adopted varying professional duty to warn requiring disclosure of otherwise protected information to third parties. For its part, the Minnesota legislature has been modest in extending a professional duty to warn to physicians. In Minnesota, a statutory duty to warn only applies to psychologists licensed under Chapter 148 and, even then, only

as it relates to “specific, serious threat[s] of physical violence against a specific, clearly identified or identifiable potential victim.”2 Even if such a duty were to extend to clinical genetic information, it is difficult to imagine many scenarios in which information would relate to a harm imminent or actionable enough to justify a duty to warn. Some courts have, nevertheless, extended a Tarasoff-like duty to warn in the context of genetic information. In its 1995 Pate v. Threlkel ruling,3 the Florida Supreme Court created a duty to warn of genetic risk by holding that a physician has a duty to warn both the patient and the patient’s child of the genetically transferable nature of the condition for which the patient is being treated. Although the court found that this duty extended to a patient’s child, the court also held that the duty to the child is satisfied by warning the patient of the familial implications of genetic testing, therefore not requiring a physician to actively warn a third party about a patient’s genetic condition. In 1996, the New Jersey Supreme Court issued a decision in Safer v. Estate of Pack that went even farther than Pate,4 finding that, not only does a physician have a legal duty to warn those known to be at risk of avoidable harm from a genetically transferable condition, but that counseling a patient about the risks of inheriting the disease may not be enough to satisfy that obligation. This ruling, limited to New Jersey, implies that a physician could face an active duty to warn a relative of a patient’s

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genetic risk despite the professional duty of confidentiality. The Minnesota Supreme Court considered a more nuanced question relating to the duty to warn of genetic risk. As part of a complex medical malpractice claim in 2004, the court was tasked with deciding in Molloy v. Meier whether a physician’s legal duty to his or her patient could extend to a patient’s parent.5 In Molloy, the plaintiff alleged that a physician failed to accurately diagnose the plaintiff ’s child with Fragile X Syndrome. As a result of this failure, the plaintiff alleged, the plaintiff was unaware of the implications of the child’s condition and, as a result, conceived another child who was also born with Fragile X Syndrome. In its ruling, the Minnesota Supreme Court found “[the physician] should have foreseen that parents of childbearing years might conceive another child in the absence of knowledge of the genetic disorder” and, ultimately, that “a physician’s duty regarding genetic testing and diagnosis extends beyond the patient to biological parents who foreseeably may be harmed by a breach of that duty.” Although not precisely extending a duty to warn to all relatives who may be impacted by an inheritable condition, the court did find that a physician could be liable for failure to inform a parent of the implications of their child’s genetic condition. Interestingly, despite the emergence of clinical genomics, litigation regarding a duty to warn of genetic risk has slowed significantly following Molloy. Three factors likely contribute to this stagnation. First, both the Pate and Safer cases predate the HIPAA Privacy Rule, meaning that the court did not need to grapple with the privacy protections afforded by HIPAA that would have prevented a physician from disclosing the information at issue in the cases. Second, the Molloy case is unique in that it pertained to genetic information to which a parent would already be privy, given that they were active in the care of their child. MetroDoctors

Therefore, the case did not require a physician to actively “warn” others of their genetic risk; rather, it recognized a legal harm in a parent not receiving information that would have otherwise been provided. Finally, professional societies such as the American Society of Human Genetics and the American College of Medical Genetics and Genomics created materials following these decisions to help physicians understand their legal obligations and the importance of educating patients about the implications of genetic testing.6 Innovative technologies and treatments are inevitably accompanied by unforeseen legal consequences and, in that way, clinical genetics is no exception. But, at least as it pertains to a familial duty to warn, clinicians have an abundance of resources available to them to understand their legal and ethical obligations.7 Becca Branum, JD, is Policy Counsel for the Minnesota Medical Association. Ms. Branum brings several years of experience navigating the law and ethics of health and human services delivery following positions at the Minnesota Department of Human Services, the Consortium on Law and Values in Health, Environment, and the Life Sciences, and the U.S. Senate. Ms. Branum is a graduate of Boston University and the University of Minnesota Law School. References: 1. 17 Cal. 3d 425 (1976). 2. Minn. Stat. 148.975. 3. 661 So.2d 278 (1995). 4. 291 N.J. Super 619 (1996). 5. Disclosure: The MMA was a party to this action as an amicus curiae. 6. See, e.g., http://www.ashg.org/pdf/policy/ ASHG_PS_February1998.pdf. 7. Disclaimer: The information in this article is not legal advice, does not create an attorney-client relationship, and is not a substitute for the advice of an attorney. It is best practice to obtain legal advice from an attorney with experience in the relevant subject matter and jurisdiction. The Minnesota Medical Association and the Twin Cities Medical Society make no guarantee as to the information in this article.

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January/February 2018

Sponsored Content

Progress Toward Effective, Individually Tailored Breast Cancer Therapies Contributed by Douglas Yee, MD, with Paul Mamula, PhD

Breast cancer is the most commonly diagnosed cancer among women in the United States and the second most common cancer cause of death, exceeded only by lung cancer. Early detection and improved therapies have led to a 38% decrease in deaths from breast cancer from 1989 to 2014,1 and newer therapies may accelerate the trend.1,2 Breast cancers, however, are heterogeneous, making selection of optimal therapy challenging. Triple negative breast cancer, for instance, represents a disparate group of tumor types, and about 80% of this cancer overlaps with the basal-like breast cancer types.2 An aggressive cancer, triple negative breast cancer presents a higher likelihood of relapse and often metastasizes to other organs and the central nervous system. Characterizing biomarkers for different cancer subtypes can allow for more effective therapy.3,4 Recent research efforts have focused on expediting the study of therapies targeting speciﬁc cancers. Research into the causes and origin and predisposition to breast cancer has also led to advances in development of new therapies.5,6 One new phase II clinical trial, the I-SPY 2 initiative, proceeds on a new clinical trial design and has allowed the rapid identiﬁcation of targeted breast cancer therapies. The I-SPY 2 Trial: A New Trial Paradigm I-SPY 2 Trial (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and molecular AnaLysis 2; NCT01042379) improves collaborations across institutions to speed the testing of novel therapies in patients who have 20

January/February 2018

recently been diagnosed with advanced, local breast cancer. All trial treatment data can be collected, verified, and shared in real-time among academic, medical industry, and regulatory partners through the multisite database. By making findings across sites immediately available, the trial allows researchers to more efficiently determine which agents are most effective with which types of breast cancer tumors. It also helps identify which early indicators of response may be predictors of treatment success.5,6 In traditional drug trials, researchers may need to wait years until they obtain sufficient statistical evidence of a drug’s effectiveness. Findings within the I-SPY 2 Trial model, however, can be amassed and evaluated after a 24-week treatment period. Drugs shown to have an impact in causing the complete disappearance of invasive cancer from the breast and lymph nodes can “graduate” to phase III trials, as improvements in pathologic complete response (pCR) are the trial’s primary endpoint.7 The trial also allows additional genetic analysis of tumors and new drugs to be incorporated for evaluation. This approach offers treatment flexibility and faster completion of clinical trials.5 Masonic Cancer Center, University of Minnesota is among the trial’s planned 24 sites nationally and serves as one of two sites in the state. Patients can access the trial through University of Minnesota Health. All sites offer all trial clinical protocols, and sites adhere to rigorous reporting requirements. Final data collection for the primary outcome measure is expected to be complete in 2020.

I-SPY 2 Trial participants with clinical stage II-III disease have tumors biopsied and evaluated for MammaPrint expression. Initially, the assignment of patients to drugs is random, but over time, the assignment of patients may “adapt” based on results from previous treatments. A drug can “graduate” as a treatment across 10 distinct cancer biomarker signatures. The trial’s adaptive design allows treatment assignment to be based on which drug is most effective for a patient’s biomarker signature. The treatment group receives an investigational drug targeted for a speciﬁc tumor type and standard chemotherapy. The control group receives standard-ofcare chemotherapy alone. After 24 weeks, patients proceed to surgery and lymph node biopsy. pCR is the primary endpoint for the trial and is considered a surrogate marker of longer-term survival.7 Trial participants also receive four MRI scans as part of the study.

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MRI and surgery allows investigators to assess response and identify drugs that work and eliminate those that have no benefit over standard-of-care chemotherapy. Findings are added to the database and monitored by a central biostatistical team. As the trial progresses, patients who have a specific biosignature can be assigned to a particular drug based on its previous success in patients possessing those biomarkers. Patients who do not respond can be given other trial therapies as those deemed more specific to their tumor type emerge. Successes and Advances in Treatment Drug regimens evaluated in I-SPY 2 have begun to show effectiveness. Veliparib combined with carboplatin and paclitaxel, when compared to paclitaxel alone, demonstrated promise in treating three cancer signatures: HER2–negative, HR positive/HER2-negative, and triple negative. Among patients with triple negative breast cancer in this trial, 51% obtained an estimated pCR compared with 26% of control patients receiving standard-of-care chemotherapy with paclitaxel alone. Veliparib added to carboplatin and paclitaxel was tested in a phase III trial, as the I-SPY 2 data suggested an 88% predictive probability of success for this drug combination in patients with triple negative breast cancer.8 The trial randomized patients to paclitaxel, paclitaxel plus carboplatin, or paclitaxel, carboplatin, and veliparib. While this trial reproduced the I-SPY 2 results, veliparib was not found to contribute to the increased pCR rate.9 Nonetheless, I-SPY 2 showed how drugs can be developed in this neoadjuvant setting. This drug combination represents the first drug to “graduate” from I-SPY 2 based on its strong efficacy. Neratinib, a tyrosine kinase inhibitor, was shown to be effective in patients with HER2 positive, hormone receptornegative cancer. The mean estimated rate of pCR was 56% for the treatment group compared with 33% in the control group of trastuzumab and paclitaxel. Researchers suggest a predictive probability of success of 79% in phase III testing.10 Pembrolizumab has also demonstrated success. According to findings presented at the 2017 ASCO Annual Meeting, patients with high-risk breast cancer who received pembrolizumab and chemotherapy had MetroDoctors

a 40% absolute response increase over that obtained with chemotherapy alone (60% vs. 20%).11 Among patients with HER2-negative breast cancer in the trial, pembrolizumab produced a 30% absolute increase in the estimated pCR rate over that produced through standard-of-care therapy (46% vs. 16%).11 Pembrolizumab has been successfully used in treating bladder and other cancers. The therapy works by increasing the ability of the body’s immune system to help detect and fight tumor cells. A humanized monoclonal antibody, pembrolizumab functions as a checkpoint inhibitor. It blocks the interaction between PD-1 and its ligands (PD-L1, PD-L2), thus activating T-lymphocytes. A circulating tumor DNA (ctDNA) technology (SignateraTM) has also been added to the I-SPY 2 trial. It is being tested as a way to monitor patients after they complete therapy.12,13 The technology allows analysis of whole-exome sequencing data from a tumor sample and lets researchers develop assays specific to the patient. It screens for 16 or more genetic mutations specific to an individual patient’s tumors. The technology requires detection of multiple mutations for a positive test and can also track additional mutations, as many as several hundred for clinical studies. Used recently in early lung cancer cases, the technology has demonstrated potential usefulness in detecting residual disease, measuring response to treatment, and identifying recurrence as much as 11 months earlier than is typically the case under standard of care.12 The Possibility of Targeted, Personalized Therapy As data from I-SPY 2 trials are analyzed, additional findings are emerging. Currently, eight research manuscripts are in various stages of preparation for publication, with additional submissions planned. It is clear, however, that by allowing faster assessment of drugs targeting specific tumor biomarkers and speeding their delivery to patients, I-SPY 2 has aided in the development of therapies. For patients for whom a given therapy is not successful, the trial’s researchers hope to re-assign these patients to a potentially more suitable agent for their tumor type. I-SPY 2 may also help elucidate steps in the cancer process

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and provide additional targets for future therapies. Douglas Yee, MD, is director of the Masonic Cancer Center, University of Minnesota. A professor in the Departments of Medicine and Pharmacology, Dr. Yee holds the John H. Kersey Chair in Cancer Research. He is known for his laboratory research on the growth regulation of tumors by the insulinlike growth factors and the clinical translation of these findings. Dr. Yee’s curriculum vitae includes over 210 publications. He also maintains a clinical practice in breast medical oncology through University of Minnesota Health Cancer Care. References 1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan 67(1):7-30. 2. Shao F, Sun H, Deng CX. Potential therapeutic targets of triple-negative breast cancer based on its intrinsic subtype. Oncotarget, 2017;8(42):73329-733442017. 3. Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017 [Published online 23 Oct 2017] doi: 10.1038/ nature24284. 4. Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nature Genetics. 2017 [Published online 23 October 2017] doi: 10.1038/ng.3785. 5. Carey LA, Winer EP. I-SPY 2—Toward more rapid progress in breast cancer treatment. N Engl J Med. 2016 375(1):83-84. 6. Harrington D, Parmigiani G. I-SPY 2—A glimpse of the future of phase 2 drug development? N Engl J Med. 2016;375(1):7-9. 7. I-SPY 2. Available at http://www.ispytrials.org/ home. Accessed October 31, 2017. 8. Rugo HS, Olopade OI, Yau C, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1)2334. doi: 10.1056/NEJMoa1513749. 9. Geyer CE, O’Shaughnessy J, Untch M et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). 2017 ASCO Meeting abstract. J Clin Oncol. 2017; 35 (suppl; abstr 520). https://meetinglibrary.asco.org/record/152332/abstract. 10. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375(1):11-22. 11. Nanda R, Liu MC, Yau C, Asare S, Hylton N, van’t Veer LJ, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2. Abstract 506. Presented June 5, 2017. 2017 Annual American Society of Clinical Oncology Meeting, Chicago, Illinois. 12. Brophy M. Natera’s personalized CtDNA technology now a part of I-Spy 2 TRIAL. http:// www.ispytrials.org. Accessed October 23, 2017. 13. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):44651. doi: 10.1038/nature22364.

January/February 2018

Genetic Testing

Pharmacogenomics and Optimal Opiate Prescriptions: A Quick Guide

or many medications, one size does not fit all. This is especially true for opiates. “High interindividual variability” is the new term which means optimal opiate effectiveness requires a personalized approach. For many opiates, genetic variability means that there is no true equianalgesic dosing. Now, when considering medication choices and doses, we must go beyond the well-known acronyms of BMI, GFR and LFT’s and incorporate two relatively new terms: CYP2D6 and CYP3A. Understanding these will then support next step learning about SNPs (single-nucleotide polymorphisms) for COMT, OPRM1, UGT2B7, ESR1 and many more acronyms for genes that can affect drug response. The bottom line is that effective pain management requires us to consider how a patient’s genomic profile will affect their response to medications. Three potential responses to pain medications exist: beneficial response, toxic response or no response. The new discipline of pharmacogenomics, the combination of pharmacology and genomics, provides predictive power for optimal drug choice as well as optimal drug dosing. Less guesswork and better advance knowledge means increased efficacy and safety at lower cost. At present, genotype testing is routinely performed in only a few clinical practices. However, patients can now directly obtain and then share their genomic information with their prescribing By Gregory A. Plotnikoff, MD, MTS, FACP

January/February 2018

physicians as well as their surgeon/anesthesiologist. In fact, some medical systems, like Minnesota’s Ridgeview Medical Center, have explicitly requested that their patients obtain this information. Why? Understanding genomic variations in metabolism can prevent an adverse drug reaction or an altered drug response. What does pharmacogenomics look like in practice? Already, routine genomic testing is in place for medication choice for such goals as immune suppression (azathioprine and TPMT) or cancer eradication (ado-trastuzumab and HER2). However, treatment of pain is a more universal concern and therefore represents a great place to start learning pharmacogenomics. This means learning the implications of variations in CYP2D6 and CYP3A, key metabolizing enzymes in phase I liver detoxiﬁcation. CYP2D6

CYP2D6 is one of 57 cytochrome P450 (CYP) liver enzymes responsible for the oxidative metabolism. CYP2D6 metabolizes approximately 25% of all prescription

drugs including many opioids as well as antidepressants, antipsychotics, anti-arrythmics, anti-hypertensives, anti-emetics as well as tamoxifen. In a typical clinic, one can expect to see immense variation in the enzyme activity of CYP2D6. Measured CYP2D6 activity ranges from ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). Overall, approximately 39% of the U.S.

Table 1. Pain Medications that Require CYP2D6 Activation: Codeine (Procet) Dihydrocodeine Hydrocodone (Vicodin, Norco, Lorcet, Lortab, Oncet, Xodol, Zydone) Oxycodone (OxyContin, Percocet) Tramadol (Ultram) Note that for persons with slow CYP2D6 metabolism and/or use of a CYP2D6 inhibitor(s), these pain medications will have very poor efﬁcacy.

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population is expected to be either a poor metabolizer or ultrarapid metabolizer. And, of these patients, more than 30% with a poor or ultrarapid CYP2D6 phenotype may experience an adverse outcome after being prescribed codeine, tramadol, oxycodone, or hydrocodone. How could this be? Some of these pain medications are actually pre-painmedications (pro-drugs). They must be activated by CYP2D6. (See Table 1). For example, codeine becomes morphine, hydrocodone becomes hydropmorphone and tramadol becomes desmetramadol. In fact, codeine, hydrocodone, tramadol are only available by mouth because they must be activated to their most active forms by the liver’s CYP2D6. Other medication delivery methods such as sublingual, buccal, skin patch, subcutaneous, intravenous or intrathecal routes specifically bypass the liver and thus bypass the pain medication’s activation. When CYP2D6 is ultra-fast, codeine is quickly transformed into morphine and the result is the physiological equivalent of a significant bolus of IV morphine. A standard dose is suddenly an overdose with the accompanying risk of decreased mental status to delirium to respiratory arrest. This is of particular concern for persons less than 18 years of age or for persons with impaired airways due to obesity or obstructive sleep apnea. Likewise, when CYP2D6 is poorly metabolized, hydrocodone medications (i.e. vicodin) cannot be sufficiently transformed into hydromorphone and pain relief is not achieved. Failure to achieve pain management goals can be considered a form of adverse outcome. But there are others. For example, patients prescribed hydrocodone but still seeking relief can be misidentified as addicts seeking drugs. For optimal pain management, all prescribers now need to know that CYP2D6 can be inhibited by many common medications. (See Table 2 for a list of the most potent inhibitors). Potent inhibition means that the addition of a new medication may adversely slow the MetroDoctors

Table 2. Drugs that Strongly Inhibit CYP2D6

Table 3: Drugs that Strongly Inhibit CYP3A4

Buproprion (Wellbutrin)

Clarithrymycin

Cinacalcet (Sensipar)

Telithromycin Chloramphenicol

Duloxetine (Cymbalta)

Ketoconazole

Fluoxetine (Prozac)

Itraconazole

Metaclopramide (Reglan)

Nefazodone

Paroxetine (Paxil)

Ritonavir Indinavir

Quinidine Terbinaﬁne (Lamisil) metabolism and thus the effectiveness of CYP2D6-dependent pain medications, even in persons without known CYP2D6 poor metabolizer status. (See Table 2). This translates into a signiﬁcant concern for all clinics and pain programs. With the addition of inhibiting medications, patients could report that opiates that once worked are no longer as effective. This reduced effectiveness can be mistaken for a tolerance effect rather than a metabolism effect. The clinical response might be to increase the dose. However, given what is now known about opiate-induced hyperalgesia, an increased dose may cause even greater pain. The unfortunate result could be a patient on higher doses with even greater pain due to misinterpretation of the situation. In contrast to the multiple agents that can inhibit CYP2D6, this P450 enzyme is

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Nelﬁnavir Saqinavi largely non-inducible. However, there are two important exceptions: dexamethasone and rifampin. Logical options exist for opiate prescribing. (See Table 4). CYP3A4

Cytochrome P450 3A4 (CYP3A4) metabolizes about 50% of all prescription medications. This enzyme is well known for its inhibition by ingestion of grapefruit juice. However, other many other inhibitors exist. These include anti-HIV protease inhibitors, calcium channel blockers (verapamil and diltiazem), macrolide antibiotics, chloramphenical, azole anti-fungals and anti-depressants including ﬂuoxetine, ﬂuvoxamine and nefazadone. (See Table 3). (Continued on page 25)

Table 4: Non-CYP2D6 Dependent Pain Medications and their Metabolism Fentanyl (CYP3A4 metabolized) Hydromorphone (Dilaudid) (glucuronidation by UGT2B7) Morphine (glucuronidation by UGT2B7) Methadone (CYP3A4, CYP2B6 plus CYP2C8, CYP2C19, CYP2D6, CYP2C9) Oxymorphone (Opana) (glucuronidation by UGT2B7) Tapentadol (Nucynta) (glucuronidation by UGT2B7) Of note, variations in UGT2B7 activity may exist.

January/February 2018

HELP PROMOTE

Health Equity Month

IN MINNESOTA!

THANKS TO OUR PARTNERS Aquí Para

In January 2018, the Minnesota Medical Association, along with partner organizations, will kick oﬀ a campaign to raise awareness of health disparities in the state. During the month, we will have several opportunities for physicians to learn more about how we can all work together to achieve health equity in Minnesota. Be prepared to promote the month with the MMA and its partners. Health Equity Learning Opportunity Wednesday, Jan. 17 (Noon - 1pm) (watch on MMA’s Facebook Live feed) Health Equity Forum Wednesday, Jan. 24 (5:30 - 8pm) 317 on Rice Park Event Center | 317 Washington Street | St. Paul 55102

Find out more here: www.mnmed.org/healthequityMN

Pharmacogenomics and Optimal Opiate Prescriptions (Continued from page 23)

But CYP3A4 is also induced by many medications and natural products. Commonly prescribed inducers include statins, anti-convulsants, barbituates, modaﬁnil, glucocroticoids as well as some bacteriocidals like rifampicin, some of the nonnucleoside reverse transcriptase inhibitors and some hypoglycemics. Commonly used natural products that can induce function include St. John’s Wort, quercetin and capsaicin. Few opiates are signiﬁcantly affected by CYP3A4 activity. (See Table 4). The two drugs to know are fentanyl and tramadol. Induced CYP3A4 is a risk factor for seizures with tramadol administration especially if prescribed with tricyclics and SSRI anti-depressants. From this review of CYP2D6 of CYP3A4, comes three considerations when prescribing. 1. Activated Medications: CYP2D6 is required to transform the pain medications called codeine and hydrocodone into their respective active forms called morphine or hydromorphone. If CYP2D6 is slowed or impaired, then this activation cannot take place. This means that taking these medications will not treat pain like they would for other people. In such persons, these medications are very poor choices for pain control. Generalized Rule: Slowed cytochrome P450 metabolism can result in non-responsiveness to pro-drug medications that require transformation to their active forms. 2. Deactivated Medications: Slowed CYP2D6 metabolism can mean higher blood levels of many medications such as the anti-nausea medication ondansetron (Zofran) or the heart rate slowing medication called propafenone. Persons with slowed metabolism of ondansetron will have much better reductions of nausea than persons with normal metabolism. Likewise, persons with slowed metabolism of propafenone will have a much greater MetroDoctors

For Further Information on Pharmacogenomics Deﬁnition

ghr.nlm.nih.gov/handbook/genomicresearch/pharmacogenomics From Genetics Home Reference. Glossary www.genome.gov/Glossary/?id=151 From the National Human Genome Research Institute (NHGRI) Talking Glossary of Genetic Terms. Fact Sheet nigms.nih.gov/education/pages/factsheet-pharmacogenomics.aspx From the National Institute of General Medical Sciences. Interactive Tutorial http://www.phgfoundation.org/tutorials/pharmacogenomics/ From the Foundation for Genomics and Population Health. Source: https://www.genome.gov/27530645/faq-about-pharmacogenomics/#al-5 accessed November 1, 2017.

reduction in heart rate than those with normal CYP2D6 metabolism. In such persons, the medication can accumulate in the blood stream and cause an excessively slow heart rate. This means that the dosing frequency would need to be adjusted or a different medication would need to be used. Generalied Rule: Slowed phase 1 cytochrome P450 metabolism can result in either increased effectiveness or increased sensitivity and toxicity to prescribed medications. 3. Drug-Drug Interactions: Commonly prescribed medications like Prozac or Paxil and over-the-counter medications like anti-histamines can block CYP2D6. Starting one of these medications can cause amphetamine-based medications for ADHD to accumulate over time. Common amphetamines include Adderall and Ritalin. With slowed metabolism of the ADHD medications, the patient may demonstrate increased irritability and a reduced loss of focus. These are the very symptoms the ADHD medications

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are prescribed to treat. This means that the prescribing physician, quite possibly, could increase the dosing of the ADHD medication dosage to correct the ADHD symptoms actually caused by the high blood levels of the ADHD medication. Generalized Rule: CYP2D6 or CYP3A4 inhibitor medications can cause a second drug to accumulate and result in toxic levels. The key point of this review is that understanding genomic variations in metabolism can prevent an adverse drug reaction or an altered drug response. This goal is clearly shared by patients, physicians and health systems. And now, with widely available direct-to-consumer genomic testing, physicians can anticipate that their patients will expect interpretive guidance. My hope is that this article will provide guidance and insight for beginning to do so. Gregory A. Plotnikoff, MD, MTS, FACP is the founder and Senior Consultant at Minnesota Personalized Medicine in Minneapolis. January/February 2018

Genetic Testing

Revisiting Direct-to-Consumer Genetic Testing: What are the Ethical Issues?

irect-to-consumer (DTC) genetic testing has had a rocky history in the United States, as regulators and entrepreneurs struggled to balance medical innovation and consumer protection. Shortly after the emergence of the first DTC genetic testing products, Congress launched an investigation into the nascent industry. A report issued by the Government Accountability Office in 2010, titled “Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices,” raised questions about the marketing and accuracy of DTC genetic testing. These concerns prompted the Food and Drug Administration (FDA) to send cease-and-desist letters to several DTC genetic testing companies, warning them that they were selling an unapproved medical device. These letters cast a shadow on the industry and for the next several years, the only genetic tests available directly to consumers were for non-medical features such as genetic ancestry. Although many clinicians celebrated the FDA’s actions, patient advocates criticized the agency’s regulatory stance as overly cautious and contrary to the interests of consumers. A middle ground began to emerge in 2015 when the FDA and 23andMe, the largest US-based DTC genetic testing company at that time, reached an agreement on a carrier screen for a rare genetic condition called Bloom syndrome. In approving the Bloom syndrome test, the FDA opened the door for the approval of other DTC carrier screening products, dropping them from a Class 3, highrisk, medical device classification. Following on the heels of this success, in 2017 23andMe received approval to market a DTC disease panel that included a gene linked to Alzheimers disease (APOE4). The FDA has since described a modified regulatory approach to DTC products that will make it easier for companies to bring new DTC tests to market. As regulatory barriers to developing DTC genetic test products have become less onerous, new companies have entered the marketplace. In 2016, an Illumina spin-off called Helix announced plans to create a new DNA marketplace in which consumers could have their DNA sequenced on one occasion and later purchase a range of genetic testing products that examine those data to assess everything from the potential appearance of future children, to the risks of developing specific diseases. Despite its rocky start, DTC genetic testing appears to be thriving. The largest US companies, 23andMe and Ancestry. By Megan Allyse, PhD and Richard R. Sharp, PhD

January/February 2018

Megan Allyse, PhD

Richard R. Sharp, PhD

com, have millions of consumers. The success of these companies makes it likely that clinicians in all parts of the country will soon come into contact with DTC testing, whether due to patient inquiries about its usefulness or as a result of requests to help interpret speciﬁc test results. Now that DTC genetic testing has gone mainstream, what are the ethical issues involved? Consent and Privacy

Consent is a complex issue in DTC genetic testing. Because a consumer is buying a product directly, traditional models of physician-guided consent do not apply. Nonetheless, to the extent that these products may discover health information that requires medical follow up, some form of prospective consent seems warranted. Similarly, although consumers are voluntarily sending a DNA sample to a for-profit company, that sample contains what would in a medical setting be considered sensitive health information, subject to Federal protections such as HIPAA. It is important for consumers to review the privacy protections described by DTC companies, specifically the terms that apply to the sharing of DNA samples and genetic information. Many consumers were upset, for instance, when 23andMe announced that it had filed a patent for a genetic variant linked to Parkinson’s disease. Once a DTC test is purchased, the consumer has agreed to allow the company to hold that genetic information, including information related to health conditions and future disease risks, in its database and potentially sell that data to third parties. In the absence of protections that exist in healthcare settings, law enforcement agencies pursuing criminal investigations might also seek access to this information via legal subpoena. Additionally, if a DTC company goes bankrupt, or otherwise ceases business operations, personal genetic information could be sold or repossessed by creditors. Consumers should understand that the privacy MetroDoctors

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protections that support DTC testing differ substantially from those that exist in conventional healthcare settings. Data Interpretation and Follow-Up

As providers engage with patients who have purchased DTC tests, it is important to remember that these tests generally are not considered diagnostic. Most DTC genetic testing companies rely heavily on data from genome-wide association studies that seek to associate areas of the genome with specific phenotypic properties, such as a propensity to disease. These studies have many limitations. For example, historically these studies have been done in largely European populations. The range of genetic variation found in Europeans may not be typical of other populations, limiting the potential value of DTC products for consumers of non-European ancestry. In addition, most complex diseases, such as heart disease or cancer, are the result of a combination of genetic, environmental, and behavioral contributions. With few exceptions, lifestyle choices are a far better predictor of an individual’s likelihood of developing such diseases. Contextualizing the relative contributions of genetic and non-genetic risk factors is critical to DTC report interpretation. Providers may need to help consumers understand that DTC tests have significant limitations and that, in some cases, no medical response may be needed. One of the most significant ethical concerns about DTC genetic testing centers on the potential for providers to order unnecessary medical tests based on information provided by DTC reports. In a time when medical resources are being stretched, observers have voiced concerns that DTC tests

may increase healthcare costs and exacerbate health disparities by directing medical resources away from less advantaged populations. Providers will need to balance their attendance to legitimate health risk factors identiﬁed by DTC tests and the management of misplaced patient concerns resulting from mistaken interpretations of DTC results. Conclusion

Many people are rightfully excited about a future in which both patients and providers have direct access to genomic data and use this information to inform health-related choices. Despite recurring predictions of the demise of DTC genetic testing, these products are of much interest to many patients. The ethical challenge facing clinicians is how best to guide patient enthusiasm for DTC genetic testing toward well-established activities that promote health and support disease prevention. Toward that goal, we encourage providers to learn more about these testing options and their limitations. Megan Allyse, PhD, is an Assistant Professor of Biomedical Ethics at Mayo Clinic and a member of the Center for Individualized Medicine Bioethics Program. She holds a dual appointment in Obstetrics and Gynecology. Contact: allyse.megan@mayo.edu. Richard R. Sharp, PhD, is a Professor of Biomedical Ethics and Medicine at Mayo Clinic, where he directs the Bioethics Program for the Center for Individualized Medicine. Contact: sharp.richard@ mayo.edu.

THE STRENGTH TO HEAL

and stand by those who stand up for me.

Learn the latest treatments and play an important role in the care of Soldiers and their families. As a physician on the U.S. Army Reserve health care team, you’ll continue to practice in your community and serve when needed. You’ll work with the most advanced technology and distinguish yourself while working with dedicated professionals. You’ll make a difference. To learn more about joining the U.S. Army health care team, visit healthcare.goarmy.com/gx14 or call 952-854-8489.

MetroDoctors

The Journal of the Twin Cities Medical Society

January/February 2018

Environmental Health — Pipelines, Tar Sands Oil, and the Health of Minnesotans

here are moments when a single decision can have a very large impact on events. Such a moment is facing Minnesota regulators as they consider whether to allow Enbridge Energy to build Replacement Pipeline 3 that will double the amount of tar sands oil carried across treaty-protected native lands, pristine natural areas, and the headwaters of the Mississippi. These Minnesota concerns are reason enough to deny this project but there are larger issues. Health Professionals for a Healthy Climate, a Minnesota organization, recently provided testimony before the Minnesota Public Utilities Commission recommending against approval of this project because it will contribute to serious health risks for patients and communities. The problems extend beyond Minnesota to the Canadian Tar Sands that will supply the product transported in this line. The Alberta Tar Sands mines are one of the largest sources of microparticulate air pollution in North America generating pollutant levels greater than the Northeast US.(1,2) And Tar Sands oil is a thick sandy mix requiring energy intensive processing that emits twice the greenhouse gas emissions per barrel than oil from other sources.(3) Weather extremes related to Minnesota’s changing climate have damaged homes, businesses, and crops and threaten the hospitals and clinics we rely on. Minnesota’s warming climate and fossil fuel generated pollution effect and worsen many aspects of health including heart and lung diseases; asthma and allergies; cancers; stroke and

mental decline; infectious diseases; and developmental disorders. We must also consider that likely pipeline ruptures will release highly toxic substances into surface and ground waters in the especially sensitive areas crossed by the selected pipeline route. Denying this pipeline project would be an important step in slowing investment and development of the Alberta Tar Sands. The environmental damage from Tar Sands oil will adversely impact current

and future generations of Minnesotans. Reason enough for physicians to express our concerns. References: 1. Oil sands found to be a leading source of air pollution in North America. https://www. theglobeandmail.com/news/national/oilsands-found-to-be-a-leading-source-of-airpollution-in-north-america/article30151841/. 2. Air Pollution and the Tar Sands–Canadian Association of Physicians. https://cape.ca/wpcontent/uploads/2015/09/AirandTarSandsReport_FINAL.pdf. 3. Oil Sands Development–A Health Risk Worth Taking? D Tennebaum. Environmental Health Perspectives 117:A150-6 ,2009.

Health Professionals for a Healthy Climate Health Professionals for a Healthy Climate is pleased to announce an exciting day-long conference, “Code Blue for Patient Earth: Responding to the Urgent Threat of Climate Change to One Health” on April 20, 2018, at the Science Museum of Minnesota in St.Paul. We will have some very exciting speakers including: David Thorson — Polar Explorer, Sailor; and Author and Professor Mac Baird, Chair (retired) of the UMN Department of Family Medicine and Community Health. We wanted you to be one of the ﬁrst to know, as we expect the conference to ﬁll quickly. Please mark your calendar.

By Bruce D. Snyder, MD, FAAN

January/February 2018

MetroDoctors

The Journal of the Twin Cities Medical Society

Charles Bolles Bolles-Rogers Award

JAMES A. DANIEL, MD, passed away on November 24, 2017. A graduate of the University of Minnesota Medical School, Dr. Daniel was a cardiologist and founding member of the Minneapolis Health Institute and Foundation. He joined the medical society in 1988.

lie Gertner MD, FRCP (C), FACP, a specialist in Internal Medicine and Rheumatology, at Regions Hospital in St. Paul, received the 2017 Charles Bolles Bolles-Rogers Award from the Twin Cities Medical Society Foundation (TCMSF). Chris Johnson, MD, chair, TCMSF Board of Directors, presented the award on Tuesday, November 28, 2017, at a meeting of Regions Hospital Medical Staff held at the University Club. The Charles Bolles Bolles-Rogers Award is given to a physician nominated by colleagues and who, in the opinion of the members of the TCMSF selection committee, by reason of his/her professional contribution to medical research, achievement or leadership, has become the outstanding physician of this and other years. The award, a bowl, is named after Mr. Charles Bolles Bolles-Rogers, an aristocratic gentleman who lived in the Minneapolis area for 37 years and was especially interested in the health and hospital needs of the city. Mr. Bolles-Rogers served on the (former) St. Barnabas Hospital Board of Trustees and was president of that board for many years. Prior to his death he made provision for the Charles Bolles Bolles-Rogers Award to be given annually to an outstanding physician. Elie Gertner, MD is a brilliant clinician with a strong commitment to education and research. Known as “Dr. House” when challenging or mysterious illnesses present, Dr. Gertner is often consulted to assist in determining the diagnosis and a course of treatment. His amazing knowledge in Internal Medicine and Rheumatology, an ability to recognize illnesses, and a passion to teach not only residents, but all staff makes him an invaluable colleague. His compassion and tireless advocacy for his patients make him equally loved by his patients, who are usually referred to him, locally and across the country, with MetroDoctors

In Memoriam

TCMSF Chair Chris Johnson, MD (left) presents Charles Bolles Bolles-Rogers Award to Elie Gertner, MD.

extremely complex and rare autoimmune diseases. Educating future physicians is a great passion and priority for Dr. Gertner. He is the program leader for all Internal Medicine trainees (medical students, residents, and fellows) at Regions and HealthPartners. In particular, the Rheumatology rotation at Regions Hospital is the most highly-rated rotation, and many residents have chosen to undertake Rheumatology fellowship training after their desire for further knowledge in this specialty was sparked by Dr. Gertner’s expertise and enthusiasm. He often maintains longdistance relationships with residents and fellows post-training. Dr. Gertner is Professor of Medicine at the University of Minnesota Medical School and Vice Chair of the Department of Internal Medicine. As a researcher, Dr. Gertner chairs the Institutional Review Board at Regions Hospital, has authored numerous papers and abstracts in Rheumatology and Internal Medicine, and mentors students and residents in research programs. Highly esteemed for his commitment to patient care, education, research…and his smile, the Twin Cities Medical Society Foundation is honored to award the Charles Bolles Bolles-Rogers award to Elie Gertner, MD.

The Journal of the Twin Cities Medical Society

WILLIAM ENGEL, MD, passed away on June 12, 2017. He attended medical school ﬁrst at the University of Washington and then the University of Minnesota. Dr. Engel was a urologist practicing with Urology Associates. He joined the medical society in 1970. SEYMOUR HERBERT LEVITT, MD, D.SC, passed away on September 30, 2017. Dr. Levitt received his medical degree from the University of Colorado. Residencies in Internal Medicine and Radiology, and an American Cancer Society Clinical Fellowship, were followed by 10 years of medical leadership in Radiation Therapy and Oncology. He ended his career serving as the Professor and Head and Clinical Chief, Department of Therapeutic Radiology at the University of Minnesota Hospital. He retired in 1999. Dr. Levitt joined the medical society in 2006. FRANKLIN C. NORMAN, MD, passed away on June 16, 2017. Dr. Norman graduated from the University of Michigan with his medical degree. Dr. Norman was an internist, afﬁliated with the group Miller, Nuessle, Norman & Vagneur. He joined the medical society in 1963. THOMAS A. POLTA, MD, passed away on October 25, 2017. Dr. Polta received his medical degree from the University of Minnesota. He practiced Anesthesiology at Unity and Mercy Hospitals. He joined the medical society in 1976.

January/February 2018

CAREER OPPORTUNITIES

Senior Physicians Association Mark your calendar! Tuesday, February 20, 2017 William Walsh, MD, Deputy Chief Innovation Ofﬁcer, Upstream Health Innovations, and Facial Plastic and Reconstructive Surgeon Department of Otolaryngology, Hennepin County Medical Center, will speak on “Housing is Medicine.” This presentation explores the devastating effects of homelessness on health, the root causes of homelessness, and potential role the healthcare system can play to help house everyone who needs it. You won’t want to miss this talk! Watch your email for registration and bring a friend!

See Additional Career Opportunities on page 31.

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January/February 2018

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CAREER OPPORTUNITIES

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Family Medicine Physician HEALTHPARTNERS MEDICAL GROUP – HUGO, MINNESOTA We are actively recruiting a family medicine physician to join our primary care team at our Hugo clinic. This is a part-time or full-time, outpatientonly family medicine (no OB) position. Our primary care team includes family medicine physicians, pediatricians, advanced practice providers and chiropractic services. This role offers potential for physician leadership and urgent care coverage at the clinic, as well. We use the Epic medical record system in all of our primary care and specialty care clinics and admitting hospitals. Epic experience is helpful, but not required. HealthPartners Medical Group continues to receive nationally recognized clinical performance and quality awards. We offer a competitive salary and benefits package, paid malpractice and a commitment to providing exceptional patient-centered care. For more information, please contact diane.m.collins@healthpartners.com or call Diane at 952-883-5453; toll-free: 800-472-4695. Apply online at healthpartners.com/careers and search for Job ID 42519. EOE

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With just one click you will ﬁnd information on the latest TCMS news, events and legislative issues; Board and committee actions; past issues of MetroDoctors; and new career opportunities!

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The Journal of the Twin Cities Medical Society

January/February 2018

LUMINARY of Twin Cities Medicine By Marvin S. Segal, MD

ROBERT JAMES GORLIN, DDS A listing of the purely factual accomplishments of our Luminary would take hours of time, reams of paper and volumes of ink — but there was so much of Dr. Robert Gorlin that wasn’t purely objective. Let’s survey many of the personal qualities that made him the marvelous person we knew. His all-too-short 83-year life began in New York and ended after some 50 years of residence in his beloved Minnesota. Essentially abandoned as a child and raised by indifferent and underprivileged relatives, he was fortunate to have a slice of bologna between two pieces of bread as his school lunchtime sustenance. He eventually tutored fellow classmates in chemistry, a subject that came easily to him, for the princely sums of 5 or 10 cents per session. Very fortunately, a perceptive schoolteacher recognized his brilliance and aided in obtaining a scholarship at Columbia University. Dr. Gorlin’s career path as a dentist, a “syndromologist” and a world renowned oral pathologist traversed decades of achievement including: his dental degree at Washington University; pathology fellowships at Columbia and NIH; a masters degree from the University of Iowa; military service in both the Army (WW II) and Navy (Korean war); five honorary doctorates spanning the globe; 27 major awards — from a Fulbright to our U of M Regents’ Professorship plus so much in-between; the description of over 80 new syndromes; over 600 peer reviewed articles; and final completion just prior to his death of the 5th edition of his acclaimed Syndromes of the Head and Neck. Despite the thousands of patients’ lives he benefitted as a clinician and the innumerable doctors’ skills he enhanced as an educator, Gorlin attempted to minimize what he had done “compared to the true heroes working to solve the ‘real problems’ of our society — infant mortality, childhood poverty and insufficient educational funding — I have done nothing.” He never bragged, though was privately very proud of his successes, once exclaiming, “I’m enclosed in a magical filter to screen out flattery.” Some have questioned whether his well-known penchants as a valiant defender of those less fortunate or his quick and hilarious sense of humor were secret and personal survival techniques to compensate for his troubled early years. Guess we’ll never really know if Bob’s wise counsel to an organizationally conflicted young associate (“Fight the bastards . . . and I’ll help you all the way”) or his entertaining dramatic animal sounds for delighted young 32

January/February 2018

children and his humorously bizarre commentaries to figuratively trapped elevator audiences did play roles in assuaging some of the pain from his youth. Dr. Gorlin, though not exactly a workaholic, was incredibly academically productive. Time spent at the family kitchen table while working on his next paper was never more important than meaningful conversations and activities with his wife, Marilyn, and their children, Cathy and Jed — both currently successful professionals in their own right. Bob’s 1959 keen observation of a constellation of clinical findings in a patient seen while he was “moonlighting” in a Minneapolis dental office skillfully led to his discovery of Gorlin’s Syndrome — which he modestly preferred referring to descriptively as Basal Cell Naevus Syndrome. The ongoing evolution of the field of Molecular Biology was profoundly exciting to him as it addressed connecting the causative “how and whys” to his brilliant clinical descriptions. Dr. Bob’s curiosity was boundless — his students asked questions and he learned by answering them. His generosity was unselective and unconditional — delightfully giving of his precious time, wisdom and, in many instances, the limelight to colleagues and students. The qualities so often used to define Dr. Bob Gorlin — bright, warm, inspiring, curious, disciplined, funny — individually barely do him justice . . . that is until we put them together and realize he had an abundance of them all — a Luminary of whom we are so proud. (Thanks to Dr. Gorlin’s family for providing information used in this article.) This last page series is intended to honor esteemed colleagues who have contributed significantly to Twin Cities medicine. Please forward names of physicians you would like considered for this recognition to Nancy Bauer, Managing Editor, nbauer@metrodoctors.com.

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