Genetic Counseling in Cancer: A Status Report

This special reference on genetic counseling in cancer is timely,given the explosive progress that has been made in cancer geneticsin general and molecular genetics in particular during the pastdecade. For example, the discovery of "cancer-prone genes"and the identification of "new" hereditary cancer syndromeshave had extensive coverage in both the scientific and lay press.As a result, patients around the world have been avidly seekinginformation from their physicians about how genes may be controllingtheir cancer destiny.

In turn, the slightest evidence of cancer in a patient's familymay provoke crippling fright and anxiety. In some individuals,such responses may partially be due to their misinterpretationof the media accounts. Occasionally, however, the media presentationsmay be wholly or substantially inaccurate. The reports may haveplayed down the importance of genetics in a particular cancer,giving patients a false sense of security or, alternatively, mayhave exaggerated genetic risk factors, thereby provoking unnecessaryalarm and instigating expensive cancer screening.

The Physician's Responsibilities

A subset of these concerned patients may request some form ofimmediate remedial action, such as prophylactic removal of theirbreasts or ovaries, even though there may not be any solid geneticbasis for their perception of increased cancer risk. In each case,it becomes the physician's responsibility to accurately interpretwhether there is a reality base for patients' concerns about theirgenetic risk and to counsel them accordingly.

This requires that the physician accrue a sufficiently detailedfamily history with adequate documentation of cancer occurrencesat all anatomic sites in order to formulate (or rule out) a hereditarycancer syndrome diagnosis. If such a diagnosis is established,the patient then needs to be informed about his or her personalrisk for cancer and about available surveillance and managementstrategies, including their advantages and limitations.

When DNA testing is indicated, an explanation of the testing proceduremust be conveyed to the patient. The possible penalties of geneticdisclosure must be discussed as well. For example, there is arisk that insurance companies may refuse coverage for cancer surveillanceor even surgical prophylaxis (such as prophylactic oophorectomyin a BRCA1 carrier) because it is a "preexisting condition"or designate gene carriers as "uninsurable." Employers,especially those with self-insurance, may find it in their financialinterests to discriminate against gene carriers.

As with any family, families with hereditary cancer are composedof individuals, with different emotional traits, experiences,and motivations that influence personal decisions. The resultsof gene testing for one individual may reveal the gene statusof another who is adamantly opposed to that revelation. The emotionalimpact of identification as a gene carrier will vary from oneindividual to another, but patients need to be encouraged to anticipatetheir own reaction based on past experiences and existing supportsystems. Even noncarriers may feel guilty about their gene status(so-called survivor guilt). Clearly, all of these matters areintegral features of the genetic counseling process.

Information Supply Lags Behind Demands

Are physicians sufficiently knowledgeable and ready to performgenetic counseling? Are they adequately trained to supervise cancergenetic counselors? Are guidelines for cancer genetic counselingavailable? Are there enough available certified genetic counselorswho are sufficiently knowledgeable about cancer genetics and thenatural history of these disorders? This knowledge is essentialso that patients can receive, and intelligently act upon, recommendationsbased on accurate genetic risk information, so that, in turn,appropriate choices about surveillance and management strategies(inclusive of their limitations) can be entertained.

A gap exists between what is known about cancer genetics and patients'counseling needs and their demands for information and realisticcancer prevention measures. Such a state of affairs should notbe surprising, however, given the embryonic status of the newlyemerging disciplines of cancer genetics and molecular genetics.For example, we are still low on the learning curve relative toour understanding of the variation in penetrance and expressionof cancer-prone genes, particularly with respect to age of onset,tumor spectrum, pathology, and prognosis. Questions about eachof these issues abound.

We also have insufficient information about the multifaceted legal,ethical, and moral issues that may impact on genetic counseling.For example, what is the potential for malpractice litigationthat may emanate from the genetic counseling process?

Appropriate Action Needed

The list of potential concerns about genetic counseling in hereditarycancer could be extended almost interminably. While full and completeanswers to these questions may require many years of research(and some may be so elusive as to never be fully clarified), we,nevertheless, must appreciate the fact that if the medical communitydoes not take appropriate action about cancer genetic diagnosis,genetic counseling, and management, patients will seek advicefrom individuals with less training. Given market demands, untrainedhealth-care professionals may be pressured into providing serviceswith implications that they neither understand nor appreciate.

In order to meet these many needs of patients and their physiciansin relation to hereditary cancer, we have opened a HereditaryCancer Prevention Clinic in Omaha, Nebraska (fax, 402-280-1734).This clinic will provide various services for patients with allvarieties of cancer, including cancer genetic diagnosis, geneticcounseling, surveillance, and management.

Should DNA Testing Be Put on Hold?

A constant theme in this symposium centers around the explosiveadvances in molecular biology and genetics and how these discoverieshave outpaced the physician's ability to translate this knowledgeinto patient management. In this regard, highly skilled geneticcounseling is mandatory before patients undergo DNA testing and,of course, during and after disclosure of the results. Intensivecontinuing medical educational programs in the medical schoolcurriculum and postgraduate programs could close the informationgap. These programs would enable physicians to become more knowledgeableabout the diagnostic capabilities of DNA testing. They would alsolearn about its limitations, including discrimination that mightbe inflicted on patients by insurers and employers, as well asthe psychological sequelae that may befall patients and theirfamilies.

These concerns have led to the suggestion by some that we puta halt to DNA testing for genetic disorders until the intellectualvoid in this transitional period is closed! Several documentsissued in the United Kingdom [1], the United States [2], and theNetherlands [3] have pointed to the need for caution when translatingmolecular genetic knowledge into clinical practice. These admonitionshave included breast cancer genetic susceptibility testing [4],as well as the genetic testing of children [5,6].

In reviewing this subject, Harper [7] notes that several Europeancountries, as well as the European Union, have considered theintroduction of laws to regulate genetic tests, whereas Norwayhas already enacted such legislation [8].

Power to Save Lives

Of course, caution is advisable in any new discipline. However,it would seem foolhardy to wait for new insights to emerge whenwe have at hand the power to save lives through the utilizationof DNA knowledge. This concern is best demonstrated in the paperon MEN-2 by Grosfeld et al. Prior to RET testing, the identificationof patients at risk for MEN-2 required biochemical testing (pentagastrinstimulation of calcitonin). However, false-negative and false-positiveresults were known to occur and, in certain cases, were disastrous.

These problems have been largely circumvented by the use of theRET test; at present, once an MEN-2 family is recognized, childrenat risk can be tested, thereby enabling primary prevention (totalthyroidectomy in the RET- positive individuals) before the developmentof even small foci of medullary carcinoma. The point is, had weput a halt to DNA testing and its clinical application, the medicalbenefit to countless MEN-2 patients who are candidates for prophylacticsurgical thyroidectomy would have been curtailed, with resultantmorbidity and mortality.

How many patients with other hereditary cancer-prone disordersmay benefit from the primary prevention afforded by DNA knowledge?Should we put these matters on hold, until, for example, moreknowledge is accrued about the adenomatous polyposis coli (APC)germ-line mutation in familial adenomatous polyposis (FAP), orabout the mutated genes in hereditary nonpolyposis colon cancer(HNPCC); namely, MSH2, MLH1, PMS1, and PMS2? For such disorders,DNA evidence is the only way of determining profound cancer susceptibility,given the absence of premonitory stigmata (the Muir-Torre variantof Lynch syndrome II excepted).

A Complex Issue

The issue, as we perceive it, is a very complex one. However,we have elected to use the molecular genetic knowledge gleanedthrough the discovery of the genes responsible for the hereditarybreast-ovarian cancer (HBOC) syndrome and the Lynch syndrome IIin genetic counseling [9,10]. We have done so primarily becauseof our conviction that knowledge of individuals' germ-line mutationstatus for cancer can reduce morbidity and mortality through earlydetection or prophylactic surgery.

Clearly, we have restricted this DNA-based genetic testing tofamilies for which we are highly confident that a hereditary cancer-pronesyndrome exists and for which family members have provided informedconsent prior to DNA testing and disclosure of results of suchtesting. When our research studies were initiated many years agoin some of the HBOC and Lynch syndrome kindreds in our resource,we advised these high-risk patients that one day scientific progresswould likely enable many of the discoveries that have since takenplace and that are now common knowledge to the medical profession,as well as to the laity.

More Research Clearly Mandatory

Given this perspective, it is clearly mandatory that more researchbe performed with respect to all facets of DNA testing and geneticcounseling, as well as surveillance and management approachesbased on the powerful translational potential of knowledge ofDNA findings. Furthermore, we believe that it would be preferablefor this research to be performed at centers where physiciansare highly experienced in oncology and genetics and have workedextensively with cancer-prone families. Ideally, such groups shouldhave consultants who are skilled genetic counselors, social workers,and psychologists who are knowledgeable about how this DNA informationmay impact upon insurability, employability, intrafamily strife,and emotions, as discussed in both special issues of this journal.

It would seem to be at cross-purposes to withhold this informationfrom patients when benefit could be accrued. Thus, given thisbackground, we believe, with all due respect to caution, thatclinicians have a compelling and, indeed, an ethical responsibilityto provide DNA test results to informed and consenting familymembers.

The Psychological Impact of Testing

Lerman and Croyle have been pioneers in elucidating the psychologicalimpact of DNA testing. They have studied the manner in which underlyingsocietal and psychological stress may influence health education,risk perception, and compliance, and thereby, how this stressmay modify health behavioral changes among individuals at highrisk for cancer who might benefit from genetic testing services.These authors modestly suggest that their work has highlightedonly a small subset of issues and research findings from the behavioralsciences that are relevant to clinical practice. They appropriatelyconclude that "only by overcoming the boundaries of discipline,department, degree, and tradition will the new genetics eventuatein a better quality of life for patients, their families, andthe clinicians who serve them." This concern is most fittingand challenging, and should be an impetus to move ahead with continuedcaution and an abundance of compassion for patients who continueto help us learn how to use DNA findings in the interest of cancercontrol.

Role of the Genetic Counselor

Peters and Stopfer clarify how the genetic counselor fits intothe overall scheme of DNA translation in the albeit often ambiguousrelationship between the physician and the patient, a problemthat is best defined by them in terms of the need for "...acommunication process between health care professionals and anindividual concerning the occurrence, or risk of occurrence ofcancer in his or her family [which]...is comprehensive in scope,and includes a strong emphasis on the familial nature of cancerand an analysis of genetic and related risk factors."

Cancer Genetics and the Law

How does the legal profession view cancer genetics, the implicationsof DNA testing, and the needs of the cancer-susceptible individualto benefit from those scientific advances, where particular attentionmust be given to the responsibilities of the physician and geneticcounselor? Dr. Severin, an epidemiologist and a lawyer, reviewsthis subject by depicting several early civil suits filed by thelawyers of dissatisfied patients or their families. In these cases,charges were made against physicians because of their presumednegligence and liability during the management of the particularpatient.

The usual legal issues have been litigated in these settings,including harm to patients by failure to diagnose a hereditarycancer syndrome, in particular, where this failure resulted ina significant alteration of the prognosis and/or the timelinessof targeted therapy. Case reports highlight instances where therewas a physician's "...failure to suggest monitoring or screeningprocedures for the siblings, children, or even parents of thepatient with an identifiable hereditary cancer, [and] failureto keep adequate records of cancer incidence in a family whenthe physician assumed the care of the family with a heritablecancer history."

If readers become frustrated because of the often complex problemsin the genetic counseling of patients at risk for hereditary canceraddressed by the contributors to these special issues, we willconsider our mission to have been accomplished. Historically,scientific advances in medicine have been furthered by strifeand conflict. DNA-based genetic counseling is no exception tothis axiom!

Many of the concerns discussed in this overview are addressedby my colleagues in this special ONCOLOGY reference. The authorsfully appreciate the fact that, in many cases, before the inkhas dried, newly emerging data will have made their remarks obsolete.I wish to express my gratitude to these contributors who unselfishlytook time from their very busy research and clinical activitiesto prepare manuscripts for this reference.

References:

1. Nuffield Council on Bioethics: Genetic Screening: Ethical Issues.London, Nuffield Foundation, 1993.

2. Andrews LB, Fullerton JE, Holtzman NA, et al: Assessing GeneticRisks: Implications for Health and Social Policy. Washington DC,National Academy Press, 1994.

3. Genetic Screening. Report of a Committee of the Health Councilof the Netherlands. The Hague, Health Council of the Netherlands,1994.

4. Statement of the American Society of Human Genetics on genetictesting for breast and ovarian cancer predisposition. Am J HumGenet 55:1-4, 1994.

5. Working Party of the Clinical Genetics Society: The genetictesting of children. J Med Genet 31:785-797, 1994.

6. American Society for Human Genetics/American College of MedicalGenetics report: Points to consider: Ethical, legal and implicationsof genetic testing in children and adolescents. Am J Hum Genet57:1233-1241, 1995.

7. Harper PS: Genetic testing, common diseases, and health serviceprovision. Lancet 346:1645-1646, 1995.

8. Biotechnology Related to Human Beings. Oslo, Ministry of Healthand Social Affairs, 1993.

9. Lynch HT, Watson P, Conway TA, et al: DNA screening for breast/ovarian cancer susceptibility based on linked markers. Arch InternMed 153:1979-1987, 1993.

10. Lynch HT, Drouhard T, Vasen HFA, et al: Genetic counselingin a Navajo hereditary nonpolyposis colorectal cancer kindred.Cancer 77:30-35, 1996.