A model of survivorship in cancer genetic care

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Seminars in Oncology Nursing, Vol 20, No 3 (August), 2004: pp 196-202

OBJECTIVES: To propose a shift in the paradigm of survivorship in genetic cancer care.

DATA SOURCES: Published articles and research studies.

CONCLUSION: Previous models of survivorship are insufficient to address the evolving needs of patients and families with heritable cancers. The construction of a new model of survivorship is needed to address the unique concerns of individuals who have undergone hereditary cancer risk assessment and counseling.

IMPLICATIONS PRACTICE:

FOR

NURSING

Health care providers must be familiar with the recommendations for treatment, surveillance, and follow-up care for individuals and families with heritable cancers to maximize their quantity and quality of life.

Linda A. Jacobs, PhD: Coordinator, Living Well After Cancer Program, Clinical Assistant Professor, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA. Ellen Giarelli, EdD: Research Assistant Professor, University of Pennsylvania, School of Nursing, Philadelphia, PA. Address correspondence to Linda A. Jacobs, PhD, RN, BC, Living Well After Cancer Program, University of Pennsylvania Cancer Center, 34th and Spruce Sts, 14 Penn Tower #1428, Philadelphia, PA 19104-4283.

© 2004 Elsevier Inc. All rights reserved. 0749-2081/04/2003-0007$30.00/0 doi:10.1053/j.soncn.2004.04.006

A MODEL

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SURVIVORSHIP IN CANCER GENETIC CARE LINDA A. JACOBS

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ELLEN GIARELLI

ITH THE advent of genomic medicine, prior conceptualizations of cancer survivorship are insufficient to guide the delivery of care to a growing population of patients and families with heritable diseases. The purpose of this article is to propose a new paradigm of survivorship related to hereditary cancer susceptibility. Specifically, this article will discuss two scenarios that illustrate survivorship issues: (1) when a patient has been diagnosed with a heritable cancer; and (2) when a person has inherited a genetic predisposition to cancer but does not have the disease. The authors propose that there has been a shift in the paradigm and not just a change in the context of the meaning of survivorship as it relates to the diagnosis of or risk of a heritable cancer. This paradigm shift must be understood to address the survivorship issues in genetic cancer care. Brief case studies will illustrate the two scenarios. What does it mean to be a survivor? In cancer care the terms “survivor” and “survivorship” cover a range of states, from mere existence despite disease to total cure. The concept of survivorship applies to many aspects of life after cancer. Quality of life has been called the most frequent and important measurement of survival1; however, even when quality of life is dismal, one is still surviving. Consequently, conceptual models of survivorship have changed as the options for health care have changed. The term “survivorship” was historically used to describe family members that survived the loss of a loved one to cancer.2 When cancer care offered limited treatments, rare cures, and little prospect of hope for patients and their families, the model for survivorship focused on helping family members grieve and accept personal loss. As treatments improved, patients lived longer and survivorship was redefined in terms of disease-free intervals. A newer model of survivorship was constructed with issues faced by the patient who responded to treatment, went into remission, or

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was cured. A cancer survivor was the individual whose cancer did not recur in the 5, 10, and more years following diagnosis and treatment. Over the years, the contemporary idea of survivorship after a diagnosis of cancer has evolved along with the scientific advances that improve the quality and quantity of life.3 Because cancer has been categorized as a chronic disease; patients and families are situated on a continuum of care. The period when patients are characterized as survivors is optimized as they live a longer, cancer-free life, and die of causes other than cancer. Models of survivorship evolve as cancer treatments improve. Each patient’s experiences with illness and therefore survivorship are personal, intimate, and unique to the individual and family’s experience with cancer, as well as their socioeconomic status and cultural heritage. With the addition of the single word “genetic” to qualify “cancer care” one could assume that there simply has been the inclusion of an additional cause of disease and subsequently another aspect of care. In practice, however, this single qualifier changes the nature of care in disease management, counseling, surveillance, and assessment of the psychosocial impact on patients and family members. Provider and patient discussions expand from individual to generational issues, and surveillance changes from monitoring for recurrence to waiting for expression of the genetic condition. Patients and family members struggle to understand the impact of knowing one’s genetic risk of cancer, the fear of losing insurance and employment, and the feelings of grief, fear, relief, and confusion that may be associated with learning genetic test results. While these shifts in focus may seem merely semantic, underlying them is a scientific revolution that has advanced nursing into the genomic era of medicine and introduces priority areas for nursing research. With the emergence of the genetic theory of disease, there has been a shift in the way we think about cancer, design treatments, and plan life-long care. What survivorship actually encompasses in genetic cancer care is also expanding.

developing an action plan that outlined how public health can address critical cancer survivorship issues. This action plan was developed by expert participants who addressed each of the following public health areas in the context of cancer survivorship: surveillance and research; communication, education and training; programs, policies, and infrastructure; access to quality care and services; and evaluation and quality improvement. In the last year, survivorship has also been identified as a new priority for The National Cancer Institute which outlined an action plan for fiscal year 2004 that focuses on survivorship issues as they relate to areas of public health similar to those outlined by the Centers for Disease Control and Prevention and the Lance Armstrong Foundation. Although to date the term “cancer survivor” has not been used when describing an individual who has been identified as genetically at risk for developing cancer, the Centers for Disease Control and Prevention/Lance Armstrong Foundation and National Institutes of Health initiatives included a discussion of genetics in the action plans for addressing survivorship issues. Advances in genetic technology and pharmacotherapeutics have dramatically altered the treatment course and long-term outcomes for many cancer patients and their families. For example, the decoding of the human genome and the identification of genes associated with individual susceptibility to treatment-related late effects affect treatment decisions and are leading to the tailoring of individual cancer treatments.4-6 In addition, patients with hereditary cancers are surviving longer and reproducing generations of individuals with genetic cancer predisposition. Consequently, the way we apply the concept of survivorship must evolve. For the purpose of discussing survivorship issues, patients will be divided into two groups: individuals who have developed cancer and afterward have genetic mutation testing, and those who know they have a genetic alteration (genotype) that predisposes to cancer but have not yet developed a cancer (phenotype).

BACKGROUND

SURVIVORSHIP ISSUES IN AN AFFECTED INDIVIDUAL WHO IS A MUTATION CARRIER

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n June 2003, the Centers for Disease Control and Prevention and the Lance Armstrong Foundation conducted a workshop called, “Building Partnerships to Advance Cancer Survivorship and Public Health,” which focused on

A

traditional model of survivorship has the prerequisite of a diagnosis of a disease to which one does not succumb. This model of sur-

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vivorship may be applicable to individuals with cancer who have an inherited, genetic predisposition to cancer, in so far as they have been diagnosed with a disease; many of the survivorship issues are similar to the issues of individuals who have had sporadic cancers. These issues include surviving the diagnosis and initial treatment, adapting to physical limitations, and managing the long-term late effects of cancer that will require screening for physiological problems, psychosocial adaptation, and ultimately restoring and maintaining a high quality of life. However, there are survivorship issues encountered by patients with hereditary cancer syndromes that are not relevant for survivors of sporadic cancers. For example, decisions regarding prophylactic surgery and disease-specific surveillance recommendations for the individual diagnosed with a sporadic cancer are very different for an individual with a cancer resulting from an inherited genetic predisposition. The broader family discussion with unaffected siblings, children, and parents regarding their cancer risk, including treatment and longterm surveillance options, are issues that must be considered when managing the care of an individual with a hereditary form of cancer. The broad range of disease-specific survivorship issues that can be identified for every hereditary cancer syndrome are beyond the scope of this article. Survival issues for patients and families with BRCA1 and MEN2 mutations will be used to illustrate many of the complex survivorship issues that may be encountered when dealing with individuals with hereditary cancer syndromes. The intricacies and detail required to dissect the following could be the entire focus of this article; however, it is presented with the intent of provoking thought and providing the reader with a general overview of survivorship issues in genetic cancer care. Scenario A 40-year-old white woman presents with a mass in her left breast noted on mammogram. She reports that her mother was diagnosed with breast cancer at age 46 and died of her disease and her sister was diagnosed at age 38 and is doing well. She has two additional sisters and a brother who are well. The patient is premenopausal, has one daughter and two sons, and is married. A breast biopsy reveals a 2 cm lesion and 1 to 2 positive left axillary sentinel lymph nodes. Her tumor is estrogen- and progesterone receptor-positive, and she was treated with a mastectomy, four cycles of

doxorubicin and cyclophosphamide, and radiation therapy to her left chest wall, followed by tamoxifen. She tested positive for the BRCA1 gene. To date, no one else in her family has had genetic testing. Treatment and Recurrence Issues Many factors influence treatment decisions for breast cancer patients, whether they have an inherited predisposition to breast cancer or sporadic breast cancer. The effect of genes, hormones, and/or biomarkers on responsiveness to treatment, recurrence risk, and long-term diseasefree survival has the potential to alter the course of treatment and ultimately, long-term survival for individuals with inherited breast cancer. For example, the clinical significance of BRCA1 mRNA levels was recently identified in tumor tissues as possible predictors of response to anthracyclinecontaining chemotherapy in breast cancer patients7 and BRCA-associated breast cancers have an increased risk of contralateral breast cancer compared with women with sporadic breast cancer.8 In addition, the role of radiotherapy and radiation sensitivity of breast tissue in women who are mutation carriers of BRCA1/2 has been explored, with the ultimate determination that there is no significant difference between toxicity or treatment response between women with heritable breast cancer compared with women with sporadic breast cancers.9-11 By comparison, the role of radiotherapy for patients who are mutation carriers continues to be questioned and associated sequelae evaluated.10 These known germline mutations, with autosomal dominant transmission, explain only part of the familial aggregation of breast cancer. Recent genetic epidemiology studies have shown evidence of inheritance patterns that are non-Mendelian and familial residual risk caused by the multiplicative effects of several genes that are more frequent in the population and confer moderate risks for cancer.12 Consequently, it is evident that ongoing scientific advances influence treatment decisions and therefore the nature of the survivorship experience, including surveillance issues and treatment decisions for patients and families with heritable cancers. Surveillance and Survivorship Issues During the last few years, numerous studies have explored issues associated with the decision to undergo genetic testing. A number of patients

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and/or family members continue to choose not to undergo testing, and for many this decision will determine the recommended cancer treatment and surveillance. There are specific recommendations for affected individuals and their close relatives (first- or second-degree relatives) if a germline mutation associated with a particular cancer syndrome has been identified in the affected individual. For example, prophylactic surgery, including prophylactic mastectomy and prophylactic salpingo-oophorectomy, is presented to women who are unaffected BRCA 1 or 2 mutation carriers as an option to prevent breast and ovarian cancer. For a carrier who has been diagnosed with breast cancer, there is a 20% chance of developing a second primary breast cancer or relapsing within 5 years of their original diagnosis. For these individuals, mastectomy and prophylactic surgery (including prophylactic contralateral mastectomy and prophylactic bilateral salipingo-oophorectomy) may increase survival over surveillance alone and decrease the risk of relapse or a second primary breast cancer.13,14 However, although commercially available, genetic testing is not always offered to patients who meet the guidelines for clinical genetic testing nor is it available across care settings, and it is important to understand that standard of care does not mandate that patients and family members who are at increased genetic risk of breast and ovarian cancer be offered genetic testing. The information gained through genetic testing has the potential to significantly alter the course of treatment and subsequent surveillance recommendations for patients and their families. The survivorship experience may include lifelong uncertainty about recurrence risk, the risk for development of other cancers, as well as worry regarding cancer risk in family members of cancer patients who are identified at risk for a germline mutation and do not undergo testing.15 Although genetic testing can be beneficial for high-risk individuals, test results can be inconclusive. Consequently, the only time that clinical genetic testing effects the estimation of risk of developing cancer is when a genetic test is a true-positive or -negative. Women with breast cancer who have a significant family history of breast or ovarian cancer suggestive of an autosomal dominant inheritance pattern related to these cancers should be offered genetic education, counseling, and testing. However, because test results may be uninformative, these individuals should be managed as high-risk patients with appropriate surveillance and management recommendations in the absence of a true negative test result.

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There are general surveillance recommendations for individuals with inherited breast cancer tailored for each individual based on the patient’s profile. The American Cancer Society recommendations for breast cancer screening take into account a number of factors including age and family history.16 For example, the screening recommendations and survivorship issues for a breast cancer patient with a family history of cancer who is a mutation carrier and was treated with a left mastectomy and chest radiation and did not choose to have bilateral mastectomies or oophorectomies will be different than the recommendations for a similar patient that had prophylactic surgery. Also, if an individual decides to have bilateral mastectomies, they can eliminate the need for mammograms and other breast surveillance options such as breast ultrasounds, regular clinical breast examinations, and breast magnetic resonance imagings. These seemingly complicated options make it critical that cancer patients with hereditary susceptibility to cancer, health care providers, and the general public be informed regarding the risks and benefits of genetic testing, as well as how test results influence treatment options and decisions, and ultimately the course of the survivorship experience, as illustrated in the next example. The decision-making process regarding BRCA1/2 testing, as well as testing for all of the inherited cancer mutations, remains potentially complex and difficult despite the benefits to be gained by quantifying individual and familial cancer risk, and the guidance that could be provided for subsequent treatment decisions and long term surveillance and survivorship issues. Genetic testing decisions affect many psychosocial functions, including health practices, family relationships, reproductive decision-making, insurance issues, and finances. Patients and family members must consider what this information will mean for unaffected family members and have an understanding of the benefits, risks, and limitations of increased surveillance, prophylactic surgery, or other preventive strategies if they are to undergo genetic testing.17

SURVIVORSHIP ISSUES FOR AN INDIVIDUAL AT HIGH GENETIC RISK OF CANCER

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ssues of survivorship arise at the nexus of a patient’s health needs and the ability of the health care system to meet them. One may say

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that survivorship issues are generated from the healing relationship established between a patient and a health care provider. In this relationship the patient’s health care needs are identified and the health care provider offers information, treatment options, and resources to meet these needs. In the case of a patient with known disease, as soon as health care providers inform the patient of the diagnosis, both begin to identify survivorship issues because information and treatment choices must be made that will optimize the quantity and quality of life. The nature of the healing relationship between the patient and health care provider for at-risk individuals in genetic cancer care is different than for the patient with cancer; therefore, survivorship issues are different. In this case, patients may learn long before a cancer diagnosis that they are at 40% to 85% risk of developing breast cancer and 20% to 40% risk of developing ovarian cancer in their lifetime. The individual that tests positive for a gene mutation associated with cancer begins to identify treatment choices that will influence survivorship issues. For example, at-risk individuals who undergo prophylactic surgery consent to removing an otherwise healthy and functioning body part to prevent future disease. The potential side effects of prophylactic surgery should be clearly discussed during education and counseling. Pellegrino18 describes three components of the healing relationship in health care: the act of medicine, the fact of illness, and the act of profession. Genetic testing (the act of medicine) generates the diagnosis of heritable risk (the fact of illness).19 The act of profession generates risk management strategies including life-long surveillance or watching and waiting for cancer. Surveillance and Survivorship Issues When an individual who carriers a mutation that predisposes them to developing cancer is identified, (eg, RET, APC, BRCA1, BRCA2) they will be asked to think about risk management to improve survival. They will also begin life-long incidental and planned20 surveillance for phenotypic expression of the altered genotype. Chemoprevention may also be considered. All of this occurs in the absence of cancer and on a presumption of penetrance or risk of disease. Already the model for understanding survivorship has shifted to include “risk of disease” instead of “actual disease” as the source of survival issues. In the next scenario, the patient has a positive

genetic test and a strong family history that confer an increased risk of cancer. The genetic risk becomes proxy for the diagnosis. Survival issues change from “attempts to improve” to “attempts to guarantee” the quantity and quality of life. This takes the form of watching and waiting for early signs of disease, and may also include preventing disease by removing, when possible, the at-risk organs. Survivorship issues in genetic cancer care of someone at-risk for cancer are poignantly illustrated by the experiences of a child with a RET mutation. Scenario A single mother, age 35, was found to have nodules on both lobes of her thyroid gland. A biopsy revealed bilateral medullary thyroid carcinoma and c-cell hyperplasia widely dispersed throughout the lobes. A family history and pedigree uncovered significant history of thyroid cancer, Hirschsprung’s disease, and adrenal tumors in first- and second-degree relatives in the maternal lineage. Genetic testing was performed on the proband and her 8-year-old daughter. Both had a missense mutation at codon 620 of the RET protooncogene on chromosome 10 and both were diagnosed as having multiple endocrine neoplasia type 2a (MEN2a.) The mother underwent neck dissection and total thyroidectomy. Her medullary thyroid carcinoma was encapsulated and lymph nodes were negative. The daughter underwent a total prophylactic thyroidectomy. Her thyroid tissue was disease-free. After surgery both mother and daughter began thyroid hormone replacement therapy and calcium supplementation. Both were advised to adhere to life-long surveillance guidelines that would include annual 24hour urine analysis for catecholamines and annual analysis of serum levels of thyroid stimulating hormone, T3, T4, calcium, and calcitonin. Biochemical analyses are used to evaluate the occurrence of adrenal hyperplasia associated with MEN2a, appropriate thyroid hormone activity, hyperparathyroidism, and medullary thyroid carcinoma recurrence or expression, respectively. In this scenario the mother’s survival can be understood in terms of disease-free intervals. Her survivorship issues will be similar to those of other cancer patients who measure life in 5, 10, and longer years of life after cancer. Her quality of life will be maintained with careful medical management of thyroid hormone replacement therapy and minimization of the complement of adverse

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physiological effects of thyroidectomy. After this point the similarities end and survivorship issues unique to genetic cancer care become most apparent. Both mother and daughter have a life-long variable risk for the development of other tumors associated with MEN2a. They have a 30% to 50% chance of developing pheochromocytoma and a 10% to 30% chance of developing parathyroid tumors.21,22 There are no data to predict the occurrence of medullary thyroid carcinoma from in situ thyroid cells post-thyroidectomy, and there is a 50% chance that the RET mutation will be passed to offspring in the autosomal-dominant inheritance pattern characteristic of MEN2a.23 Because expression is variable, no patient can know when neoplasia will develop. The mother’s disease represents the child’s risk of disease, and the responsibility for monitoring oneself is extended to monitoring one’s offspring. The child’s situation is different. She did not have cancer. She was cancer-free. Her survival issues, while not urgent, still focus on quantity and quality of life. They result directly from her genetic predisposition and mutation status, and a critical point is that these issues are not based on the “fact” of disease, but rather on the probability of disease. The at-risk person will comply with surveillance guidelines on “faith” (or the trust in something without visible proof of its existence) in the accuracy of genetic technology and the state of the science of genetic cancer care. Her daily life may be infused with incidental surveillance events as she attends to physical feelings that may (or may not) be associated with RET mutation expression or medical management.20 Her future choice to conceive children will be affected by the probability of passing the genetic mutation to offspring. Thus, the issue of personal fertility becomes an issue of family viability. Personal survival is coexistent with family survival, and cancer prevention is not individual but generational. At this young age, at-risk individuals begin to participate in highly structured, life-long relationships with health care professionals for the purpose of early detection of a disease from which there may not be a favorable outcome. Her genotype may be further expressed in which case illness becomes factual. In the event that there is no further expression of MEN2a, she may regret years of worry and question decisions that were made based on her genetic risk. Although it may not be possible for many, the ideal outcome for cancer-free patients identified

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TABLE 1. Shifting Concepts Related to “Survivorship” Cancer Care

Genetic Cancer Care

Individual Personal longevity Absolute risk Recurrence Conventional treatment Monitoring self Lifelong surveillance Nurse–patient relationship

Generational Family longevity Relative risk Penetrance and expression New models of treatment Monitoring self and others Lives-long surveillance Nurse-extended family relationship Unknown cost of care Reproductive potential

Calculable cost of care Personal fertility

at-risk for a heritable cancer is that they never develop disease. At-risk individuals may embrace life-long surveillance as a way to experience a sense of control over an otherwise uncontrollable process. Patients and providers know that genetic technology widens the range of health care options and favorably transforms cancer care as well as the nature of the entire survivorship experience. Consequently, previous models of survivorship are of limited value. The paradigm of survivorship is beginning to shift and in doing so it will accommodate the constantly advancing fluid science of genomic medicine (see Table 1). At this time we have limited terminology to competently describe the survivorship experiences of individuals with heritable cancer syndromes, and are only beginning to understand the structure of this fluid model of survivorship in genetic cancer care.

DISCUSSION

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FUTURE DIRECTIONS

he shift to a genomic focus for cancer care has required that health care providers re-evaluate the assessment, management, and follow-up recommendations for patients and families at risk for and with a diagnosis of a heritable cancer. Furthermore, the application of the idea of survivorship in genetic cancer care requires the reconstruction of prior theory and evaluation of prior fact that, as Kuhn24 states, is “an intrinsically revolutionary process.” Nurses cannot take a common body of belief for granted, but rather they must search for new facts with which to rebuild a field of study, to construct a model that is compatible with the science and suitable for the mul-

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tifarious survivorship and other issues of a growing cohort of people at genetic risk for cancer. This article ends with a call for research and an invitation to set aside preconceived models of cancer evaluation, treatment, and survivorship care. Recall the survivorship issues discussed in the scenarios and the components of the healing relationship, and consider the following questions: What are the effects of creating a “fact of illness,” as described in this article, on a person’s quality of life? How does prophylactic surgery impact qual-

ity of life and longevity of families? How can nurses change life-long individual surveillance to “lives”-long generational surveillance? And, how can we further individualize treatments according to genotype and gene-environment interactions? Ultimately, the answers to these and other questions will generate the common language we need to converse with our patients about their genetic cancer survivorship issues, and will help to clarify the evolving concepts of cancer survivorship and survivorship in relation to genetic cancer care.

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cancer: after the BRCA1 and BRCA2 genes, what next? Bull Cancer 2003;90:587-594. 13. Sakorafas GH, Tsiotou AG. Genetic predisposition to breast cancer: a surgical perspective. Br J Surg 2000;87:149162. 14. Eeles R. Future possibilities in the prevention of breast cancer intervention strategies in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 2000;2:283-290. 15. Kinney A, DeVellis B, Skrzynia C, Millikan R. Genetic testing for colorectal carcinoma susceptibility. Cancer 2001; 91:57-65. 16. Smith R, Saslow D, Sawyer KA, et al. American Cancer Society guidelines for breast cancer screening: update 2003. CA Cancer J Clin 2003;53:141-169. 17. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CTM, et al. Considerations in genetic testing and prophylactic measures. Lancet 2001;5:117-120. 18. Pellegrino ED. Toward a reconstruction of medical morality: the primacy of the act of profession and the fact of illness. J Med Philosophy 1979;4:32-55. 19. Giarelli E. Safeguarding being: a bioethical principle for genetic nursing care. Nurs Ethics 2003;10:255-268. 20. Giarelli E. Bringing threat-to-the-fore: participating in life-long surveillance for genetic risk of cancer. Oncol Nurs Forum 2003;6:945-955. 21. Modigliani E, Vasen H, Raue K, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. J Intern Med 1995;238:363-367. 22. Pausova Z, Soliman E, Amizuka N, et al. Role of the RET proto-oncogene in sporadic hyperparathyroidism and in the hyperparathyroidism of MEN type 2a. J Clin Endocrinol Metab 1996;81:2711-2718. 23. McKusick FA. Mendelian inheritance in man: a catalog of human genes and genetic disorders. Ed 12. Baltimore, MD: Johns Hopkins University Press: 1997. Available at: www. ncbi.nlm.nih/gov/htbin-post/Omim.htm (accessed Oct 7, 2003). 24. Kuhn TS. The structure of scientific revolutions. Chicago, IL: The University of Chicago Press: 1962.