Hereditary cancer: guidelines in clinical practice—general overview

Annals of Oncology 15 (Supplement 4): iv121 – iv125, 2004 doi:10.1093/annonc/mdh915

Hereditary cancer: guidelines in clinical practice—general overview P. A. Daly Department of Haematology and Oncology, St James’s Hospital and Trinity College, Dublin, Ireland

Introduction

Current and future impact on oncology practice

Cancer genetics care and syndrome recognition

The recognition of a proven or possible inherited predisposition to cancer identifies a need for increased medical services to individuals who find themselves in this position. The majority of these approaches are driven by expert opinion rather than by the findings of randomised clinical trails. Screening for breast cancer is based on clinical evaluation, and mammography though the use of magnetic resonance imaging is being studied and shows superiority in some respects [10, 11]. It is generally accepted that mortality and morbidity

Cancer genetics care aspires to provide information on the genetics of hereditary predisposition to cancer [28, 29]. It assists in defining the risk to individuals while outlining the benefits and limitations of genetic testing. It should facilitate decisions regarding genetic testing and provide a service for this testing to be undertaken. Ultimately, too, it must help individuals to cope with their circumstances and provide facilities aimed at risk reduction. A range of skills is therefore required by the medical oncologist. These include a knowledge of hereditary

q 2004 European Society for Medical Oncology

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The late 20th century and early part of the 21st have seen a major interest among people worldwide in their origins in terms of place and genealogy. There has been recognition too that the profile of illness and cause of death among families are of great significance for some [1]. In this context, cancer genetics is coming of age [2]. Clinical oncology practice now encompasses situations where major surgical and other interventions are practised towards cancer prevention with the ultimate goal of preventing cancer deaths. Women readily address issues such as prophylactic mastectomy [3, 4], prophylactic oophorectomy [5– 7], and increased screening [8–11] and chemo-prevention [12 –16]. Many people too will subject themselves to endoscopic procedures and preventive surgery in the context of colorectal cancer risk [17–19]. Rarely parents have to address these issues for their children, and thyroidectomy at the age of 5 years is now recommended for some who carry RET oncogene germline mutations [20, 21]. Many rare cancer syndromes exist and are being increasingly defined. Others, such as familial melanoma, though long recognised, are complex disorders without as yet full molecular definition and remain controversial in terms of genetic testing [22]. Increasingly, cancer genetics is becoming a component of standard cancer care. Clinical problems in this area present daily to practicing oncologists in all disciplines (Table 1). Therefore, a knowledge and understanding of clinical practice in this area and its scientific basis is necessary for doctors caring for cancer patients and their families. Medical oncologists need to be informed and active in this area of clinical practice, where possible in collaboration with their colleagues in Clinical Genetics.

from inherited forms of colorectal cancer can be reduced through the identification of risk and the application of a highly targeted programme of surveillance and surgical management [17–19]. Physicians need to be familiar with the application of screening methods and also the use of prophylactic surgery among those at high risk of breast cancer and colorectal cancer. Whereas breast and colorectal cancer may pose the major risk in the common syndromes of breast/ovarian cancer and hereditary non-polyposis colorectal cancer (HNPCC), it is important to recognise that other risks exist, and prophylactic salpingo-oophorectomy and hysterectomy are important considerations where there are mutations in BRCA1 or 2, or the genes associated with HNPCC [5 –7, 17, 23]. To date the full benefit of chemoprevention remains undefined for carriers of mutations in BRCA1 and 2 [24]. Studies with tamoxifen and raloxifene are in progress and will hopefully bring clarity to this area. Chemoprevention is also a consideration for those at high risk of colorectal cancer. Aspirin and non-steroidal agents are the main drugs under investigation in this area [25–27]. To date, no clear recommendations can be made based on current evidence. Those at high risk of cancer will need ongoing care throughout their lives. Many will undergo treatment and interventions such as those described. Careful study will be needed of the impact of these treatments in terms of physical and psychological outcomes. While it may appear rational to carry out a thyroidectomy on a 5-year-old child thereby removing cancer risk, the long-term effects of such a procedure on subsequent physical and psychological development will need to be studied carefully. Similarly, the late effects of prophylactic mastectomy or oophorectomy on young women must also be carefully defined.

iv122 Table 1. Clinical circumstances in oncology which necessitate genetic evaluation to assess a possible inherited predisposition to cancer Disease

Alerting factors

Genes

Breast cancer

Family history

BRCA1

Early age of onset

BRCA2

Bilateral disease

CHEK2

Breast/ovarian cancer

TP53

Ancestry Male breast cancer Ovarian cancer

Family history

BRCA1

Early age of onset

BRCA2

Breast cancer

MLH1

HNPCC

MSH2

Peutz– Jeghers syndrome

STK11

Male breast cancer

Malignant melanoma

Family history

APC

Early age of onset

MLH1/MSH2

Polyposis syndromes

PMS2

Other associated cancers

MSH3 / MSH6

Family history

CDKN2A

Dysplastic naevi

CDK4

Pancreatic cancer Gastric carcinoma

Family history

CDH1

Early age of onset Diffuse type Renal cell cancer

Family history

VHL

Early age of onset

MET

Sarcomas

Family history

TP53

Multiple endocrine neoplasia

MEN 1

MEN1

MEN 2A

RET

SBLA tumours

Genetic counselling

MEN 2B MTC HNPCC, hereditary non-polyposis colorectal cancer.

cancer syndromes, the capacity to provide risk assessment, an ability to take an individual through the genetic testing process and to structure a programme towards risk reduction. Hereditary cancer syndromes are a mixture of rare entities and of more common syndromes that account for 5% to 10% of common cancers. Recognition of those cancers most frequently encountered is clearly important but the capacity to recognise the rarer syndromes is also important. There are many books and publications in this area, and a recent publication gives a useful outline of inherited cancer syndromes, common cancers with associated specific genes and chromosomal abnormalities in cancer [30]. Inherited cancer syndromes are associated with germline mutations in oncogenes, tumour suppressor genes and mismatch repair genes [31]. Susceptibility is inherited in an

Cancer genetics brings together elements of medical care previously delivered through the separate disciplines of clinical oncology and clinical genetics. Genetic counselling is a new departure for medical oncologists and, once a cancer syndrome is suspected, it becomes the key component of the process of care. Informed consent for the individual going through this process is the dominant consideration. Genetic counselling is a time-intensive activity that depends on accurate data gathering. It provides personal risk assessment for individuals and discusses and addresses multiple issues with them [34, 35]. To be successful, genetic counselling must allow sufficient time for full discussion to occur. The motivation of the individual for attendance at the genetics clinic must be assessed. It is also necessary to assess the perception of risk of individuals and their wishes with regard to the definition of risk and how it is to be conveyed. The timing of the visit may be relevant in terms of events that occurred within the family such as deaths from cancer and the anniversaries associated with cancer development and death. Children should not be involved in this process unless specifically indicated, where there is a risk of the onset of disease in childhood.

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Colorectal cancer

autosomal dominant inheritance pattern, affects multiple generations and in any generation ~50% inherit the genetic predisposition to cancer. Since the presentations to follow in this supplement will focus on the commonly encountered areas of breast/ovarian and colorectal cancer, they will not be elaborated further here. It is worth mentioning, however, that our understanding of these syndromes remains incomplete, that there is significant cross-over in terms of the cancer profile within such families and that further genes remain to be discovered that will explain inherited cancer risk among those not shown to harbour mutations in the genes discovered to date. In rare circumstances, the phenotype of an individual will suggest an inherited cancer syndrome. Generally, however, the family history compiled in a detailed fashion is the cornerstone of identification of inherited cancer syndromes. Details on at least three generations should be compiled, the cancers within these families clearly documented and confirmed where possible through pathology records and death certificates, and unaffected family members should be recorded as well as those affected by cancer. This is important in identifying the inheritance pattern, which is usually autosomal dominant. The major features associated with inherited cancer predisposition are early age of onset, cancer in multiple family members, bilateral cancers in paired organs, multiple primary tumours in an individual and specific cancer constellations along with the autosomal dominant pattern of inheritance [32]. It is also important to take note of precursor lesions such as polyps, to be aware of phenotypic manifestations such as genodermatoses and to record ethnic origin such as Ashkenazi descent, which may affect risk through the existence of founder mutations [33].

iv123 predictive testing, and finally at the third visit a blood sample is taken. The second and third visit should generally be initiated by the concerned individual, whereas the first session is usually on the basis of a referral. Ideally there should be an interval of at least a month between the final phases of the testing process. While this may appear tedious, it offers the best assurance that the individual is fully informed, that they have considered their circumstances in full and, above all, that coercion is avoided [30]. Personal attendance is essential to receive the result of a predictive test or the result of genetic screening. Where possible, a clear outline of the process should be given at the outset, as well as the anticipated time-scale.

Cancer care and risk reduction Whether people go through the genetic testing process and emerge with definitive information or whether they are at high risk and their genetic status remains undefined, they still require ongoing care. Naturally, the more complete the information, the more secure the physician will be in making recommendations and the individual in accepting or rejecting them. As carers, we must acknowledge the imperfection of our knowledge and we must recognise and impart to patients that the options for risk reduction and care after testing have both strengths and limitations. Screening evaluations, while useful, are not foolproof, and with high-risk populations the occurrence of interval cancers will always be a risk. Preventive surgery is frequently mutilating and can be associated with adverse psychological and physical outcomes. Great care needs to be taken with the education of patients before proceeding with any radical measures such as prophylactic surgery. Time spent in preparation and discussion will always bear fruit in limiting adverse outcomes. Whereas some information on chemoprevention as a successful intervention exists for high-risk populations in general, as yet we have little definitive information for those who carry mutations conferring a high cancer risk [24]. For the future, the outcome of studies currently underway will help to guide such therapy and will be useful in constructing lifestyle advice for high-risk individuals. Unfortunately, medical advice is not always accepted, as has been proven by the smoking epidemic, although individuals at high-risk of malignancy may be more open to advice. It is very important that those with inherited predisposition to cancer do not feel stigmatised as being genetically inferior. It is important that they recognise that each person born has a genetic composition that makes them susceptible to various degenerative diseases. It is important too that society adopts an enlightened approach to genetic predisposition to diseases by ensuring that there is no discrimination by insurance companies or employers. Legislative bodies in all countries and unions need to address this and to enact laws that protect people from potential discrimination. In this way, people will feel free to address potential inherited risk and will participate in research, thereby providing knowledge that will be of major

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The main objective is to provide a personalised assessment of risk for each individual. To this end, models exist that can be used to predict the risk for breast/ovarian and colorectal cancers. Some reports describe the risk of developing cancer [36–40], whereas other models assess the risk of harbouring a mutation in a specific gene [32, 41 –44]. For those who are truly at high risk of developing cancer, most models underestimate the risk of developing the disease. Genetic screening of DNA for inherited mutations is not a simple process. An increasing number of genes have been cloned. Informed choices have to be made as to which gene or genes should be the subject of interest. Once a specific test is requested, the process is labour-intensive and is often slow. Screening for a mutation is generally undertaken on blood samples from live, affected persons. The goals in screening for a mutation are to detect a mutation that will help to guide the future care of that individual but that will also offer the opportunity for relatives, either affected or unaffected, to have predictive testing to determine whether or not they carry the deleterious gene copy. A common occurrence is where an affected individual opts for genetic screening and a negative result is obtained. Various explanations for this finding have to be considered. First, a mutation may truly not be present; secondly, for technical reasons a mutation may exist but may have escaped detection; and thirdly, a mutation exists in a gene or genes yet to be identified to confer predisposition. Because of these issues and uncertainties, the discussion should include options for risk estimation without proceeding with genetic testing. Whether a test is a screening test or a predictive test it must be carefully explained in terms of indication, accuracy and possible cost. People must be aware that the outcome may reveal a positive test, a negative test or a result that is indeterminate. Knowledge of this and how the results can be interpreted is vital before proceeding. In terms of predictive testing for a mutation known to exist within a family, the discussion must include risks associated with such mutations. As well as considering the position of the individual, the implications for the wider family of a mutation result must be discussed. Major issues exist here such as the problem of unwanted disclosure of another individual’s genotype. Unaffected individuals who present for predictive testing must have explored with them how they might cope with learning that they are at high risk of developing cancer. They also need to know that there is the possibility of their receiving good news. It is always wise to advise people to seek financial advice before they proceed with testing. This is to ensure that they avoid, where possible, discrimination in terms of insurance provision [45–47]. There is a real risk of psychological distress resulting from genetic testing [48]. To avoid this it is recommended that the process be divided into three counselling sessions. The first is a general information session to discuss family history, risks perceived and real, and options such as risk estimation without genetic testing or proceeding through the genetic testing process. A second session is important for those considering

iv124 assistance in preventing cancer deaths in the future. Professionals involved in cancer care owe it to their patients and society to become educated in this area so that they can in turn educate their colleagues and society at large in these matters. Cancer genetics has arrived, and in the future must be a core component of cancer care.

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