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BRCA1/2 Testing: Complex Themes in Result Interpretation

From the Department of Oncology/Division of Cancer Control, Lombardi Cancer Center, Georgetown University, Washington, DC.

Address reprint requests to Beth N. Peshkin, MS, CGC, Georgetown University, 2233 Wisconsin Ave, NW, Suite 317, Washington, DC 20007; email: peshkinb{at}gunet.georgetown.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION CASE 1: SURGICAL DECISION... DISCUSSION REFERENCES

 
ABSTRACT: Since the cloning of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become more widespread. However, interpretation of test results is not always straightforward. To illustrate this point, five vignettes adapted from actual cases are presented. As these cases demonstrate, in many high-risk families, a deleterious mutation in BRCA1 or BRCA2 is not identified in an affected proband. There are several potential explanations for such a finding, namely that an undetected mutation in BRCA1 or BRCA2 may exist, or there could be a mutation in a rare or undiscovered gene. In addition, the possibility that women with breast cancer represent sporadic cases within hereditary cancer families must also be considered. Finally, the occurrence of BRCA1/2 variants of uncertain significance, often missense mutations, further complicates the risk assessment. In some of these instances, extending testing to relatives can be helpful to clarify results. When hereditary breast cancer cannot be ruled out, individuals may still be at increased risk for cancer and therefore need to obtain appropriate surveillance. The process of genetic counseling is critical both before and after testing to ensure that patients understand the potential medical and psychosocial implications of testing and are aware of available options and resources. A multidisciplinary approach to service delivery, which includes clinicians in genetics and oncology, can facilitate patients’ decision making and provide continued access to information and support.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CASE 1: SURGICAL DECISION... DISCUSSION REFERENCES

 
ONE OF THE MOST exciting and highly anticipated breakthroughs in cancer genetics was the cloning of BRCA1 and BRCA2 (BRCA1/2) in 1994 and 1995.^1,2 Since that time, it has been interesting to observe the spectrum of experiences that have occurred as cancer genetic counseling and testing have permeated research and clinical settings. Before these events, predictive testing could be performed only by linkage analysis, which yields a probability about whether one carries a gene marker. Scientists and clinicians struggled to determine whether to disclose these types of results to patients, and if so, what margin of error was acceptable.³ Dramatic examples of life-altering decisions were published, setting the bar for the anticipation that would ensue about the promise of genetic testing for breast cancer risk. For example, in 1992, a healthy woman who found out that she had a 98% chance of not carrying her family’s BRCA1 marker was spared from having prophylactic mastectomy days before the surgery was scheduled to occur.³ In the same family, a 40-year-old woman who learned that she had the BRCA1 marker rushed to have her first mammogram in 2 years, only to learn that a 6-mm malignant tumor was present—small enough that her chance of cure was very high.³

Now, several years after BRCA1 and BRCA2 were cloned, we have a better understanding of the pertinent scientific and psychosocial issues but are still faced with many of the complexities and uncertainties we encountered earlier. We know that patient decision making about genetic testing and how to use such information is not a simple process. Even when a positive result (ie, a deleterious mutation) is identified, the associated cancer risks cannot be precisely quantified and the efficacy of management options is still very uncertain.^4-6 When a negative result is obtained, it could be good news fraught with survivor guilt (in the case of a true negative for a familial mutation), or, as is the focus of this article, a negative result could be completely ambiguous and raise more questions than it answers. Addressing this issue is especially important because a significant proportion of high-risk families do not harbor deleterious mutations in BRCA1 or BRCA2. For example, studies have demonstrated that 16% to 66% of high-risk families do not carry detectable mutations in these genes.^7-9

Thus even though interpretation of BRCA1/2 results is relatively straightforward in many circumstances, complex cases are not infrequently encountered in the clinical setting. In such instances, alternative explanations for test results need to be considered, additional family members may need to be tested, or participation in research studies may be indicated. The focus of this article is to illustrate some of these complex themes in genetic counseling. We present five vignettes based on actual cases drawn from our clinical research program, through which high-risk individuals receive genetic counseling and testing at no cost. These vignettes and pedigrees have been modified to protect patient and family confidentiality. The commentaries following each case highlight concepts that can be applied globally to the process of cancer risk counseling. The clinical research program from which these cases were drawn has received institutional review board approval from Georgetown University.

	CASE 1: SURGICAL DECISION MAKING IN A NEWLY DIAGNOSED BREAST CANCER PATIENT

TOP ABSTRACT INTRODUCTION CASE 1: SURGICAL DECISION... DISCUSSION REFERENCES

 
Presentation
The proband, AB, was a 51-year-old woman of Ashkenazi Jewish descent who was recently diagnosed with a small single focus of ductal carcinoma-in-situ (DCIS) in her right breast. The only treatment she had had at the time of her initial genetic counseling session was a wide re-excision with clear margins. Her family history, depicted in Fig 1, was remarkable for her sister, diagnosed with early-onset breast and ovarian cancer, and her mother, who had ovarian cancer at age 50 years. Her paternal history was noncontributory. AB was informed by her surgeon that she was a candidate for breast-conserving therapy; however, in light of her family history, she was planning to have bilateral mastectomies regardless of her BRCA1/2 test results.

View larger version (13K): [in this window] [in a new window]   Fig 1. Surgical decision making in a newly diagnosed breast cancer patient. Abbreviations: hx, history; dx, diagnosis.

AB’s sister promptly participated in our genetic counseling and testing program, and indeed tested positive for a BRCA1 mutation (5382insC). She immediately shared this result with AB, and at this point, approximately 1 month had elapsed since AB’s initial genetic counseling session. Given her sister’s results, we concluded that AB’s breast cancer did occur sporadically and her risks for ipsilateral and contralateral breast cancers were the same as those encountered by other women with breast cancer in the general population. In considering this information, she did not opt for bilateral mastectomies, but she did proceed with radiation therapy as recommended by her physicians. In addition, this result indicated that, despite her family history of ovarian cancer, AB was not at high risk for this cancer. Also, her children were reassured about their cancer risks. Although AB’s sister opted to get tested primarily for the sake of gaining information for AB, there were medical implications to her with respect to contralateral breast cancer risks. This was an important consideration for her because she was in good health and had no evidence of disease. In addition, testing would now be informative to many at-risk relatives, such as AB’s sister’s adult children, her other siblings, and her maternal cousins.

Commentary
This case presents a striking example of how genetic counseling and testing altered the course of surgical cancer treatment and spared a newly diagnosed breast cancer patient from having extensive breast surgery. The proband, AB, thought initially that genetic testing would not impact her surgery decision because she believed that she would be at high risk regardless of whether she tested positive or negative. However, there is an important distinction between an affected proband who tests negative for BRCA1/2 mutations, yielding an uninformative result (for example if AB tested negative and we were never able to test her sister), versus a proband who obtains a true-negative result, as in this case. To make this pivotal determination, it was worthwhile for the patient to make a surgical decision only after waiting to obtain not only her results, but her sister’s results as well. In general, results for the panel of common mutations are available sooner than full sequencing, which may take approximately 3 weeks.¹¹ For some patients, such as those ascertained immediately after diagnosis or who are undergoing neoadjuvant or adjuvant chemotherapy before radiation therapy, this timeframe is usually acceptable.

This case also illustrates the importance of collecting a detailed family history and evaluating it carefully to determine who has the highest a priori chance of testing positive, although in AB’s family, both she and her sister had very high probabilities of testing positive. Models assessing carrier probability are available, which are generally designed for clinical application.^8,12-14 For example, the BRCAPRO model based on the work of Parmigiani et al¹⁴ predicted AB’s probability of carrying a BRCA1 or BRCA2 mutation to be 0.93, with her sister’s probability being 1.0,¹⁵ although in practice, it is unwise to counsel that the probability of testing positive is as definitive as 100%. The sister’s risk was higher because she had both breast and ovarian cancer and because she was young when diagnosed with these cancers. However, the BRCAPRO model does not distinguish between invasive and noninvasive breast cancer. The sister’s prior probability of testing positive is lower (at 71%) when AB’s cancer history is excluded, according to the model by Frank et al.⁸ In light of these considerations, if AB had not been faced with an imminent surgical decision, it would have been prudent to offer testing to her sister first.

In general, BRCA1/2 probabilities obtained from mathematical models should be considered in combination with traditional pedigree-based (ie, qualitative) assessments that take into account the family structure; factors that may affect penetrance and variable expression within the family; nonbreast, nonovarian manifestations of BRCA1/2 mutations (such as prostate and pancreatic cancer)^10,16; and the possible existence of other hereditary cancer syndromes. In addition, data regarding pathologic features of BRCA1/2 tumors are sometimes helpful in determining whom to test first or the likelihood of obtaining a positive result. Although mathematical calculations based specifically on the pathologic findings of affected individuals can be used,^17,18 some qualitative factors are relatively easy to integrate into routine risk assessment. For example, although germ cell tumors of the ovary are often diagnosed at young ages,¹⁹ it is important to inform probands with this condition that nonepithelial tumors such as these are not thought to be associated with BRCA1/2 mutations.^20,21 In BRCA1/2 carriers, the predominant tumor types are epithelial ovarian cancers, namely serous adenocarcinomas.^20,21 With respect to breast cancer pathology, several studies have shown that medullary carcinomas occur in excess in women with BRCA1 mutations.²² In addition, some studies have shown that certain tumor types may occur less frequently in women with hereditary breast cancer. For example, studies have demonstrated that DCIS is less common in BRCA1/2 carriers compared with sporadic cases; nonetheless, it may still be observed.^23-25

The issues surrounding genetic counseling and testing in newly diagnosed breast cancer patients are receiving increasing attention in the clinical arena. All women who have had breast cancer have an increased risk of developing a new primary breast cancer, regardless of whether they have had breast-conserving therapy or a unilateral mastectomy.²⁶ However, when a BRCA1 or BRCA2 mutation is identified, these risks are substantially elevated. Although the risk for ipsilateral breast cancer is not clearly defined in women with hereditary breast cancer, the risk does seem to be elevated over long follow-up periods.²⁷ Continuing study in this area is very important to obtain more precise information.²⁸ On the other hand, the increased risks for contralateral breast cancer are well established.^8,29-33 These risks are generally quoted as lifetime risks of approximately 50% (BRCA2) and 65% (BRCA1).^16,29,30

With respect to local treatment, although theoretical concerns exist about the potential adverse effects of radiation therapy in carriers,^34,35 Pierce et al³⁶ did not find evidence of increased radiation sensitivity or sequelae in carriers. As this question and the issue of long-term survival continue to be assessed, there is concomitant investigation into the efficacy and appropriateness of different surgical options for carriers.^37,38 Thus, in the absence of formal recommendations, and in considering their risks for second cancers, newly diagnosed breast cancer patients who test positive for a mutation in BRCA1 or BRCA2 may opt for more aggressive surgical procedures. This decision may be based in part on data showing that bilateral mastectomies substantially reduce the risk of breast cancer in high-risk women, including carriers.^39,40 However, because many carriers are younger than age 50 years at diagnosis,^7,29,30 an age group in which breast-conservation therapy is often a preferred option and is therefore performed frequently,^41,42 more extensive surgery may not be desirable. It is thus encouraging that in addition to the ample evidence that tamoxifen reduces the risk of contralateral breast cancer in unselected patients, data also suggest that tamoxifen may offer protection against contralateral breast cancer in women with a BRCA1 or BRCA2 mutation.^43,44 For carrier breast cancer patients who would not be recommended to take tamoxifen based on the characteristics of their tumor (eg, because it is estrogen receptor–negative), decision making may be especially complicated. Further research about the optimal treatment for newly diagnosed breast cancer patients who carry mutations in BRCA1/2 as well as the psychosocial impact of obtaining this information is critical to help guide patients and providers through the process of genetic counseling and medical decision making.

CASE 2: INTERPRETING FULL NEGATIVE BRCA1/2 RESULTS
Presentation CD had a history of left-sided breast cancer diagnosed at the age of 41 years, for which she underwent a unilateral mastectomy. Her paternal family history, as shown in Fig 2, was significant for six cases of breast cancer in three generations, including four early-onset cases (ie, diagnosed before age 50 years), one case of bilateral breast cancer, and one male breast cancer. Her maternal history was not significant. The proband underwent full sequencing of BRCA1 and BRCA2, and no mutations or variants were identified. Given the strength of the family history, this result was considered to be uninformative, as hereditary breast cancer could not be ruled out. Therefore, women in this family still need to be vigilant about breast cancer screening and aware of possible options for risk reduction, based on the guidelines in Table 1.^5,45-47 In addition, men should also be informed about potential breast cancer risks.

View larger version (11K): [in this window] [in a new window]   Fig 2. Interpreting full negative BRCA1/2 results. Abbreviation: bil, bilateral.

Another possible explanation for CD’s result is that she has a mutation in another breast cancer susceptibility gene. Other hereditary breast cancer syndromes such as Li-Fraumeni and Cowden disease should be considered; however, because this family contains only cases of breast cancer, testing for mutations in the associated genes (p53 and PTEN, respectively) is not strongly indicated. Specifically, criteria for the diagnosis of Li-Fraumeni syndrome include the presence of a sarcoma diagnosed when the patient is younger than 45 years, as well as breast and possibly other cancers,⁵⁴ and operational diagnostic criteria for Cowden syndrome indicate that features other than breast cancer should be present, such as mucocutaneous or thyroid lesions (eg, follicular carcinoma).⁵⁵ Thus, in this family, if a mutation in another gene exists, it is likely to be in a gene that has not yet been localized.

Finally, the possibility must be considered that CD’s cancer represents a phenocopy, or a sporadic case within a hereditary breast cancer family. Although this explanation does not seem probable given that she was diagnosed at the youngest age within the family and is a first-degree relative of a male breast cancer case, it cannot be completely excluded. In instances such as this, it is reasonable to offer full BRCA1/2 sequencing to one of CD’s affected cousins. If one of the cousins were to test negative, the chances become highly unlikely that both tested women in this family developed sporadic breast cancer. Further, because there are three living women affected with breast cancer and several unaffected individuals, it is appropriate to make a referral to additional research studies, such as those offering indirect approaches to BRCA1/2 mutation screening (eg, using linkage analysis, which has been informative in some families when no mutation has been identified).⁵⁶ In addition, the proband’s DNA may be reanalyzed using techniques such as Southern blotting, which can detect genomic rearrangements in BRCA1/2.⁵³ It is also hoped that new technologies, such as the conversion approach (in which the two copies of a gene are separated for analysis), may help increase the sensitivity of existing means of mutation detection.⁵⁷ With respect to novel genes, this family and others like it could be instrumental in identifying new breast cancer susceptibility loci, such as the putative locus on 13q21.⁵⁸

CASE 3: CLARIFYING THE SIGNIFICANCE OF GENETIC VARIANTS
Presentation EF was diagnosed with unilateral breast cancer at the age of 48 years, for which she was treated with lumpectomy and radiation. Her family history was significant for two maternal aunts with postmenopausal breast cancer ( Fig 3). Her mother was alive and well at the age of 70 years, with no history of cancer or prophylactic breast or ovarian surgery. Her paternal history was noncontributory. EF’s test results indicated that a deleterious mutation was not identified in BRCA1 or BRCA2; however, a variant of uncertain significance was found in her BRCA2 gene. In other words, this variant could be associated with increased cancer risks or it could represent a benign polymorphism (normal change) in the gene. Because this distinction could not be demonstrated either biologically or empirically, these test results were considered uninformative. Thus EF could still be at increased risk for developing another cancer, although her personal and family history of breast cancer were not highly suggestive of an inherited predisposition. Because of the uncertainties associated with interpretation of this result and the fact that it should not be used as the basis for making medical management decisions, predictive testing was not extended to at-risk relatives such as the proband’s sisters. However, EF’s mother was tested and did not have the BRCA2 variant, which meant that the variant was not tracking with the breast cancers in the family (ie, EF inherited the variant from her father). Subsequently, the variant was identified in a few high-risk breast cancer patients who also carried a deleterious mutation in BRCA1 or BRCA2, further decreasing the likelihood that this variant is risk-conferring. Nevertheless, the proband and her relatives could still be at somewhat increased risk for developing breast cancer, and therefore they may opt for close surveillance, as outlined in Table 1.^5,45-47

View larger version (12K): [in this window] [in a new window]   Fig 3. Clarifying the significance of genetic variants. Abbreviation: d, deceased.

Patients must also be informed about the possibility that one or more variants in the BRCA1/2 genes may be identified. In our clinical research program, 10% of high-risk probands received ambiguous results (ie, variants of uncertain significance) (unpublished data), which is consistent with the observations by Frank et al.⁸ As more individuals are tested, and as testing is extended to more ethnically diverse and clinically representative populations, often from families that are not considered to be highly suggestive of hereditary breast cancer, it is likely that the number of individuals found to carry variants will also increase. Just as specific deleterious mutations recur in certain ethnic populations, such as those of Ashkenazi or Icelandic descent,^10,59 the frequency of reported variants may also be elevated in certain ethnic groups such as African-Americans.⁶⁰

The variant identified in this family is a missense mutation, which means that one component of DNA was substituted for another. It had not been observed frequently, and although the mutation occurred in a coding, or functionally important part of the BRCA2 gene, the resulting change in amino acid sequence did not result in a truncated BRCA2 protein—a common occurrence with deleterious mutations.^51,61 Other variants may include mutations in intronic regions or in very distal portions of the gene.¹¹ Some missense mutations are known to be clinically significant, such as C61G and C64G, which disrupt the RING finger (a critical domain of the BRCA1 protein).^51,62

However, in the absence of widely available functional tests, the most accessible data about the interpretation of variants arise from clinical observations. For example, if a variant does not track with the breast and ovarian cancers in several families, or if it is seen in conjunction with known deleterious mutations, it may be inferred that the variant is less likely to be of clinical significance.^11,63 Further, variants may be classified as benign polymorphisms if they are observed in control samples (ie, from unaffected individuals in the general population), but it is difficult to know what frequency in the controls is sufficient to make that judgment.⁵¹ Nonetheless, when factored into Bayesian computations, these types of observations may also help determine the significance of variants.⁶⁴

In rare instances, if a variant tracks with breast and/or ovarian cancers in several families, is not present in control samples, and the genetic change is likely to be of functional significance (eg, because it results in the substitution of a highly conserved amino acid that is critical for cell cycle regulation), there may be a high level of suspicion, but not definitive proof, that the variant is risk-conferring.^51,61,63 From a genetic counseling perspective, explaining this type of result to families is very challenging. In response, we have developed specific educational materials about variants for probands and family members to help explain the interpretation and implications of such results. These materials are especially helpful because on a case-by-case basis, and with careful consideration of the specific variant involved, it may be appropriate to offer predictive testing to at-risk individuals. As always, pre- and posttest counseling and follow-up are imperative. Because results may then be used for medical management, which could include aggressive means of risk reduction in female carriers, and the discontinuation of heightened surveillance in noncarriers, such actions must be undertaken with extreme caution. It is also critical that patients understand that the classification of variants is subject to change as functional tests are developed⁵¹ and that some variants may confer a modified risk for breast and/or ovarian cancer compared with most recognized deleterious mutations. In addition to published articles, information about the classification of variants may be found on-line via the Breast Cancer Information Core⁶⁵ and/or through revised reports issued by the laboratory. It is important to maintain current contact information for patients in the event that it is necessary to update them about such new developments.

CASE 4: DETERMINING THE PARENTAL ORIGIN OF AN IDENTIFIED MUTATION
Presentation GH pursued genetic counseling and testing because her sister, a proband in our program, recently tested positive for a BRCA1 mutation (her BRCA2 gene was normal). GH understood that she was at 50% risk for inheriting the BRCA1 mutation identified in her sister, and in fact, she tested negative for this mutation. However, it was emphasized that even though she tested negative, we could not state that her cancer risks were reduced to the levels observed in the general population.

In this case, the family history, as depicted in Fig 4, was significant for cancer on both sides of the family. There were five cases of breast cancer on the maternal side of the family, with at least three of these occurring at early ages (although records were not available to confirm the diagnoses in GH’s maternal grandmother or her siblings). This history was strongly consistent with hereditary breast cancer, and we suspected that the mutation was likely arising from the maternal side. However, on the paternal side of the family, a first cousin (the daughter of an uncle) had early-onset breast cancer and GH’s grandmother had breast cancer in her 70s. This history is much less compelling than the history on GH’s maternal side, but because the cousin was diagnosed with breast cancer at a young age and is linked to GH through two males, it is not out of the question that the mutation could be present on this side of the family. In other words, hereditary breast cancer may be present on both sides of GH’s family, but only one side is transmitting the identified BRCA1 mutation. Further complicating matters was the fact that GH’s paternal cousin’s mother had ovarian cancer. Thus another possible interpretation is that the cousin’s breast cancer may be attributable to a mutation passed down through nonblood relatives to GH. If this were the case, then the breast cancer in GH’s paternal grandmother very likely occurred sporadically.

View larger version (13K): [in this window] [in a new window]   Fig 4. Determining the parental origin of an identified mutation.

1. 1. Testing for the single BRCA1 mutation was offered to GH’s maternal aunt with breast cancer (Fig 4). Consistent with our clinical interpretation, the BRCAPRO model, although it could not capture the entire structure of the proband’s family, predicted that the aunt had a very high chance of testing positive (whereas the cousin’s chance was significant, but much lower).¹⁵ The aunt’s results revealed that the BRCA1 mutation was ruled out. Full sequencing of BRCA1 and BRCA2 was then performed, which did not reveal the presence of a mutation. Explanations for this result, as discussed in case 2, include the possibility that GH’s aunt developed sporadic breast cancer or that the BRCA1 mutation identified in her niece was inherited from the other (paternal) side of the family. In either instance, hereditary breast cancer on GH’s maternal side was not ruled out.
   
2. 2. Testing GH’s maternal uncle was also a possibility, but he declined to be tested.
   
3. 3. GH’s paternal cousin with breast cancer was offered testing for the single BRCA1 mutation, but she also declined to be tested.
   

Therefore, because it could not be determined in which side of the family the BRCA1 mutation was segregating and/or whether another mutation was present, GH was offered the opportunity to undergo additional genetic testing consisting of full BRCA1/2 analysis. However, because of cost concerns (this additional testing was made available clinically) and the strong possibility that a distinct mutation would not be present in her, she did not pursue that option. Thus GH was counseled that she still may be at increased risk for breast cancer and may also have an increased risk for other cancers, such as ovarian cancer. She opted to continue with close surveillance and to consider options for chemoprevention.

Commentary Although hereditary breast cancer is a rare occurrence, accounting for only up to 10% of all breast cancers,⁶⁶ in many instances, individuals will have family histories on both sides that are suggestive of an inherited predisposition. As in this case, one side of the family seemed to be more compelling than the other side. When attempting to determine from which side of the family a mutation was inherited, it may be necessary to extend testing to family members. In some cases, it may be feasible to perform single-mutation analyses on archived paraffin-embedded tumor tissue from affected relatives who are deceased, although there are limitations in this process.⁶⁷ Acquiring the tumor block from GH’s mother was not possible because she was diagnosed more than 30 years ago, but if she had been diagnosed more recently, testing her tumor tissue for the single BRCA1 mutation may have been an option. In other instances, offering testing to unaffected individuals may be warranted (eg, GH’s maternal uncle). Although this process can be time-consuming if there are several unaffected individuals in the family, the practice is sometimes fruitful.

Once a mutation is identified in a family, the standard practice is to test relatives only for the presence or absence of that mutation, except for Jewish individuals, who should be tested for all three founder mutations.^10,68 Thus it is tempting to reassure individuals about their cancer risks when they test negative for a familial mutation. However, the interpretation of a test result as true negative can be done only when both sides of the family are assessed. In addition, when distant relatives (eg, cousins) have had cancer, it is critical to inquire about the cancer family history of both of their parents, as risk may not be conferred through the bloodline of the person seeking risk information.

If there are features of the family history that raise concern, it is important to counsel individuals that because their risk may be substantially higher than average, screening guidelines for the general population may not be adequate. This principle applies when both sides of the family are suggestive of the same hereditary cancer syndrome and when other cancer(s) or cancer clusters are present.

CASE 5: RE-EVALUATING RISK ASSESSMENT BASED ON AN EVOLVING FAMILY HISTORY
Presentation In 1997, the proband IJ presented for genetic counseling and testing because she wanted to know why, at the age of 29 years, she had been diagnosed with breast cancer, for which she underwent a lumpectomy followed by radiation and chemotherapy. At the time, no immediate family members were affected with breast or ovarian cancer ( Fig 5). Her paternal family history was not significant for any cases of cancer and her mother’s family history, which consisted of many unaffected women, did not seem to be suggestive of hereditary breast cancer even though her aunt was diagnosed with breast cancer at an early age. Of note, IJ reported initially that another maternal aunt had ovarian cancer, but review of medical records indicated that she had undergone total abdominal hysterectomy/bilateral salpingo-oophorectomy because of uterine bleeding and the presence of benign ovarian cysts diagnosed at age 53 years. IJ underwent full sequencing of BRCA1 and BRCA2, and no mutation or variants were identified. Therefore, she was counseled that her breast cancer probably developed sporadically, despite her young age at diagnosis. Nevertheless, based on empiric data, she was informed that her sisters’ and mother’s risk for breast cancer was elevated⁶⁹ and that they should be screened appropriately.

View larger version (14K): [in this window] [in a new window]   Fig 5. Re-evaluating risk assessment based on an evolving family history.

Commentary This vignette, like others presented in this article, addresses the complex nature of interpreting uninformative test results. However, the crux of this case surrounds the evolving aspects of the family history and how this information affects interpretation of test results. As illustrated here, risk assessment is only as accurate as the family history on which it is based. Therefore, it is important to encourage patients to obtain information about their family history from relatives, and to follow-up by requesting confirmation of diagnoses whenever possible. Although review of pathologic reports is ideal, in instances when these are not available, review of death certificates can be helpful. It is not uncommon for cancer diagnoses to be misreported, especially in more distant relatives.⁷⁰ Misreporting may include an incorrect primary site (eg, colon cancer reported as liver cancer or ovarian cancer reported as stomach cancer) or confusion between malignant and benign conditions (eg, benign prostatic hyperplasia reported as prostate cancer or ovarian cysts reported as ovarian cancer). These types of errors can result in a significant underestimate or overestimate of risk, which may affect the screening and prevention guidelines provided to the patient.⁷¹ In particular, because the presence of ovarian cancer is such a strong predictor for the identification of BRCA1/2 mutations,^8,12 determining the presence or absence of this malignancy is very important.

In addition, because family history does evolve over time, it is prudent for providers of genetic counseling services to encourage a two-way line of communication regarding changes in the clinical status of the patient or the family history.⁷² This process helps to ensure that cancer risks are reassessed accordingly and new research developments can be discussed.⁷² Invariably, other breast cancer genes will be identified, and it is likely that the first individuals to partake of new testing options will be those who received uninformative BRCA1/2 results.

	DISCUSSION

TOP ABSTRACT INTRODUCTION CASE 1: SURGICAL DECISION... DISCUSSION REFERENCES

 
The vignettes presented in this article demonstrate that the interpretation of BRCA1/2 results is often not straightforward. However, even within these complex cases, certain themes in risk assessment and result interpretation emerge, as summarized in Table 2. Critical components of genetic counseling include a discussion of the many medical and scientific issues related to risk assessment and genetic testing, as well as concomitant psychosocial issues.^73,74 Although the latter was not a focus of this article, it is important to note that published studies have found that most BRCA1 genetic testing participants do not experience significant adverse psychologic effects in the short term.^75,76 It is encouraging that both patients and providers believe that the medical and psychosocial aspects of genetic testing are important to address during genetic counseling for hereditary cancer.⁷⁷ A thorough understanding and consideration of this spectrum of issues, including the potential benefits, limitations, and risks of testing, can be obtained through the process of informed consent—a process that is folded into the components of pretest education and counseling.^74,78,79 Informed consent should also be obtained in writing before any patient undergoes genetic testing.⁷⁴

Based on our experience, we realize that the time-consuming nature of pretest and posttest genetic counseling, in addition to its many complexities, may make it difficult for many oncologists to provide comprehensive services at the point when patients are ready to consider genetic testing or to get their results. Therefore, a referral to a cancer genetic counseling provider (ie, a genetic counselor or a nurse specializing in genetics) is appropriate. However, knowledgeable physicians can offer a great deal of information and support to patients when they ask for recommendations about whether to be tested and how to manage their risk of cancer. This is especially important, as most genetics providers are not likely to have ongoing contact with patients, whereas oncologists and oncology nurses see their patients at regularly scheduled appointments for screening or other follow-up. The growing partnership between genetics and other medical specialties has and will continue to enable patients to gain the most potential benefit from cancer genetic testing and will serve as a paradigm for service delivery once predisposition testing for other adult-onset disorders becomes available.

	ACKNOWLEDGMENTS

 
Supported by United States Department of Defense grant no. DAMB 17-96-C-6069, grant no. R01 HG01846 from the National Human Genome Research Institute, grant no. R01 CA74861-03 from the National Cancer Institute/National Institutes of Health, and institutional funds from the Lombardi Cancer Center.

We thank all of the men and women who participated in this study, as well as the physicians and nurses who referred patients to us. We are grateful to Dr Marc Lippman for his support of this study; Camille Corio, MA, for performing data management; Annalisa Dialino-Felix, BS, for preparing the figures and providing helpful comments; and to Anahita Nikzad, MS, for performing BRCAPRO analysis. BRCA1/2 gene testing was performed by the Institute for Molecular and Human Genetics at Georgetown University, Myriad Genetic Laboratories (special thanks to Dr Tom Frank, Medical Director), and the University of Pennsylvania Genetic Diagnostic Laboratory.

	NOTES

 
Presented in part during a poster session at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.

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TOP ABSTRACT INTRODUCTION CASE 1: SURGICAL DECISION... DISCUSSION REFERENCES

 
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Submitted October 10, 2000; accepted February 5, 2001.

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