Ann Surg Oncol (2014) 21:3209–3215 DOI 10.1245/s10434-014-3906-0

ORIGINAL ARTICLE – BREAST ONCOLOGY

Genetic Testing Today David Euhus, MD Johns Hopkins Hospital, Baltimore, MD

ABSTRACT Background. The commercial introduction of next-generation sequencing has made it possible to test for mutations in all known or suspected breast cancer predisposition genes in one panel, at one time, for about the same cost as a BRCA gene test. Clinicians are increasingly presented with the challenge of advising patients with mutations in rare breast cancer predisposition genes. Methods. Literature review and personal experience with panel tests. Results. Panel tests are more likely to identify a variant of uncertain clinical significance than a deleterious mutation. In addition, not all of the genes included in panel tests are unequivocally linked to increased breast cancer risk, and for most genes the penetrance is highly variable, making it difficult to translate a specific mutation into an absolute breast cancer risk. The three-generation cancer family history should be used to select truly high-risk families for panel testing, and then referred to again when the results are received in order to guide risk-management decisions. Knowing a breast cancer patient’s mutation status can influence decisions about local–regional and systemic therapy, but turnaround times for many tests are still too long to incorporate them into the initial evaluation of a new breast cancer. Conclusion. The commercialization of next-generation sequencing has the potential to greatly enhance the identification and management of individuals with an inherited predisposition to breast cancer. A period of uncertainty is anticipated before the full potential of this new technology is realized.

Ó Society of Surgical Oncology 2014 First Received: 6 April 2014; Published Online: 17 July 2014 D. Euhus, MD e-mail: [email protected]

By the mid-nineteenth century, Herbert Lebert and Paul Broca had recognized the possibility of inherited cancer predisposition and described some of the essential features.1,2 They recognized that familial cancer predisposition was relatively rare, that women were disproportionately affected with cancer compared with men, and that cancer rates in affected families were at least 15-fold greater than those observed in the general population. It was about this time that Gregor Mendel elucidated the basic principles of inheritance3 and Friedrich Miescher isolated DNA;4 however, it was not until 1944 that Oswald Avery recognized that DNA is the medium of genetic transmission.5 Modern approaches for amplifying specific DNA sequences were not described until the 1980s,6 but by 1990 it was recognized that inherited DNA changes in the chromosomal location, later named BRCA1, were associated with predisposition to breast and ovarian cancer.7,8 By April 2003, the entire human genome had been sequenced.9 Notably, the Human Genome Project, which used twentieth century technology, required more than a decade to complete at a cost of $2.7 billion. Since that time, DNA technology has advanced at an astronomical rate. With the advent of massive parallel sequencing, or next-generation sequencing, it is now possible to sequence an entire human genome in a few weeks for less than $5,000. These rapid technological advances are reducing the cost of genetic testing and providing answers for some high-risk families with negative BRCA gene tests. At the same time, interpretation of genetic test results has become more complex, and some results are simply uninterpretable given the current state of knowledge. BRCA1 was cloned in 199410 and BRCA2 in 1996.11–13 The subsequent commercialization of BRCA gene testing created demand for clinical cancer genetics services in order to identify individuals likely to carry a mutation, educate patients about the potential risks and benefits of exposing their germ line sequences, help patients decide about testing, and then interpret and act on the results. As more predisposition genes were identified, the three-generation cancer family history was used to decide whether additional testing was warranted when a BRCA test was

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Familial

Sporadic

BRCA1 BRCA2 CHEK2 PALB2 ATM CDH1 TP53 RAD50 UNKNOWN VUS BRIP1 NBN RAD51C PTEN MRE11A

Possibly Familial

FIG. 1 Only 12–30 % of breast cancers have a significant genetic component, and known genes account for only 35 % of these. The most common genes have already been identified. The balance is likely due to very rare mutations or combinations of mutations each unique to just a few families. VUS variant of uncertain clinical significance

negative. This could take the form of more extensive testing of the BRCA genes, or testing for mutations in other genes. The availability of next-generation sequencing is challenging this serial testing strategy as it is now possible to simultaneously test for mutations in all known or suspected breast cancer predisposition genes for about the same cost as a BRCA gene test. This creates new challenges for pre-test counseling and post-test results interpretation. GENETIC COMPONENT OF BREAST CANCER Twin studies suggest that only 12–30 % of breast cancer is primarily genetic in origin,14–16 and modeling studies implicate autosomal dominant inheritance of single genes as the most important mechanism.17,18 Despite the recent rapid pace of discovery, it is estimated that only 35 % of apparently hereditary breast cancer can be explained by

TABLE 1 Providers of hereditary predisposition panel tests

Provider

Test name

Myriad Genetics, Inc. myRisk

known gene mutations (Fig. 1).19 The balance is likely due to very rare mutations which will be difficult to identify.20 THE PANEL TESTS The number of laboratories offering breast cancer predisposition panel tests is increasing rapidly (Table 1). The number of genes reported ranges from just a few to more than 40. It is important to recognize that inclusion of a gene on a panel test does not mean that mutations in that gene are unequivocally linked to increased breast cancer risk. Since a Supreme Court decision in June 2013, most of the panel tests have included BRCA1 and BRCA2. Some of the panels limit additional genes to those for which there are established clinical management guidelines, including CDH1, PTEN, STK11, and TP53. This is a rational strategy that simplifies interpretation of the results, but it does exclude PALB2, which is among the more frequently mutated non-BRCA genes that has been associated with significant breast cancer risk in some families. Other genes are included on the panel tests because of epidemiological data suggesting increased breast cancer risk. This often takes the form of case–control data where the mutation is observed more frequently in breast cancer cases than controls. For some, there is reasonable biological plausibility based on their interactions with BRCA1 for accurate DNA repair or cell division. These include the five Fanconi anemia genes, FANCD1/BRCA2, FANCJ/BACH1/BRIP1, FANCN/PALB2, FANCO/RAD51C, and FANCA,21 as well as ATM, CHEK2, and TP53. The most reliable approach for confirming a breast cancer association is a linkage analysis where the mutation of interest is consistently seen in family members affected with breast cancer, but not family members never diagnosed with breast cancer. This type of data is simply lacking for many genes included on panel tests, and for some of the included genes, linkage is incomplete.19 The clinician tasked with interpreting a panel test that is

URL https://www.myriad.com/products/myrisk-hereditary-cancer-panel/

Ambry Genetics

BreastNext

http://www.ambrygen.com/tests/breastnext

University of Washington GeneDX

BROCA

http://tests.labmed.washington.edu/BROCA

Emory Genetics Laboratory

Various

http://genetics.emory.edu/egl/

Ethigen

Various

http://www.ethigen.net./

Invitae

Various

https://www.invitae.com/en/

Baylor College of Medicine

Various

https://www.bcm.edu/research/medical-genetics-labs/tests.cfm

OncoGeneDx http://www.genedx.com/oncology-genetics/

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BRCA1 BRCA2 PTEN

Gene

TP53 PALB2 CDH1 STK11 CHEK2 ATM RAD51C 0

20

40

60

80

100

Lifetime Risk (%) FIG. 2 It is common to try and classify predisposition genes as high, moderate, or low penetrance, but the cancer risk associated with each of these genes is highly variable between families. The threegeneration cancer family history is the best guide for estimating penetrance for a given family

positive for a rare deleterious mutation in one individual must remain critical and avoid assuming that this mutation accounts for all of the breast cancer cases in the family. RAD51C provides one example of ongoing controversy. While some epidemiological studies suggested a strong association with breast cancer,22 others have found that this is an ovarian cancer predisposition gene with no relationship to breast cancer at all.23 In the next-generation sequencing era, it is theoretically possible to sequence the entire genome and report out on mutations that may influence the risk for diseases other than cancer. Panel tests are constructed, analyzed, and reported with an intentional blindness to all but a specifically selected list of genes. Clinicians should be cognizant of which genes were not reported when interpreting a test result. There are really no significant technical factors capable of distinguishing one panel test from another. One provider could be chosen over another based on cost alone, but other important factors include insurance precertification services, accurate disclosure of out-of-pocket costs, time to report results, and procedures for handling variants of uncertain clinical significance (VUS). It is expected that VUS rates will be high initially with any new genetic test. Providers who have robust informatics approaches for classifying variants and who offer no charge testing to additional affected and unaffected family members are to be preferred. In addition, until more is generally known about the rare predisposition genes, the best test providers will provide detailed guidance for interpreting test results in their reports. INTERPRETING GENETIC TEST RESULTS The first task after receiving a genetic test result is to incorporate that information into a revised estimate of the

patient’s age-specific and cumulative cancer risk over time. This is not easy, even for well-studied genes such as BRCA1 and BRCA2. Every family has a unique genetic background that will modulate the ultimate effects of deleterious mutations in major predisposition genes (Fig. 2).24 The threegeneration cancer family history is helpful for getting a sense of ages at diagnosis in a specific family, as well as the magnitude of risk. Quantitative family history models such as BRCAPRO,25 BOADICEA26 or Tyrer-Cusick27 can be used to estimate risk, but these are designed for hereditary breast–ovarian cancer syndrome. There is a need to develop new models for estimating risk in individuals who carry mutations in rare predisposition genes. The pedigree has become more important than ever in the era of panel testing, both for deciding who to test and for understanding what the test result may mean. Interpretation of panel test results is easier if the patient comes from a very-high-risk family with many cancer cases. In the future, when quite a lot more is known about the rare predisposition genes and how they interact with a family’s unique genetic background, panel tests may be offered widely with minimal pre-test selection. However, for now, when little is known about many of the genes, it seems best to limit panel tests to families with very strong cancer family histories, and to always test the individual in the family who is most likely to carry a mutation.28 As with any genetic test, clinicians need to be mindful that a negative test result in a family that has no positive test result is classified as a non-informative negative test that has not been helpful in refining the risk estimate. In general, a negative test in a family whose cancer cases have been adequately explained by positive test results means that that individual is not at increased risk for cancer with the caveat that, for some of the rare genes, it is not yet clear that the mutations are sufficiently well-linked to the cancer cases to make this judgment. GENETIC COUNSELING In 2012, the American College of Surgeons Commission on Cancer accreditation program (www.facs.org/ cancerprogram/index.html) mandated that cancer risk assessment, genetic counseling, and genetic testing services be provided to patients by a qualified genetic professional either on site or by referral. Practice guidelines for genetic counselors have been well articulated by the National Society of Genetic Counselors.29 Obtaining informed consent is part of pre-test counseling. This includes educating the patient about inherited predisposition and the potential benefits and risks of genetic testing. The possible test results are explained in Table 2. The patient must understand that the result may not be helpful at all if it returns a mutation in a gene we know little about, or, more commonly, if it returns a variant that has

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TABLE 2 Interpreting genetic test results Test result

Interpretation challenge

Deleterious

Penetrance (how much cancer risk) This mutation This gene

Higher penetrance families can be recognized from the pedigree.30 CHEK2 has rarely been associated with a LiFraumeni-like syndrome, and although some mutations may increase the risk for other cancers, such as thyroid, kidney, colorectal, and prostate,31 no specific screening for these cancers is warranted.

This family Variant of uncertain clinical significance

No risk information Manage risk according to clinical and family history features Burden to contact individual when variant reclassified

Variant suspected benign ‘Probably’ not increasing risk Manage risk according to clinical and family history features Definitely benign/ negative

Usually no increased risk if there is a known deleterious mutation in the family No information if there is no known deleterious mutation in the family Manage risk according to clinical and family history features

not yet been classified as benign or deleterious. It is important to recognize that a panel test is more likely to return a VUS (20–30 %) than a deleterious mutation (8–10 %). Pretest counseling is also the time to start developing a plan for responding to any of the possible test results—negative, variant suspected benign, VUS, or deleterious (Table 2). The result is disclosed and explained at the time of post-test counseling. This includes revising the cancer risk estimate if possible. A management strategy is discussed and required referrals made. For patients with a VUS, risk estimates, and management recommendations are based on the three-generation cancer family history. It is important to have a mechanism for recontacting VUS patients when the result is eventually reclassified as deleterious or benign. THE MOST COMMON RARE SYNDROMES Mutations in BRCA1 or BRCA2 still account for the greatest fraction of hereditary breast cancer. Apart from BRCA1 and BRCA2, panel tests are most likely to identify deleterious mutations in CHEK2, PALB2, ATM, and CDH1. Table 3 lists the most frequently encountered genes in order of frequency, along with a few key clinical observations for each gene. A few words touching on the main features of a few of these syndromes may be helpful. CHEK2 CHEK2 is associated with a modest increased risk for breast cancer, particularly hormone-sensitive breast cancer.

PALB2 PALB2 can be considered as BRCA3. It is one of the most common rare genes and is similar to BRCA2 in most respects, except for a lack of strong association with ovarian cancer. ATM Homozygous ATM mutations cause ataxia-telangiectasia, an inherited syndrome associated with leukemia and lymphoma. Panel testing is identifying individuals with heterozygous mutations, some of which may be at increased risk for breast cancer. These mutations are difficult to interpret because some truncating mutations that are likely to affect protein function have not been convincingly linked to breast cancer, while others have. The pedigree must serve as the guide to interpretation. Although radiation should be avoided in homozygous ataxia telangiectasia patients,32 there is no clear evidence for increased radiation effects in heterozygous mutation carriers.33,34 TP53 Li-Fraumeni syndrome has been considered a very rare cancer predisposition syndrome associated with high risk for very early onset (before 35 years of age) estrogen receptor- and human epidermal growth factor receptor 2 (HER2/neu)-positive breast cancer, as well as increased risk for other cancers such as sarcoma, brain, and adrenocortical cancer. Panel testing is identifying many new ‘LiFraumeni’ families. Although penetrance is likely to be lower in individuals identified in this fashion, it is reasonable to manage these patients according to established guidelines.35 CDH1 CDH1 mutation causes hereditary diffuse gastric cancer syndrome which is associated with very high risk for earlyonset diffuse signet cell carcinoma of the stomach, and moderate risk for infiltrating lobular carcinoma of the breast. The gastric cancers are extremely difficult to diagnose by endoscopy at an early stage so these patients may be best managed in specialized centers. Enhanced

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TABLE 3 Frequency, breast cancer risk, and clinical features of some of the recognized syndromes Gene

Clinical mutation positivity rate (%)a

Lifetime breast cancer risk (%)

Key features

BRCA1

5–10

65–81

Basal-type triple-negative breast cancer; ovarian cancer

BRCA2

5–10

45–85

Hormone-sensitive breast cancer; male breast cancer; melanoma; pancreas cancer

CHEK2

0–3

20–44

Hormone-sensitive breast cancer

PALB2

1–4

25–91

Hormone-sensitive breast cancer; male breast cancer; pancreatic cancer; similar to BRCA2

ATM

1–3

15–60

Certain mutations increase risk, others do not. Difficult to interpret results

CDH1

\1

39–52

Hereditary diffuse gastric cancer; infiltrating lobular carcinoma

TP53

\1

[50

Very early onset, high-grade, hormone-sensitive, and HER2-positive breast cancer

RAD51C

\1

10–20

Ovarian cancer families

PTEN

\1

77–85

Cowden syndrome. Macrocephaly, extensive benign breast disease, thyroid and endometrial cancer

STK11

\1

24–32

Peutz–Jegher syndrome. Mucocutaneous pigmentation; hamartomatous polyps; early-onset breast cancer; pancreas and GI cancer

HER2 human epidermal growth factor receptor 2, GI gastrointestinal a

Fraction of tested families positive for a deleterious mutation. Highly variable depending on the age and family history criteria used for selection

surveillance with breast magnetic resonance imaging (MRI) is indicated for women with this syndrome and some will opt for risk-reducing mastectomy. STK11 STK11 mutation is the cause of Peutz–Jegher syndrome, which is recognized clinically by pigmented mucocutaneous lesions and hamartomatous gastrointestinal polyps. These patients are at moderate to high risk for early-onset breast cancer and high risk for pancreatic cancer (about 35 %). The de novo mutation rate is high for this gene so many affected individuals will have no significant family history of cancer. MANAGING RISK IN MUTATION CARRIERS Risk-management strategies are developed based on the estimated cancer risk and the time course for manifestation of that risk. Published guidelines are available for some of the genes.35 It is reasonable to encourage a lifestyle that includes abundant recreational physical activity and dietary practices directed at avoiding weight gain. There is some evidence that this can delay breast cancer development in gene mutation carriers.36,37 The American Cancer Society has endorsed screening MRI for women with a lifetime breast cancer risk that exceeds 20 %.38 Most women with deleterious mutations in one of the breast cancer predisposition genes shown in Table 3 will meet this threshold. Screening with annual MRI and mammography can begin 10 years before the earliest age of breast cancer diagnosis in the family, but mammography could be delayed until

after 30 years of age because of the growing evidence that exposure to medical radiation before that time may increase breast cancer risk.39–41 Chemoprevention with tamoxifen,42 raloxifene,43 examestane,44 or anastrazole45 could be considered based on the patient’s menopausal status and estimated risk. Chemoprevention may be most attractive in women with mutations in genes associated with the development of hormone-sensitive breast cancer, including BRCA2, PALB2, CHEK2, and TP53, but there is some evidence that tamoxifen reduces risk in BRCA1 mutation carriers as well.46,47 Risk-reducing salpingoophorectomy reduces breast cancer risk by 37–72 %,48,49 with greater effects in women predisposed to develop estrogen receptor-positive breast cancer. Bilateral salpingo-ophorectomy has also been associated with reduced breast cancer-specific and all-cause mortality, especially in BRCA1 mutation carriers.48,50 Risk-reducing appendectomy at the time of oophorectomy is being considered to reduce the risk of subsequent intraperitoneal carcinomatosis.51 Risk-reducing bilateral salpingo-ophorectomy is generally considered around 35–40 years of age or after completion of childbearing. Bilateral prophylactic mastectomy reduces breast cancer risk by more than 90 %.52–54 A nipple-sparing approach with thin areolar flaps and thorough removal of the axillary tail is acceptable.55 MANAGING BREAST CANCER IN MUTATION CARRIERS Genetic test results can influence decisions about the local and systemic treatment of breast cancer, but the time

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from blood draw to reporting for most panel tests is currently too long to routinely incorporate them into initial evaluation for treatment planning. Discovery of a deleterious mutation in a recently diagnosed breast cancer patient should evoke two planning processes: (i) how best to treat the breast cancer; and (ii) how to reduce the risk of subsequent cancers. It is perfectly acceptable to focus on treating the breast cancer while postponing implementation of a risk-management strategy. Although the inherited predisposition syndromes are associated with an increased risk for second primary breast cancers, breast conservation is still a reasonable option for the well-informed patient.56,57 However, data are accumulating, suggesting that bilateral mastectomy is associated with improved breast cancer-specific survival, but this benefit is not realized until the second decade.58,59 Patients with mutations in DNA repair genes such as BRCA1, BRCA2, PALB2, RAD51C, BACH1/BRIP, ATM, and CHEK2 may have relative resistance to taxanes 60,61 and increased sensitivity to platins62–66 and poly(ADP-ribose) polymerase (PARP) inhibitors.67–69 Clinical trials are available that target BRCA1 and BRCA2 mutation carriers; patients with other syndromes may be eligible for platin or PARP inhibitor trials if they have triple-negative breast cancer. DISCLOSURE

None.

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Genetic testing today.

The commercial introduction of next-generation sequencing has made it possible to test for mutations in all known or suspected breast cancer predispos...
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