11
Cancer and RISK Assessment
It is estimated that approximately 5% to 10% of cancers are inherited as a result of germline mutations. Inherited cancer syndromes result in an increased risk of a specific type of cancer as well as other cancers or conditions. This chapter focuses on hereditary cancer syndromes associated with breast and colon cancers. Like that of other genetic conditions, the importance of risk assessment is key to early recognition of the syndromes so that appropriate management of risk can be implemented, which includes enhanced surveillance, chemoprevention, or risk-reduction surgery, if applicable.
Objectives
1. Discuss the RISK assessment process when evaluating individuals for inherited breast cancer syndromes
2. Discuss the RISK assessment process when evaluating individuals for inherited colon cancer syndromes
3. Identify resources for risk communication and risk management when suspecting individuals for inherited cancer syndromes
Breast Cancer and Hereditary Breast Cancer Syndromes
Breast cancer is the most common form of cancer in women. Approximately one in eight women in the United States, or 12%, will develop invasive 148breast cancer during their lifetime (American Cancer Society [ACS], 2017e; Siegel, Miller, & Jamal, 2017). A myriad of nonmodifiable and modifiable factors are associated with breast cancer, and assessment of these factors play an important role in the risk assessment process and in identifying potential factors that may be suspect or red flags for inherited breast cancer syndromes. Table 11.1 includes examples of factors that can impact breast cancer risks.
Breast cancer risk assessment is important in identifying potential red flags that can be suspect for an inherited breast cancer syndrome. There are many types of breast cancer syndromes resulting from different pathogenic germline mutations, but the most common inherited form of the disease is that of hereditary breast and ovarian cancer (HBOC) syndrome due to mutations in the BRCA1 or BRCA2 genes (Lynch et al., 2007). Approximately 95% of families with inherited breast/ovarian cancer is due to mutation in BRCA (Ford et al., 1998). Although the syndrome is associated with increased lifetime (age 70) risk of breast (40%—80%) and ovarian cancer (15%–40% depending on the gene), there are other cancers and conditions that may occur as a result of the genetic mutation (Table 11.2; Petrucelli, Daly, & Feldman, 1998/2016). Even though HBOC makes up most of the hereditary breast cancer syndromes, there are other inherited disorders associated with breast and ovarian cancer that must be considered when assessing individuals for an inherited cancer syndrome. Therefore, it is important that when assessing individuals for familial risk of breast cancer, particularly due to genetic mutations, a comprehensive personal and family history including physical examination should be conducted to assess for red flags that may be attributed to HBOC or other inherited cancer syndromes that increase the risk of breast and/or ovarian cancers. Table 11.2 presents a list of breast cancer syndromes caused by germline mutations including the gene associated as well as other conditions/cancers associated with the syndrome.
149TABLE 11.1 Breast Cancer Risk Factors
• Noninherited/no history of germline mutation—nonmodifiable • Increasing age (age 55 and older) • Gender (women 1:8 lifetime risk; men 1:1,000 lifetime risk a) • Race/ethnicity • Caucasian high incidence; African Americans higher mortality rates and higher rates of age younger than 45 years • Increased incidence of BRCA1 and BRCA2 mutations among Ashkenazi Jews • Reproductive history • Early age of menarche (before age 12) • Nulliparity • Older age at first live birth • Older age at menopause (e.g., after age 55) • Family history (e.g., ~twofold risk with a first-degree relative [mother, sibling, daughter]; threefold increase with two first-degree relatives) • Approximately 15% to 20% of breast cancers are familialb • Breast density (mammography) • Breast lesions (examples) • Atypical ductal hyperplasia (ADH)c—four- to fivefold increase in risk (RR) • Atypical lobular hyperplasia (ALH)c—four- to fivefold increase in risk (RR) • Lobular carcinoma-in situ (LCIS)—tenfold increase in risk • Mantel radiation to the chest (children/young adults for certain cancers, Hodgkin’s disease or non-Hodgkin’s lymphoma) (e.g., prior thoraic radiation less than 30 years of age) • Noninherited modifiable • Increased body mass index after menopause • Alcohol consumption (e.g., two- to fivefold increase in risk compared to 1.5-fold in those not using alcohol) • Physical inactivity • Current or prior estrogen and progesterone hormone therapy • Decreasing risk factors • Breastfeeding • Prior oophorectomy before age 45 years • Physical activity • Prior risk-reducing therapy/surgery |
RR, relative risk.
Sources: ACS, 2016; National Comprehensive Cancer Network (NCCN, 2016a); ACS 2017e; bLynch, Silva, Snyder, and Lynch (2007); cHartman, Degnim, Santen, Dupont, and Ghosh (2015).
150TABLE 11.2 Inherited Syndromes Associated With Breast and/or Ovarian Cancer, and the Gene Mutation and Conditions and Cancers Associated With the Syndrome
Cancer Syndrome and (Inheritance Pattern) | Gene Mutation | Breast and Ovarian Cancer Risk and Other Conditions Associated With the Syndrome |
Hereditary breast and ovarian cancer (AD)a | BRCA1 | Breast (40%–80%); increased male breast cancer risk; Ovarian (15%–40%); peritoneal; fallopian tubes; melanoma; pancreatic; prostate |
Partner and localizer of the BRCA2 geneb (AD) | PALB2 | Breast (14%–35%); pancreatic cancer |
Cowden syndromec (AD) | PTEN | Breast (85% risk); endometrial cancer; follicular thyroid cancer (rarely papillary); gastrointestinal hamartomas; Lhermitte–Duclos disease (adult); skin changes (e.g., trichilemmomas; acral keratosis; oral papillomas; penile freckling; mucocutaneous neuromas; uterine fibroids; thyroid nodules/multinodular; macrocephaly |
Li Fraumenid (AD) | P53 | Breast, particularly early age onset (50%); sarcoma (e.g., osteosarcoma; soft-tissue sarcomas); leukemia; central nervous system (brain); adrenocortical |
Peutz–Jegherse (AD) | STK11 | Breast cancer (45%–50%); Ovarian (18%–21%); cancers: colorectal, gastric, pancreatic; Adenoma malignum of the cervix; benign neoplasm of ovary; Peutz–Jeghers type—hamartomatous polyps: small intestine; stomach; large bowel; mucotaneous macules predominantly in childhood |
Hereditary diffuse gastric cancer (AD)f | CDH1 | 151 Breast cancer (39%–52% lobular breast cancer); diffuse gastric cancer |
Lynch syndromeg (AD) | MLH1 | Ovarian cancer (4%–24%); cancers: colon; endometrial; stomach; urinary (renal pelvis); brain; pancreas; hepatobiliary; sebaceous neoplasma |
Ataxia-telangiectasia (AR)h | ATM | Breast cancer (28%); progressive cerebellar ataxia; telangiectasias; increased risk leukemia and lymphoma; sensitivity to ionizing radiation |
Checkpoint kinase 2i (AD) | CHEK2 | Breast (~20%–25%) increased colon, prostate |
AD, autosomal dominant; AR, autosomal recessive.
Sources: a Petrucelli et al. (1998/2016); b Antoniou et al. (2014); c Eng (2016); dMai et al. (2016); e McGarrity, Amos, and Baker (2001/2016); fKaurah and Huntsman (2002/2014); gNational Comprehensive Cancer Network (2017b); hCybulski et al. (2011); iLee et al. (2016).
152Although Table 11.2 presents a myriad of genes associated with inherited breast cancer, it is not all inclusive. Additional genes not shown in the table but associated with breast cancer include mutations in the BRIP, NBN, and RAD50, RAD51C, RAD51D, and MRE11, as well as other genes that are considered moderate penetrant genes (Kleibl & Kristensen, 2016; Mahdi, Nassin, & Nasin, 2013; NCI, 2017c; Ramus et al., 2015). Because of the various genes associated with breast and/or ovarian cancer, it is essential that advanced practice registered nurses (APRNs) without appropriate training refer patients suspect for an inherited breast cancer syndrome to an expert for appropriate genetic counseling and determination for genetic testing.
Review of History
The personal and family history is essential in determining familial and inherited (germline mutations) breast cancer risk. Important elements of the personal as well as family history are presented as each relates to the genomic risk assessment process when assessing for an inherited breast cancer syndrome.
Personal History
Current age of the proband/consultand should be obtained, including prior history of cancers and the age of onset of disease occurrence, pathology report(s), and treatment(s) given. Detailed medical and surgical history should also be obtained, including reproductive history (e.g., menstrual history; age of first birth; menopausal history) and prior surgical history, including breast biopsies and gynecological surgeries with pathology reports, as well as an annotation if prior surgery was conducted as a measure of risk-reduction, if applicable. Inquiry on the medication history, especially birth control and hormone use, should be included in the history data. Radiation exposures should also be assessed as this can increase cancer risks, including breast cancer. For instance, individuals exposed to mantel radiation for treatment of childhood cancers (e.g., Hodgkin’s lymphoma) have up to a 40% increased risk of breast cancer by age 50 years (Moskowitz et al., 2014).
A focused physical exam should be conducted as part of the assessment; this includes breast, abdominal, and pelvic exams as well as evaluation of the thyroid, head circumference, skin, and oral mucosa due to Cowden syndrome, an inherited breast cancer syndrome that can manifest with macrocephaly (occipital frontal circumference ≥97th percentile or 153≥58 cm for adult women and 60 cm for adult men; Shiovitz et al., 2010), and with dermatological characteristics and thyroid nodules (Eng, 2016; NCCN, 2017b; Table 11.2).
Family History
Check for patterns of inheritance and consanguinity on both the maternal and paternal lineages. A minimum three-generation pedigree is recommended as part of the assessment process. Always inquire about information on the ancestry of origin as some racial/ethnic groups are at higher risk for inherited breast cancer syndromes. For example, the frequency rate of BRCA mutations among individuals of Ashkenazi Jewish ancestry is one in 40 or 2.3%, compared to one in 500 or 0.2% for the general population; these rates further increase based on age and family history (Hartge, Struewing, Wacholder, Brody, & Tucker, 1999). In addition, three founder mutations—BRCA1 (185delAG or 5382insC) and BRCA2 (6174delT)—have been shown to occur frequently in the Ashkenazi Jewish population among those with HBOC (Hartge et al., 1999; Streuwing et al., 1997). Another part of the family history is to observe the family structure in the history data or depicted on the pedigree that may limit patterns of inheritance due to early-age onset of death for some members, paternal inheritance with few to no females on the paternal lineage, or adoption (see Figures 7.1 and 7.2). Current age of family members; pertinent medical/surgical history, particularly cancer history and age of onset of disease; type of cancers; bilaterality; chemoprevention; and risk-reduction surgery should also be assessed, documented, and reviewed as it pertains to family members (NCCN, 2017b).
Identify Red Flags
There are personal, familial, and clinical manifestations that are considered red flags for hereditary breast cancer syndromes. Table 11.3 provides examples of some elements of risk that are considered red flags for possible inherited breast cancer syndromes, warranting APRNs to consider the need for further follow-up.
Select a Risk Probability
If identified red flags are present, discuss with the patient genetic referral for counseling, further evaluation, and possible genetic testing. If needed, 154have the patient procure personal pathology reports and medical records as well as death certificates, if needed, of cancer, medical disorders, or cause of death is uncertain or ambiguous and/or the family member’s diagnosis of cancer warrants confirmation. Individuals with a known gene mutation in the family are considered at high risk for breast cancer until genetic testing has been conducted and reveals no mutation found for the mutated gene; this would constitute a true negative finding.
TABLE 11.3 Red Flags That May Be Suspect for a Familial or Inherited Breast Cancer Risk
• Early age onset of breast cancer in proband or family member • Male breast cancer (personal or family history) • Multiple family members with breast cancer • One or more close family member (first, second, or third degree) with ovarian/fallopian tube or primary peritoneal cancer at any age • Personal history of ovarian cancer • Triple negative breast cancer diagnosis (estrogen, progestin, and HER2 negative) at age 60 or younger • Known family member with a germline mutation for an inherited cancer syndrome • High-risk/at-risk groups/populations based on ancestry of origin (e.g., Ashkenazi Jewish ancestry), particularly with a history of breast, ovarian, or pancreatic cancer • Cancer or medical history in the proband or family members suspect for other inherited cancer syndrome (e.g., macrocephaly and Cowden syndrome or clinical manifestations) |
HER2, human epidermal growth factor receptor 2.
Sources: ACS (2016); NCCN (2016a, 2017b).
Individuals without a personal or family history of risk factors, including no behavioral/lifestyle or environmental risks, are considered at population or average risk. The population risk for breast cancer is approximately 12%, or one in eight for women and one in 1,000 for men.
Keep Individuals Informed
Keep the individuals informed of findings through risk communication and risk management.
155Risk Communication and Management
Individuals without a personal or family history suggestive of breast cancer risk or without any personal or family history of red flags are at average/population breast cancer risk and should be counseled on appropriate breast cancer screening based on age unless determined otherwise. Primary preventive measures to further reduce risk should also be a part of risk communication and management and include regular exercise, reducing alcohol consumption if applicable, and maintaining a healthy weight. Breast cancer risk estimate based on age, personal reproductive history, and family history can also be evaluated using an empiric risk model like that of the Gail model. This model may be useful in determining the need for chemoprevention counseling. Other models are also available to determine the empiric risk for breast cancer (e.g., Claus model; Tyrer-Cuzick model).
Individuals with an above-average breast cancer risk, but whose personal and/or family history is thoroughly assessed and NOT suggestive of an inherited syndrome because of lack of red flags, should be informed of their risk and provided appropriate measures to manage and prevent future breast cancer risk. Empiric breast cancer risk models can be used as a means to establish a quantitative measure of risk that can be used to implement measures to prevent or reduce breast cancer risks depending upon age, personal/family history, or other factors associated with the model (ACS, 2015; see Table 11.4). Based on empiric risk assessment, moderate risk breast cancer with a noninherited genetic mutation may still warrant enhanced surveillance (e.g., magnetic resonance imaging [MRI]), consideration of chemoprevention, and/or other therapeutic alternatives. Chemoprevention using receptor modulators (e.g., tamoxifen and raloxifene) or aromatase inhibitors (e.g., anastrozole and exemestane) may be considered to reduce breast cancer risks. For example, a woman with a 5-year Gail model risk of greater than or equal to 1.67% may be a candidate for chemoprevention to reduce her breast cancer risk and appropriate counseling should be provided to “inform” her of the advantages/disadvantages of chemoprevention (Pruthi, Heisey, & Bevers, 2015). Enhanced surveillance using MRI in addition to mammography may also be warranted for individuals based upon empiric family risk models (e.g., Claus model) that reveal a greater than or equal to 20% lifetime breast cancer risk.
156TABLE 11.4 Risk Assessment (Empiric) Models for Assessment of Risk Based on Selected Personal and Family History Risk Factors
Empiric Breast Cancer Risk Assessment Model | Description |
• Modified Gail modela—National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 Study (breast cancer risk assessment tool); www.cancer.gov/bcrisktool | Empiric breast cancer risk assessment model for individuals of age 35 years and older and without a personal history of breast cancer, medical history of ductal carcinoma-in-situ (DCIS), radiation therapy to the chest for Hodgkin’s lymphoma, or whose history may be suspect for a germline mutation; provides a 5-year and lifetime breast cancer risk; assess risk based upon: (a) age; (b) age at start of menstruation; (c) age at first live birth; (d) number of first-degree relatives with breast cancer; (e) number of previous breast biopsies; (f) history of atypical hyperplasia of the breast. Five-year risk of greater than or equal to 1.67% can be used for chemoprevention counseling to reduce risk. |
• Tyrer-Cuzickb,c—International Breast Intervention Study Risk Tool (IBIS); www.ems-trials.org/riskevaluator | Breast cancer risk assessment tool determines 10-year and lifetime likelihood of developing breast cancer; incorporates: (a) family history and personal history (b) hormonal and reproductive factors; (c) age; (d) body mass index; and (e) benign breast disease. |
• Claus modeld,e—based upon data from Cancer and Steroid Hormone Study (CASH); CaGene provides a display of Claus model; www4.utsouthwestern.edu /breasthealth /cagene /default.asp | Lifetime breast cancer risk focusing on family history; considers number and ages of breast cancer in first- and second-degree relatives on maternal and paternal lineages. Greater than or equal to 20% estimates can be used for high-risk surveillance for MRI. |
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