In 2017, over 1.6 million people in the United States were diagnosed with cancer, causing death in approximately 600,000 individuals. Additionally, cancer was the second leading cause of death, after heart disease, in that same year. Cancer is uncontrolled cellular growth, which may result in significant mortality and morbidity. The American Cancer Society (ACS) estimates 20% of all cancers may be prevented given excessive alcohol and tobacco use, physical inactivity, and poor nutrition are risk factors for certain types of cancer. These are acquired risk factors. Although individuals may have control over these risk factors and can make positive lifestyle changes to reduce their cancer risks; there are other cancer risk factors that cannot be lowered simply by becoming more active, avoiding alcohol and tobacco, or having a healthy diet.
Besides acquired risk factors, an individual’s cancer risk is also dependent upon their personal and family history of cancer, in addition to race or ethnicity. These risk factors are not under patient control, and may pose a larger risk than any cancer risk-reducing lifestyle changes a person may employ. A family history is a valuable tool healthcare providers use in order to assess cancer risk for an individual patient, or even an entire family. When taking a family history, it is important to ask what type of cancer there is in the family, establish the degree of relationship between the patient and family member with cancer, age of onset, risk-reducing surgeries or other preventative measures, type(s) of tumor(s), age of death, and obtain available genetic test results. As part of the patient history, patient race/ethnicity should be documented, as well as the presence of any acquired risk factors.
Types of Cancer
Cancers may be grouped into different categories, depending on risk:
1) Sporadic. Most cancers fall within this group. There is no particular pattern of cancer type, age of onset, or inheritance. There is no obvious hereditary basis.
2) Cancers Induced by Carcinogens. The pattern of cancer is environmentally induced. Examples may include occupational hazardous exposure such as radiation, toxic chemicals, heavy metals, etc. Family members may have similar cancers or may be associated with a particular geographic location. This may resemble a pattern within the family.
3) Familial Cluster of Cancer. There are a few family members with cancer, but there is no clear inheritance pattern. This type of family history may moderately increase cancer risk in the patient if close family members are affected with cancer. The pattern is likely caused by a combination of environmental and genetic effects.
4) Hereditary Cancer. There is a relatively high lifetime risk for specific cancer(s), depending on the family history and/or familial genetic mutation. These cancers are due to the inheritance of a gene that predisposes an individual to develop cancer. Cancer in the family may have these features:
a. Relative diagnosed at a younger than usual age.
b. A relative with more than one primary form of cancer (not a secondary cancer that metastasized from another primary organ system).
c. Bilateral tumors (example – breast cancer).
d. Common tumor diagnosed at an unusual age.
e. Rare cancer types.
f. Absence of environmental risk factors.
Race and ethnicity may also impact cancer risk assessment. It is well established there are 3 founder mutations for BRCA1 and BRCA2 genes in the Ashkenazi Jewish population, which increase the risk for breast, ovarian, and prostate cancer, among others. A founder mutation is a genetic variation observed with high frequency in a group that is or was geographically or culturally isolated. There is evidence in the literature of founder mutations in hereditary cancer genes in other populations as well. Additionally, race and ethnicity may impact cancer incidence and death rates, apart from genetic risk factors.
In addition to family history, there are several risk assessment models that clinicians may use to assist in patient care. These models are not comprehensive; and each has their own advantages and disadvantages. These risk assessment models are not stand-alone tools, and some healthcare providers may use multiple models to evaluate the same patient or family. However, depending on the patient risk, these and other models may help clinicians provide a more personalized comprehensive cancer risk assessment for their patients.
The Tyrer-Cuzick model (also known as the International Breast Cancer Intervention Study Breast Cancer Risk Evaluation Tool) estimates the likelihood that a patient is a carrier of a pathogenic BRCA1 or BRCA2 mutation using the patient’s personal and family history:
- Patient’s age
- Patient’s body mass index (BMI)
- Patient’s age at menarche
- Patient’s age at menopause (if applicable)
- Personal history of ovarian cancer
- Personal history of benign breast condition(s) that may increase risk of breast cancer (hyperplasia, atypical hyperplasia, LCIS)
- Patient’s use of hormone replacement therapy (if applicable)
- Family history (breast/ovarian cancer, Ashkenazi Jewish ethnicity, genetic test results)
Depending on the patient’s risk score from this model, clinicians may make management decisions or offer genetic testing. A limitation of this model is it may over-estimate a patient’s risk if there is a personal history of atypical hyperplasia.
Similar to the Tyrer-Cuzick model, the BRCAPRO model estimates a patient’s chance of carrying a pathogenic mutation in the BRCA1 and BRCA2 genes. BRCAPRO uses information about a patient’s personal cancer history and the family history of breast and ovarian cancer. This may include relationships among family members; race/ethnicity; age(s) of breast and/or ovarian cancer diagnosis; and current age if living, or age of death (if applicable) for unaffected members. BRCAPRO has undergone several enhancements and revisions since it was first made clinically available.
PENN II model
Another statistical model that estimates the chance a patient may carry a pathogenic mutation in the BRCA1 and BRCA2 genes is the PENN II model, which is available online. For PENN II, the reported family history of cancer should be restricted to third-degree relatives and closer. Only one lineage can be evaluated. Therefore, if there is a maternal and paternal history of cancer, this information should be inputted separately and each lineage will have their own risk assessment.
If a family is considered high risk for a hereditary cancer syndrome, genetic testing may be performed, depending on the clinical indication. Historically, prior to next generation sequencing (NGS) technology, genes were tested for sequentially. This proved to be time consuming and costly. Currently, there are many cancer panels clinically available, some of which test for dozens of genes simultaneously. If there is a known familial variant, quite often, family members are tested for this specific variant only. However, there have been documented case reports of more than one familial pathogenic variant present in a family, although this scenario is not common.
Genetic testing may deliver different types of results, regardless of how many genes are included in the panel. Testing may be negative, with no pathogenic variants identified. Testing may be positive, with a known pathogenic mutation identified. Healthcare providers may make management decisions based on the positive result, which may include surgery, or a specific type of chemotherapy. If the patient has not been diagnosed with cancer, they may choose to undergo a preventative risk-reducing surgery, depending on the cancer risk. Finally, the testing may show one or more variants of uncertain significance (VUS). These are genetic changes where there is not conclusive evidence in the literature if it’s benign or pathogenic. A VUS result may bring about uncertainty for the patient and family. Patients should be managed based on their personal or family history of cancer. VUS results should not change cancer management. Furthermore, VUS results may be reclassified in the future as more knowledge is gained (either benign or pathogenic) which can change patient management.
Performing a complete cancer risk assessment has the ultimate goal of providing personalized care that will allow the best possible outcome for the patient, which may include treatment (if there already is a cancer diagnosis) or prophylactic risk-reducing surgery. While there are many available tools and risk assessment models for cancer, it is important for those patients who are concerned about their cancer risk to specifically discuss this with their physician. While lifestyle changes may mitigate against acquired cancer risk factors such as diet and exercise, there may be genetic risk factors that far outweigh healthy lifestyle choices. Indeed, a comprehensive cancer risk assessment may be needed for multiple family members, especially if they are considered at high risk for a hereditary cancer syndrome.
- American Cancer Society Facts and Figures. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf (Accessed 08/05/2020)
- National Vital Statistics Report Vol 68, Number 9.
- Offit K. Clinical Cancer Genetics: Risk Counseling and Management. ISBN 978-0-471-14655-1
- Schneider K. Counseling About Cancer, Second Edition. ISBN 0‐471‐37036‐3
- Kim HS, Kim YJ, Seo YR. An Overview of Carcinogenic Heavy Metal: Molecular Toxicity Mechanism and Prevention. J Cancer Prev. 2015 Dec; 20(4): 232–240.
- ASCO (American Society of Clinical Oncology) https://www.cancer.net/sites/cancer.net/files/cancer_family_history_questionnaire.pdf (Accessed 08/05/2020)
- Hamel N, Kotar K, Foulkes WD. Founder mutations in BRCA1/2 are not frequent in Canadian Ashkenazi Jewish men with prostate cancer. BMC Med Genet. 2003;4:7. Published 2003 Aug 11. doi:10.1186/1471-2350-4-7
- Kwong A, Ng EK, Wong CL, et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012;7(9):e43994. doi:10.1371/journal.pone.0043994
- Gomaa Mogahed SH, Hamed YS, Ibrahim Moursy et al. Analysis of Heterozygous BRCA1 5382ins Founder Mutation in a Cohort of Egyptian Breast Cancer Female Patients Using Pyrosequencing Technique. Asian Pac J Cancer Prev. 2020;21(2):431-438. Published 2020 Feb 1. doi:10.31557/APJCP.2020.21.2.431
- NCI (National Cancer Institute). https://www.cancer.gov/about-cancer/understanding/disparities (Accessed 08/05/2020)
- Himes DO. Root AE, Gammon A et al. Breast Cancer Risk Assessment: Calculating Lifetime Risk Using the Tyrer-Cuzick Model. The Journal for Nurse Practitioners. Volume 12, Issue 9, October 2016, Pages 581-592
- Boughey JC, Hartmann LC, Anderson SS, et al. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010;28(22):3591-3596. doi:10.1200/JCO.2010.28.0784
- Biswas S, Atienza P, Chipman J, et al. Simplifying clinical use of the genetic risk prediction model BRCAPRO. Breast Cancer Res Treat. 2013;139(2):571-579. doi:10.1007/s10549-013-2564-4
- Mazzola E, Blackford A, Parmigiani G, et al. Recent Enhancements to the Genetic Risk Prediction Model BRCAPRO. Cancer Inform. 2015;14(Suppl 2):147-157. Published 2015 May 10. doi:10.4137/CIN.S17292
- https://pennmodel2.pmacs.upenn.edu/penn2/ (Accessed 08/05/2020)
- Cohen SA, Tan CA, Bisson R. An Individual with Both MUTYH-Associated Polyposis and Lynch Syndrome Identified by Multi-Gene Hereditary Cancer Panel Testing: A Case Report. Front Genet. 2016;7:36. Published 2016 Mar 16. doi:10.3389/fgene.2016.00036
- Eccles BK, Copson E, Maishman T, et al. Understanding of BRCA VUS genetic results by breast cancer specialists. BMC Cancer. 2015;15:936. Published 2015 Nov 25. doi:10.1186/s12885-015-1934-1