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Genetic Connections to Breast Cancer - February 14, 2023
This document discusses genetic connections to breast cancer. It begins by outlining the learning objectives, which are to understand the importance of collaboration between genetics and non-genetics experts for hereditary breast cancer patients, emphasize obtaining accurate family histories, and discuss benefits and limitations of next generation sequencing panel tests. It then discusses genetic counselors' role in oncology, hereditary cancer risks and patterns, BRCA genes, obtaining family histories, genetic testing options like multi-gene panels, interpreting results, cancer screening recommendations, and prophylactic surgery options. Resources and established risk models are also referenced.
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Genetic Connections to Breast Cancer - February 14, 2023
- 1. Genetic Connections toBreast Cancer Susan R. Capasso EdD, MS, CGC February 14, 2023 1
- 2. Learning Objectives By theend of this session, attendees will be able to: ā¢ Understand the importance of developing a collaborative partnership of non-genetics and genetics experts to address the growing number of patients at risk for hereditary breast cancer. ā¢ Emphasize the importance of obtaining an accurate family history with continual updates. ā¢ Discuss the benefits and limitations of Next Generation Sequencing Panel Tests. 2
- 3. Delivery of HereditaryCancer Care ā¢ Today, there are many healthcare providers who participate in the delivery of cancer risk assessment and testing. ā¢ A collaborative healthcare team composed of non-genetics and genetics experts is ideal to address the growing number of patients at risk for hereditary breast cancer.
- 4. Genetic Counselors Have played anintegral role in the delivery of care in oncology for many years. .
- 5. What is the Roleof a Genetic Counselor in Oncology? ā¢ Referrals may be done to a genetic counselor by a physician or another member of the medical team to discuss family history and genetic risks, or before or after having genetic testing. ā¢ Genetic Counselors help patients understand: ā Their genetic risks based on their family history. ā Their genetic risks for certain cancers or other diseases. ā Whether genetic testing might be right for them. ā What the results of genetic tests may mean for them and their family.
- 6. Cancer Most cancers occurin people who do not have a strong family history of that specific cancer: SPORADIC Some families have more of the same kind or related kinds of cancer than expected in the general population with no specific pattern of inheritance, likely caused by a combination of genetic and environmental factors: FAMILIAL
- 7. Hereditary Cancer ā¢ Those individualsin which cancer is passed down generation through generation by inheriting pathogenic variants: HEREDITARY ā¢ Only 5-10% cancers
- 8. BRCA Genes ā¢ Dr.Mary-Claire King ā¢ BRCA1 gene discovered in 1994 ā¢ BRCA2 gene discovered in 1995 ā¢ Hereditary Breast and Ovarian Cancer
- 9. Hereditary Cancer Determining which familieshave cancer related to an inherited gene mutation is important since the cancer risks in hereditary cancer families are much higher than the general population. Following published guidelines for increased surveillance, chemoprevention and preventive surgeries cancer risks have been reduced in many individuals with inherited cancer predispositions.
- 10. Family History Obtaining a three generationpedigree is a very powerful tool including: ā Type of cancer ā Age of diagnosis ā Ethnicity ā Results of any cancer testing in any relative
- 11. Hereditary Risk ā¢ Recognizinga patientās hereditary risk may identify: ā risks for certain cancers ā treatment options ā at-risk family members ā long-term management
- 12. Genetic Red Flags ā¢ Familyhistory of multiple affected relatives ā¢ Condition in the less often affected sex ā¢ A known mutation in a cancer susceptibility gene ā¢ Earlier age at onset of disease than expected ā¢ Multiple primary tumors in the same person ā¢ Bilateral disease ā¢ Non-cancer findings suggestive of a syndrome ā¢ Ethnic predisposition ā¢ Consanguinity ā¢ Autosomal dominant inheritance pattern
- 13.
- 14. Pathogenic Variants ā¢ Patients whohave an increased risk for cancer may have germline testing using a saliva or blood sample to identify pathogenic variants ā¢ In addition, a genomic tumor test(somatic testing) may identify that a patient has a hereditary cancer syndrome.
- 15. Goal of GenomicTumor Testing ā¢ Identify biomarkers that have predictive or therapeutic significance for an active cancer. ā¢ Some of the DNA variants detected are relevant for therapeutic decisions can also be associated with hereditary cancer risks (e.g., BRCA1, BRCA2).
- 16.
- 17. Lifetime cancer risksassociated with HBOC Cancer Type BRCA1 BRCA2 General Population Breast >60% >60% 12.3% Male Breast 1.2% 7-8% 0.1% Ovarian 39-58% 13-29% 1.6% Pancreatic ā¤5% 5-10% 1.6% Prostate Increased* 15-20%* 12% Melanoma No increase Increased 2.3% *prostate cancer risks for BRCA1/2 carriers by age 65
- 18. Prevalence of HBOC ā¢About 5-10% of breast cancer and 10-15% of ovarian cancers are attributed to HBOC. ā¢ An estimated 1 in 333-500 individuals in the general population have a disease-causing BRCA1 or BRCA2 mutation. ā¢ About 1 in 40 individuals of Ashkenazi Jewish ancestry carry a BRCA1 or BRCA2 mutation. ā¢ Tend to develop cancer at an earlier age than the general population. 18
- 19. Criteria for referral ā¢A known mutation in a cancer susceptibility gene ā¢ Ovarian cancer ā¢ Male breast cancer ā¢ Pancreatic cancer ā¢ Prostate cancer ā¢ Breast cancer diagnosed ā¤ 45 ā¢ Breast cancer diagnosed > 45 with family history of related cancers ā¢ Triple negative breast cancer diagnosed at any age ā¢ Two primary tumors in the breast ā¢ Ashkenazi Jewish ancestry and breast cancer at any age ā¢ BRCA1/2 mutation identified in tumor profiling
- 20. Other genes thatContribute to Breast and Ovarian Cancer ā¢ Other hereditary cancer syndromes that increase the risk for breast cancer ā Cowden syndrome: PTEN ā Li-Fraumeni syndrome: TP53 ā¢ The presentation of these syndromes in a family may overlap with HBOC ā¢ But can have characteristic features ā¢ Other moderate genes risk genes
- 21. Multigene Panel Testing Genetic Testing hasexpanded due to new technology utilizing Next Generation Sequencing (NGS) technology which allows for rapid and inexpensive analysis of large chunks of the genome Multigene NGS panels allow simultaneous sequencing of many genes associated with a specific family cancer phenotype or multiple phenotypes
- 22. Identification of Carriers of Pathogenic Variants Importantto identify patients at risk for other breast cancer syndromes. Multi-gene panels are increasingly recommended For example TP53, PALB2, PTEN Knowledge of these other genes can influence radiation therapy and chemotherapy decisions
- 23. Benefits of Multi-Gene Panel Testing forBreast Cancer Risk Provides better diagnostic yield compared with a limited BRCA1/2 genetic test for patients at risk for hereditary breast cancer or individuals diagnosed with breast cancer. In a retrospective comparison of multiple genetic tests there was no difference between the multi-gene panel test and the limited BRCA1/2 test in the detection of potentially harmful BRCA pathogenic variants.
- 24. Multigene Panel Testing Includes āintermediateā penetrant genes of unclearaction Should be offered in the context of professional expertise with pre & post test counseling. More cost effective and time effective than sequential testing Can reveal more than one pathogenic mutation
- 25. Risks of Multigene Testing Results canbe complicated to interpret Testing may find gene mutations that show a moderate or uncertain risk of cancer It may be hard to know what you should do with the results
- 29. Positive Test Result ā¢ Ifidentified: ā Increased risk for certain types of cancer ā Different mutations are linked to increased risks for different types of cancers ā The risks may differ for the different mutations ā Some are very high, others less but ā Still more than the general public
- 30. Positive Test Result May be offeredspecial or more frequent cancer screening exams to find any cancers that develop as early as possible: dependent on the specific mutated genes Originally there were concerns that some mutations on multi-gene panels have no clear guidelines about the best screening exams to use or how often NCCN guidelines are increasing
- 31. Prophylactic Surgery ā¢ Patientsmay be offered certain types of surgeries that may help reduce risk of developing cancer ā Most commonly mastectomy, oophorectomy and hysterectomy
- 32. Family members If an individualis positive for a genetic mutation then family members may also carry this same mutation 1st degree relatives at 50% risk to have inherited same mutation, 2nd degree relatives 25%, 3rd degree relatives 12.5% A genetic counselor can help identify who in the family is at risk of having the mutation, who should be tested and when they should be tested
- 33. Negative Test Result You could havea pathogenic variant in a gene but technology not there yet. Some types of cancer may occur in several people in a family without being caused by a genetic mutation. There may be a pathogenic variant in other members of your family but you did not inherit it.
- 34. Variant of Uncertain Significance (VUS) Seen inaffected and not affected These are single nucleotide DNA polymorphisms that are neither confirmed benign nor pathogenic Rates are going down and there are ACMG guidelines and lab data available
- 35. VUSs ā¢ More arefound in individuals with non-European ancestry who have been historically underrepresented in genomic research. ā¢ The classification of a variant ā benign, uncertain, or pathogenic ā can change over time as labs generate more data about specific variants. ā¢ In some cases, a VUS may be reclassified as "actionable" as new data is obtained.
- 36. Established Models ā¢ Therisk of developing breast cancer can be calculated utilizing various models ā Tyrer-Cuzick ā Gail ā Claus ā¢ These typically have short-term and long-term cancer risk estimates ā¢ Other factors that can increase risk include such factors as family history, reproductive history, and number of biopsies.
- 37. Resources and References ā¢American College of Obstetricians and Gynecologists (2019) Committee Opinion #793: Hereditary Cancer Syndromes and Risk Assessment ā¢ American Society of Clinical Oncology(2020) Hereditary Breast and Ovarian Cancer ā¢ Berliner J.et al(2021). Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer Syndromes-Practice Resource of the National Society of Genetic Counselors ā¢ Jackson Laboratories Hereditary Cancer Modules ā¢ National Comprehensive Cancer Network(v.1.2022): Genetic/Familial High- Risk Assessment: Breast, Ovarian and Pancreatic 37
Editor's Notes
- #10Ā Nccn guidelines
- #11Ā Powerful tool but needs to be updated In addition to the National Comprehensive Cancer Network (NCCN) guidelines for identifying patients appropriate for genetic testing there are numerous assessment tools including those online.
- #14Ā : Autosomal dominant inheritance Affected individuals in every generation Any child of an affected individual has a 50% chance of inheriting the trait; unaffected family members do not pass it to their children Males and females equally likely to be affected (although there may be sex-limited expression, such as with ovarian cancer)
- #23Ā Multiple genes can contribute to the breast/ovarian cancer phenotype or other phenotypes Higher mutation detection rate reduces the number of families with uninformative results Increase the number of patients who can be provided tailored surveillance, risk reduction options and testing of at risk family members
- #27Ā TP53 Li Fraumeni rare inherited disease that greatly increases oneās risk for developing cancer during their lifetime LFS develop multiple cancers and multiple tumors often in childhood or as young adults osteosarcoma, breast, brain, acute leukemia, adrenal cortical tumors, melanoma Wilms tumor of the kidney had stomach colon, pancreas
- #28Ā By analyzing additional clinically actionable genes, we see that a population of 1951 breast cancer patients would benefit from an increase in mutation detection by ~46%. There are significant number of mutation carriers that would be missed and therefore, undermanaged. Patients associated with hereditary colon cancer or ovarian cancer are also expected to see a similar increase in mutation detection with additional genes analyzed.
- #30Ā Risks and Benefits of Genetic Testing Genetic Testing can have emotional effects especially if a mutation is found It can impact other family members Some may not want to know
- #31Ā To
- #32Ā Those found to have the gene but who currently do not have cancer may choose prophylactic surgery
- #33Ā Whether affected or not
- #34Ā Familial Cancer
- #35Ā Some patients are quite concerned because they want to know do I have a mutation or not Seen in affected and not