Hereditary Breast Cancer Testing. clinician guide

Transcription

1 Hereditary Breast Cancer Testing clinician guide

2 Ambry s test offerings are designed to provide flexible, comprehensive options tailored to your patients personal and family histories. New Solutions for Hereditary Breast Cancer Identifying and understanding the genetic contribution to breast cancer allows for individualized disease management, and provides insight into personal and familial risks for cancer. For the portion of breast cancer that is due to inherited causes (up to 10%), modified treatment, surveillance, and risk-reducing options may be appropriate. total hereditary breast cancer BRCAplus and BreastNext BRCA1 and BRCA2 We Offer Several Testing Options for Hereditary Breast Cancer: 1. Comprehensive BRCA1/2 sequencing and deletion/duplication (i.e. large rearrangement) analyses 2. BRCAplus: a next generation sequencing (NGS) panel of 6 breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53) 3. BRCAplus-Expanded: a NGS panel of 8 breast cancer susceptibility genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, TP53) 4. BreastNext: an NGS panel of 17 breast cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, TP53)

3 BRCA1 and BRCA2 Hereditary breast and ovarian cancer (HBOC) is a cancer predisposition syndrome most commonly caused by germline (inherited) mutations in BRCA1 and BRCA2. Mutations in these two highly penetrant genes increase the risk for cancers of the breast, ovaries, pancreas, and prostate. brca1/2 lifetime cancer risks (%) General Population BRCA1/2 Mutation Carrier brca1 and brca increased Breast Cancer Ovarian Cancer Male Breast Cancer Prostate Cancer Pancreatic Cancer BRCA1/2 mutation carriers often develop cancer at younger than typical ages and have an increased risk for second primary tumors. Target Populations for BRCA1/2 Testing BRCA1/2 genetic testing is indicated for individuals with a personal and/or family history of any of the following: 1. Early-onset breast cancer (diagnosed < 45 years of age) 2. Triple negative (ER-/PR-/HER2/ neu-) breast cancer diagnosed < 60 years of age 3. Ovarian, fallopian tube, or primary peritoneal cancer at any age 4. Bilateral or multiple primary breast cancers 5. Male breast cancer at any age 6. Ashkenazi Jewish descent with breast cancer at any age 7. 3 or more cases of breast, ovarian, pancreatic, and/or high-grade prostate cancer at any age 8. Known BRCA1 or BRCA2 mutation in the family

4 Recommendations for Patients with a BRCA1/2 Mutation brca1 and brca2 WOMEN Breast Cancer Management Breast awareness starting at 18 Clinical breast exam every 6-12 months and breast MRI annually, starting at age 25 Annual breast MRI and mammogram at age Optional risk-reducing mastectomy Discuss chemoprevention options Ovarian Cancer Management Risk-reducing bilateral salpingo oophorectomy between age 35-40, or after completion of childbearing Consider transvaginal ultrasound and CA-125 every 6 months, beginning at age 30 or 5-10 years before earliest ovarian cancer in family Discuss chemoprevention options MEN Breast Cancer Management Prostate Cancer Management Breast self-exam training and education, starting at age 35 Clinical breast exam every 6-12 months, starting at age 35 Consider mammogram at age 40; annual mammogram if indicated based on baseline study findings Consider prostate screening starting at age 40 with digital rectal exam and PSA Recommendations for Patients with No Mutation Detected For those with a personal history of breast cancer, stage appropriate care and follow-up are recommended. For those with a family history of breast cancer (no personal history): Clinical breast exam every 6-12 months Annual breast imaging beginning at age 35, or 5-10 years earlier than youngest breast cancer in family For women with a lifetime breast cancer risk of greater than 20%, annual imaging with mammogram and breast MRI may be indicated If there is a known BRCA1/2 mutation in the family and your patient has negative genetic testing, general breast screening is most likely appropriate. If there are other types of cancers in the family, other screening and prevention options may be appropriate, specific to cancers in the family.

5 BRCAplus/BRCAplus-Expanded BRCAplus is a multi-gene test that analyzes 6 breast cancer susceptibility genes, all with medical management guidelines (listed in blue). BRCAplus-Expanded includes 8 high-risk and moderate-risk breast cancer susceptibility genes, all with medical management guidelines (listed in blue and black, respectively). GENE ASSOCIATED CANCER(S) SYNDROME/ADDITIONAL CHARACTERISTICS BRCA1, BRCA2* CDH1 PALB2* PTEN Breast, ovarian, pancreatic, prostate, male breast Breast, gastric, colorectal Hereditary breast and ovarian cancer (HBOC) - Fallopian tube and primary peritoneal cancers - Triple negative (ER-, PR-, HER2/neu-) breast cancers common with BRCA1 mutations - Founder mutations are known for many populations (e.g. Ashkenazi Jewish, Portuguese, Icelandic, Danish, and more) Fanconi anemia (BRCA2 only)* Hereditary diffuse gastric cancer - Diffuse gastric cancer - Lobular breast cancer - Signet ring carcinoma Breast, ovarian, Fanconi anemia* pancreatic, male breast Breast, thyroid, uterine, colorectal, kidney PTEN hamartoma tumor syndrome (PHTS) Cowden syndrome (CS) - Cutaneous lesions (trichilemmomas, acral keratosis, papillomatous papules) - Macrocephaly and other clinical findings - Lhermitte-Duclos disease - GI hamartomas or ganglioneuromas brcaplus/brcaplus-expanded TP53 Breast, sarcoma, brain, adrenocortical, leukemia, gastrointestinal, genitourinary Li-Fraumeni syndrome (LFS) - Childhood onset cancers - Increased radiation sensitivity - Risk for multiple primary tumors ATM* Breast, pancreatic Ataxia-telangiectasia - Risk for lymphoma and leukemia in homozygous mutations carriers CHEK2 Breast, colorectal * Biallelic mutations in these genes are associated with respective syndromes described under Additional Characteristics.

6 lifetime breast cancer risks by brcaplus-expanded gene (%) General Population 12 BRCAplus-Expanded Gene Mutation ATM 2-4 fold BRCA1, BRCA CDH CHEK2 2 fold PALB PTEN up to 50 brcaplus/brcaplus-expanded TP53 Benefits of Testing significantly * Breast cancer is the most common cancer in women with TP53 mutations. Although the breast cancer risk with a TP53 mutation is significantly elevated above the general population, the specific risk is not well defined. Knowing your patient has an increased cancer susceptibility can aid in medical management. For example: 1. Increased breast screening for ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, and TP53 mutation carriers: Clinical breast exams more frequently Breast imaging with mammogram and breast MRI Initiate screening at a younger age 2. Discuss option of risk-reducing bilateral mastectomy with BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53 gene mutation carriers 3. Avoid radiation treatment, if possible, for TP53 mutation carriers 4. Targeted surveillance and prevention options specific to the gene mutation and syndrome identified 5. Identify at-risk family members with targeted genetic testing for identified familial mutation, and develop an individualized cancer screening and prevention program 6. Assist couples in reproductive decision making (e.g. advise mutation carriers about assisted reproduction options including pre-implantation genetic diagnosis)

7 BreastNext BreastNext is a multi-gene panel including 17 breast cancer susceptibility genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NF1, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, and TP53. lifetime breast cancer risks by breastnext gene (%) ATM 2-4 fold BreastNext Gene Mutation BARD1 BRCA1, BRCA BRIP1 CDH CHEK2 MRE11A, RAD50, NBN MUTYH NF1 2 fold 3-5 fold PALB2 PTEN up to 50 RAD51C RAD51D TP53 significantly * **Breast cancer risk associated with a BARD1, BRIP1, MRE11A, MUTYH, NBN, RAD50, RAD51C, or RAD51D mutation is elevated above the general population but is not well defined. **Breast cancer risk associated with a TP53 mutation is significantly elevated above the general population but is not well defined. breastnext

8 BreastNext Genes, Associated Cancers, and Characteristics BRCAplus is a multi-gene test that analyzes 6 breast cancer susceptibility genes, all with medical management guidelines (listed in blue). BreastNext includes 17 high-risk and moderate-risk breast cancer susceptibility genes (in blue and black, respectively). GENE BRCA1, BRCA2* CDH1 PALB2* PTEN TP53 ASSOCIATED CANCER(S) Breast, ovarian, pancreatic, prostate, male breast Breast, gastric, colorectal Breast, ovarian, pancreatic, male breast Breast, thyroid, uterine, colorectal, kidney Breast, sarcoma, brain, adrenocortical, leukemia, gastrointestinal, genitourinary SYNDROME/ADDITIONAL CHARACTERISTICS Hereditary breast ovarian cancer (HBOC) - Fallopian tube and primary peritoneal cancers - Triple negative (ER-, PR-, HER2/neu-) breast cancers associated with BRCA1 mutations - Founder mutations are known for many populations (e.g. Ashkenazi Jewish, Portuguese, Icelandic, Danish, and more) Fanconi anemia (BRCA2 only)* Hereditary diffuse gastric cancer - Diffuse gastric cancer - Lobular breast cancer - Signet ring carcinoma Fanconi anemia* PTEN hamartoma tumor syndrome (PHTS) Cowden syndrome (CS) - Cutaneous lesions (trichilemmomas, acral keratosis, papillomatous papules) - Macrocephaly and other clinical findings - Lhermitte-Duclos disease - GI hamartomas or ganglioneuromas Li-Fraumeni syndrome (LFS) - Childhood-onset cancers - Increased radiation sensitivity - Risk for multiple primary tumors breastnext ATM* Breast, pancreatic Ataxia-telangiectasia - Risk for lymphoma and leukemia in homozygous mutations carriers BARD1 Breast, ovarian BRIP1* Breast, ovarian Fanconi anemia* * Biallelic mutations in these genes are associated with respective syndromes described under Additional Characteristics.

9 Continued: BreastNext Genes, Associated Cancers, and Characteristics GENE CHEK2 MRE11A* ASSOCIATED CANCER(S) Breast, colorectal Breast, possibly ovarian SYNDROME/ADDITIONAL CHARACTERISTICS Ataxia-telangiectasia-like disorder* MUTYH* Breast, colorectal MUTYH-associated polyposis (MAP)* - Tens to hundreds of GI polyps NBN* NF1 RAD50* Breast Possibly ovarian Breast, optic glioma, CNS, GIST, PGL/PCC Breast, possibly ovarian Nijmegen breakage syndrome* Neurofibromatosis type 1 (NF1) - Hyperpigmented skin lesions - Neurofibromas - Lisch nodules - Many additional characteristics Nijmegen breakage syndrome-like disorder* RAD51C* Breast, ovarian Fanconi Anemia* RAD51D Breast, ovarian * Biallelic mutations in these genes are associated with respective syndromes described under Additional Characteristics. CNS: central nervous system GIST: gastrointestinal stromal tumor PGL/PCC: paragangliomas/pheochromocytomas

10 Target Population for Multi-Gene Breast Cancer Panels BRCAplus or BreastNext may be informative for individuals with a personal and/or family history of any of the following: 1. Early-onset breast cancer (diagnosed < 45 years of age) 2. Bilateral or multiple primary breast cancers 3. Male breast cancer at any age 4. Breast and ovarian cancer in the same woman 5. 3 or more cases of breast cancer* 6. 3 or more cases of breast, ovarian, and/or pancreatic cancer* 7. 3 or more cases of breast, uterine, and/or thyroid cancer* 8. Multiple close family members with breast and other cancers* * On the same side of the family Genetic Test Results Explained A patient undergoing genetic testing will receive one of three possible results: positive, negative, or inconclusive (i.e. variant of unknown significance or VUS). RESULTS Positive Negative Inconclusive EXPLANATION A mutation was found in one of the genes tested Increased risk for cancer specific to the gene mutation Cancer screening and prevention recommendations specific to gene Testing at-risk relatives for specific mutation will be indicated No clinically significant genetic changes identified in any of the genes tested Cancer risk is based on personal and family history Cancer screening and prevention recommendations based on family history Genetic testing may or may not be indicated for family members A genetic change was identified, but current knowledge cannot predict if the change is disease-causing or benign Cancer risk is based on personal and family history Cancer screening and prevention recommendations based on family history Family studies may be indicated

11 VUS Rates and Family Studies Program Variants of unknown significance (VUS) are more common in multi-gene panels because they analyze multiple genes simultaneously. As information is accumulated, updated VUS rates will be made readily available. The possibility of inconclusive results warrants careful discussion in pre- and post-test counseling sessions, particularly for multi-gene panels. Detailed interpretation of any VUS identified is included in the test report. We are committed to careful analysis and timely reclassification of VUS. If a VUS is identified, complimentary testing of informative relatives may be offered through our Family Studies Program. Familial tracking (segregation studies) can assist in clarifying the nature of a VUS. When enough evidence has been accumulated to reclassify the VUS as either disease-causing or benign, you will be automatically notified. We have invested heavily in both research and clinical collaborations to ensure the quality and accuracy of our variant analyses and interpretations. For more information, please visit: Specimen Requirements Blood: Collect 6-10cc blood in purple top EDTA tube (preferred) or yellow top citric acetate tube. Storage: 2-8 C and do not freeze. Shipment: Room temperature for two-day delivery. For transfusion patients: Wait at least two weeks after a packed cell or platelet transfusion and at least four weeks after a whole blood transfusion prior to blood draw. Blood Spot: Blood spots are not accepted. Saliva: Fill 1 tube with saliva up to black line (1cc of saliva) in Oragene Self Collection container. After tube is closed 1cc of buffer will mix with saliva for a total volume of 2cc. Store at room temperature in sterile bag. Shipment: Room temperature for two-day delivery. DNA: 20 μg of DNA in TE (10mM Tris-Cl ph 8.0, 1mM EDTA); preferred 200 μl at ~100 ng/μl. Please provide DNA OD ratio (preferred ) and send agarose picture with high mw genomic DNA, if available. Store at -20 C. Ship frozen on dry ice (preferred) or ice.

12 Ambry Expertise support Board-certified genetic counselors, laboratory directors, and medical directors are readily available to assist with test selection, case reviews, and result interpretation. insurance Ambry is contracted with the majority of commercial insurances and Medicare. All out-of-network patients are treated as in-network to minimize out-of-pocket costs. Medicaid coverage varies by state and preverification is recommended. patient protection plan Ambry s billing policy is to preverify insurance coverage (with or without patient sample) for genetic testing. We will contact the patient after their sample is received, if their out-of-pocket cost is estimated to exceed $100. We are committed to working with you and your patients to make the genetic testing process as simple and cost-effective as possible, and our Billing Department is available to answer any questions your patient may have. Our Billing Department can be reached by phone at or billing@ambrygen.com. progeny s family history questionnaire (fhq) With Progeny s FHQ, patients can complete their family health history at their own pace. Pedigrees are automatically generated and managed along with all submitted data. With no re-entry of data, referral and clinical decisions can be made immediately. Template FHQs are available for use in your clinic at no cost, or custom questionnaires can be designed for you. Visit progenygenetics.com/clinical/trial for more. about ambry genetics Ambry Genetics is a privately-held healthcare company with the most comprehensive suite of genetic testing solutions for inherited and non-inherited diseases. Since 1999, Ambry has tested approximately half a million patient samples benefiting 90% of all U.S. patients covered by public and private insurers. Ambry is dedicated to scientific collaboration by offering its rapidly growing database of anonymized genomic data (variant frequencies) free to the global medical research community to fulfill the promise of the human genome to cure or manage all human disease. Ambry is dedicated to the belief that human health should not be patented or owned, and genomic data should be freely shared so we can try to understand all human disease. To order your complimentary sample submission kits, please contact: Ambry Genetics 15 Argonaut Aliso Viejo, CA USA info@ambrygen.com For more details about these tests, visit ambrygen.com References used to develop clinical content are available at ambrygen.com 15 Argonaut, Aliso Viejo, CA USA Toll Free Fax _v5 HBCTCBRO