Hereditary Breast Cancer Testing. Diagnostic

Transcription

1 Hereditary Cancer Testing Diagnostic

2 New solutions for hereditary breast cancer. Identifying and understanding the genetic contribution to breast cancer allows for individualized disease management and provides insight to personal and familial risks for cancer. For the 10% of breast cancer that is due to inherited causes, modified treatment, surveillance and risk-reducing options may be appropriate. Ambry Genetics offers several testing options that include BRCA1/2: - Comprehensive BRCA1/2 sequencing and deletion/ duplication (i.e. large rearrangement) analyses - BRCAplus: a next generation sequencing (NGS) panel of the six clinically-actionable breast cancer genes (BRCA1, BRCA2, CDH1, PTEN, STK11, TP53) - Next: an NGS panel of 18 breast cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) Ambry s test offerings are designed to provide flexible, comprehensive options tailored to your patients personal and family histories.

3 BRCA1 & BRCA2 Hereditary breast-ovarian cancer (HBOC) syndrome is a cancer predisposition syndrome caused by germline BRCA1/2 mutations. Mutations in these two highly penetrant genes increase the risk for cancers of the breast, ovaries, fallopian tubes, pancreas and prostate. brca1/2 lifetime cancer risk (%) BRCA1 & BRCA General Population BRCA Positive Cancer Ovarian Cancer Male Cancer Prostate Cancer BRCA1/2 mutation carriers often develop cancer at younger than typical ages and have an increased risk for second primary tumors. Target population for BRCA1/2 BRCA1/2 genetic testing is recommended 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 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. Clustering of three 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 BRCA1 & BRCA2 women Recommendations for patients with a BRCA1/2 mutation Cancer Management 1. awareness starting at Clinical breast exam every 6-12 months starting at age Annual mammogram and breast MRI starting at age Optional risk-reducing mastectomy 5. Discuss chemoprevention options Ovarian Cancer Management 1. Risk-reducing bilateral salpingo oophorectomy between age or after completion of childbearing 2. Consider transvaginal ultrasound and CA-125 every 6 months beginning at age 30 or 5-10 years before the earliest ovarian cancer in the family. 3. Discuss chemoprevention options Cancer Management 1. self-exam training and education starting at age Clinical breast exam every 6-12 months starting at age 35 Prostate Cancer Management 1. Consider prostate screening starting at age 40 with digital rectal exam and PSA men 3. Consider mammogram at age 40; annual mammogram if indicated based on baseline study findings Recommendations for patients with no mutation detected For patients with a personal history of breast cancer, follow stage appropriate care and follow-up. For patients 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 the youngest breast cancer in the 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 BRCA mutation in the family and your patient tests negative, 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 is a multi-gene panel including comprehensive analyses of the six clinically-actionable breast cancer susceptibility genes (BRCA1, BRCA2, PTEN, TP53, STK11, CDH1). Recommendations are available for all six BRCAplus genes, which provide treatment, surveillance and prevention option for mutation carriers. Gene Cancer(s) Additional Characteristics BRCA1 BRCA2 Ovaries Pancreas Prostate Male Hereditary -Ovarian Cancer syndrome (HBOC) - Fallopian and primary peritoneal cancers - Triple Negative (ER-, PR-, HER2/neu-) breast cancers common with BRCA1 mutations - Founder mutations are known for many populations (ex: Ashkenazi Jewish, Portuguese, Icelandic, Danish, and more) PTEN Thyroid Endometrium Kidney PTEN Hamartoma Tumor syndrome (PHTS) Cowden syndrome (CS) - Mucocutaneous lesions (trichilemmomas, acral keratosis, papillomatous papules) - Macrocephaly - Adult Lhermitte-Duclos disease - GI hamartomas or ganglioneuromas - Benign breast, thyroid, and uterus lesions - Nonmedullary thyroid cancer BRCAplus TP53 Sarcoma Brain Adrenocortical Leukemias Li-Fraumeni syndrome (LFS) - Soft tissue and osteosarcomas - Colorectal and many other cancers - Childhood onset cancers - Increased radiation sensitivity - Risk for multiple primary tumors STK11 Ovaries Duodenum Peutz-Jeghers syndrome (PJS) - Childhood onset mucocutaneous pigmentation and GI hamartomas - Risk for additional cancers - Can see cervical and gonadal tumors Pancreas CDH1 Gastric Hereditary Diffuse Gastric Cancer - Diffuse gastric cancer - Lobular breast cancer - Signet ring carcinoma

6 BRCAplus gene specific lifetime breast cancer risks General Population 12% BRCAplus Genes BRCA1, BRCA % PTEN up to 50% TP53 up to 93%* STK11 up to 45% CDH % * cancer is the most common cancer in women with TP53 mutations. Although the breast cancer risk associated with a TP53 mutation is significantly elevated above the general population, the specific risk is not well defined. Combined lifetime cancer risk is shown. BRCAplus Benefits of testing Knowing your patient has an increased cancer susceptibility can aid in medical management. For example: 1. High-risk breast screening for BRCA1, BRCA2, PTEN, TP53, CDH1 and STK11 mutation carriers: - Clinical breast exams more frequently - imaging with mammogram & breast MRI - Initiate screening at a younger age 2. Discuss the option of riskreducing bilateral mastectomy with patients who have a BRCA1, BRCA2, PTEN or a TP53 mutation 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 family mutation and devise an individualized cancer screening and prevention program 6. Assist couples in reproductive decision making (e.g. advise BRCA1, BRCA2, PTEN or TP53 mutation carriers about assisted reproduction options including pre-implantation genetic diagnosis)

7 Next Next is a multi-gene panel including comprehensive analyses of 18 breast cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NF1, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11 and TP53). * Low penetrance SNPs have been identified in these breast cancer susceptibility genes. These low penetrance genes do not influence clinical management and are thus not included in Ambry s panels. BRCAplus includes six clinically actionable breast cancer susceptibility genes with clear management guidelines. Next includes high-risk and intermediate-risk breast cancer genes represented in pink and blue. High-risk genes - BRCA1, BRCA2, PTEN, TP53, STK11, CDH1 - confer up to a 40-87% lifetime breast cancer risk. Next

8 Next genes, associated cancers and other characteristics Gene Cancer(s) Additional Characteristics BRCA1 BRCA2 Ovaries Pancreas Prostate Male Hereditary -Ovarian Cancer syndrome (HBOC) - Fallopian and primary peritoneal cancers - Triple Negative (ER-, PR-, HER2/neu-) breast cancers common with BRCA1 mutations - Founder mutations are known for many populations (ex: Ashkenazi Jewish, Portuguese, Icelandic, Danish, and more) PTEN Thyroid Endometrium Kidney PTEN Hamartoma Tumor syndrome (PHTS) Cowden syndrome (CS) - Mucocutaneous lesions (trichilemmomas, acral keratosis, papillomatous papules) - Macrocephaly - Adult Lhermitte-Duclos disease - GI hamartomas or ganglioneuromas - Benign breast, thyroid, and uterus lesions - Nonmedullary thyroid cancer TP53 Sarcoma Brain Adrenocortical Leukemias Li-Fraumeni syndrome (LFS) - Soft tissue and osteosarcomas - Colorectal and many other cancers - Childhood onset cancers - Increased radiation sensitivity - Risk for multiple primary tumors STK11 Ovaries Duodenum Peutz-Jeghers syndrome (PJS) - Childhood onset mucocutaneous pigmentation and GI hamartomas - Risk for additional cancers - Can see cervical and gonadal tumors Pancreas Next CDH1 BARD1 Gastric Possibly Ovaries Hereditary Diffuse Gastric Cancer - Diffuse gastric cancer - Lobular breast cancer - Signet ring carcinoma

9 Continued: Next genes, associated cancers & other associated findings. Gene Cancer(s) Additional Characteristics CHEK2 Prostate Thyroid Kidney - Brain tumors have been reported NF1 Neurofibromatosis Type 1 RAD51D Ovaries ATM* BRIP1* Pancreas Possibly Ovaries Ataxia-Telangiectasia - Risk for lymphoma and leukemia in homozygous mutations carriers Fanconi Anemia* MRE11A* Possibly Ovaries Ataxia-telangiectasia-like disorder* MUTYH* NBN* Possibly Ovaries MUTYH-associated polyposis (MAP)* s colorectal polyps - Can see gastric, ovarian, endometrial and liver cancer Nijmegen breakage syndrome* PALB2* Pancreas Fanconi Anemia* RAD50* Possibly Ovaries Nijmegen breakage syndrome-like disorder* RAD51C* Ovaries Fanconi Anemia* * Biallelic mutations in these genes are associated with respective syndromes described under Additional Characteristics column.

10 Target population for panel genetic testing BRCAplus or Next 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. and ovarian cancer in the same woman 5. Family with three or more cases of breast cancer (on the same side of the family) 6. Clustering of three or more cases of breast, ovarian, &/or pancreatic cancer (on the same side of the family) 7. Clustering of three or more cases of breast, uterine, &/or thyroid cancer (on the same side of the family) 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 [VUS]). positive A gene mutation was found in one of the genes tested Increased risk for cancer specific to the gene mutation Cancer screening and prevention recomendations specific to gene Testing at-risk relatives for specific alteration will be recommended negative 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 recomendations based on family history Genetic testing may or may not indicated for family members inconclusive 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 recomendations based on family history Family research studies may be indicated

11 VUS rates and family studies program Our BRCA1/2 VUS rate is approximately 4% and BRCAplus VUS rate is approximately 6-7%. VUSs are more common in the Next panel because this panel analyzes 18 genes simultaneously. As data 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 the Next panel samples. Detailed interpretation of the variant is included in the test report. Ambry Genetics is committed to careful analysis and timely reclassification of VUSs. If a VUS is identified, complimentary testing of informative relatives may be offered through Ambry s family studies program. Familial tracking can assist in clarifying the nature of a VUS. When enough data has been accumulated to reclassify the VUS as either disease-causing or benign, clinicans will be automatically notified. Ambry has 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 draw blood. Blood Spot: Blood spots are not accepted. Saliva: Accepted for all BRCA1/2 related tests. Fill 1 tube with saliva up to black line (1cc of saliva) in Oragene Self Collection container (Next requires 2 tubes). After tube is closed 1cc of buffer will mix with saliva for a total volume of 2cc. Store at room temperature in sterile bag. Ship 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 Genetic counselors 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 pre-verification is recommended. max out of pocket If patient out-of-pocket financial responsibility is potentially greater than $100, Ambry will contact the patient for verbal approval prior to initiating the test. We remain committed to working with you and your patients to make the genetic testing process as simple and cost effective as possible. about ambry genetics In 13 years of offering genetic testing services, we ve performed hundreds of thousands of genetic tests and identified more than 45,000 mutations in greater than 500 different genes. Ambry Genetics offers a full menu of diagnostic solutions and is the world wide leader in hereditary cancer testing. Our comprehensive menu of over 40 individual cancer genes is the largest available in the US. To order your free sample submission kits, please contact: (866) info@ambrygen.com 15 Argonaut Aliso Viejo, CA For more details about these tests, visit ambrygen.com D MKG-00