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genetics in breast cancer and its surical application 3.pptx
- 1. GENETICS IN BREAST CANCER ANDITS CLINICAL APPLICATION IN SURGERY Dr Merlyn S Henriques Moderator – Prof Piyush Ranjan, Dr Ankita
- 2. Content • Introduction • GlobalBurden • Genetics in Breast cancer • Criteria for Genetic Testing • Genetic Counselling • Hereditary breast cancer and role of surgery • Role of Surgery in Moderate and Low penetrance cancer genes • Genetic testing – evolution and approaches • Genetic testing in India • Our experience
- 3. Introduction • Globally, breastcancer is the most common cancer type among women and second most common cancer type overall • An estimated 2.3 million new breast cancer cases and 670 000 breast cancer-related deaths occurred worldwide in 2022 Globocan, 2022
- 5. Why do weneed Genetic Testing? • Certain mutations are associated with recurrence of breast cancer in ipsilateral & contralateral breast • Risk of other malignancies – Genetic testing offers for screening and early detection • To tailor surgical and systemic treatment • Proactive prevention • Family risk management
- 6. Genetics and BreastCancer • 70–75% breast cancer cases - sporadic • Familial breast cancer - 15-20% - clustering of sporadic cases, common genetic background, shared environment, lifestyle choices, or a combination of these factors • Hereditary breast cancers - dominant inheritance pattern, pathogenic/likely pathogenic (P/LP) variants in breast cancer susceptibility genes - 5–10% of breast cancer cases Discovery of BRCA1 and BRCA2 >30 years ago, led to the search and discovery of several other breast cancer related genes
- 7. The burden ofbreast cancer predisposition variants across the age spectrum among 10,000 patients Guerra et al https://doi.org/10.1111/jg
- 8. Breast Cancer SusceptibilityGenes High Penetrance • BRCA1 • BRCA2 • CDH1 • PALB2 • PTEN • STK11 • TP53 Moderate Penetrance • ATM • BARD1 • BRIP1 • CHEK2 • MSH2 • MSH6 • MLH1 • PMS2 • EPCAM • NF1 • RAD51C • RAD51D Low Penetrance • FANCC • MRE11A • MUTYH heterozygotes • NBN • RECQL4 • RAD50 • RINT1 • SLX4 • SMARCA4 • XRCC2 Pal et al. World Journal of Surgical Oncology https://doi.org/10.1186/s12957-024-03553-9
- 9. Cancer risk inBRCA mutations Cancer type BRCA1 BRCA2 Primary breast F – 60-72% C/L breast - >20% M – 0.2 -1.2% F – 55- 69% C/L - >20% M – 1.8 – 7.1% Epithelial Ovarian 39-58% 13-29% Pancreatic <5% 5-10% Prostate 7-26% 19-61%
- 10. Other Mutations Gene Breastcancer risk Other cancers and risk CDH1 37 – 55% Diffuse gastric cancer PALB2 32 – 53% Epithelial ovarian ca – 3-5% Pancreatic – 2-5 % PTEN Cowden Syndrome 40 – 60% Thyroid, colorectal, endometrial, renal STK11 Peutz-Jegher Syndrome 32 – 54% Pancreatic >15% Non-epithelial ovarian neoplasms (usually benign) (sex cord tumor with annular tubules) - >10% TP53 Li Fraumeni Syndrome >60% Pancreatic – 5% Prostatic - 25 – 50% Other – soft tissue sarcoma, osteosarcoma, CNS tumor, ACC, melanoma, colorectal, and gastric.
- 11. Who needs aGenetic test?
- 13. General Testing Criteria Testingclinically indicated in - • Individuals with known blood relative having P/LP variant • Previously tested negative with limited genetic panel • P/LP variant in tumor genetic testing, that may have clinical implications • To aid in systemic therapy/ surgical planning • Individuals who meet Li Fraumeni, PTEN Hamartroma tumor syndrome, Cowden syndrome or Lynch syndrome testing criteria • Personal or family history of - Breast, Ovarian, Pancreatic, Prostatic, Colorectal cancer Testing may be considered in – Ashkenazi Jewish ancestry, personal history of serous endometrial cancer
- 14. Genetic Testing inBreast Cancer Personal history of breast cancer with - • ≤50 y • Any age: • Treatment indications - treatment decisions using PARP inhibitors • Adjuvant treatment decisions with Olaparib for high-risk,HER2-negative breast cancer • Pathology/histology TNBC Multiple primary breast cancers (synchronous or metachronous) Lobular breast cancer with personal or family history of diffuse gastric cancer • Male breast cancer • Ancestry: Ashkenazi Jewish • Family History - 1 close blood relative – breast Ca <50y, male ca breast, ≥ ovarian, pancreatic or prostate cancer Family history criteria: • Unaffected or affected but does not meet above criteria • Individual with a first- or second-degree blood relative meeting any criteria listed • Individuals who have a probability >5% of a BRCA1/2 P/LP variant based on prior probability models (eg - TYRER-CUZICK, BRCAPRO, CANRISK) BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, TP53
- 15. Genetic Testing inBreast Cancer Testing may be considered • Personal history of breast cancer 65 y not meeting any above criteria ≤ • Personal history of breast cancer at any age with 1 close blood relative with prostate cancer with ≥ intraductal/cribriform histology • Individuals (unaffected, or affected but does not meet above criteria with a 2.5%-5% probability of BRCA1/2 P/LP variant based on prior probability models (eg, Tyrer-Cuzick, BRCAPro, CanRisk) • Personal history of malignant phyllodes tumors Low probability (<2.5%) that testing will have findings of documented high-penetrance genes in : • Female with breast cancer >65 y, with no close relative with breast, ovarian, pancreatic, or prostate cancer
- 16. Genetic Counselling • Patientcentric process • Help understand and adapt to medical & psychological implications of genetic conditions • Clarify familial implications of information provided • Guide through the process
- 17. Process of GeneticCounselling Family and Medical history taking Risk Assessment and Evaluation Education and Pre-test Counselling Test selection and informed consent Test result interpretatio n and Post- test counselling Managemen t and or Surveillance plan Cascade testing of at risk family members Follow up & support
- 18. Pre-test Counselling Evaluate Familyhistory ● Patient's needs and concerns ● Knowledge of genetic testing for cancer risk, including benefits, risks, and limitations ● Goals for cancer family risk assessment ● Comprehensive family history ● Assessment of family history with relatives with similar disease phenotype ● Type of cancer, bilaterality, age at diagnosis, subtype, and pathology report ● Ethnicity
- 19. Pre-test Counselling Medical &surgical history • Prior genetic testing results for patients or family members • Personal cancer history (eg- age, histology, laterality) • Pathology reports • Carcinogen exposure • Reproductive history • Hormone or oral contraceptive use • H/o risk-reducing surgeries Educate ● On basic genetics ● Inheritance patterns ● Penetrance ● Variable expressivity ● Possibility of genetic heterogeneity ● Psychological and emotional implications
- 20. Pre-test Counselling Prepare Possible outcomes oftesting Positive (P/LP) Negative Uncertain variants (VUS) Mosaic results Informed consent Written informed consent Risk Benefits Limitation of testing Result Disclosure Release test result information to relatives or spouse in case of patient incapacitation Implications Management options Importance of result for therapeutic decision making Possible risk to relatives, cascade testing & management Cost
- 21. Post-test Counselling Result disclosure • Discussion •Associated medical risks • Result interpretation based on personal & family history Interpretatio n • Inheritance pattern • Penetrance • Expressivity • Risk of similar disease in other family members Discussion • Importance of notifying family members • cascade testing of at risk family members • Management options for family members Cascade testing • Discussion of recommended medical management options • Therapeutic implications • Support groups • Consider next tier of testing if needed
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- 25. Are these testingcriteria fool-proof? 1000 patients enrolled 959 reports analysed 49.95% met criteria 9.39% had P/LP variants 50.05% did not meet criteria 7.9% had P/LP variants Beitsch PD, Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J Clin Oncol. 2019 50% of patients do not meet the established testing criteria Solution: Universal Testing
- 26. Germline Testing Approaches SingleGene/ Syndrome specific BRCA1/2, Lynch syndrome Multi-gene Panel testing High, moderate and low penetrance genes Multi-gene Panel testing High penetrance genes
- 27. Hereditary Breast Cancer HBOC– Hereditary Breast Ovarian Cancer syndrome – most well known and studied syndrome associated with breast cancer • Mutations in BRCA 1 and BRCA 2 genes • BRCA1 /2 – tumour suppressor genes • Mutations in these two genes account for 25 % of hereditary breast cancer and 5% of all breast cancers
- 28. • BRCA 1– chr 17 (17q21) – involved in DNA repair and regulation of cell cycle checkpoints • BRCA 2 – chr 13 (13q12) – involved in repair of replication-mediated double stranded DNA breaks • Both have high penetrance. Estimated penetrance range – 41%-90 % lifetime risk for breast cancer, with an increased risk for contralateral breast cancer • >90% of hereditary families with both breast and ovarian cancers are caused by mutations in the BRCA 1 /2 genes BRCA genes
- 29. Histology • BRCA 1 -basal-like phenotype - Majority are TNBC • BRCA 2 - Similar to non BRCA tumours Ovarian cancers – predominantly serous papillary carcinoma or other cancers of epithelial origin.
- 30. BRCA Mutation –Breast Ca Screening - Clinical breast exam, every 6–12 months - starting at 25y • Breast screening 25–29y - annual breast MRI screening or mammogram, if MRI unavailable 30–75y - annual mammogram and breast MRI >75 y - management on individual basis BRCA P/LP variant treated for breast cancer and have not had bilateral mastectomy - screening with annual mammogram and breast MRI should continue as above
- 31. Males – Breast self-examtraining and education starting at age 35y • Clinical breast exam, every 12 months, starting at age 35y • Consider annual mammogram, especially in BRCA2 P/LP variants in whom lifetime risk of breast cancer is up to 7%, • starting at age 50 or 10 years before the earliest known male breast cancer in the family BRCA Mutation – Breast Ca
- 32. • RRM -case-by-case basis • Counseling - discussion of extent of cancer risk reduction/protection, risks associated with surgeries, breast reconstructive options, and management of menopausal symptoms • Psychosocial and quality-of-life aspects of undergoing risk-reducing surgical procedures BRCA Mutation – RRM
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- 34. • BRCA1/2 mutationsplay a significant role in the development of BIA-ALCL in women with breast cancer reconstructed with textured implants • Age-adjusted rate of developing BIA-ALCL for women with BRCA was 16 times the rate of BIA-ALCL without BRCA DOI: 10.1182/bloodadvances.2025016810
- 35. Reproductive Considerations -If desired, refer to fertility specialists - in vitro fertilization, egg- and embryo-cryo-preservation, preimplantation genetic testing. gestational carrier, adoption • P/LP BRCA1 variant may have earlier menopause and oocyte aging Non-surgical risk reduction • combination estrogen/progestin contraception (OCP) for ovulation suppression (studies in P/LP variant carriers support significant risk reduction benefits for ovarian cancer) • Levonorgestrel intrauterine device (LNG-IUD) - shown to reduce risk for ovarian cancer in the average-risk population BRCA Mutation - Risk Reduction Surgical risk eduction with bilateral salpingo- oophorectomy • Based on age-related risks of ovarian/fallopian tube cancer: BRCA1: RRSO – 35-40y BRCA2: ovarian cancer onset - 8–10 years later than in BRCA1 - RRSO until age 40–45y (unless age at diagnosis in family warrants earlier) • CA-125 and pelvic ultrasound for preoperative planning • Principles of Surgery - surgical and pathologic expertise - SEE-FIM (Sectioning and Extensively Examining the Fimbriated End) protocol for pathologic assessment and pelvic washings should be performed • Serous tubal intraepithelial carcinoma (STIC lesion) found - > consultation with gynec oncologist • premenopausal - > oophorectomy likely reduces risk of developing breast cancer (magnitude is uncertain and may be gene-specific) • residual risk for primary peritoneal cancer after risk reducing RRSO. HRT is generally not contraindicated and thus should be discussed with premenopausal patients who do not have a personal history of breast cancer.
- 36. Salpingectomy - reducesrisk of ovarian cancer, option for premenopausal patients not ready for oophorectomy • If patients undergo salpingectomy, completion oophorectomy is recommended as per gene-specific guidelines, unless specified by clinical trial protocol • SEE-FIM protocol and pelvic washings • CA-125 and pelvic USG for preope planning • Consider continuation of combination OCP or hormonal IUD for continued ovarian cancer risk reduction if ovaries remain in place • Option for average or uncertain risk patients if surgical sterilization desired Hysterectomy - • Limited data - slight increased risk of serous uterine cancer - clinical significance unclear. BRCA Mutation – Risk Reduction
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- 40. Cancer risk managementintervention may be recommended when a carrier’s absolute risk exceeds that of the average-risk population (i.e. 12%–13% for breast cancer and 1%–2% for ovarian cancer, based on SEER registry data
- 41. Role of surgery– Moderate Penetrance Genes • Moderate penetrance genes - ATM, BARD1, BRIP1, CDH1, CHEK2, MSH2, MSH6, MLH1, PMS2, EPCAM, NF1, PALB2, RAD51C, RAD51D and STK11 • Breast screening should continue as recommended based on age • Breast awareness starting at age 18 years • Clinical breast examinations - 6 to 12 months, beginning at 25y (5–10 y before earliest known breast cancer in family, whichever comes first) • Insufficient evidence to recommend RRM in carriers • RRSO considered when risk of developing ovarian cancer exceeds that of the average-risk population (threshold of 5%)
- 42. • Low penetrancegenes – FANCC, MRE11A, MUTYH heterozygotes, NBN, RECQL4, RAD50, RINT1, SLX4, SMARCA4, and XRCC2 • Insufficient evidence of association with breast cancer • Risk management recommendations for these genes should take into account family history and other clinical factors Role of surgery – Low Penetrance Genes
- 43. Understanding and Interpretinga Genetic Test
- 44. Evolution of GenomicSequencing
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- 56. Our Experience • ~2000cases counselled for testing • Uptake ~10% - ~200 got tested • Around ~120 have tested positive and are under follow up • Major issue – Unavailability of in house testing and cost of testing • Other issues – Family pressure, fear, social stigma, consanguinity, blaming the proband
- 57. Germline Testing Single Gene/ Syndrome specific BRCA1/2, Lynch syndrome Multi-gene Paneltesting High, moderate and low penetrance genes Multi-gene Panel testing High penetrance genes COST?? Other labs – BRCA1/2 germline testing – 7-8k NGS MLPA – High, moderate and low penetrance genes – 14-15k
- 58. access to geneticcounsellors provider factors cost genetic discrimination patient factors : knowledge, attitude, beliefs, anxiety, fear, guilt, disbelief insurance factors risk management following testing
- 60. “Cancer is stilla word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action” - Angelina Jolie, NYT, 2013
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Editor's Notes
- #10 Partner and localizer of BRCA2 in Fanconi anemia
- #14 Any gene that increases the risk of br ca to >/= 4 times that of the general population risk - high penetrance BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53
- #18 Assessment of family history (first-, second-, and third-degree relatives on each side of the family, particularly around individuals with a diagnosis of cancer Types of cancer, bilaterality, age at diagnosis, subtype, and pathology report confirmation Ethnicity
- #19 Detailed medical and surgical history including: Documentation of prior genetic testing results for patients and their family members Personal cancer history (eg- age, histology, laterality) Pathology reports of primary cancers and/or benign lesions Carcinogen exposure Reproductive history Hormone or oral contraceptive use History of risk-reducing surgeries Generate a differential diagnosis and educate the patient on basic genetics, inheritance patterns, penetrance, variable expressivity, and the possibility of genetic heterogeneity with psychological and emotional education
- #20 Prepare for the possible outcomes of testing, including positive (pathogenic, likely pathogenic [P/LP]), true negative and uninformative negative, uncertain variants, and mosaic results Obtain written informed consent, and document the informed consent in the patient’s medical record Discuss plan for results disclosure when appropriate, including the possibility of the patient consenting to Release of Information of test results to a close relative or spouse when results are released in case patient is incapacitated Potential risk, benefits and limitation of testing Discuss possible management options if a P/LP variant is identified (enhanced surveillance, risk-reducing agents, and risk-reducing surgery) Discuss that their results may be important to therapeutic decision making Advise about possible inherited cancer risk to relatives, options for risk assessment, testing, and management Discuss cost of genetic testing
- #21 Preferably done by genetic counsellor
- #32 40% RISK OF CONTRALATERAL BR ca in 10y if rrm and oophorectomy aren’t done
- #34 Breast implant associated – anaplastic large cell lymphoma 11 y follow up 13 cases for Lymphoma matched as 1:3 with patients with br ca and implant – 5/13 had BRCA mutation
- #35 RRSO reduces mortality at all ages in carriers of a P/LP BRCA1 variant BRCA2 variants - RRSO is only associated with reduced mortality in ages of 41 and 60 years
- #38 Germline mutations in TP53 Highly penetrant cancer syndrome – almost 100% penetrance Soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma and brain tumours Higher incidence of HER2 positive breast cancers Therapeutic RT for cancer should be avoided unless locoregional risk reduction or overall survival from RT is greater diagnostic radiation should be minimized to an extent feasible without sacrificing accuracy Patients with breast cancer - mastectomy preferred over lumpectomy/radiation to reduce radiation-induced sarcoma risk
- #40 Surveillance epidemiology and end results
- #44 Second gen - 50–500 bp in length. This makes them an excellent fit for resequencing projects, SNP calling, and targeted sequencing of very short amplicons. First gen - One dna strand at a tme in first gen Ngs - enable simultaneous sequencing of millions of DNA fragments. This makes it possible to swiftly and cost-effectively sequence complete genome Third gen Single-molecule sequencing (SMS) technologies, individual DNA molecules directly as opposed to previous sequencing techniques that rely on the amplification of DNA fragments,
- #45 Next-Generation Sequencing (NGS) Multiplex Ligation-dependent Probe Amplification (MLPA) report, focus on the copy number variations (CNVs)
- #46 +/- direction of dna - 3-5, 5-3 Each gene has multipe Transcript – main transcript in brackert (c. coding, g. – gene – intron and exon 3 or its multiple deletion – not frmaesjift Fs frameshift Coding DNA – between nucleotide 2808 -2811 – deletion of 4 base pairs – protein – alanine replaced by proline at 938 position, causing frame shift mutation and termination at 21amino acid Adenin guanine cytosine thymine
- #48 Adenin guanine cytosine thymine
- #50 Adenin guanine cytosine thymine
- #52 Glutamine , threonine Adenin guanine cytosine thymine
- #54 Adenin guanine cytosine thymine