Cancer Genetics - Hereditary Breast+Gyn

Breast Anatomy

• 15-20 Lobes per breast

• 20-40 Lobules per lobe

• 6-8 Ducts drain lobes to the nipple

  • Most breast cancers occur in the ducts

• Nerves throughout the breast

• Lymph Nodes and Blood Vessels: help fight infection

Gynecological System

• Vagina: external to Uterus

• Cervix: Opening and bottom portion of uterus

• Uterus: Endometrial lining

  • Polyps

  • Fibroid

• Fallopian Tubes

• Ovary

  • Cysts

Non-Modifiable Risk Factors for Breast Cancer

• Being female (prevalence 1/8 vs 1/700 men)

• Aging

• Ethnicity

  • Black women 4% lower incidence than white women, but 40% higher death rate

• Certain breast conditions : (LCIS, atypical hyperplasia)

• Hormone exposure: age at mensche/menopause, breast feeding

• Fam Hx of cancer

• Inherited gene mutations

Modifiable Risk Factors for Breast Cancer

• Obesity

• Alcohol use

• Physical inactivity

• Ionizing radiation exposure

Breast Finding: Not Cancer w/ Negligible Increased Cancer Risk

• Cyst

• Fibroadenoma

• Hyperplasia

• Papilloma

• Calcifications

• Radical Scar

• Benign Phyllodes tumor

Breast Findings Not Cancer w Increased cancer risk

• Lobular Carcinoma in situ (LCIS)

• Atypical ductal hyperplasia (ADH)

• Atypcial lobular hyperplasia (ALH)

• Flat epithelia (FEA)

Breast Finding Cancer

• Ducal carcinoma in situ

• Invasive carcinoma

  • Ductal

  • Lobular

  • Tubular

  • Muscions (Colloid)

  • Medullary

  • Paget’s Disease

• Malignant Phyllodes tumor

• Inflammatory breast cancer

Breast Cancer Treatment- Chemotherapy

Anticancer drug used after radiation and surgery

Breast Cancer Treament Radtiaiton

• straightforward: ionzing radtion to breast cancer tissue

Breast Cancer Therapy - Hormonal Therapy

• Tamoxifen: targets estrogen and/or progesterone receptor positive cancers

• Aromatase inhibitors: used in the tretment of breast cancer in postmenopausal women and men by stopping an enzyme in fat tissue (aromastase) from converting hormones into estrogren

Breast Cancer Therapy - Immunotherapy

• uses body’s own immune system to help fight cancer

Breast Cancer therapy - PARP Inhibitors

• Effective in BRCA1/2 mutation Cancers (Breast, Ovarian, prostate and Pancreatic)

• These BRCA1/2 cancer rely heavily on PARP to fix single strand DNA breaks suppressing PARP leads to furthe double strand breaks that BRCA1/2 would normally repair

• Lack of BRCA1/2 means double breaks cnnaot be repaired, leading to irrevserible DNA breakdown and cel ldeath

Breast Cancer - Surgical Options

• Lumpectomy

• Masectromy / Bilateral Masetcomy

Lumpectomy

removal to trumo from breast plus neoadjuvant radtion

Masectomry

• Removal of entire breast tissue and often involves nipple and areola

• may include SLNB and ALND

Non-Modifiable Risk Factors for Gynecological Cancer

• Again

• Being female

• chronic conditions (endometriosis, PCOS, diabetes)

• Hormonal factors (early menarche, late menopause, nulliparity)

• Infertility

• Hereditary

Modifiable Risk Factors for Gynecological Cancer

• Medications (excess estrogen exposure without adequate opposition by a progestin, tamoxifen)

• Obesity

• Smoking

Gynecological Tumors

Screening Tests for Endometrial/Ovarian Cancers

• Pelvic exam

• Ultrasound/Sonogram

• MRI

• Tumor marker 9blood test)

• Biopsy (usually follow finding by imaging or blood test)

Ovarian/Endometrial Surgical Treatment

• Hysterectomy (TAH/TH)

• Bilateral salpingo-oophorectom (BS)

• LymphNodeBiopsy

• OMental Biopsy

• Pelvic Washing

• Debulking cytoreduction: get all visible cancer out

Ovarian/Endometrial Cancer Radiation therapy

• Only for Endometrial Cancer NOT Ovarian Cancer

Ovarian/Endometrial Cancer Hormonal Therapy

• Alternative to hysterectomy to preserve fertility

• Ex Progesterone

  • Synthetic forms of the naturally-occuring hormone porgesterone; Presnet ina llforms of hormonal birth control

  • Preveny pregnay by inhibiting ovulation

  • Unopposed Estrogen can cause an overgrowth of the endometrium, which may lead to endometrial canca becoming cancersours

Hereditary Breas-Ovarian Cancer Syndrome (HBOC)

HBOC General Testing Criteria - Clinically indicated

HBCO General Testing Criteria - Testing may be concidered

Breast Cancer Susceptibility Genes Testing Criteria

• Less than 50yo at diagnosis

• To aid in Systemic treatment decision: PARP (BRAC1/2), Olaparib (HER-2Negative)

• Pathology/Histology:

  • Triple negative Breast Cancer (Estrogen, Progesterone, HER-2 receptors)

  • Lobular Breast Cancer w history of DIFFUSE GASTRIC CANCER

  • Multiple Primaries

• Male Breast Cancer

• Ashkenazi Jewish Ancestry

• Family history

  • 1 close blood relative with: <50yo Breast, male Breast, Ovarian, Pancreatic, Metastatic Prostate

  • 3 Diagnosises of Breast and/or on same side of the family

HBOC Guide Lines: Risks and Management

BRCA1 Cancer Risks

• Breast:

  • Primary: 60-72%

  • Contralateral: 30-40%

  • Male: 0.2-1.2%

• Epithelial Ovarian: 39-58%

• Prostate: 7-26%

• Pancreatic: <5%

BRCA2 Cancer Risks

• Breast:

  • Primary: 55-69%

  • Contralateral: 25%

  • Male: 1.8-7.1%

• Epithelial Ovarian: 13-29%

• Prostate: 19-61%

• Pancreatic: 5-10%

• Melanoma: unknown

General Population Cancer Risks

• Breast 12-13%

• Ovarian 1-2%

• Prostate 12-13%

• Pancreatic 1-2%

  ALWAYS compare to general population RISK!

Risk REduction for HBOC - Breast

• Hormonal Therapy: 50% reduction

• Masectomry: 90% reduction

• Bilateral Salpingo-Oophorectomy (removal of both sides fallopian tube and ovary): 50% reducation (in pre-menopausal women)

Risk Reduction for HBOC - Ovarian Cancer

• Bilateral Salpingo-Oophorectomy (BSO): 96% reduction

• Oral Contraceptive Pills (OCPs): 50% reduction (if taken for ~10years)

BRCA Positive Clinical Management - Breast Cancer

Women

• At 25yo: Clinical Breast Exam 6-12 Months

• 25-29yo: MRI imaging

• 30-75yo: Annual mammogram and MRI

• >75yo: management considered on an individual basis

Men

• At 35yo: Self Exam + Annual Clincial Exam

• 50yo: consider mamogram

BRCA Positive Clinical Management - Ovarian/Fallopian/Perioneal/Uterine

Surgical risk reduction of Ovarian/Fallopian Cancer

• BRCA1: Recommend Risk-Reducing Salpingo-Oophorectomy (RRSO) at 35-40yo

• BRCA2: Recommend Risk-Reducing Salpingo-Oophorectomy (RRSO) at 40-45yo {Why? BRCA2 Ovarian cancer present 8-10 years later than BRCA1}

BRCA Psotive Clinical Managment - Prostate

• Screening/Surveillance: at 40yo

  • BRCA1: consider prostate screening

  • BRCA2: recommend prostate screening

BRCA Positive Clinical Management - Pancreatic Cancer

• only with Pos. BRCA AND with a Fam Hx of Pancreatic Ca

  • start at 50yo or 10years younger than relative’s diagnosis

  • Endoscopic Ultrasound ( )

  • Magnetic Resonance Cholangiopancreatography (a technique for viewing the bile ducts and pancreatic duct, pancreas gallbladder and liver)

PARP Inhibitor

• Targets the Poly (ADP-Riobse) Polymerase enzyems: repair single strand breaks via base excsion repair

• BRCA1/2 cancers have no Double Stranded Break repair system

Founder Mutations in BRCA1/2

PTEN Hamartoma Tumor Syndrome (PHTS)

• PHTS syndrome includes the following phenotypes:

  • Cowden Syndrome

  • Bannayan-Riley-Ruvalcaba

  • Adult L’hermite-Duclos disease

  • Protus-like syndrome

  • Autism spectrum disorder with Macrocephaly

Diagnosing Cowden Syndrome

Major

• Breast Cancer

• Epithelial thyroid cancer (NON-MEDULLARY)

• **** Macrocephaly *****

• Endometrial carcinoma

  Minor

• other thyroid lesions

• Intellectual disability

• Hamartomas intestinal polyps

• Lipomas

• Fibromas

• Genitourinary tumors

• Uterine fibers

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

PTEN Hamartoma Variant

• Macrocephaly

• Intestinal hamartomous polyposis

• Lipomas

• Pigmented macules of the glans penis

Proteus Syndrome

• CAN BE a PTEN Hamartoma Variant

• Highly variable disorder—> clinical diagnosis hard, molecular diagnosis preferred

• Hamartoma growth of multiple tissues

  • connective tissue nevi

  • epidermal nevi

  • hyperostoses

Testing Criteria for PTEN

• Not meeting clinical criteria for CS/PHTS but with:

  • Autism AND Macrocephaly

  • Two or more Trichilemmomas

PTEN Hamartoma Tumor Syndrome Cancer Risks

• Breast: 85%

• Thyroid (NEVER MEDULLARY): 35%

• Renal Cell: 34%

• Endometrial: 28%

CS/PHTS (PTEN) Clinical Managment

• Thyroid: US starting at 7yo

• Breast: Screening at 25yo

• Colorectal: Screening at 35yo

Li-Fraumeni Syndrome (LFS)

Li-Fraumeni Diagnosis/Testing Criteria

• TP53 positive

  or

• Three classic clinical positive

Li Fraumeni Chompret

LFS should be suspected in individuals who meet the chompret criteria

• Has LFS tumor (breast, sarcoma, osteosarcoma, CNS tumor, adrenocortical tumor) AND realtive with LFS tumor before 56yo

• Multiple tumors, two of which are LFS tumor before 46yo

• Adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma

• Breast cancer before 31yo

Therapeutic Considerations for Lif Fraumeni

• Radiation therapy should be minimized: potential for downstream malignancies

Li-Fraumeni Screening/Surveillance

• Breast: 20yo every 6-12 months (Clinical+MRI)

• Other Cancers: 25yo endoscopy, 18yo Skin exam

• Pediatric

  • Annual Brain+Body MRI starting in infancy

  • Ultrasound every 3-4 months in infancy

Li-Fraumeni Testing Consideration

• somatic TP53 detection can confound germline testing: can be detected in blood or slavia —> increase with age, NGS suspetiable

• Must test tissue other than blood and salvia

• Comepltle blood count nad perhihpal blood smear must also be done in TP53 postive detection

Hereditary Diffuse Gastric Cancer

Breast Cancer Genes

• BRCA1 +2, CDH1, PALB2, PTEN, STK11, TP53

CLassic vs ChomperatCriteria for Diagonis of Li Fraumni

Skin Fibroblasts

• the best option for germline testing tissue for TP53 mutations (Li Fraumeni)

• Li Fraumni has alot of potenaitl for somatic mutation, blood samples can confound germline many times so skin fibroblasts are the best option

Hereditary Diffuse Gastric Cancer

Signet Ring Cells

• Associated with Diffuse Gastric Cancer syndrome: presence pathologically confirms diagnosis of DGCS

Controversy on Gastric Cancer Risk reduction surgery

• Gastrectomy reduces risk <1%

• But: Quality of life dramatically affected —> major dissatisfaction

Adult vs Child Hereditary Cancer syndromes

• Adult syndromes: MonoAllelic mutatations

• Childhood Syndromes: BiAllelic mutations

Francoi Anmeia

• Bi allalic mutations in BRCA1, BRCA2, BRIP1, PALB2, RAD51C

Ataxia-Telangiectasis

• Bi allelic pathogenic mutations in ATM gene

Bloom Syndrome

• Bi allelic pathogenic mutations in BLM