Breast + Gynae Flashcards
What are the different types of breast cancer?
A. NONINVASIVE
- Ductal Carcinoma In Situ (DCIS)
- Lobular Carcinoma in Situ (LCIS)
B. INVASIVE (INFILTRATING)
- Invasive ductal carcinoma is the most common subtype of invasive carcinoma (>80%)
- Invasive lobular carcinoma (>10%)
- Medullary carcinoma
- Colloid carcinoma
- Tubular carcinoma
What is paget disease?
PAGET DISEASE of the nipple is caused by the extension of DCIS up the lactiferous ducts and into the contiguous skin of the nipple, producing a unilateral (one breast only) crusting exudate over the nipple and areolar skin. In almost all cases, an underlying carcinoma is present, and approximately 50% of the time this carcinoma is invasive.
Risk factors for breast cancer
Decreasing risk
- Genetic factors
- Chest radiotherapy < 30yo
- Dense breast tissue
- Previous atypical DCIS/LCIS
- Fam hx of breast cancer
- Hormonal factors; HRT, nulliparity, menarche < 12
Endogenous estrogen excess involves increased exposure to estrogen due to long reproductive life and late age at birth of first child.
- Lifestyle Factors: obesity, sedentary lifestyle, alcohol, smoking
BRCA1 and BRCA 2
- What are they
- Mode of inheritance
- Associated Cancers
- DNA repair genes (tumour suppressor genes)
- Autosomal dominant
- BRCA1 mutations develop breast and ovarian earlier than BRCA2
Associated with higher risk of ovarian cancer (BRCA 1 > BRCA2)
Also:
- Pancreatic cancer
- Prostate cancer (BRCA 2)
- Slight increase risk in stomach and head + neck cancers
BOPP
BRCA1 - tend to be triple negative
BRCA2 - more likely to have ER/PR receptors
BRCA1 and BRCA2 association with Breast Cancer
BRCA 1:
- Increased risk of triple negative breast cancer
- 35% chance of developing ovarian cancer; risk >40 years; chromosome 17.
BRCA2 - typically associated with increased risk of hormone receptor positive breast cancers
BRCA 2: a/w post menopausal and male breast cancers; 60% chance of developing breast cancer and 30% chance of developing ovarian cancer; risk >50 years ; usually ER(+) breast cancer; chromosome 13
Other genetic mutations that increase the risk of breast cancer
- Li Fraumeni: p53 sarcoma, breast cancer, brain cancer (particularly glioblastoma) and adrenocortical carcinoma. - Cowden: PTEN - Peutz Jegher: STK11 - Ataxia Telangiectasia: ATM - Diffuse Gastric Cancer: CDH1 - Lynch Syndrome
What is the scoring system used for working out the risk of a patient having BRCA1/2 gene
Manchester scoring system
Score >15 = 10% risk of carrying BRCA1 or BRCA2 mutation
Management of high risk women with BRCA1/2 mutations
Consider:
- Prophylactic Surgery
- Bilateral risk reducing mastectomy - decrease risk 90%
- Bilateral risk reducing salpingoophorectomy (ovaries + fallopian tubes) once childbearing is complete (before 40 years of age if possible) - Screening
- Increased surveillance consider from 30 years of age including breast MRI
- in young women with dense breasts US > mammogram
- MRI breast especially pre-menopausal, dense breasts - Chemoprevention (rarely done)
- SERMS: tamoxifen
- Aromatase inhibitors in post menopausal
Chemoprevention with tamoxifen, anastrazole or exemestan
Breast cancer screening
- Women aged 50- 74 years are invited for beast mammogram 2 yearly in Australia
- Women aged 40- 49 years and > 74 years are not invited, but have access to free screening
Clinical factors associated with germline BRCA1 BRCA2 mutations:
What are the early breast cancer syndromes?
Clinical factors associated with germline BRCA1 BRCA2 mutations:
• Invasive breast cancer ≤ 30 years
• Triple negative breast cancer < 60 years
• Male invasive breast cancer of any age
• Ovarian or primary peritoneal cancer
• Ashkenazi Jewish heritage
Increasing Aggressiveness:
Luminal A: ER+, PR+, HER2-, low Ko67, low grade
Luminal B: ER+, PR + HER2 +
Non Luminal: ER-, PR-, HER2+
Basal Like: triple negative
Management of early breast cancer
Stage 1 -3
CURATIVE intent
- Wide local excision or mastectomy + Sentinal node biopsy + axillary node clearance if senital node positive + adjuvant chemotherapy (anthracycline and/taxane based) + adjuvant radiotherapy + hormone therapy + additional targeted therapy
- Adjuvant Chemo
- Doxorubicin + cyclophosphamide followed by paclitaxel or docetaxel + cyclophosphamide
- Radiotherapy must be performed with WLE to obtain appropriate local control.
Consider RT post mastectomy if poor prognostic RF:
- <40yo
- > 4cm primary
- > 4 LN
- Positive surgical margins
(A) Adjuvant Tamoxifen reduces contralat breast ca
(B) HER2 (+): Transtuzumab
(C) ER(+)/PR(+)/Her2(-) Type A:
- Premenopause: Tamoxifen or ovarian suppression with gosrelin + tamoxifen
- Post menopause: Aromatase inhibitor or tamoxifen
(D) ER(+)/PR(+)/Her2(+): Type B
- Transtuzumab
Side effects of:
- Doxorubicin
- Paclitaxel
- Cyclophosphamide
- Doxorubicin (anthracycline): cardiotoxicity, infertility, alopecia
- Paclitaxel (taxane): peripheral neuropathy, nail changes, alopecia
- Cyclophosphamide: cystitis, alopecia
What is the endocrine therapy available for early stage breast cancer who are ER+ or PR+
(A) Aromatase Inhibitors - inhibits peripheral conversion of testosterone to oestradiol
POSTMENOPAUSAL WOMEN ONLY
- Anastrozole, Letrozole, Exemestane
- SE: osteoporosis, hot flushes, vaginal atrophy
(B) Selective Estrogen Receptor Modulators - ALL WOMEN AND MEN
- Tamoxifen
ER blocker in breast, ER agonist in bone (osteoprotective)
- SE: DVT, endometrial cancer
(C) Ovarian Suppression
- Gonadotropin releasing hormone agonist (GnRH agonist)
- Pre-menopausal woman
- Triptorelin or goserelin
- Benefit when added to SERM or AI
What is Ki67 a marker of in breast cancer?
Marker of proliferation
Aromatase Inhibitors
Anastrozole, Letrozole, Exemestane
MOA: Block DHEA and thus block estrogen biosynthesis
Only use in POST MENOPAUSAL women
SE:
- Hot flushes
- Arthralgia
- Weight gain
- Dryness - skin, mouth, vagina
- Mood change
- Osteoporosis
- Hyperlipidemia
Tamoxifen
MOA: SERM - Selective estrogen receptor modulator, ER blocker in breast tissue but ER agonist in bone, uterus, liver
Thus osteoprotective
Use in pre and post menopausal women
SE:
- DVT as tamoxifen is an AT III inhibitor
- Endometrial cancer - acts as estrogen agonist in uterus
- Vasomotor symptoms: hot flushes
- Increases BMD in post menopausal women
Ovarian Suppression
Goserelin
- Usually sex hormones are released in a pulsatile fashion
- Continuous high doses of GnRH agonists downregulate GnRH receptors in the pituitary
- After a short term upward spike, this decrease LH and FSH and hence decrease ovarian steroidogenesis
HER2 positive disease
Trastuzumab monoclonal antibody against HER 2
- Stops dimerisation with other HER2 receptors
- Induces antibody dependent cell mediated cytotoxicity
In early stage breast cancers, patients can receive neoadjuvant and adjuvant chemo after surgery.
If there is residual disease detected in the surgical specimen - switch to drug-antibody conjugate TRASTZUZUMAB EMTASINE (KADCYLA)
SE
- Very well tolerated
- Usually mild flu like symptoms
- Rarely: nausea, diarrhoea, CARDIOTOXICITY
Asymptomatic LVEF decline in 13.3%
Mostly reversible
Increased risk if anthracyclines are used eg: doxorubicin
- No CSF penetration however
Another HER 2 inhibitor is Pertuzumab
- Stops dimersation of HER2 with HER3 molecules
- Used in combination with trastuzumab - slightly higher cardiac failure and diarrhoea
- Binds to dimerisation domain of HER2 receptor but also prevents binding with itself or other EGFR
- Improves survival 1st line combined with trastuzumab + taxane
What medication can be used for HER 2+ and BRCA 1/2+ breast cancer?
PARP inhibitor - Olaparib
PBS appproved >1 year for BRCA + ovarian cancer
SE:
- N+V, diarrhoea
- Mucositis
- Pancytopenia
- Prostate cancer: VTE
- Infrequent - pneumonitis
- Possibly secondary malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)
SE
- Hepatotoxicity
- Pulmonary toxicity
- MDS/AML
What are PARP inhibitors
- BRCA1 and BRCA2 interact with another protein called RAD51
- This complex is responsible for HOMOLOGOUS RECOMBINATION which functions to REPAIR DOUBLE STRANDED DNA BREAKS
- Without this function, any cell with a double strand DNA break cannot repair itself and it will die
- Single cell DNA breaks are much more common than dsDNA breaks
PARP - Poly -(ADP ribose) polymerase
- Involved in single strand break DNA repair, also expression of inflammatory genes and programmed cell death
PARPi + Homologous Recombination Deficiency (due to BRCA1/2 mutation)
- Single strand DNA break
- PARP attaches to single strand break and attempt base-excision repair
- PARP inhibitor blocks base excision repair but also binds PARP to the single strand break and stops other DNA damage repair proteins
- Damage converts to double strand DNA damage, which is irreparable in those with BRCA mutations –> cell death
-ib vs -mab
- Drugs that end in “ ib ” are small molecular inhibitors that target intracellular signaling
Usually administered orally - Drugs that end in “ mab ” are monoclonal antibodies that target cell surface receptors
Usually administered intravenously
What medications can be used for metastatic breast cancer?
• Cyclin dependent kinase 4/6 inhibitors for ER+ PR+
EG: Palbociclib, Ribociclib, Abemaciclib
• Alpha specific PI3 kinase inhibitors
Alpelisib
Alpha specific PI3 kinase inhibitors: Alpelisib + Fulvestrant can be used for ER+ PR + HER2 -metastatic breast cancer after failure of CDK4/6 i in those with activating PIK3CA mutations
• Antibody drug conjugates
Trastuzumab emtansine for HER 2+
Sacituzumab for triple negative
• Checkpoint blockade (immunotherapy)
Pembrolizumab - PD1 inhibitor
Atezolizumab - PDL1 inhibitor for triple negative
Cyclin dependent kinase 4/6 inhibitors
Palbociclib, Ribociclib, Abemaciclib
Cyclin D/cyclin dependent kinases 4/6 (CDK4/6)- retinoblastoma protein pathway. CDK4 and CDK6 function in complex with Cyclin D1 to phosphorylate and inactivate the tumour suppressor Rb
MOA: cyclin dependent kinase inhibitors
- CDKs promote pathways to transition from G1 to S phase in cell cycle
- CDK4/6 inhibitors prevent phosphorylation of the RB tumour suppressor, thereby invoking cancer cell cycle arrest in G1 and prevent cell cycle progression
Used for ER + PR+ HER2 -metastatic cancer
Palbociclib/ribociclib + AI/fulvestrant involves PFS + OS
SE: neutropenia, raised LFTs, QT prolongation (Ribo), N+V, diarrhoea
- Palbociclib, Ribociclib: neutropenia
- Ribociclib: severe LFT derangement, QT prolongation
- Abemacicilib: persistent diarrhoea, less neutropenia
Alpha specific PI3 kinase inhibitors
Alpelisib
Indication: Significant progress free survival in endocrine resistant HR+ HER2- metastatic breast cancer - 2nd line after CK4/6 inhibitors
Use: Alpelisib + Fulvestrant (selective oestrogen receptor downregulator)
SE
- Rash
- Hyperglycemia
- N+V
- Diarrhoea
Trastuzumab emtansine T-DMI
- Trastuzumab emtansine is an antibody drug conjugate
- Trastuzumab covalently linked to the cytotoxic agent DM1 (microtubule inhibitor)
- Used as 2ND LINE for METASTATIC HER2 + breast cancer
Trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor, whereas DM1 enters cells and destroys them by binding to tubulin –> Ab mediated cytotoxicity
SE
- Thrombocytopenia
- Liver toxicity
- No increased risk of cardiotoxicity
Where is PD-1/PD-L1 located
PD-1 sits on T cells
PD-L1 sits on APC
- The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells.
- Its ligands, PD-L1 and PD-L2, are expressed on the surface of dendritic cells or macrophages
- PD-L1 is overexpressed on tumor cells
- PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
PD-1 inhibitors:
Nivolumab
Pembrolizumab
PD-L1 inhibitors:
Atezolizumab
Where is PD-1/PD-L1 located
PD-1 sits on T cells
PD-L1 sits on APC
- The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells.
- Its ligands, PD-L1 and PD-L2, are expressed on the surface of dendritic cells or macrophages
- PD-L1 is overexpressed on tumor cells
- PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
What is CTLA4
CTLA-4 is expressed on T cells and binds to B7 co-stimulatory receptors on APC preventing T cell activation.
CTLA-4 inhibitors e.g. Ipililumab block the binding of CTLA-4 to B7 resulting in T cell activation and immune clearance of tumour cell
Checkpoint inhibitors in advanced triple negative breast cancer
PDL1 inhibitor is used in advanced triple negative breast cancer
Atezolizumab (PDL1 inhibitor) + Nab-paclitaxel
Brain mets and breast cancer
The most common breast cancer metastasis sites are the bones, the lungs, the brain, and the liver.
Brain metastases are particularly common in advance triple negative and HER2 positive breast
cancer
Sacuitizumab govitecan
Not available yet
Sacuitizumab govitecan for metastatic triple negative breast cancer
Antibody-drug conjugate that targets Trop2, a protein that is overexpressed in triple negative breast cancer for the selective delivery of SN38, active metabolite of irinotecan.
SUMMARY OF BREAST CANCER TREATMENT
ADJUVANT
(A) ER+ PR +
Endocrine therapy (AI/SERM) +/- chemo
(B) HER2 +
Trastuzumab + chemo
(C) TRIPLE NEGATIVE
Chemotherapy
(D) BRCA + HER2 -
PARPi (Olaparib)
METASTATIC
(A) ER+ PR +
- Fulvestrant (selective esotrogen receptor down regulator) + AI
- ET + CK4/6 inhibitors (Palbociclib, ribociclib, abemaciclib)
- Alpha specific PI3 kinase inhibitors: Alpelisib + Fulvestrant can be used for ER+ PR + HER2 -metastatic breast cancer after failure of CDK4/6 in those with activating PIK3CA mutations
(B) HER2 +
- 1st Line: Trastuzumab + Pertuzumab
- 2nd Line: Trastuzumab Emtansine (T-DMI/Kadcyla)
(C) TRIPLE NEGATIVE
- Immunotherapy: PDL1 inhibitor Atezolizumab + nab-paclitaxel
- Sacituzumab govitecan - targets Trop 2 (antibody-drug conjugate)
Lobular breast cancer
- More likely to present with bilateral breast cancer
- Under detected on standard mammogram/US -> MRI
- Even MRI often underestimates –> large, node positive
- Considered chemo insensitive
- More hormone sensitive
Indications for radiotherapy in breast cancer
Bone pain
Spinal cord compression
Cerebral mets
Ulcerating skin/primary lesions
Risk factors for ovarian cancer
- Age
- BRCA 1/2 mutation, Lynch syndrome
- Unopposed oestrogen: early menarche, late menopause, OCP , obesity, nulliparity
- Infertility, endometriosis, polycystic ovarian syndrome, use of an intrauterine device, and cigarette smoking (for mucinous carcinomas)
Protective: previous pregnancy, history of breastfeeding, oral contraceptives, and tubal ligation
Causes of elevated Ca125
- Ovarian cancer
- Pancreatic, breast, colon, lung cancer
- Menstruation, PID, endometriosis, fibroids
- CIrrhosis
- Pancreatitis
- Cardiac failure
- Ascites, pleural effusions
- Pregnancy
BRCA1/2 and ovarian cancer
- Presenting in 15% of patients with ovarian cancer
- BRCA1: risk starts to increase from 40yo
- BRCA2: risk starts to increase from 50yo
Some patients have SOMATIC BRCA mutations without germline mutations
Clinical Features of Ovarian Cancer
Normally incidental finding Majority present with advanced disease - Constitutional symptoms of malignancy - Abdominal bloating + distension - Abdominal/pelvic pain - Disturbance in bowel + urinary fx - Respiratory symptoms
Staging of ovarian cancer
FIGO Staging
Stage 1: limited to ovary
Stage 2: spread to pelvic organs
Stage 3: spread to rest of peritoneal cavity, omentum, positive LN
Stage 4: distant mets, liver parenchyma, lung
Diagnosis + Ix for Ovarian Cancer
- Abdomino-pelvic examination
- Ultrasound/TV Scan (specialist radiologist)
- FBC, U&E, LFT, CA125, CEA
- AFP, HCG, LDH if pre-menopausal
- CXR, CT/MRI to assess peritoneal, omental and retroperitoneal disease
- Radiologically (USS/CT) guided biopsy or Cytology of ascitic tap
- Gynae-oncology MDT to discuss upfront surgery versus chemo
How does ovarian cancer spread?
usually intra-peritoneal mostly, more rarely through lymphatics
Management of advanced ovarian cancer
(A) SURGERY
- Total abdominal hysterectomy + bialteral salpingoophectomy
- Comprehensive staging and debulking
Aim is to resect all macroscopic disease and minimise the amount of residual disease
(B) CHEMOTHERAPY
- Adjuvant chemotherapy for selected patients with Stage 1, all patients with stage 2-4.
- Carboplatin + Paclitaxel (standard treatment)
- Carboplatin + Paclitaxel + Bevacizumab for Stage IV and sub-optimally debulked stage III patients
(C) BRCA MUTATION
PARP inhibitor - olaparib, niraparib
What are the types of ovarian cancers?
There are 3 main types of primary ovarian tumours:
- Epithelial ovarian tumours (most common),
- Germ cell tumours (egg producing cells within the body of the ovary – rare)
- Sex cord stromal tumours (often produce steroid hormones).
- Epithelial (Surface Cells) Ovarian Tumours
The major types of epithelial ovarian tumours include:
- Serous Adenocarcinoma (40% malignant)
- Mucinous adenocarcinoma (20% malignant, better prognosis than serous)
- Endometrioid Adenocarcinoma (usually malignant)
- Brenner Tumour: usually benign
- Clear Cell Adenocarcinoma - Germ Cell Tumours are derived from egg producing cells within the body of the ovary
They primarily occur in children and teenagers and are rare compared to epithelial ovarian tumours
The major types include; can be divided into:
- Yolk Sac Tumour (malignant; produces AFP)
- Teratoma
- Dysgerminoma (malignant)
- Choriocarcinoma (malignant; secrets hCG) - Sex Cord Stromal Tumours are rare and often produce steroid hormones.
3 main types include:
- Granulosa Theca Cell Tumours: estrogen secreting
- Fibroma-Thecomas: often associated with Meig’s Syndrome
- Sertoli Leydig Cell Tumours: androgen secretion - There are also metastases which may spread to the ovaries:
- From breast, lung, GIT
- Transcavitatory spread of gastric carcinoma - Krukenberg tumour
What is mucinous ovarian cancer associated with?
Associated with smoking
Not BRCA mutation, nulliparity, early menarche/late menopause
Risk factors for Endometrial Cancer
Genetics associated with endometrial
Obesity Metabolic syndrome: diabetes, PCOS Nulliparity Early menarche / Late menopause Use of tamoxifen or unopposed oestrogen HRT Lynch syndrome/HNPCC (5%)
Protective Factors
High parity
Exercise
Long-term use of the combined oral contraceptive pill
GENETICS
- Lynch syndrome (27x) is the most common genetic syndrome associated with endometrial cancer and a marked increased risk of colon cancer (right sided, mucinous)
- Cowden syndrome, a rare autosomal dominant disorder characterised by multiple hamartomas and an increased risk for breast and thyroid and endometrial cancer (5x). PTEN mutation, autosomal dominant
Histological Groups
Clinical features of endometrial cancer
Endometroid (80%) Non Endometroid (carcinomas) - poor prognosis - Post menopausal bleeding, intramenstrual bleeding
Management of endometrial cancer
- Hysterectomy (normally provides cure)
RF for Recurrence
- Higher stage of disease
- Grade of disease
- Lymphovascular space invasion
- High-risk histology eg serous or clear cell
- Adjuvant Radiotherapy (vaginal vault brachytherapy or external beam RT) +/-
- Chemotherapy - carboplatin/paclitaxel
- Mismatch Repair Deficient - PD1 inhibitor pembolizumab + Lenvatinib (anti-angiogenic) = still in trials
Risk factors for cervical cancer
- HPV infection : 70% due to subtypes 16 and 18
- High parity
- Increased number of sexual partners
- Young age at time of first sexual intercourse
- Long-term use of oral contraception
- Smoking history
- HIV infection
High risk serotypes of HPV (16,18,31,45) are able to integrate two of their main oncoproteins, E6 and E7 into the host DNA.
- The E6 protein binds and inactivates the tumour suppressor gene, p53 where mutated cells avoid apoptosis. E6 also enhances the integration of foreign DNA into host cell genome and degrades the proapoptotic protein BAK
- The E7 protein binds and inactivates the tumour suppressor gene Rb allowing cells to proliferate rapidly. E7 also binds and inactivates CDK (cyclin dependent kinase) inhibitors p21 and p27, allowing cells to overcome G1/S cell cycle arrest
Low Risk: HPV 6,11
- Clinical Features
- Pathogenesis of cervical cancer
CLINICAL FEATURES
Post coital bleeding, menorrhagia
PATHOGENESIS - Arise at squamo-columnar junction - Progression from pre-invasive lesions to invasive cancer in 10-25 years - 70% squamous cell - 15-20% adenocarcinoma
Squamous > Adenocarcinoma (stronger viral link)
CIN: premalignant lesions noted
1. Low grade, dysplasia to basal 1/3 of epithelium
2. Moderate grade, dysplasia to basal 2/3 of epithelium
3. Severe dysplasia to >2/3 basal epithelium
Staging of Cervical Cancer
- Stage 1: Confined to cervix
- Stage 2: Beyond cervix but not to pelvic wall or lower 1/3 of vagina
- Stage 3: Disease to pelvic wall or lower 1/3 of vagina
- Stage 4: Invades bladder, rectum or metastasise
Cervical cancer screening
Cervical swab + HPV test between 25 to 74 q5 years
- If positive –> risk stratification
- High risk: colposcopy
- Moderate risk: further liquid based cytology and risk restratification. If unsatisfactory cytology, repeat in 12 months and risk stratify
Management of Cervical Cancer
Small lesion: surgical resection +/- chemoradiation (cisplatin + paclitaxel) if stromal invasion or if positive margins +/- HRT for post-operative symptom management
Locally advanced: Definitive chemo (cisplatin + paclitaxel + bevacizumab) AND Cervical brachytherapy + PET scan in 3-4 months afterwards
Advanced disease: incurable; palliative radiotherapy
Pemprolizumab + nivolumab has shown some effect
For HER2/EGFR breast cancer, what agent can be used?
- HER2 overexpressed in 20% of breast cancer and 15% of gastric/GOJ cancers.
- Associated with more aggressive phenotype
- Predictive marker for efficacy for anti-HER2 therapy
Iapatinib - TKI
SE: diarrhoea, N+V, mucositis, fatigue, rash, hepatotoxicity
ER + and HER2+ and associated mets
ER + : bone
HER2 overexpressed: brain
