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
