Oncology 3 - Breast cancer and lung cancer Flashcards
What are risk factors of breast cancer?
Female gender Increasing age Older age at 1st birth Oestrogen exposure (endogenous/exogenous) EtOH Family Hx
What are genetic features of breast cancer?
20-30% of breast ca pts have affected relative
only 5-10% is gene related
BRCA1, BRCA2, PTEN, p53, ATM, MLH1, MSH2
Some high risk patients have no identifiable gene
What are determinants of high risk breast cancer patients?
Multiple relatives with breast or ovarian ca
Early age of onset
>1 primary Ca (contralateral breast or ovarian Ca)
Vertical transmission (including men)
Rare malignancies in FHx - i.e. sarcomas, breast Ca in Li-Fraumeni syndrome (p53)
Which women with ovarian cancer should undergo BRCA testing?
All women with ovarian cancer, especially those who are
What is the relative contribution of genes to hereditary breast cancer?
BRCA1 - 20-40%
BRCA2 - 10-30%
TP53 -
What are features of BRCA1 and BRCA2 mutations?
DNA repair genes (TSGs)
Autosomal dominant inheritance
Ashkenazi Jews
50-66% lifetime risk of breast cancer
Ovarian cancer 40% BRCA1 risk, 20% BRCA2 risk
Prostate cancer: 40% BRCA2
Pancreatic cancer 5-10% BRCA 1 and 2
Male breast cancer: 2% BRCA1, 5-10% BRCA2
What syndrome is associated with BRCA1?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
Hereditary breast/ovarian Ca
Breast cancer risk by 70 50-66%
Ovarian cancer risk 20-40% by 70.
Associated Ca = pancreas
What syndrome is associated with BRCA2?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
Hereditary breast/ovarian cancer.
Risk of breast cancer 40-60% by 70.
Risk of ovarian cancer by 70 - 10-20%
Associated Ca = prostate and pancreas
What syndrome is associated with p53?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
Li-fraumeni syndrome
>90% risk of BrCa by 70. N/A risk of ovarian Ca.
Associated: soft tissue sarcoma, osteosarcoma, brain tumours, adrenocortical cancer, leukaemia, colon Ca
What syndrome is associated with PTEN?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
Cowden syndrome
25-50% risk of breast Ca by 70.
~1% risk of ovarian Ca by 70.
Associated: thyroid, endometrial, GU
What syndrome is associated with STK11/LKB1?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
Peutz-Jagher’s sydnrome.
50% risk of breast cancer by 70.
Sex cord tumour risk.
Associated tumours: Small intestine, colorectal, uterine and testicular.
What syndrome is associated with CDH1?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
Hereditary diffuse castric cancer
40% risk of lobular breast cancer by 70yo.
N/A ovarian risk.
Associated = diffuse gastric cancer.
What syndrome is associated with MLH1, MSH2, MSH6, PMS1, PMS2?
What is breast ca and ovarian ca risk by 70yo?
What is an associated Cancer?
HNPCC/Lynch syndrome
N/A breast cancer risk
10% risk of ovarian Ca by 70.
Associated: small intestine, colorectal, stomach, uterus, ureter/renal
What are fundamental principles of Mx high risk women?
Consider prophylactic surgery:
- Bilat mastectomy reduces risk by 90%
- BSO reduces risk of breast Ca by 50% (premenopausal), ovarian Ca by 90%
Screening: BSE + q6m clinical breast exam.
Annual mammogram from 40yo (or 5y younger than 1st affected relative)
MRI breast, esp premenopausal.
What role does chemoprevention have in high risk women?
Tamoxifen reduces risk by 40% in pre/post menopausal women.
Raloxifene post menopausal.
OCP reduces ovarian Ca risk, may increase BrCa risk.
What investigations are required when a breast lump is detected clinically?
Triple testing:
- clinical examination
- mammogram +/- USS
- FNA/Core Bx
If palpable lesion is thought to be malignant, should be reviewed by breast surgeon pre Bx
What are poor prognostic features in Breast Cancer? (7)
Positive axillary LNs (MOST IMPORTANT) Increasing size Higher grade (1, 2, 3) Negative hormone receptors (considered positive if ER or PR +ve) Positive HER2/neu (c-erb B2) Younger age Lymphovascular invasion
What are principles of early stage breast cancer management?
Disease confined to breast and axilla.
1) Surgery - WLE/Total mastectomy, sentinel node Bx. Proceed to axillary dissection if sentinel node Bx +ve - straight to axillary dissection if clinically node +ve pre op
2) Adjuvant chemo - 3-6/12
- usually anthracycline and/or taxane based
What are complications of adjuvant chemo?
Hair loss, lethargy, nausea, mucositis
Pancytopenia
Cardiac - anthracyclines, traztuzumab
Anthracyclines (-icin) cause secondary leukaemias in 0.5-1.5%
What is the risk reduction in adjuvant chemotherapy in early stage breast cancer?
40% RR - absolute reduction is related to risk.
Risk of toxicities however are static.
What is an example of a 1st, 2nd and 3rd gen adjuvant regime in early breast ca?
1) Cyclophosphamide, MTX, 5-FU
2) 5-FU, epirubicin, cyclophosphamide
3) dose dense Adriamycin, cyclophosphamide
What advantage does radiotherapy provide in WLE and post-mastectomy?
Provides local recurrence rates similar to mastectomy when used post breast conserving surgery.
Indicated in post mastectomy patients with >5cm breast cancer or >=4 LNs. Recent data shows survival benefit for 1-3 positive LNs.
What is the role of adjuvant endocrine therapy in early breast cancer?
~40% RRR for recurrence
What are examples of SERMs, their MoA, role in early breast cancer and AEs?
tamoxifen, toremifine.
Antagonist on E-receptor in breast or cancer tissue
Agonist on bone, uterus and liver E-receptors
Adjuvant, Used for 5 years, further small red in mort in 10y
Increases BMD in post menopausal women.
risk of VTE, uterine cancer.
What are examples of SERMs, their MoA, role in early breast cancer and AEs?
Anastrozone, letrozole, exemestane.
Block DHEA - which in turn reduces peripheral pdn of oestrogens.
Will not reduce pdn in pre-menopausal women (ovaries) - post menopausal only.
Slightly more effective than tamoxifen. (2.6% DFS at 5 yrs)
Reduces BMD, arthralgias common. No increased risk of VTE or uterine Ca.
What regime shows improved freedom from breast cancer in premenopausal women with early stage breast cancer who previously had chemo?
exemestane + oophrectomy/salpingectomy (0.65 HR)
What is the significance of HER2 +ve early stage breast cancer?
HER2 +ve are 15% of breast cancers.
Higher risk of mets and relapse.
Chemo + traztuzumab indicated in all tumours.
(except v. small,
What is the MoA of herceptin and it’s AEs?
Given with chemo = monoclonal Ab against HER2 receptor.
12 months therapy, q1-3weekly
40% RR for recurrence on top of chemo.
Cardiomyopathy - usually reversible, unlike anthracycline.
What are the basic principles of locally advanced breast cancer?
Inoperable - requires multimodality Tx Chemotherapy Consider surgery if operable post chemo Radiotherapy Hormonal therapy
15y survival is ~30%
What is the role of neoadjuvant chemo in locally advanced disease?
Downstaging large breast primary to allow breast conservation.
In inoperable cancer: T4 - involving chest wall or skin/inflammatory breast ca.
N3c - ipsilateral SC LN
What are the principles of management of metastatic breast cancer?
Generally incurable.
Aim for Sx control, QoL, improved survival.
Endocrine Tx only if ER and or PR+Ve.
(not if rapid response is required - liver or visceral disease)
Chemo:
improved QoL
Balance tox and benefits.
Anthracyclines, cyclophosphamide, 5FU, paclitaxel, docetaxel, capecitabine, vinorelbine, gemcitabine, platinums.
When can mTOR inhibitors be used in metastatic breast cancer?
when everolimus is combined with exemestane for patients failing 1st line therapy - improved survival c/w exemestane alone.
What role does palbociclib have in breast cancer?
CDK4/6 inhibitor - used with fulvestrant (SERD) - improves PFS vs fulvestrant alone.
What is the role of trastuzumab in metastatic breast Ca?
Monoclonal Ab against HER2 - benefit with single agent or with chemo?
What is the benfit of lapatinib vs traztuzumab in metastatic breast Ca?
oral small molecule TKI - appears to have activity against cerebral mets, whereas trastuzumab does not cross BBB.
active in trastuzumab refractory disease.
What is the MoA of pertuzumab in the treatment of metastatic breast cancer?
Monoblona Ab which binds to dimerisation domain of HER2, also prevents binding with itself or other EGFR. (prevents dimerisation)
Improved 1st line survival when combined with traztuzumab and docetaxel as 1st line therapy.
What is the MoA of trastuzumab emtansine?
Conjugate trastuzumab with antimicrotubule agent (DM!)
Improved PFS and less toxicity than traztuzumab and taxane.
What are possible treatment methods of triple negative breast cancer?
PARP inhibitors - inhibit 2nd DNA repair damage mechanism, causing apoptosis.
olaparib
veliparib
What are the main indications for radiotherapy in metastatic breast cancer?
bone pain
spinal cord compression
cerebral masses
ulcerating skin/primary lesions
What is the role of skeletal protection in bone disease?
Reduces risk of SREs
- bone pain, fracture, hypercalcaemia, cord compression
- risk - hypocalcaemia, ONJ, renal impairment
Denosumab slightly more effective than bisphosphonates.
What are risk factors for lung cancer?
Smoking - 90% of lung cancers occur in smokers
Radiation/inhaled radon gas
Enviromental toxins
- passive smoking, asbestos, inhaled metals
Pulmonary fibrosis
HIV
Genetic factors
What is the proportion is histology in lung cancer?
Adenocarcinoma 40% SCC 20% Large cell 7% Small cell 13% Other 20% - bronchoalveolar, carcinoid
What are presenting symptoms of lung cancer?
Often late presentation Cough Haemoptysis Chest pain Dyspnoea - bronchial obstruction, pleural effusion Hoarse voice SVC obstruction Extrathoracic mets - liver, bone, brain
What tumour is associated with pancoast?
superior sulcus usually NSCLC pain in shoulder/neuropathic arm pain horner's syndrome wasting of the hand muscles (T1)
What causes hypercalcaemia in lung cancer
bony mets
PTHrP - NSCLC
What tumour most common causes SIADH in lung cancer?
SCLC
What tumours are most strongly associated with HPOA in lung cancer?
squamous/NSCLC
What are features of SCLC?
early mets, high mitotic rate classically bulky lymphadenopathy chemo/radiosensitive doesn't cause clubbing can cause para-neoplastic syndromes strongly associated w smoking
What are poor prognostic factors in SCLC? (5)
Extensive stage poor performance status hyponatremia elevated ALP elevated LD
What are features of limited stage SCLC?
all disease within one radiation field (i.e. ipisilateral lung and hilar/medisatinal LNs)
curable (20-30%) with concurrent chemoradiotherapy
What are features of extensive stage SCLC?
generally incurable BUT expect excellent response with chemo or RT Even in very unwell patients Median survival: - 2 months w/o chemo - 10-12 months with chemo Chemo: platinum and etoposide
What are risk factors for mesothelioma?
tobacco + asbestos = 10-20x risk of mesothelioma
Asbestos also increases the risk of NSCLC
Long latency - 30-40 years
Usually pleural or peritoneal
What are treatment methods in mesothelioma?
Generally incurable
- radical treatment = extrapleural pneumonectomy
Palliative chemo improves survival - cisplatin + pemetrexed
What is involved in staging NSCLC?
Histology - CT lung Bx, bronchoscopy, sputum
TNM
CT CAP, PET, mediastinoscopy
Consider CT brain, bone scan
PET important for all patients prior to radical treatment
What is the definition of stage IA NSCLC?
T1
What is the defn of stage IB NSCLC?
Tumour is T2a and 3-5 centimetres.
Easy to resect, node -ve.
What is the definition of stage IIA NSCLC?
larger tumour, T2b 5-7cm OR
Stage IA/B with proximal nodes involved (ipsilateral hilar) - N1
What is the definition of stage IIB NSCLC?
Tumor >7cm
T3 - invading chest wall
T3N0M0, T2bN1M0
Generally resectable
What is the definition of stage IIIA NSCLC?
T4 - invasion of mediastinum or ipsilateral lung nodules T4N0-1M0 T3N1-2M0 T1-2N2M0 occasionally resectable
What is the definition of Stage IIIB NSCLC?
N3 - contralateral hilar nodes
TxN3M0
T4N2M0
What is the definition of Stage IV non-small cell lung cancer?
M1a - pleural effusion or contralateral lung nodules
M1b - distant mets
What are the principles of management of stage I-II lung cancer?
generally resectable
cure rates 40-70% w surgery
lobectomy vs pneumonectomy
When are stage I-II lung cancers deemed unresectable?
Poor RFTs FEV1
What are indications for adjuvant chemo in NSCLC?
Consider in all fit stage II-III pts post resection.
No conclusive benefit in stage I
Generally 4 months of cisplatin and vinorelbine
Absolute improvement in 5 year survival 5-15%
What is treatment of stage III NSCLC?
occasionally resectable:
- if no bulky mediastinal or contralateral lymph nodes
Radical combined chemoradiotherapy
- generally 6 weeks of RT, concurrent chemo
- Cure rate 20-30%
Neoadjuvant chemo can be considered in borderline resectable cases
Aim to downstage tumor to allow resection
What is the median survival of stage IV NSCLC without therapy?
6 months
incurable
What is the general principle in chemotherapy used to treat stage IV NSCLC?
Cisplatin/carboplatin +
- vinorelbine
- paclitaxel/docetaxel
- gemcitabine
- pemetrexed (non-squamous NSCLC)
Can use single agent in frail patients - less benefit/tox
What are important driver mutations in lung cancer? (3)
EGFR
ALK rearrangement
ROS1 fusion
What is the rate of overexpression of EGFR on IHC in NSCLC?
What patients have activating mutations in EGFR?
50-70% of NSCLC.
Approx 15% of patients with lung adenocarcinoma have specific activating mutations. Asians, non-smokers, adenocarcinoma (almost always), female.
What oral EGFRi are available?
Tyrosine kinase inhibitors - gEfitinib, Erlotinib
single agent
more effective than chemo as a 1st line agent
What are AEs of EGFR inhibitors in NSCLC?
acne like rash diarrhoea nausea rarely pulmonary fibrosis DO NOT cause cytopenias
What are features of ALK gene rearrangement in NSCLC?
fusion oncogene EML4-ALK
5% lung adenoca
non-smokers, younger patients
FISH or IHC
What is a medication targeting ALK gene rearrangement in NSCLC?
crizotinib - inhibitor of ALK
- high response rates and disease control
What medication is used in ROS1 fusion NSCLCs?
2% of lung adenoca have ROS1 fusion.
Also respond to crizotinib
non-smokers, younger patients
What is the role of bevacizumab in NSCLC?
anti-VEGF mAb
small benefit in RR/survival when combined with chemo as 1st line therapy
increased bleeding risk - C/I in haemoptysus and SCC due to increased risk of fatal bleeding
What is the role of nivolumab and pembrolizumab in NSCLC?
PD-1 inhibitors - improved survival as 2nd line therapy c/w docetaxel.
Less toxic.
Immune mediated toxicity - less than CTLA4 inhibitors.
Rash, immune colitis, hepatitis, pneumonitis
Endocrine - hypophysitis
What is the epidemiology of adenoca of unknown origin?
Common - 2% of all cancers
Poor prognosis - median survival 4-6/12
Mostly pancreas, hepatobiliary, lung primary
What is the primary goal in Ix of Adenoca of unknown origin?
RULE OUT CONDITIONS WITH SPECIFIC TX
- lymphoma, myeloma, melanoma, non-malignant - usually on Histo
- Germ cell tumours - AFP, BhCG, young men, midline L/A, testicular US
- Breast CA - axillary LNs, breast exam, mammogram, breast MRI
- Ovarian Ca/peritoneal carcinomatosis: CA125, TVUS
- oropharyngeal cancer - panendoscopy, cervical LNs
- prostate ca: men with bone mets, PSA
What are reasonable Ix in Adenoca of unknown primary?
Tumour markers: AFP, BhCG, CEA, PSA, CA125, CA153, CA19.9
Mammogram, breast and pelvic exam in women
PSA and rectal ex an men
CT CAP
Panendoscopy if cervical LNs
Gastroscopy/colonoscopy only if Sx or FHx
PET reveals primary in 40%
What are relevant tumour markers?
CEA - colon Ca CA125 - ovarian Ca CA15.3 - breast cancer CA19.9 - pancreas/biliary cancer aFP - germ cell tumours/hepatocellular Ca PSA - prostate Ca
What is the ECOG score?
ECOG: 0 - nil Sx I - symptomatic, but well/active 2 - resting for 50% of waking hours 4 bedbound
Karnofsky Peformance status 0-100% (0 =dead)
What is the oral bioavailability of morphine?
~40%
What is the conversion of fentanyl patch from parenteral morphine?
fentanyl patch in mcg/hr = mg of parenteral morphine/24 hours
What is the equivalence of oxycodone
1.5 x stronger than morphine
What is the equivalence of codeine to morphine?
30mg x 8 tablets of codeine/day = 40mg of morphine/day
What is the difference between gabapentin and TCAs/anticonvulsants in neuropathic pain?
pregabalin works in 1-2 days, TCAs/ACs may take 2-3 weeks to work
What are definitions of hypercalcaemia of malignancy?
Mild 3.5
Treat moderate if symptomatic and moderate, always treat severe.
What is treatment of hypercalcaemia of malignancy?
IV fluids - Normal saline, may require >4 litres to rehydrate
Bisphosphonates - zoledronic acid
Can use frusemide once euvolaemic
Avoid thiazides (increase Ca2+)
What is the principle of management of spinal cord compression?
MRI if back pain and neuro Sx Urgent steroids Surgical opinion crucial Surgery if feasible and good PS Radiotherapy if non-operable
Pre-treatment function is best predictor of recovery.
Can consider chemo if highly sensitive - lymphoma, GCT, SCLC
