Breast Cancer

Risk factors
  • Strongest risk factor BRCA1/ BRCA2, but most relevant in terms of population = obesity
  • Chest radioRx age <30 gives RR10x
  • Risk factor of aggressiveness = lymph node involvement
  • Worst histological subtype = triple negative
Genetics + screening
  • BRCA --> different complexes of protein = tumour suppressor genes, increases risk of breast Ca + other Ca’s such as ovarian, prostate, pancreas, stomach
  • BRCA testing indicated if (1) 3+ Breast Ca or Ovarian Ca in family OR (2) 2 breast Ca <50yp OR (3) bilateral breast Ca OR (4) Male (5) Ashkanazi jew OR (6) Triple neg AND < 50
    • If testing have to offer counseling and always in adults
    • If BRCA + then surveillance --> yearly mammogram and MRI from age 30; Prophylactic bilateral salpingo-oophorectomy > mastectomy when done after family completion or by age 40 [improved survival, no improved survival for mastectomy but reduction in breast Ca by 90%]
  • Risk reduction
    • Mammography programs have evidence, 2y from 50 – 70, offered free to >40, younger need U/S or breast MRI [better as breast denser, indicated if breast Ca screening with inherent germline mutation = higher sensitivity]
    • Chemoprevention: evidence for tamoxifen, raloxifene [NNT = 42], exemestane [ARR = 0.34%], anastrozole [high risk ARR = 2%]
Management
  • Local Rx for early stage breast Ca
    • Option 1 if no nodal involvement and small tumour in big breast --> WLE + radiotherapy
    • Option 2 if big tumour, no nodal involvement and small breast --> mastectomy.
      • Add XRT if tumour >5cm OR 4+ nodes
      • Breast XRT + node XRT cf breast XRT decreased breast Ca recurrence but no overall survival benefit [NEJM2015]
  • For option 1 and 2 --> sentinel node bx and if + (met >2mm) --> axillary node clearance
  • Adjuvant chemotherapy [taxane; SE = diarrhea, fluid retention/ tear duct stenosis/ anthracyclines] ALWAYS for node + or high risk [triple negative/ high Ki67/ HER2 +]
  • Add Hormone Rx if ER or PR+ [50-60% Breast Ca] --> Rx for 10y [advantage over 5y previous regime for tamoxifen only, 5y for AI]
    • Tamoxifen [SE = hot flushes, uterine Ca 1%, thromboembolism 1-2%] +/- AI [decreased BMD + osteoporosis, arthralgias/ myalgias but no thromboembolism or uterine Ca] 
    • Aromatase Inhibitor [non-steroidal or steroidal] for postmenopausal [not pre-menopausal] --> upfront 5y, or 5y tamoxifen when pre-menopausal then 5y AI when post menopausal
  • Her-2 + [over-expressed in 20-25% breast Ca’s]
    • Used to be poor prognosis, HER2 = EGFR2 receptor [note unknown ligand]. Mab target = trastuzumab AND Lapatinib [downstream TKI] AND trastuzumab emtansine [Trastuzumab + MCC conjugate] AND pertuzumab
    • To access Rx need FISH/ CISH to show Her2 expression
    • Trastuzumab if HER2+ [irrerspective if node +/ -], SE = cardiac toxicity, reversible, HER-2 expression on cardiac muscles, 3/12ly ECHO, RF for cardiotoxicity = age, baseline poor LVEF, post anthracycline. DO NOT use trastuzumab with anthracyclines --> cardiac toxicity
  • Metastatic Breast Ca
    • Bone only mets --> prognosis in years
    • Visceral mets --> prognosis in months
    • If ER/PR + --> hormonal therapy, at progression switch to other, eg AI to tamoxifen or non steroidal to steroidal AI, if further resistance add mTOR inhibitor [increased survival signaling if ER/PR + and resistance], everolimus + examestane > examestane
    • If HER2+ and treatment free interval >6/12 if trastuzumab previously used --> trastuzumab + pertuzumab + CTx > trastuzumab + CTx
    • If HER 2+ and treatment free interval <6/12 if trastuzumab previously used --> Lapatanib + capecitabine
    • If bone mets --> increased skeletal related events ameliorated by zoledronic acid
      • denosumab > zoledronic acid

Prostate Cancer

Symptoms
  • Urinary Symptoms - Nocturia , Frequency, Hesitancy, Dysuria, Haematuria 
  • Hx of urinary tract infections
  • Weight loss/anorexia 
  • Lethargy
  • Bone pain
  • Palpable lymph nodes
  • Abnormal digital rectal examination 
Risk factors
  1. Age over 50 years
  2. Black/N.American/N.W Euro ethnicity
  3. FHx of prostate cancer
  4. High levels of dietary fat
Examination
  • Weight and BMI
  • Pallor (anaemia)
  • Palpable Lymph nodes (Associated with advanced metastatic disease)
  • Bone tenderness (Associated with advanced metastatic disease)
  • DRE (should be given result or say you would have done it) – looking for an Asymmetrical, nodular prostate
​Screening
  • PSA - should be age corrected
  • Screening principles: NNTS = 1410 [to prevent 48 cancers and 1 death!]
  • only one study showed reduced mortality [Schroder European trial]
  • studies were not ideal, not significant benefit and should not be routinely done, but offer to men after discussion of risk vs benefit
Investigations
  • PSA >4 micrograms/L (4 nanograms/mL)
  • Testosterone - Baseline for patients in whom androgen deprivation is considered
  • LFTs - Baseline for patients in whom androgen deprivation therapy is considered, due to risk of hepatitis
  • FBC - Normal, except for advanced metastatic disease; Symptomatic anaemia may warrant blood transfusion
  • Renal Function - Abnormal renal function tests may indicate more locally advanced disease with tumour causing obstruction of ureters, resulting in renal failure
  • Prostate Biopsy - abnormal cells in 2 different samples (Gleason score 2 to 10)
  • Bone scan – positive ? mets
  • Plain XRs - lytic or blastic lesions
  • Pelvic CT - enlarged prostate and/or enlarged pelvic lymph nodes
  • Pelvic MRI - suspicious intra-prostatic lesion on T2-weighted image or enlarged lymph node or bony lesion noted on T1-weighted image
Management
  • Options for local disease:
    • watch full waiting/ do nothing
      • Could follow up with active surveillance, noting that there is no detriment to following up in terms of mortality unless high risk [advanced stage, high grade] or PSA>10
    • radical prostatectomy
    • external beam radiotherapy
    • brachytherapy
    • Radical prostatectomy > external beam RTx/ brachytherapy. If RTx --> neoadjuvant androgen deprevation therapy [ADT]
  • Rx of metastatic disease:
    • 1st line: androgen depravation Rx +/- docetaxel OR carbazitaxel [if able to tolerate CTx].
    • NB: NEJM 2015 showed that can give docetaxel in castration naïve pts and prolongs survival, therefore in high volume metastatic disease give docetaxel.
      • ​ADT = (1) castration --> bilat orchiectomy OR GnRH agonist [but risk flare when starting] OR GnRH antagonist (2) Anti-androgens (enzlutamide, abiatarone) --> do this initially if worried about effect of tumour flare such as severe pain, impending cord compression
    • Bone events: Zoledronic acid and denosumab,
      • no effect on OS but decreased skeletal related events
      • denosumab may delay time to bone mets in castrate resistant pts without bone mets
    • Novel oral treatments
      • Enzultamide. PBS only in castrate resistant disease + after chemo or prior to chemo if not tolerant of chemo. MOA = androgen receptor antagonist. SE = lowering of seizure threshold
      • Abiraterone. Inhibits CYP17 --> stops adrenal synthesis of androgens [accounts for 10%]. Need to give with prednisolone because CYP17 decreases cortisol + increases ACTH [SE = hypertension + hypoK], survival benefit post chemo, trend to benefit pre-chemo in castration resistant disease
      • Spiulecel-T --> immune-engineering at significant costs, increased 3y survival but no measurable anti-tumour activity!

Lung Cancer

History
  • Note 25% no Sx
  • Cough, haemoptysis, chest pain, dyspnea
  • B symptoms
  • Unresolved pneumonia, effusion or abscess
  • Hoarseness, pleural effusion, SVC obstruction with sensation of “fullness in head”, weight loss.
  • Pancoasts tumour- Horner’s, wasting of hand mm.
  • Paraneoplastic (1) HyperCa (2) SIADH (3) LEMS + anti purkinje fibre (4) HPOA (5) dermatomyositis/ polymyositis (6) ectopic ACTH
Examination
  • Cachexia, Clubbing (rare in small cell ca), wasting of small mm of hands, HPO
  • Face- Horner’s, pallor of conjunctiva, hoarseness
  • Trachea deviation- towards (collapse), away (massive effusion), Pemberton’s sign
  • Chest- Fixed inspiratory wheeze, effusion
Investigations
  • Imaging- CXR, CT chest
  • Sputum- cytology, bronchoscopy
  • Biopsy- FNA, EBUS, bronchoscopy
  • Effusion- cytology, assess fluid for lights criterion
    • LIGHT’s CRITERIA: exudate-Pleural: serum protein>0.5; Pl fluid: serum LDH>0.6, Pl fluid LDH>0.7 ULN serum
  • Bloods- FBC- anaemia, thrombocytosis, polycythemia, UEC- membranous GN, hyponatremia in SIADH, LFT- mets?, CMP- hypercalcemia
  • Staging-
    • SCLC- CT chest/abdo/brain, bone scan
    • NSCLC- CT chest, PET
  • pneumonectomy surgical candidates [if cardiac disease Hx --> cardiac consult then delay if optimization needed eg 6/52, if not --> lung fx tests, DLCO OR FEV1 <80% ULN --> VO2 testing --> if <35% or 10ml/kg/m then not recommended]
Screening
  • CXR = useless, CT --> 0.3% ARR but at significant cost with 95% false positives, cost-benefit unknown, but maybe if looking at different characteristics eg volumetric doubling time with defined regime
  • Bx threshold >6mm radiological deemed lung lesion. There are guidelines to help aid the investigation of the solitary lung nodule
  • Radiological signs of malignancy: >2cm, spiculated, air-bronchogram = adenoCa, cavitation, eccentric calcification [but central calcification benign]
Histological subtypes
  • adenoCa [assoc with non-smokers therefore peripheral] > squamous Ca [smokers therefore central, stage 4 shows evidence for response with nivolumab irrerspective of PDL1] > small cell Ca [smokers therefore central] > others [note large cell is worst]
  • NSCLC mutations: Majority = KRAS [predicts resistance to targeted Rx] > EGFR >EML4-ALK
Stage for NSCLC 
  • If only ipsilateral LNs --> curable [3a = surgical then chemo or neoadj chemo then surgery], contralateral [3b = chemo-radiation] --> probably incurable
  • Stage 1 --> surgical if medically fit [see below], stage 2 --> surgical then chemo
  • Stage for small cell: limited stage [hemithorax + mediastinum + supraclavicular nodes, chemo [cisplatin + etoposide] + radiotherapy +/- prophylactic cranial irradiation for brain = sanctuary site. Increases survival according to NEJM 2007] vs extensive stage [palliative chemotherapy]
Treatment NSCL 
  • All --> early referral to palliative centre: improves QOL scores + mortality benefit!
  • Stage 1: Sx if fit (for pneumonectomy, see above for PFT guidelines), otherwise radiotherapy
  • If stage 2, 3a need adjuvant CTx with cisplatin + vinorelbine doublets x 4, maintenance with permetrexed [only for adenoCa, does not work for squamous]. Note CTX improves QOL scores!
  • Stage 4 --> Need to test for mutations
    • EGFR1: 1st gen TKI = erlotinib [reversible, prevents dimerization, SE = pneumonitis, acneform rash Rx with doxycycline, diarrhoea], 2nd gen TKI [eg rocelitinib + afatanib] overcomes T790M mutation that develops
    • EML4-ALK --> need to use breakaway probes to see [normally EML4-ALK co-localised together] --> Rx with Crizotinib [SE = light/dark visual adjustments, QT prolong, pneumonitis]
    • Research as of NEJM2014 --> ROS1 rearrangement, crizotinib has some efficacy [not RCT evidence]
  • Stage 4 all --> nivolumab in squamous and non squamous NSCLC
    • Note with immune-therapy the paradigm is that if they respond they respond for long time!
    • Response does not depend on expression of PDL1 ligand

Colorectal Cancer

Epidemiology
  • 2nd most common cancer + 2nd most common cause of cancer death
  • Age biggest RF, western diet, lifestyle, lack of physical activity, obesity
Genetics
  • Adenoma --> carcinoma sequence with KRAS mutation usually a key step. Microsatellite Instability is implicated
  • CpG methylator phenotype --> serrated polyp, BRAF mutation common
Genetic syndromes
  • 25% have a family history
  • 1% FAP: A/D, due to mutations in the APC protein, 100’s of polyps, includes duodenum, stomach, bones, skin --> prophylactic colectomy late/ early teens
  • 2-3% HNPCC (Lynch syndrome): A/D, high penetrance, right sided tumours, mucinous, high inflammatory infiltrate, other cancers include endometrial + stomach, MSI due to genetic abnormalities in mis-match repair enzymes, germline mutations occur in HNPCC, loss of expression MMR 15% sporadic CRCs b/c of methylation. FHx = 3:2:1 rule, 3 cases, 2 first deg relatives, 1 <50yoa
Cancer Chemoprevention 
  • Danish population study --> Evidence for the use of low dose aspirin. Also gives less mets and less advanced cancer at Dx
    • There is a definite benefit for aspirin in lynch syndrome and FAP
Screening and polyps
  • FOBT has the best evidence in terms of all cancer screening. Other one is breast Ca and cervical cancers
  • Program: Category 1 [low] vs category 2 [high risk].
  • Category 1 --> FOBT every 2nd yr from age 50, flexible sigmoidoscopy/ colonoscopy every 5 yrs.
    • No evidence directly for colonoscopy but still done.
  • Category 2 --> Start at age 50 or 10 yr before first Dx of cancer in first deg rel, which ever came first.
    • Always refer Cat 2 to cancer genetics program
  • FAP: Screening at age 12-25 except attenuated FAP, prophylactic colectomy at age 25 then screen for UGI cancers with endoscopy at 25yrs
  • HNPCC: annually [if germline mutation] or 2-yrly at age 25 or 5 years before earliest cancer Dx
  • If IBD then:
    • Colonoscopy every 2yrs, annually if PSC and straight away at time of diagnosis of PSC, otherwise 8yrs after pancolitis, 12-15y if left sided disease, biopsy every 10cm
  • If polyp, then f/u depends on type
    • Malignant --> 3/12 (colonoscopy), incomplete excision  --> 3-6/12 (colonoscopy), large polyp >1cm +/- high risk dysplasia +/- multiple (>2) --> 3y (colonoscopy), single small adenoma --> 5-10y (colonoscopy)
    • refer to the national bowel cancer screening guidelines 
Staging
  • Staging: CT C/A/P for Mets, pre-op CEA helps with determining recurrence, if Rectal Ca then MRI/ rectal US
  • Duke’s A: limited to mucosa/submucosa
  • Duke’s B: through muscularis propria
  • Duke’s C: regional lymph nodes involved
  • Duke’s D: Distant Metastases
Management
  • Stage 1 --> [Localised to bowel, based on thickness of invasion] wide local resection + anastomosis, no adjuvant therapy
  • Stage 2 --> [No LN involvement, greater thickness than stage 1] WLR + anastomosis. If high risk features consider CTx [5FU OR capecitabine, prodrug of 5-FU], decreases risk of death by 3 – 5%
    • If tumour is MSI+, then will not benefit from CTx --> potential for immunotherapy [research ongoing in this field]
  • Stage 3 --> Offer adjuvant in addition to WLR + anastamosis. Regimes include 5-FU [SE = palmar plantar syndrome, diarrhea, mucositis, folic acid depletion therefore need leucovorin] + oxaliplatin [SE = neuropathy, ototoxicity, nephrotoxicity] AKA FOLFOX4, capecitabine [SE = palmar plantar syndrome] + oxaliplatin AKA XELOX
  • Rx Metastatic disease
    • First principles: EGFR1 --> colon + NSCLC, EGFR2 (=HER2) --> Breast
    • Curative if --> low burden liver/ lung mets (offer surgery if medically fit)
    • KRAS and NRAS W/T --> cetuximab or panitumimab [SE = acneform rash: predicts drug working on EGFR1] + FOLFIRI [IRI = iranotacen] or FOLFOX
    • KRAS and NRAS mutant --> bevacizumab [S/E = HTN/ thromboembolism, impaired wound healing] + FOLFIRI or FOLFOX
      • mutant KRAS and NRAS --> EGFR1 monoclonal antibodies have no role
  • Surveillance post Rx
    • In first 2 years --> 3 monthly CEA + Physical including DRE +/- sigmoidoscopy in rooms, then 6 monthly for 5 yrs
    • In addition to above: CT C/A/P 6/12ly first 2 yrs, then annually until 5 yr mark
    • In addition to above: Colonoscopy at anniversary of Sx then 3 – 5 yrs after Dx and every 3-5y after that

Melanoma

Risk factors
  • 10% familial: high prevalence, low penetrance red haired pale skin MC1R, low prev high penetrance = CDKN2A
  • multiple benign naevi [note BRAF mutation usually first triggering event] or atypical naevi
  • previous melanoma
Symptoms
  • Pigmented lesions
  • New mass
Examination
  • Benign nevi: <6 mm in diameter
  • Atypical moles: >6 mm in diameter.
  • Shape: benign nevi have round distinct borders that are usually flat, atypical nevi have irregular borders with pigment fading off at the edge
  • Colour: neign nevi are uniformly brown or tan whilst atypical moles are of a mixture of brown/ black and tan colours
  • regional lymphadenopathy
  • satellite lesions
Management
  • Locoregional melanoma Rx: essentially the depth of invasion dictates the margin of invasion, modified by characteristics such as Ki67 and ulceration. If depth >1mm then it is recommended to do a sentinel node biopsy. There may be a role for IFN or ipilumimab to decrease relapse rates at the expense of toxicity
  • Metastatic disease. Best Rx is always a clinical trial, or proceed to surgery if there is oligometastatic disease and good functional status. Dacarbazine was previously used however it is toxic and does not afford good survival. 
    • ​BRAF mutations present in 45% melanomas. If present then B-RAF and/ or MEK inhibitors may be utilised. BRAF inhibitor dabrafenib used [SE = skin cancers, rash, fatigue, photosensitivity] but you get increase activity through other pathways leading to non-melanomatous skin cancers therefore evidence to use BRAF + MEK inhibitor in combo = dabrafenib + trametinib. MEK inhibitor SE = rash, diarrhea + peripheral edema but no skin cancers. Combo is PBS subsidised.
    • CTLA4 = ipilumumab [SE = hypophysitis, colitis, hepatitis Mx with discontinuation + steroids]. If a patient responds then there is durable response
    • PD1 Abs = nivolumab/ pembrolizumab > ipilumumab in terms of 1 year survival and response rates with less serious adverse effects. Pembrolizumab = standard first line Rx. If you respond to immune therapy the evidence is that it is usually long lasting remission. Nivo + ipi > ipi or nivo alone but at cost of greatest toxicity, and nivo > ipi in terms of eficacy. 
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