Oncology 1 - Melanoma, new agents, cell cycle Flashcards
What are risk factors for melanoma?
>10 dysplastic naevi
>100 common acquired naevi
Fair skin
Red hair High
intermittent sun exposure
Median age at Dx is 45-55years old Years of productive life lost exceed all other solid tumours.
What is the key depth of invasion dictating survival in melanoma?
0.76mm, 95% 5 year survival if less than this
What are the clinical signs of melanoma?
Asymmetry Uneven border Colour: variegated Diameter >6mm Enlargement or evolution Bleeding/ulceration occurs in 10% of localised melanoma and 54% of late melanoma, = poor prognostic sign
What are melanoma subtypes?
Radial growth phase: - superficial spreading - lentigo malgina - acral lentiginous Vertical growth phase: - nodular
What is the most common melanoma sub-type?
Superficial spreading 70%, related to intermittent sun exposure, median age 40s, trunk and limb location
What are features of lentigo maligna?
10-15% of melanomas from cumulative UV exposure face and neck in situ period may be long
What are features of acral lentiginous melanoma?
palms, soles and under nails do not arise from moles not caused by UV most melanomas in blacks and asians 2% of melanoma
What are features of nodular melanoma?
EFG - elevated, firm, growing progerssively
What are characteristic immunohistochemistry stains for Melanoma?
S100 Melan-A
What are the stages of melanoma?
Stage I - generally thickness
What are prognostic factors in stage III melanoma?
(essentially any tumour with positive LNs)
Number of metastatic LNs Micrometastatic vs macrometastatic
Primary melanoma ulceration
What are prognostic factors in stage IV melanoma?
Site(s) of distant metastases Elevated LDH (THE MOST PREDICTIVE OF SURVIVAL) (number of mets is not in staging system)
What are prognostic factors related to stage in melanoma?
Stage I - 1.0mm, PF = ulceration Stage III - LN mets - PFs: micro v macro mets, nodes >=3, ulceration Stage IV - distant mets - PFs: site (visceral except lung), serum LDH Other factors - male/back head and neck/ mitotic index
What is the modality of treatment of stage I and II melanoma?
Full thickness excisional Bx is the treatment of choice. If Stage I - curative Stage II - proceed to MRI brain, CT-CAP and PET and sentinal lymph node Bx (sentinal Bx is now the std of care for all stage II Dz)
What is the modality of treatment of stage III melanoma?
Surgery: - clinically positive nodal basin is treated with total LN dissection - there is no randomised data to support role of radiotherapy in stage III melanoma, except in palliative instances - no evidence for any adjuvant therapy in Stage III - SoC is observation or clinical trial - interferon alpha-2b - decreases DFS but not OS
What is the natural Hx of of stage IV melanoma?
Death in 6-9 months Most common met sites are skin, lungs, liver, brain and bone Unusually SBowel, kidney, spleen and heart Late relapses >5 years only hope of cure is surgical resection of mets if feasible - should consider metastectomy in absence of locoregional disease.
What interventions show survival advantage in melanoma brain mets?
Surgical excision Stereotactic radiosurgery if
What is the only approved chemotherapeutic agent in melanoma?
Dacarbazine does not have durable responses myelosuppression, nausea and emesis
What are advantages of fotemustine vs dacarbazine in Stage IV melanoma?
longer time to develop brain mets and lower risk of cerebral met progression.
What are mutations associated with melanoma?
Intermittent sun exposure - BRAF, NRAS, PTEN, AKT, p16 Chronic sun exposure - CDK4, Cyclin D1, KIT Acral exposure - CDK4, Cyclin D1, NRAS, KIT Mucosal exposure - CDK4, KIT
What are molecular targets in melanoma therapy, and their associated agents?
BRAF inhibitors - Vemurafenib - selective V600E mutations (no CNS activity) - Dafrafenib - inhibits all V600 mutations and has CNS activity MEK inhibitors - trametinib cKIT inhibitors - imatinib
What are rates of mutation in melanoma?
BRAF 45% NRAS 15% KIT 2-3%
What are some indications for vemurafenib?
Melanoma (50% BRAF positive) Colorectal (10% have activating BRAF mutations) Papillary, thyroid, anaplastic thyroid, cholangiocarcinoma, serous ovarian carcinomas
What are the outcomes of vemurafenib therapy in melanoma treatment?
Improved PFS 0.26HR Improved OS 0.44HR
What are AEs of vemurafenib therapy?
arthralgias rash photosensitivity fatigue SCC of skin in 23% of patients
What are outcomes in dabrafenib therapy?
Also BRAF V600E inhibitor. Shows improved PFS vs DTIC
What are outcomes of combined anti BRAF and MEK inhibition?
Dabrafenib (anti-BRAF) and trametinib (anti MEK1/2) - showed improved PFS and OS compared to vemurafenib alone
What are AEs associated with BRAF inhibitors?
Pyrexia (50%) Cutaneous SCC/keratoacanthoma Hyperkeratosis Skin papilloma Hand-foot syndrome Alopecia photosensitivity/sunburn Non-cutaneous malignancy New primary melanoma
What is CTLA-4?
receptor expressed on activated helper T-cells and CTLs. Inhibits T-cell activation and proliferation - binds to the B7 molecule on APC’s surface with higher affinity than CD-28 Stops T-cell proliferation
What are brief principles of T-cell activation
Requires two signals: TCR-APC complex = signal 1, CD-28-B7 signal 2. B7-CTLA-4 on APC/T-Cell down-regulates the response.
What is the other pathway (other than CTLA4-CD28) that down-regulates T-cell activity?
PD-L1/PD-1 binding
What is an anti-CTLA4 therapy in melanoma?
ipilimumab - mAb against CTLA-4. blocks downregulation of CD8+ T-cell response leading to tumour lysis. Leads to 25% long term response at 4 years.
What are the most common AEs in ipilimumab (irAEs)
Dermatologic 40% - rash GIT 32.1% - colitis Endocrine 3.9% - hypopituitarism, hypo/hyperthyroidism Hepatic 2.1% - hepatitis significant variability in timing of onset/antitumour responses in ipilimumab steroids generally backbone of Mx of iRAEs
What are two indications for ipilimumab?
Melanoma RCC
What is the relationship between grade III/IV iRAEs and tumour regression?
higher rates of tumour regression in pts with significant IRAEs
What ligand is selectively expressed in tumour cells in response to an inflammatory environment?
PD-L1 - interacts with PD-1 on T-cells, downregulating cytokine production and cytolitic activity of PD-1+ve tumour infiltrating CD4+ and CD8+ cells
What is an anti-PD-1 Ab?
Pembrolizumab. Binds to PD-1, blocking interaction betweel PD-L1 and PD-1 and allowing upregulation of cytolytic responses. low incidence of grade III/IV iAEs No treatment related deaths. 33% ORR, including 8% CR rate. 28.2m median duration of response. 49% survival at 2 years.
What combination therapy improves PFS and ORR in patients with melanoma?
nivolimumab (anti-PD1) + ipilimumab and nivo alone are superior vs ipilimumab in PFS/ORR. combo is better than nivo alone. No correlation between response and PD-L1 expression and ALC
What are the most important drivers of angiogenesis wrt TKI therapy?
VEGF bFGF PDGF
What is the target of bevacizumab?
VEGFR
What mAb targets VEGFR?
bevacizumab
What small molecule TKIs target VEGFR and PDGFR?
sunitinib sorafenib
What are the targets of sunitinib and sorafenib?
VEGFR and PDGFR
What is an indication for sunitinib?
RCC - improves PFS compared with interferon.
What is the most significant AE of sunitinib?
hypertension - predictive marker of response however.
What are targets of sorafenib?
Inhibits: Raf kinase VEGFR 1-3 Platelet derived growth factor beta FMS-like tyrosine kinase 3 c-kit protein RET receptor tyrosine kinases
What are significant SEs of sorafenib?
Diarrhoea Rash Fatigue Hand-foot skin reactions Alopecia Nausea Hypertension Reversible posterior leukecephalopathy Proteinuria/renal dysfunction Haemorrhage-tumour disruption Lymphopenia is the most common SE
What are toxicity of mTOR inhibitors?
Oral ulceration - ulceration/stomatitis Rash Fatigue Hypertension hand-foot syndrome diarrhoea infections pneumonitis (can be fatal if missed)
What is the first systemic treatment to show improvement in OS in advanced HCC?
sorafenib - improves OS and median TTP. New systemic std of care in advanced HCC.
What tumours show high expression of EGFR?
NSCLC 40-80% Prostate 40-80% Gastric 33-74% Breast 14-91% Colorectal 22-77% Pancreatic 30-50% Ovarian 35-70%
What are functions of EGFR pathways?
proliferation/maturation chemotherapy/radiotherapy resistance survival/anti-apoptosis angiogenesis metastasis
What are EGFR specific MAbs and TKIs
cetuximab panitumumab gefitnib erlotinib
What are functions of TKIs (EGFR)
decreased proliferation decreased invasion decreased mets decreased angiogenesis decreased adhesion increased apoptosis
What are predictors of response to EGFR TKIs in Adenocarcinoma?
non smoker female asian are more likely to have EGFR mutations
What Sx is predictive of EGFR response?
rash! acineiform eruption
What is the effect of EGFR mutation and wild-tpe on responses in NSCLC
gefitinib has WORSE outcomes vs carboplatin/paclitaxel in EGFR wild-type individuals c.f. mutated EGFR tumours
When is cetuximab successful in improving OS in CRC?
when there is wild-type KRAS.
What gene works at the G1/S DNA-damage checkpoint?
p53 - activation leads to cell cycle arrest or apoptosis lost in >50% of human cancer
What are chemo targets at G1/S checkpoint?
alkylators, platinums, antimetabolites, taxanes, vinca alkaloids
What chemo agents target the G2 checkpoint?
topoisomerase inhibitors - etoposide, irinotecan anthracyclines (also intercalate DNA)
What chemotherapy agents target the spindle checkpoint?
Taxanes - paclitaxel, docetaxel Vinca alkaloids - vincristine, vinblastine, vinorelbine
What are the significance of PARP inhibitors in BRCA +ve cancer cell mutations
Cancer cells require at least 1 repair mechanism for replication. In BRCA1/2 -ve cells (loss of DNA repair function), inhibitio of parp induces dramatic clinical responses in pt with defective homologous recombination.
