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Delta Med - Oncology > Oncology 1 - Melanoma, new agents, cell cycle > Flashcards

Oncology 1 - Melanoma, new agents, cell cycle Flashcards

1
Q

What are risk factors for melanoma?

A

>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.

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2
Q

What is the key depth of invasion dictating survival in melanoma?

A

0.76mm, 95% 5 year survival if less than this

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3
Q

What are the clinical signs of melanoma?

A

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

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4
Q

What are melanoma subtypes?

A

Radial growth phase: - superficial spreading - lentigo malgina - acral lentiginous Vertical growth phase: - nodular

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5
Q

What is the most common melanoma sub-type?

A

Superficial spreading 70%, related to intermittent sun exposure, median age 40s, trunk and limb location

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6
Q

What are features of lentigo maligna?

A

10-15% of melanomas from cumulative UV exposure face and neck in situ period may be long

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7
Q

What are features of acral lentiginous melanoma?

A

palms, soles and under nails do not arise from moles not caused by UV most melanomas in blacks and asians 2% of melanoma

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8
Q

What are features of nodular melanoma?

A

EFG - elevated, firm, growing progerssively

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9
Q

What are characteristic immunohistochemistry stains for Melanoma?

A

S100 Melan-A

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10
Q

What are the stages of melanoma?

A

Stage I - generally thickness

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11
Q

What are prognostic factors in stage III melanoma?

A

(essentially any tumour with positive LNs)

Number of metastatic LNs Micrometastatic vs macrometastatic

Primary melanoma ulceration

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12
Q

What are prognostic factors in stage IV melanoma?

A

Site(s) of distant metastases Elevated LDH (THE MOST PREDICTIVE OF SURVIVAL) (number of mets is not in staging system)

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13
Q

What are prognostic factors related to stage in melanoma?

A

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

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14
Q

What is the modality of treatment of stage I and II melanoma?

A

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)

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15
Q

What is the modality of treatment of stage III melanoma?

A

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

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16
Q

What is the natural Hx of of stage IV melanoma?

A

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.

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17
Q

What interventions show survival advantage in melanoma brain mets?

A

Surgical excision Stereotactic radiosurgery if

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18
Q

What is the only approved chemotherapeutic agent in melanoma?

A

Dacarbazine does not have durable responses myelosuppression, nausea and emesis

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19
Q

What are advantages of fotemustine vs dacarbazine in Stage IV melanoma?

A

longer time to develop brain mets and lower risk of cerebral met progression.

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20
Q

What are mutations associated with melanoma?

A

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

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21
Q

What are molecular targets in melanoma therapy, and their associated agents?

A

BRAF inhibitors - Vemurafenib - selective V600E mutations (no CNS activity) - Dafrafenib - inhibits all V600 mutations and has CNS activity MEK inhibitors - trametinib cKIT inhibitors - imatinib

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22
Q

What are rates of mutation in melanoma?

A

BRAF 45% NRAS 15% KIT 2-3%

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23
Q

What are some indications for vemurafenib?

A

Melanoma (50% BRAF positive) Colorectal (10% have activating BRAF mutations) Papillary, thyroid, anaplastic thyroid, cholangiocarcinoma, serous ovarian carcinomas

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24
Q

What are the outcomes of vemurafenib therapy in melanoma treatment?

A

Improved PFS 0.26HR Improved OS 0.44HR

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25
Q

What are AEs of vemurafenib therapy?

A

arthralgias rash photosensitivity fatigue SCC of skin in 23% of patients

26
Q

What are outcomes in dabrafenib therapy?

A

Also BRAF V600E inhibitor. Shows improved PFS vs DTIC

27
Q

What are outcomes of combined anti BRAF and MEK inhibition?

A

Dabrafenib (anti-BRAF) and trametinib (anti MEK1/2) - showed improved PFS and OS compared to vemurafenib alone

28
Q

What are AEs associated with BRAF inhibitors?

A

Pyrexia (50%) Cutaneous SCC/keratoacanthoma Hyperkeratosis Skin papilloma Hand-foot syndrome Alopecia photosensitivity/sunburn Non-cutaneous malignancy New primary melanoma

29
Q

What is CTLA-4?

A

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

30
Q

What are brief principles of T-cell activation

A

Requires two signals: TCR-APC complex = signal 1, CD-28-B7 signal 2. B7-CTLA-4 on APC/T-Cell down-regulates the response.

31
Q

What is the other pathway (other than CTLA4-CD28) that down-regulates T-cell activity?

A

PD-L1/PD-1 binding

32
Q

What is an anti-CTLA4 therapy in melanoma?

A

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.

33
Q

What are the most common AEs in ipilimumab (irAEs)

A

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

34
Q

What are two indications for ipilimumab?

A

Melanoma RCC

35
Q

What is the relationship between grade III/IV iRAEs and tumour regression?

A

higher rates of tumour regression in pts with significant IRAEs

36
Q

What ligand is selectively expressed in tumour cells in response to an inflammatory environment?

A

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

37
Q

What is an anti-PD-1 Ab?

A

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.

38
Q

What combination therapy improves PFS and ORR in patients with melanoma?

A

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

39
Q

What are the most important drivers of angiogenesis wrt TKI therapy?

A

VEGF bFGF PDGF

40
Q

What is the target of bevacizumab?

A

VEGFR

41
Q

What mAb targets VEGFR?

A

bevacizumab

42
Q

What small molecule TKIs target VEGFR and PDGFR?

A

sunitinib sorafenib

43
Q

What are the targets of sunitinib and sorafenib?

A

VEGFR and PDGFR

44
Q

What is an indication for sunitinib?

A

RCC - improves PFS compared with interferon.

45
Q

What is the most significant AE of sunitinib?

A

hypertension - predictive marker of response however.

46
Q

What are targets of sorafenib?

A

Inhibits: Raf kinase VEGFR 1-3 Platelet derived growth factor beta FMS-like tyrosine kinase 3 c-kit protein RET receptor tyrosine kinases

47
Q

What are significant SEs of sorafenib?

A

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

48
Q

What are toxicity of mTOR inhibitors?

A

Oral ulceration - ulceration/stomatitis Rash Fatigue Hypertension hand-foot syndrome diarrhoea infections pneumonitis (can be fatal if missed)

49
Q

What is the first systemic treatment to show improvement in OS in advanced HCC?

A

sorafenib - improves OS and median TTP. New systemic std of care in advanced HCC.

50
Q

What tumours show high expression of EGFR?

A

NSCLC 40-80% Prostate 40-80% Gastric 33-74% Breast 14-91% Colorectal 22-77% Pancreatic 30-50% Ovarian 35-70%

51
Q

What are functions of EGFR pathways?

A

proliferation/maturation chemotherapy/radiotherapy resistance survival/anti-apoptosis angiogenesis metastasis

52
Q

What are EGFR specific MAbs and TKIs

A

cetuximab panitumumab gefitnib erlotinib

53
Q

What are functions of TKIs (EGFR)

A

decreased proliferation decreased invasion decreased mets decreased angiogenesis decreased adhesion increased apoptosis

54
Q

What are predictors of response to EGFR TKIs in Adenocarcinoma?

A

non smoker female asian are more likely to have EGFR mutations

55
Q

What Sx is predictive of EGFR response?

A

rash! acineiform eruption

56
Q

What is the effect of EGFR mutation and wild-tpe on responses in NSCLC

A

gefitinib has WORSE outcomes vs carboplatin/paclitaxel in EGFR wild-type individuals c.f. mutated EGFR tumours

57
Q

When is cetuximab successful in improving OS in CRC?

A

when there is wild-type KRAS.

58
Q

What gene works at the G1/S DNA-damage checkpoint?

A

p53 - activation leads to cell cycle arrest or apoptosis lost in >50% of human cancer

59
Q

What are chemo targets at G1/S checkpoint?

A

alkylators, platinums, antimetabolites, taxanes, vinca alkaloids

60
Q

What chemo agents target the G2 checkpoint?

A

topoisomerase inhibitors - etoposide, irinotecan anthracyclines (also intercalate DNA)

61
Q

What chemotherapy agents target the spindle checkpoint?

A

Taxanes - paclitaxel, docetaxel Vinca alkaloids - vincristine, vinblastine, vinorelbine

62
Q

What are the significance of PARP inhibitors in BRCA +ve cancer cell mutations

A

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.

Delta Med - Oncology (4 decks)

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