Solid Tumours Flashcards

Question

What is the oncotype DX and why is it used in early stage ER+/HER- breast cancer?

Answer 1

21 genes analysed to predict chemotherapy benefit and prevent overtreatment of patients who do not need it

Answer 2

Atezolizumab is a PD-LA inhibitor that blocks the interaction between PD-L1 and PD-1, thereby promoting T cell activity. PD-L1-positive patients with metastatic TNBC showed improved progression free survival (PFS) when pembrolizumab was given in combination with chemotherapy

Answer 3

10-30% Can have bad side effects including autoimmune disease IHC of PD-L1 is used to determine who is likely to respond

Answer 4

M3.5 NTRK testing M3.6 PIK3CA M3.7 DPYD Oncotype

Answer 5

Most recurrently mutated gene in breast cancer Activating variants allows may respond to PIK3CA inhibitors- according to the SOLAR trial (11 specific variants but others may also respond)

Answer 6

More common in metastatic cancers and associated with shorter progression free survival They have been shown to be resistant to treatment with hormone therapies (AI, tamoxifen) but may respond to treatment with CDK4/6 inhibitors- clinical trials available Elacestrant (a selective estrogen receptor degrader) has been FDA approved for ESR1 mutated breast cancers- NICE under development

Answer 7

Currently not on the test directory but likely to be added soon for ESR1 - ESR1 is a known acquired resistance mechanism to hormone therapies - ctDNA would allow early detection of this resistance and variant is often not present in the primary tumour - Potential access to other therapies such as Elacestrant

Answer 8

It is derived by combining 3 main characteristics: numbers of telomeric allelic imbalances, large scale transitions, and loss of heterozygosity events (LOH), all of which are indicative of deficiency of the DNA repair system. Predicts response to PARP inhibitors- currently in clinical trials BrightNess trial

Answer 9

ctDNA Liquid biopsy blood test, for detecting the PIK3CA mutation, is approved by the FDA for breast cancer that can be used in clinical practice.

Answer 10

- Surgery/readiotherapy - Chemotherapy - Targeted: PIK3CA, NTRK, PARP, PD-L1

Answer 11

- Luminal A-like: endocrine therapy (ET) alone or with chemotherapy, in case of G3, T3 or ≥ 4 positive lymph nodes (IA) - Luminal B-like (HER2-negative): ET and chemotherapy, but not concomitantly (IID) - Luminal B-like (HER2-positive): chemotherapy and anti-HER2 (trastuzumab) and ET (IA). Only for selected cases, in which chemotherapy is contraindicated or refused by the patients, ET and trastuzumab may be considered as acceptable (VA) - HER2-positive (non-luminal): chemotherapy and anti-HER2 (trastuzumab) (IA) -Triple-negative (ductal): chemotherapy (IA)

Answer 12

ESMO recommends periodically mammography screening for women between 50 and 69 years old (IA). More specific are the NICE and German guidelines which recommend mammography for women between 50 and 70 years old every 3 and 2 years. ESMO also recommends yearly screening with MRI and mammography together or alternating every 6 months for women with a family history of breast cancer, starting 10 years prior to the diagnosis age of the earliest case in the family (IIIB).

Answer 13

Over 300,000 cases diagnosed worldwide per year, distribution varies internationally. Average 1.1% lifetime risk 6th most common cancer in women

Answer 14

Family history - First degree relative with breast/ovarian cancer, prostate cancer - Ashkenazi Jewish heritage Reproductive history - Early menarche, late menopause, fewer pregnancies - Pregnancy (before 25y), breastfeeding, late menarche, early menopause, contraceptive pill for 3+ years (↓ risk by 30-50%) Obesity Increasing age Genetic predisposition - Previous cancer such as breast - Mutations in DNA damage repair (HRD, BRCA1, BRCA2) Risk reduction - Tubal ligation, prophylactic hysterectomy/salpingo/oophrectomy

Answer 15

Patients may be asymptomatic or have non-specific symptoms that are related to involvement of abdominopelvic organs. Currently no accurate medical screening available for early-stage detection

Answer 16

- Only 20% diagnosed in early stages, when 5y survival is 94% - 80% patients present with FIGO stage III or IV, leading to low median survival (5y <30%) - Most reocur

Answer 17

The inability to repair double stranded breaks by homologous recombination This results in error prone DNA repair and genomic instability

Answer 18

Approximately 50% HGSOC harbour defects in HRR pathway genes - most are either germline or somatic BRCA variants - variants in other HRR genes e,g, RAD51D/D, BRIP1, RAD50, BARD1, CHEK2, MRE11A, NBN, PALB2- leads to a BRCA like phenotype

Answer 19

Requires recruitment of BRCA1 to double-stranded break (DSB), which then stimulates exonuclease-mediated 5’-3’ end resection to create single strand overhang. RAD51-DNA filament is created by exchange of RPA for RAD51 by complex containing RAD51, PALB2 and BRCA2. Sister chromatid is used as a template for high-fidelity DNA repair.

Answer 20

Pathogenic variants are early events in ~20% cases (account for most dHRR), consisting of germline in ~15% HGSOC patients and somatic in ~6-7% HGSOC cases

Answer 21

Reversion mutations in the BRCA genes that can reinstate homologous recombination proficiency (HRP) (i.e. cells/tumour cells are able to effectively repair DNA damage by HRR) have also been identified. This is often associated with primary or acquired Fce to PARP inhibitors, topoisomerase inhibitors or platinum salt

Answer 22

TP53 - >95% HGSOC present TP53 variants early in oncogenesis and contribute to genomic instability SMARCA4 - present in small cell carcinoma of the ovary DICER1 - Seen somatically in ~50% of SLCT and at younger patient age and with moderately/poorly differentiated tumours FOXL2 - c.402C>G, p.(Cys134Trp)-mutant - Nearly all adult granulosa cell tumours CTNNB1 and APC - Variants in most microcystic stromal tumour (MCST)

Answer 23

M2.1: BRCA1/BRCA2, SMARCA4 M2.3: NTRK M2.5: HRD M233.1: WGS M245.1: ovarian sex cord stromal tumours- FOXL2, CTNNB1, APC, DICER1 R207: germline SNV and CNV- BRCA1; BRCA2; BRIP1; MLH1; MSH2; MSH6; PALB2; RAD51C; RAD51D

Answer 24

Physical exam Imagining: Transvaginal ultrasound, CT and chest X ray Biochemistry: elevated serum CA125 (>35 units/mL but non specific) Histology: pleomorphic nuclei, high mitotic activity, necrosis, multi-nucleated cells common, prominent lymphocytic infiltrate.

Answer 25

~90% demonstrate nuclear WT1, ~95% abnormal p53 (strong diffuse staining in >80% cells, or no staining), CK7/CA125/PAX8 typically positive ER often expressed, p16 (CDKN2A) strong diffuse staining in ≥50% tumours, PTEN and ARID1A retained. These are useful in differentiating HGSOC from emdometroid

Answer 26

All ovarian and breast cancer patients are eligible for germline BRCA testing directly from oncologists to allow for treatment with PARP inhibitors

Answer 27

Tumour molecular testing recommended by NCCN after primary surgery or at recurrence/persistence if not performed at this timepoint, to inform utility of PARP inhibitors

Answer 28

Monitoring not currently performed through molecular testing equally across the U.K., CA125 routinely reviewed, however ctTNA is a focus of development for NHSE across solid tumours.

Answer 29

- Optimal surgical staging (TAH, BSO, infracolic omentectomy, bx of peritoneal deposits) - Platinum based chemotherapy- adjuvant chemo (6 x carboplatin) for high-risk Stage I (G3, or Ic) not low-risk (G1/2, Ia/b)

Answer 30

- Surgical objective to complete resection of all macroscopic disease - Intraperitoneal chemotherapy only as part of a clinical trial - Chemotherapy

Answer 31

PARP inhibitors (dependent on BRCA and HRD status) - Niraparib/rucaparib maintenance +/- after 1st line PBCT (2+ courses) - Olaparib maintenance through CDF for FIGO 3/4 after complete/partial response to 1st line PBCT+bev and is HRD+ +/- bevacizumab

Answer 32

- PARP is required in the Base Excision Repair pathway, inhibition of which causes an accumulation of DSB - Patients with deficient HRR are unable to HiFi repair DSBs, which accumulate and catastrophic DNA damage and cell death - This leads to Synthetic lethality - Most benefit derived from 1st line PBCT leading to SSB/DNA damage, then PARPi to inhibit mechanism of repair

Answer 33

NICE ESMO-ESGO consensus recommendations - recommends BRCA germline and somatic testing and HRD testing to identify patients who would respond to PARP inhibitors for maintenance therapy after platinum based chemo

Answer 34

The prostate is a male sex glandular structure Its main functions are to provide force to ejaculate semen and to add nutrient-rich alkaline fluid to the semen to maintain spermatic health post-ejaculation and enhance fertility

Answer 35

Malignant transformation of the prostate follows a multistep process, initiating as Prostatic Intraepithelial Neoplasia (PIN) followed by localized prostate cancer and then advanced prostate adenocarcinoma with local invasion, culminating in metastatic prostate cancer. PIN can be divided into two grades, low (LGPIN) and high (HGPIN). HGPIN has a high predictive value for predicting progression to adenocarcinoma.

Answer 36

1 in 6 men in the UK will be diagnosed with prostate cancer in their lifetime. In the UK, it is the most common malignancy in men with around 52,000 diagnosed with prostate cancer each year.

Answer 37

- Age - Black ethnicity - Family history - Obesity

Answer 38

Often asymptomatic - Lower Urinary Tract (LUT) symptoms (e.g. nocturia, frequency, hesitancy, urgency or retention) - Visible Haematuria - Abnormal Digital Rectal Examination (DRE) - Symptoms of advanced disease (lower back pain/bone pain secondary to bony metastasis, weight loss

Answer 39

The TMPRSS2-ERG fusion plays a significant role in the occurrence and progression of approximately 50% of prostate cancers. This fusion involves the E-26 transformation-specific (ETS)-related gene (ERG) and the transmembrane serine protease 2 (TMPRSS2). TMPRSS2-ERG regulates androgen receptor (AR) signalling

Answer 40

Enzalutamide, inhibits androgen, is more effective in cells or tumors with TMPRSS2-ERG translocations. These tumors exhibit increased AR signaling, making them more responsive to enzalutamide treatment Investigation into targeted therapies is ongoing

Answer 41

BRCA1, BRCA2 TMPRSS2-ERG NTRK1/2/3

Answer 42

Both somatic and germline BRCA variants have been reported in prostate cancer These patients are eligible for treatment with Olaparib. Testing on somatic tissue should be done first and then blood if tissue not available (R444)

Answer 43

According to ESWMP guidelines GP - a digital rectal examination (DRE) - a Prostate Specific Antigen (PSA) blood test Imaging - If elevated PSA, MRI If positive - transrectal ultrasound-guided (TRUS) biopsy - histology, grade, stage and risk stratification

Answer 44

Prostate Specific Antigen (PSA) is a protein produced by prostate epithelial cells. PSA is produced by normal prostate tissue, however levels in the blood tend to increase in malignancy. It may be used both in the diagnosis and surveillance of prostate cancer but is not perfect- threshold still in discussion

Answer 45

No There have been a number of studies that have tried to establish if a screening programme would be an overall benefit to the population. PSA testing is used sometimes but has a high false positive rate. PSA testing can be discussed with men over 50, and should be offered to those men over 50 who request it.

Answer 46

TNM using the 2018 classification for adenocarcinoma of the prostate based on primary tumour (T), lymph node involvement (N) and metastases (M)

Answer 47

The Gleason score is a histological grade assigned to prostate cancers. From the biopsy, the most common and second most common tumour pattern is assigned a score of 1 to 5 (5 being the highest grade) to give a combined score of 2 to 10. Grade 1 (score of 6): Cells look simialr to normal prostate cells Grade 5 (score 10): Cells look very abnormal

Answer 48

Using the Cambridge Prognostic Group (CPG) as low, intermediate and high on the basis the PSA, Gleason score and clinical stage.

Answer 49

- Active surveillance: an option in low-risk localised prostate cancer. It involves regular PSA measurements, digital rectal examinations and multiparametric MRIs. It is used as many with low-risk localised disease will have years without disease progression. - Radical prostatectomy: is a definitive treatment option for localised prostate cancer. It involves the removal of the entire prostate gland and surrounding tissues. - Radical radiotherapy: is a definitive treatment option for localised prostate cancer. May be combined with brachytherapy (implanting radioactive seeds directly in the prostate)

Answer 50

- Androgen-depravation therapy: this treatment aims to lower androgen levels (most common) - Gonadotropin-releasing hormone (GnRH) agonist: cause a 'chemical castration'. Goserelin is a commonly used GnRH agonist - Bicalutamide (an anti-androgen) - Bilateral orchidectomy (castration)

Answer 51

- Neoadjuvent chemotherapy (Docetaxel) - Radiotherapy - Radical prosteoectomy

Answer 52

Olaparib is NICE recommneded for relapsed BRCA positive prostate cancer patients

Answer 53

Endometrial cancer arises from the epithelial lining of the uterus. Historically classified into two classes 1.Hormonally dependent (Indolent, low grade, endometrioid carcinomas) 2.Hormonally independent – (associated with poorer prognosis, non-endometrioid – serous and clear cell morphology, clinically aggressive, that are unrelated to oestrogen stimulation).

Answer 54

- Group 1, with POLE mutations, is associated with a good prognosis. - Group 2, with MMR deficiency, is associated with an intermediate prognosis. - Group 3, showing low–copy-number alterations, is also associated with an intermediate prognosis. - Group 4 tumours, with high–copy-number alterations and TP53 mutations are associated with a poor prognosis.

Answer 55

3.4% of all new cancers Most common invasive cancer of female genital tract

Answer 56

81% 5 year survival rate

Answer 57

- The first sign is most often vaginal bleeding not associated with a menstrual period. - Pain with urination, - Pain during sexual intercourse, - Pelvic pain

Answer 58

- Obesity (In postmenopausal women, there is greater synthesis of oestrogens in body fat) - Diabetes (abnormal glucose tolerance is found in more than in 60%). - Hypertension - Infertility - Women with oestrogen secreting tumours have a higher risk of endometrial cancer. - Endometrial cancer is extremely rare in women with no ovaries

Answer 59

Endometrioid carcinoma Serous carcinoma Clear cell carcinoma Undifferentiated carcinoma Mixed carcinoma Other Carcinosarcoma

Answer 60

FIGO criteria - Non-gladular, non squamous growth and cytological atypia increases grade

Answer 61

Low grade - ER/PR, p16 High grade - ARID1A, PTEN, MMR, p53

Answer 62

Serous carcinomas represent approximately 10% of all endometrial carcinomas but account for as many as 40% of endometrial cancer–related deaths. The presence of TP53 is supportive of serous carcinoma.

Answer 63

Polymerase δ (pol δ) and Polymerase ε (pol ε) are the principal DNA replicases in eukaryotic cells. -They are coded for by the genes POLD1and POLE - Pol ε ensures accurate synthesis of the leading strand during DNA replication and is involved in proof reading and error correction

Answer 64

Loss of proofreading, catalytic and error-correction during DNA replication that results in an ultramutational state, leading to the accumulation of mutations in the genome

Answer 65

7-12% have variants in exonuclease domain

Answer 66

11 distinct pathogenic variants have been classified - accounts for 2/3s of POLE mutant EC

Answer 67

- Identifies and corrects base-base mismatches and insertions/deletions - Reduces replication-associated errors and contributes to cell cycle arrest and programmed cell death - Defects in MMR increase spontaneous mutation rate - Leads to mutagenesis in the short term and tumorigenesis in the long term

Answer 68

IHC for MMR genes - complete loss of one or one heterodimer of MMR e.g. MLH1 and PMS2 or MSH2 and MSH6

Answer 69

Reflex testing if negative in the following order: 1. POLE status (NGS) 2. MMR (IHC 3. P53 status (IHC, if inconclusive than NGS) NGS for TP53 is much more accurate than IHC

Answer 70

1. Groups are prognostically distinct 2. Groups exhibit characteristic responses to therapy that are not captured in existing treatment algorithms- POLE mutated patients are being overtreated 3. Certain groups are associated with hereditary cancer syndromes (MMR-d and Lynch Syndrome; p53-mut and BRCA1 and BRCA2) – role in screening and prevention

Answer 71

All endometrial cancers are MMR tested using IHC - if loss of expression of MLH1/PMS2 then reflex for MLH1 promoter hypermethylation as most common cause of somatic loss - If negative, refer to clinical genetics and send for germline MMR testing

Answer 72

42,896 new cases each year 16,808 deaths 6-7% lifetime risk

Answer 73

53% >10 year survival

Answer 74

- Older (age-specific incidence rates increase steeply after age 50, with the highest rates above age 85 years) - Male (RR~1.83) - Family history of CRC

Answer 75

- Change to bowel habits - Loose poo or diarrhoea outside normal for person pattern - Constipation outside normal for person pattern - Blood in poo - Increased frequency of passing stools/ increased urge to pass stool. - Abdominal pain - Abdominal bloating - Losing weight without trying - Feeling unusually tired

Answer 76

Adenocarcinoma Mucinous Signet ring cell carcinoma Squamous cell carcinoma

Answer 77

Colonoscopy Biopsy Imaging ESMO, NICe

Answer 78

Cytokeritin 20+ Cytokeritin 7- CDX2+

Answer 79

M1.1- KRAS, NRAS, BRAF M1.4- MSI M1.5- MLH1 promoter hypermethylation M1.6- NTRK1/2/3 M1.9- MLH1, MSH2, MSH6, PMS2, POLE, POLD1 (somatic lynch)

Answer 80

- Activating variants in KRAS and NRAS result in constitutive activation of the RAS/RAF/MEK/ERK pathway. - CRC would be eligible for treatment with anti-EGFR therapy e.g. cetuximab or panitumumab. - KRAS/NRAS are downstream of this point to inhibition via anti-EGFR therapy would be ineffective. - intermediate prognosis

Answer 81

BRAF variants are present in approx 5-10% of CRC cases Associated with: - Right side tumours - Older age - Female - MSI-high Activating variants in BRAF result in constitutive activation of the RAS/RAF/MEK/ERK pathway and will not respond to anti-EGFR therapy - BRAF V600E carrying CRC can access treatment with encorafenib plus cetuximab per licensing agreement.

Answer 82

Prognostic marker: - poor prognosis if present in microsatellite stable tumour - good prognosis if present in microsatellite unstable tumour

Answer 83

NICE improving outcomes recommends - Loss of MMR is indicative of lynch syndrome and starts the lynch reflex pathway

Answer 84

Improved prognosis and good response to immunotherapy Poor response to 5 FU chemotherapy

Answer 85

Wither IHC or MSI used to identtify potential lynch cases - MLH1 promoter hypermethylation - BRAF V600E testing- somatic marker - Germline testing - Somatic lynch testing if still no cause identified

Answer 86

- When repair pathways are dysfunctional then there can increased instability at repetitive regions of the genome. - Microsatellite can be assessed for integrity – please review other notes for details. - Microsatellites that show variations in size and slippage indicate that the repair pathways in a tumour have been disrupted and the patient may have Lynch syndrome or somatic Lynch-like syndrome.

Answer 87

Colorectal and endometrial cancers are all screened by IHC to identify cases showing loss of expression of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) Loss of MLH1 and PMS2 is more commonly due to sporadic events so further testing is required to investigate these IHC results. MLH1 promoter hypermethylation testing will identify cases where hypermethylation the promoter region prevents expression of MLH1. This is usually due to hypermethylation in the tumour genome but on occasion germline constitutional hypermethylation of MLH1 promoter has been observed.

Answer 88

Look for the somatic second hit in a Lynch syndrome patient’s tumour Two somatic pathogenic variants to explain IHC expression loss in a tumour when germline showed no evidence of Lynch syndrome

Answer 89

Surgery + neoadjuvent therapy If MMR-P- 5-FU If MMR-d- Capectiabine

Answer 90

MMR-P - Adjuvent chemotherapy and anti-EGFR therapy MMR-D - Adjuvent chemotherapy and anti-EGFR therapy - immunotherapy) KRAS/NRAS mut and MMR-p - adjuvent chemo KRAS/NRAS mut and MMR-d - Adjuvent chemo and immunotherapy BRAF - BRAF inhibitor plus anti-EGFR

Answer 91

Small cell lung cancer (SCLC) - 15% Non-small cell lung cancer (NSCLC) – 85% - Adenocarcinoma - Squamous cell carcinoma (SCC) - Large cell neuroendocrine

Answer 92

5-10 per 100K in never-smokers, 20-30x as high in smokers According to the World Health Organization (WHO), lung cancer accounted for 11.4% of all new cancer cases in 2020

Answer 93

- Smoking - Radon exposure - Occupational agents (asbestos, aluminium production, arsenic, coal, dioxin, radiation etc) - Air pollution - Family history - Personal history of lung disease- e.g. COPD

Answer 94

>80% present with locally advanced or metastatic disease Primary tumour - Persistent cough, - Haemoptysis (coughing up blood), - Dyspnea (shortness of breath), - Chest pain Metastasis - Headache/seizures - Bone pone - Weight loss - Fatigue

Answer 95

Imaging - Chest X ray followed by PET, CT Biopsy -Histological subtyping and TNM staging - IHC used

Answer 96

Cytokeratin AE1/3 + TTF1 + Synaptophysin + CD56 + Napsin A and p40 -

Answer 97

Cytokeratin AE1/3 + TTF1 + Napsin A + Synaptophysin - CD56 - p40 -

Answer 98

Cytokeratin AE1/3 + p40 + TTF1 - Napsin A - Synaptophysin - CD56 -

Answer 99

Stage 1: Surgery and adjuvent chemo/radiation Stage 2-4: incurable, no targeted therapies

Answer 100

TP53 and RB1 LOF High TMB Associated with heavy smokers so G>T and C>A transversions High number of CNVs

Answer 101

RB1 CNV: used in equivocal cases to aid diagnosis and to identify possible resistance mechanism to chemotherapy NTRK fusions: treatment eligibility

Answer 102

Incurable so treated with systemic therapies - Based on the presence of targeted therapy and PD-L1 expression - If <50% PD-L1: platinum based chemo +/- pembrolizumab - if >50% PD-L1: pembrolizumab +/+ pemetrexed and carboplatin - if targeted event

Answer 103

SNV: EGFR, KRAS, BRAF, MET, ALK CNV: MET Structural: ALK, ROS1, RET, NTRK1, NTRK2, NTRK3 ctDNA: EGFR, ALK

Answer 104

- 10-15% - Activating missense variants e.g. L858R, deletion in exon 19 and insertions in exon 20 - Predicts response to EGFR TKI's

Answer 105

EGFR variants e.g. T790M, C797S MET amplification

Answer 106

Erlotinib and Gefitinib - First-generation EGFR inhibition - Most common resistance mechanism is Thr790Met in exon 20 Afatinib, Dacomitinib - Second-generation ERBB family blockade Osimertinib - Third-generation, targets T790M - Most common EGFR-based resistance mechanism is Cys797Ser in exon 20

Answer 107

Will not respond to standard EGFR TKIs Mobercertinib - TKI specific for EGFR exon 20 -Now removed from NICE commissioning due to adverse affects Amivantamab - Monoclonal antibody for EGFR exon 20 - Licensed but not yet NICE recommended, may access through special circumstances

Answer 108

25% SNVs and indels affecting G12 and Q61 Poor prognosis and G12C predicts repsonse to KRAS G12C specific TKIs - Co-occurring TP53 associated with increased immunotherapy response

Answer 109

KRAS notoriously difficult to target therapeutically Sotorasib - G12C specific - Available through CDF - Second line treatment

Answer 110

Only for Class 1 V600 variants Dabrafenib plus trametinib (BRAF/MEK combination therapy)

Answer 111

1-2% Three classes of BRAF variants - Class 1: V600 variants - Class 2: Non-v600 variants, activating - Class 3: Kinase dead Class 1 BRAF variants are associated with poor prognosis and lower response to immune checkpoint inhibitors but response to BRAF.MEK inhibition

Answer 112

3-4% Splicing (exon 14 skipping) 2-4% Amplification

Answer 113

Predicts response to MET TKI- Tepotonib

Answer 114

Secondary MET amplification is associated with acquired resistance to EGFR TKI Can also be primary oncogenic event No NICE approved therapy but some evidence of response to criztonib

Answer 115

Exon skipping - DNA splicing variants - RNA exon skipping - between 60-90% concordance in DNA but RNA is gold standard Amplification - NGS CNV calling - FISH (confirmation)

Answer 116

ALK Fusions e,g, ELM4-ALK (3-7%) inv(2)(p21;p23) Predicts response to ALK inhibitor therapy- rapid response

Answer 117

Crizotinib - First generation - Approved for first and second line Certinib and Alectinib - Second generation Lorlatinib - Third generation - Sensitive to ALK resistance mutations including G1202R - no longer approved first-line (July 2023), second line only

Answer 118

ALK SNVs e.g. G1202R, L1196M ALK amplification MET amplification Different mechanisms of resistance may be sensitive to different lines of treatment

Answer 119

RET fusions 1% KIF5B-RET, CCDC6-RET Response to Selpercatinib

Answer 120

ROS1 Fusions 2% CD74-ROS1 EZR-ROS1 Response to Crizotinib - ROS1 and ALK share 49% amino acid sequence homology so crizotinib can bind to both

Answer 121

NTRK fusions 1% LMNA-NTRK1 ETV6-NTRK3 t (12; 15) (p13; q25) Response to Larotrectinib and Entrectinib - Available once all treatment options have been exhausted

Answer 122

ERBB2 - Response to ERBB2 TKI's - Amplification is a resistance mechanism to EGFR TKI PIK3CA - response to targeted therapy TP53 - increased response to immune checkpoint

Answer 123

RNA sequencing panels FISH IHC

Answer 124

EGFR and ALK ctDNA currently on the test directory - Currently delivered by a national 2-hub model for NSCLC - Can be used when a tumour is inaccessible to biopsy - Potential disease monitoring mechanism and potentially identify resistance variants prior to disease progression - More representative picture of the tumour heterogeneity.

Answer 125

NSCLC: 5-year survival 5% SCLC: 5 year survival at 2%

Answer 126

Melanoma arises from an accumulation of mutations that transforms melanocytes, most commonly in the skin.

Answer 127

Melanoma arising due to UV radiation - Low-CSD (cumulative sun damage) melanoma- superficial spreading melanoma - high-CSD melanoma- Lentigo maligna melanoma , Desmoplastic melanoma  Melanoma not associated with CSD  - Spitz - Acral - Mucosal -Uveal - Melanoma arising within blue naevi  - Melanoma arising in congenital naevi    Nodular Melanoma

Answer 128

Benign naevus - Harbours only a single mutation and no other pathogenic alterations - e.g. BRAF V600E Melanocytoma - Evolved from benign naevi with additional pathogenic mutations but have not yet reached malignant state Malignant melanoma - acquired additional pathogenic mutations and becomes malignant

Answer 129

5th most common cancer- 4% of all new cancer cases Adult incidence: 20 million cases per year

Answer 130

Caucasain: superficial spreading Asian, hispanic and African- Acral melanoma

Answer 131

86% of cases are preventable - Fitzpatrick skin type 1: never tans (always burns), fair skin, blue eyes, red/blond hair, freckles - history of blistering sunburn - genetic predisposition - immunosupression - Congenital nevi - Environmental factors (tanning beds, sun exposure)

Answer 132

New/changing pigmented skin or mucosa lesions. Lesions may be crusting, itching and may bleed. ABCDE model A - Asymmetry: Asymmetric in shape, size, or color. B - Border Irregularity: The edges of the mole or lesion are irregular, ragged, notched, or blurred, rather than smooth and well-defined. C - Colour Variation: The mole or lesion exhibits uneven colouring or multiple colours D - Diameter: >5mm or is increasing in size over time. E - Evolution: The mole or lesion has undergone changes in size, shape, colour, or texture over time, or new symptoms such as itching, tenderness, or bleeding have developed

Answer 133

SNVs: BRAF, NRAS, KIT Structural: NTRK1/2/3 CNVs: MYB, RREB1, CCND1, MYC, CDKN2A- for equivocal cases

Answer 134

50% - most commonly superficial spreading melanoma BRAF V600 are the most common Associated with aggressive disease and makes patient eligible for NICE approved targeted therapy BRAF/MEK combination therapy (only V600 variants): Dabrafenib+Trametinib/ Encorafenib+binimetinib

Answer 135

15-20% of melanoma NRAS Q61 are the most common, typically mutually exclusive with BRAF V600 Associated with aggressive disease There is no targeted treatment but there is some evidence that patients may respond to MEK inhibitors

Answer 136

NRAS variants can be found with Class 3 BRAF variants. This results in elevated oncogenic potential through activation of the MEK/ERK pathway and these tumours may be more likely to respond to MEK inhibitors.

Answer 137

Present in 10.8% of melanomas, most commonly high CSD (Lentigo maligna melanoma) Targeted treatment: Fair responses to TKIs such as imatinib and sorafenib but this is not licensed

Answer 138

NTRK fusions are present in <1% cutaneous/mucosal melanoma but 20-30% spitzoid melanomas ETV6:NTRK3 t(12 15)(p13 q25) Can aid in diagnosis of spitzoid neoplasm NICE approved targeted treatment available for these patients- NTRK inhibitors Larotrectinib and entrectinib- only once all treatment options have been exhausted

Answer 139

BRAF, NRAS, NF1

Answer 140

10-15% of melanomas LOF variants in NF1 are particularly common in lentigo maligna melanoma. Associated with very high TMB Not a test directory target for melanoma but there is some preclinical evidence that these patients may respond to MEK inhibition.

Answer 141

Codon Q209 hotspot variant dominates Uveal (and Blue Neavi) melanoma, whilst BRAF V600 is unusual in this subtype Some response to MEK inhibitor, but no improvement in overall survival

Answer 142

3-4% ocular melanoma PARP inhibitors being explored for these patients Germline variants associated with BAP1 predisposition syndrome Associated with greater metastatic disease potential

Answer 143

43% melanomas, especially non-acral skin Associated with older age, sun exposure, thicker tumours, BRAF variants Most common in superficial spreading Associated with poorer prognosis

Answer 144

Copy number panel either using array or FISH - RREB1 - MYB - CCND1 - C-MYC - CDKN2A - Centromere 6 This is particularly useful when diagnosing spitz melanoma which can be diagnostically challenging to distinguish Spitzoid melanoma from benign Spitzoid melanocytic lesions

Answer 145

Tumour Mutation Burden (TMB) The total number of somatic/acquired mutations per coding area of a tumour genome (Mut/Mb).

Answer 146

Melanoma is known to have some of the highest TMB scores compared with other solid tumour types. TMB however varies within melanoma subtypes, with NF1 mutated and High CSD cutaneous melanoma having the highest TMB High TMB is a positive predictor of response to immunotherapy with checkpoint inhibitors such as anti-PD1 (nivolumab, pembrolizumab) and anti-CTLA4 (ipilimumab), Not all high TMB tumours will respond to immunotherapy

Answer 147

Imaging Sentinel lymph node biopsy Scar re-excision Histology to subtype and stage IHC for protein overexpression or loss of expression, e.g p16 (CDKN2A) Equivacol cases: FISH, SNP arrays or NGS to detect a CNV ‘melanoma pattern’ or variants that may inform on subtypes.

Answer 148

S100 MelanA HMB45 SOX10

Answer 149

TNM: tumour nodes metastases T: Breslow thickness (depth of tumour in mm from skin), Ulceration N: Largely based on number of involved nodes M: Location of distant metastases

Answer 150

Stage Serum LDH BAP1 loss/monosomy 3 is poor prognosis in uveal melanoma BRAF/NRAS poor prognosis

Answer 151

Surgical removal/resection, with or without radiotherapy (depending on histological types and resection margins) Sentinel lymph node biopsy is recommended for Breslow thickness of >1mm, ulcerated thinner melanoma may also be indicated for SLNB

Answer 152

Stage III Surgical resection followed by PD-1 inhibitor OR BRAF plus MEK inhibitor in V600 mutant melanoma Lymphadectomy of involved LN if benefit is likely to outweigh the significant rate of morbidity associated with this procedure Unresectable III and untreated stage IV Checkpoint inhibitor combination therapy Pembrolizumab, Nivolumab (anti-PD-1); Ipilimumab (anti-CTLA-4)) BRAF plus MEK inhibitor if immunotherapy unsuitable or rapid progression/high disease burden) - Dabrafenib+Trametinib/Encorafenib+binimetinib; Chemotherapy or best supportive care Previously treated stage IV Check point inhibitor Combination or monotherapy BRAF-MEK inhibitor

Answer 153

Patients with localised disease, and tumours <1mm deep have a >95% survival rate at 5 years. Relapse occurs in a significant proportion of people with stage IIA to IIC melanoma (up to 50% at 5 years in people with stage IIC melanoma) <30% diagnosed with distant metastasized melanoma survive over 5 years

Answer 154

ESMO NICE NCCN

Answer 155

Start with immunotherapy Long-lasting effect, and still have targeted therapy in the bag if/when needed But relatively high rate of side effects, and significant rate of non-response But fairly slow onset Start with targeted therapy Rapid effect (days/weeks) Generally higher response rate Lower rate of side effects But relatively short duration of response

Answer 156

Glioblastoma: annual incidence is approximately 3 per 100,000 per year and increases with age and male sex.

Answer 157

Age Obesity Exposure to vinyl chloride – glioma EBV infection – implicated in primary CNS lymphoma Transplant recipients and patients with AIDS – increased risk of primary CNS lymphoma Ionising radiation Radiofrequency radiation Occupational exposures e.g. Meningiomas may be associated with lead exposure. Family syndromes: NF1, NF2, VHL, LFS

Answer 158

Headaches Seizures Visual changes GI symptoms e.g. loss of appetite, nausea, vomiting Personality, mood, mental capacity, concentration changes

Answer 159

Imaging MRI: used as standard as has good tissue resolution. CT scan used when MRI is contradictory PET: used to determine tumour from necrotic regions (metabolically active) Histology Biopsy- morphology, staining, IHC to determine grade/stage Molecular IDH1, MGMT, ATRX, 1p/19q codeletion, histone mutations All involved in determining the subtype

Answer 160

Age >40 years Progressive disease Tumour size >5cm Tumour crossing midline Contrast enhancement on MRI WHO performance status (>1) Neurological symptoms Less than gross total resection

Answer 161

The 2021 WHO classification emphasizes molecular diagnostics alongside traditional histopathology- integrated diagnosis. Gliomas have also been distinguished into adult and paediatric Introduced grading within tumour types

Answer 162

Adult-type diffuse gliomas Pediatric-type diffuse low-grade gliomas Pediatric-type diffuse high-grade gliomas Circumscribed astrocytic gliomas Glioneuronal and neuronal tumors Ependymal tumors Embryonal tumors Meningioma

Answer 163

1. Diffuse Astrocytic and Oligodendroglial Tumors IDH-mutant gliomas - Astrocytoma, IDH-mutant (graded 2, 3, or 4) - Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (graded 2 or 3) IDH-wildtype gliomas - Glioblastoma, IDH-wildtype (automatically grade 4) - Diffuse midline glioma, H3 K27-altered (grade 4) - Diffuse hemispheric glioma, H3 G34-mutant (grade 4) 2. Circumscribed Astrocytic Gliomas (Non-diffuse) - Pilocytic astrocytoma (grade 1) - Pleomorphic xanthoastrocytoma (grade 2) - Subependymal giant cell astrocytoma (grade 1)

Answer 164

Learn diagram IDH (Isocitrate Dehydrogenase) Status IDH-mutant: Associated with a better prognosis. IDH-wildtype: Often associated with a poorer prognosis 1p/19q Codeletion Presence of this codeletion is characteristic of oligodendrogliomas. Histone Mutations Mutations in histone genes such as H3 K27M (common in diffuse midline gliomas) and H3 G34R/V. ATRX: rules out oligodendroglioma

Answer 165

Grade 1: Typically benign, slow-growing, and well-circumscribed tumors (e.g., Pilocytic astrocytoma). Grade 2: Low-grade, but infiltrative and have potential for malignant transformation. Grade 3: Anaplastic, more aggressive than grade 2. Grade 4: Highly malignant and aggressive, such as glioblastomas and certain diffuse midline gliomas

Answer 166

SNVs: IDH1, IDH2, ATRX, H3-3A,H3C2, BRAF, TERT promoter Structural: NTRK, EGFR vIII, BRAF Methylation: MGMT

Answer 167

IDH1 R132 and IDH2 R172 First stage of WHO classification (astrocytomas and oligodendrogliomas) Better prognosis compared to IDH-wildtype gliomas. Associated with a more favorable response to treatment, including radiotherapy and chemotherapy

Answer 168

Isocitrate dehydrogenase (IDH) enzymes, of which there are three isoforms, are essential enzymes that participate in several major metabolic processes, such as the Krebs cycle, glutamine metabolism, lipogenesis and redox regulation. Mutations usually in the isocitrate binding site, reducing isocitrate binding and altering cellular metabolism

Answer 169

IHC - R132H-specific Ab - 85-90% R132H but can't detect other variants NGS - Panel genes, full gene sequencing Targeted hosptot

Answer 170

Characteristic of oligodendrogliomas. Associated with a better prognosis and response to therapy. Key criterion for differentiating between oligodendrogliomas and astrocytomas.

Answer 171

ATRX IHC: Surrogate marker based upon mutual-exclusivity with 1p19q co-deletion. Rapid, relatively cheap, and labour unintensive. FISH: Reliable and cost effective. FISH cannot differentiate between whole chr. Arm deletion from smaller focal deletions. SNP arrays: can identify whole-arm co-deletion with higher reliability – better choice but labour intensity PCR based microsatellite analysis: can allow detection of LOH at selected loci and NGS-based methods also useful

Answer 172

Commonly found in IDH-mutant astrocytomas, rules out oligodendroglioma. ATRX mutation is mutually exclusive with 1p19q co-del

Answer 173

Frequently found in IDH-mutant astrocytomas Can be detected by IHC or NGS

Answer 174

Promoter methylation Predicts response to alkylating agent chemotherapy (e.g., temozolomide) in glioblastomas- associated with longer survival

Answer 175

Removes alkyl groups and repairs mutagenic DNA lesions, preventing DNA damage and subsequent apoptosis. Therefore key in maintaining DNA integrity, but can provide a survival / cell death resistance mechanism by preventing cancer cells from entering the apoptotic pathway when subject to chemo-radio therapy.

Answer 176

Bisulfite conversion: Convert unmethylated cytosine residues to uracil, using bisulphitation of DNA (methylated cytosine is resistant to this chemical alteration) Pyrosequencing MLPA Methylation specific PCR

Answer 177

Almost all IDH-mutant, 1p/19q-codeleted oligodendroglial tumours have activating mutations in TERT gene promoter region – valuable diagnostic marker. Associated with a poor prognosis. TERT promoter mutations, along with EGFR amplification and +7/-10 copy number changes, are indicative of glioblastoma, IDH-wildtype.

Answer 178

c.-124C>T, c.-146C>T Produces a binding site for ETS transcription factors- gains the ability to recruit transcription factors that might upregulate TERT protein expression. Leads to telomere maintenance in tumour cells Detected by NGS

Answer 179

H3 K27M: Found in diffuse midline gliomas, particularly in the brainstem, thalamus, and spinal cord; associated with a very poor prognosis (2 year surival <10%) and classified as WHO grade 4, paediatric H3 G34R/V: Found in diffuse hemispheric gliomas, typically in children and young adults; also associated with a poor prognosis.

Answer 180

Common in pediatric low-grade gliomas V600E in ganglioglioma KIAA1594-BRAF fusion present in 70% pilocytic astrocytoma- aids diagnosis Can be targeted by specific inhibitors (e.g., vemurafenib) in cases of refractory or recurrent tumors.

Answer 181

V600E - BRAF/MEKi FDA approved but not yet NICE approved - Could access compassionally KIAA1549:BRAF - MEK inhibitor trial

Answer 182

Indicative of a more aggressive tumor and associated with poor prognosis in IDH-mutant astrocytomas. Important for grading and determining the aggressiveness of the tumor.

Answer 183

Most frequently amplified in glioblastoma (30-40%), often associated with structural abnormalities e.g. mutant protein EGFRvIII – exon 2-7 skipping, characterised by deletion of extracellular domain (seen in ½ of all with amplification). Most useful in diffuse gliomas lacking IDH mutations which fail to show high grade features (necrosis, MVP), a confounding presentation; EGFR amp confirms GBM, IDH-WT, WHO IV. Poor prognosis Potential therapeutic target

Answer 184

Pediatric-type diffuse low-grade gliomas - Diffuse astrocytoma, MYB- or MYBL1-altered - Angiocentric glioma - Polymorphous low-grade neuroepithelial tumor of the young - Diffuse low-grade glioma, MAPK pathway-altered Pediatric-type diffuse high-grade gliomas - Diffuse midline glioma, H3 K27-altered - Diffuse hemispheric glioma, H3 G34-mutant - Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype - Infant-type hemispheric glioma

Answer 185

Replaces Peripheral neuroectodermal tumour (PNET) Predominantly occur in children Histologically characterised by high cellularity with densely packed, poorly differentiated small cells and marked mitotic activity.

Answer 186

Includes: Medulloblastomas Embryonal tumours with multi-layered rosettes (ETMRs) Atypical teratoid/rhabdoid tumours (AT/RTs) + heterogenous group of other embryonal CNS tumours

Answer 187

WNT activated SHH activated/TP53 WT SHH activated/TP53 mutant Non-WNT

Answer 188

10% >90% carry CTNNB1 mutation Children have good prognosis but adults less favourable

Answer 189

30% Infants and adulthood PTCH1 or SUFU germline mutations

Answer 190

Small percentage of SHH-activated medulloblastomas Predominantly children Show large cell/anaplastic phenotype Poor prognosis Up to 50% have germline TP53 mutation

Answer 191

Group 3 and group 4” molecular categories Group 3 = 20% Group 4=40% Children and infants Lack of easily accessible diagnostic tools - grouped together Histologically almost always show classic or large cell/anaplastic phenotype

Answer 192

Underlying defect in SMARCB1 or rarely SMARCA4 Products of these are essential components of SWI/SNF chromatic remodelling complex.

Answer 193

Primarily affects children Highly aggressive C19MC Amplification or TTYHI-C19MC. This amplification is a key diagnostic marker. LIN28A overexpression, a protein involved in the regulation of microRNAs and embryonic development.

Answer 194

RB1 (RB transcriptional corepressor 1) mutations (+/- germline defect) and DICER1 (Dicer 1, ribonuclease III) mutations linked to pineoblastoma Pituitary – DICER1 mutation key predisposing event

Answer 195

The standard of care in newly diagnosed GBMM includes maximal safe surgical resection, followed by concurrent radiotherapy and temozolomide (TMZ) and six monthly cycles of adjuvant TMZ. Treating symptoms- steroids, Anti-convulsant (seizures)

Answer 196

90% Median PFS of 1.5–6 months and median OS of 2–9 months

Answer 197

WHO NICE ESMO

Answer 198

The thyroid gland is an endocrine gland in your neck. It makes two hormones that are secreted into the blood: thyroxine (T4) and triiodothyronine (T3). Regulates vital functions including breathing, heart rate, nervous system and body temperature

Answer 199

GLOBOCAN 2018 database, thyroid cancer (TC) accounts for 3.1% of all new cancer diagnoses worldwide and, therefore, ranks in 9th position with regard to incidence CRUK states TC represents 1% of all UK cancers (2016-18 data)- 20th most common in UK Estimated annual 41,000 deaths,

Answer 200

History of radiation therapy administered in infancy or childhood for benign H&N conditions Radiation exposure as a consequence of radioactive fallout Family history of thyroid disease or multiple endocrine neoplasia (MEN) / other inherited syndromes Frequent sporadic variants A history of goitre (swelling of thyroid, deficient function, >90% due to iodine deficiency) Female sex (2-3 times more likely) Age (in 30's and over 60s)

Answer 201

Majority are asymptomatic May present witha painless lump or swelling in the front of the neck Sore throat Difficulty swallowing (dysphagia) Unexplained hoarseness

Answer 202

Thyroid lesion that is palpable and/or distinct from the surrounding area Over 90% are small, non-palpable, benign lesions; however, identification of clinically significant, malignant thyroid nodules that will cause morbidity if not diagnosed early is important.

Answer 203

Physical examination and history Ultrasound Laryngoscopy Fine-needle aspiration biopsy of the thyroid Tissue Biopsy Blood test: Blood hormone studies (TSH…), blood chemistry studies (calcitonin, CEA) CT scan

Answer 204

Usually by ultrasound and histopathology Sometimes definitive classification can be challenging and molecular profiling can aid classification as well as stratify targeted therapy

Answer 205

Thyroid cancers are derived from either follicular thyroid cells or neuroendocrine cells According to WHO 2022 Differentiated thyroid cancer - Papillary - Follicular - Poorly differentiated Undifferentated thyroid cancer - Anaplastic Neuroendocrine - Medullary

Answer 206

60-80% of all cases 5 year survival of 90% Good prognosis Mean age <40

Answer 207

30-50% 5 year survival of 90% Good prognosis Mean age 40-60

Answer 208

5-7% More aggressive, less differentiated form of follicular-derived thyroid cancer, intermediate between differentiated thyroid cancer and anaplastic thyroid cancer.

Answer 209

2% 5 year survival of 10% Very poor prognosis Mean age >60 Almost always presents with metastasis, mortality is 100%

Answer 210

5-7% 5 year survival of 80% Poor prognosis Mean age 10-60

Answer 211

Progression from Follicular thyroid cells to papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC) is marked by mutations activating the MAPK- or PI3K-AKT signalling pathways Further progression to poorly differentiated thyroid cancer (PDTC) is characterised by additional mutations and rearrangements, affecting both signalling pathways simultaneously. Anaplastic thyroid cancer (ATC) is characterised by further genetic events, especially in oncogenes like TP53, as well as epigenetic alterations and infiltration of immune cells, creating an intracellular microclimate that favours genetic instability and oncogenesis.

Answer 212

Caused by germline change in the RET gene About 20% cases are caused by this If multiple tumours seen then known as multiple endocrine neoplasia type 2 (MEN2) MEN2A is associated with pheochromocytomas (tumours that make adrenaline) and with parathyroid gland tumours. MEN2B is associated with pheochromocytomas and with benign growths of nerve tissue on the tongue and elsewhere called neuromas

Answer 213

The MAPK-signaling pathway is crucial for growth and proliferation of the cell. The signaling cascade is initiated on the cell surface by a “mitogen” stimuli, a growth factor, that binds to the tyrosine kinase receptor (RTK) and ultimately results in the phosphorylation and activation of Mitogen-Activated Protein Kinase (MAP2K), which is also known as MEK, and the downstream extra cellular signal-regulated-kinase (ERK).

Answer 214

The PI3K/AKT signalling pathway is involved in the regulation of apoptosis, proliferation, cell cycle progression, angiogenesis, cytoskeleton integrity, and energy metabolism, and ultimately leads to AKT and mTOR activation.

Answer 215

RAS mutations can activate both MAPK- and PI3K/AKT pathways. However, it seems like RAS mutations preferable activate the PI3K-AKT pathway in thyroid oncogenesis. There are three isoforms of RAS-NRAS, HRAS and KRAS, where NRAS is the most commonly mutated in human TC. RAS mutation is thought to be a premalignant mutation, and that additional mutations are needed to set off carcinogenesis

Answer 216

SNVs: BRAF, KRAS, NRAS, HRAS, RET, TERT promoter, TP53 Structural: RET, ALK, NTRK1, NTRK2 and NTRK3

Answer 217

BRAF V600E Exclusive in papillary thyroid cancer and papillary thyroid cancer derived anaplastic thyroid cancer Poor prognosis May respond to BRAF/MEK inhibition- not NICE approved, FDA approved

Answer 218

Codons 61, 12 and 13 Common in follicular adenomas

Answer 219

Poor prognostic marker, associated with aggressive disease Even worse prognosis if found in combination with BRAF V600E

Answer 220

M918T most common Found in medullary thyroid carcinoma Associated with poor prognosis RET inhibitors available for these patients- cabozantinib is approved and may be given regardless of RET status. Selpercatinib available through CDF as second line

Answer 221

CCD6::RET NCOA4::RET Found in 7% of papillary thyroid cancers- highly specific. Also ATC (derived from papillary) RET inhibitors available for these patients- cabozantinib is approved and may be given regardless of RET status. Selpercatinib available through CDF as second line

Answer 222

TP53 mutations are rare in differentiated thyroid cancers but are more common in anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC). They are associated with: Highly aggressive disease. Poor prognosis. Resistance to conventional therapies.

Answer 223

Seen in a small number of anaplastic thyroid cases Associated with younger patient age Potential response to ALK inhibitors e.g. Crizotinib but not NICE approved

Answer 224

LMNA-NTRK1 ETV6-NTRK3 l t(12;15) (p13; q25) Most commonly seen in papillary thyroid cancer but still rare Eligibility for treatment with NTRK inhibitors entrectinib and lorentrectinib- exhausted all treatment options

Answer 225

ESMO guidelines indicate that asymptomatic patients with stable disease should undergo active surveillance only (CT; serum TG and TgAb) Progressive disease: - thyroidectomy (low risk can have lobectomy) - If high risk ( tumour >2cmm, nodal and metastasis), radioidine therapy is used If refractory, sorafenib / lenvatinib > cabozantinib TKI's which are VEGFR inhibitors NTRK/RET inhibitors if suitable

Answer 226

Surgery resection is primary treatment- thyroidectomy Do no respond to radioactive iodine or conventional chemotherapy Two kinase inhibitors, vandetanib (multi-kinase inhibitor of VEGFR, EGFR, RET) and cabozantinib, are approved for advanced medullary thyroid cancer without predictive testing but reserved for patients with structural disease progression Pralsetinib and selpercatinib should be considered for RET mutant tumours.

Answer 227

Debulking surgery to remove tumour blocking the airway External beam irradiation therapy with radio-sensitizing chemotherapy Adjuvent radiotherapy in all cases Consider targeted therapies e.g. BRAF/MEKi

Answer 228

Diagnostic power of miRNAs in thyroid cancer has been evaluated by several groups. miRNAs not only can differentiate malignant tissues from non-malignant tissues, but also have differential expression in different stages of thyroid cancer. Assessment of serum levels of miRNAs is a practical non-invasive method for follow-up of patients after thyroidectomy.

Answer 229

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract with an annual incidence of approximately 10–15 cases per million. They usually present sporadically in older adults (median age 60–65 years) with slight male predominance. Strong female predilection is seen in paediatric SDH-deficient GIST.

Answer 230

Hereditary GIST - Germline variants in KIT or PDGFRA (5%)

Answer 231

GISTs present asymptomatically in 18% of cases, especially in cases of smaller tumours of the intestinal tract. These tumours are usually found incidentally on abdominal CT scans, during endoscopy, or during surgical procedures for other manifestations. Symptomatic patients may present with nonspecific symptoms of nausea, vomiting, abdominal distension, early satiety, abdominal pain, and rarely as a palpable abdominal mass. Larger tumours may cause obstruction of the gastrointestinal lumen leading to dysphagia, obstructive jaundice, or constipation, depending on the location of the mass.

Answer 232

Imaging - CT - MRI - PET Histology - Biopsy - IHC, normally positive for CD117 and/or DOG1- helps distinguish GISTs from other mesenchymal tumours Molecular - KIT and PDGFRA mutations can help diagnose - In KIT/PDGFRA wt GIST, SDHB to idenify SDH- deficient GIST - BRAF and NTRK variants can also be found - In quadruple-negative GIST (for KIT/PDGFRs/BRAF/SDH), an unrecognised underlying NF1 syndrome should be excluded

Answer 233

Tumour - Size: larger tumours increased risk - Mitotic rate: >5 mitoses per 50HPF - Location: Gastric GISTs better prognosis than intestine - Metastasis: worse prognosis Molecular - KIT mutated more aggressive than PDGFRA - KIT exon 9 have the worst outcome - SDH deficient tumours are less predictable

Answer 234

Localised: 95%. Metastasis - 84%. Distant metastasis - 52%.

Answer 235

SNVs: KIT, PDGFRA RNA: NTRK1/2/3

Answer 236

SDH Mutations: Pediatric GISTs often exhibit a deficiency in the succinate dehydrogenase complex, particularly SDH subunits (SDHA, SDHB, SDHC, SDHD). Loss of SDHB Expression: This is a hallmark of SDH-deficient GISTs, identified by immunohistochemistry. NF1 related deficiency KIT and PDGFRA variants not normally seen

Answer 237

Carney-Stratakis Syndrome: A hereditary condition characterized by the presence of GIST and paragangliomas due to germline mutations in SDH subunits. Carney Triad: A non-hereditary syndrome involving GIST, paragangliomas, and pulmonary chondromas, often associated with SDH deficiency. NF1- associated GISTs

Answer 238

80% of GISTs Lead to constitutive activation which activates downstream Ras/Raf/MAPK and the PI3K/AKT pathway

Answer 239

Most frequent, affecting the juxta-membrane domain. They are mostly caused by in-frame deletions within codon Gln550 and Glu560, missense mutations and duplications Deletions affecting codons 557–558 of exon 11 of the KIT gene have been reported in up to 28% of all GISTs and have been associated with high-risk tumors Repsond to imatinib

Answer 240

10% of cases Affecting extracellular domains Duplications of Ala502- Tyr503 These tumors are commonly located in the small bowel and are often associated with a more aggressive phenotype. Double dose Imatinib is recommended for these variants.

Answer 241

8-10% of GISTs Exon 12, 14 and 18 (most common) mutations Favourable prognosis Respond to treatment with Imatinib Often located in the stomach

Answer 242

Results in a distortion of the kinase activation loop, tilting the protein conformation in favour of the activated structure. Imatinib can only bind inactive form Resistant to treatment with imatinib Avapritinib is specifically designed to target D842V

Answer 243

Primary resistance- tumour progression within the first 6 months of treatment PDGFRA D842V Mutation- prevents imatinib from binding Wild type GIST: lacking both KIT and PDGFRA variants KIT exon 9 mutations: require double dosage, standard dose is insufficient

Answer 244

Secondary KIT mutations- usually occur in 12-36 months - These mutations typically occur in exons encoding the ATP-binding pocket (exon 13 and 14) or the activation loop (exon 17 and 18)- alter the binding site of the TKI, reducing its effectiveness e.g. V654A in exon 13 of the KIT gene. Alternative pathway activation: activation of the PI3K/AKT/mTOR pathway or the upregulation of other receptor tyrosine kinases.

Answer 245

Surgical excision of lesion Adjuvant therapy with imatinib 400 mg/day for 3 years for patients with a significant risk of relapse. KIT exon 9 mutation: adjuvant imatinib at a higher dose of 800 mg PDGFRA exon 18 D842V: avapritinib (specifically designed)

Answer 246

Standard second-line treatment is sunitinib. Regorafenib is the standard third-line therapy. Ripretinib is the standard fourth-line treatment.

Answer 247

Approximately 10–12% of all GISTs lack mutations in KIT and PDGFRA and are called wt-GISTs. Can be sub-classified in an SDH-competent and an SDH-deficient group SDH IHC used to help classify

Answer 248

NF1 mutant GIST - NF1 is an inherited, autosomal dominant disease - Approximately 7% of patients with NF1 develop GIST - somatic inactivating NF1 mutations have also been seen BRAF, KRAS and PIK3CA-Mutant GISTs - BRAF mutations (V600E) have been found in approximately 8–13% of wt-GISTs - mutually exclusive with KIT/ PDGFRA - Rare - BRAF/MEKi available ETV6-NTRK3 - Rare - NTRK inhibitors

Answer 249

Defect in the SDH complex (mitochondrial complex or succinate reductase) which is composed of 4 subunits SDHA, SDHB, SDHC and SDHD. The SDH enzyme is a key enzyme in the Krebs cycle and electron transport chain SDH-deficient GISTs usually occur in patients younger than 40 years of age, have a female predilection, occur in the stomach

Answer 250

KIT, PDGFRA: Imatinib PDGFRA D842V: Avapritinib NTRK Fusion: Entrectinib, loretrectinib BRAF: BRAF/MEKi (not NICE approved)

Answer 251

Tumours that develop in the muscle, bone, nerves, cartilage, tendons, blood vessels and the fatty and fibrous tissues. Named after tissue in which they originate. Include: - Soft tissue - Primary bone - GIST Commonly harbour gene fusions

Answer 252

Soft tissue tumours are a type of sarcoma and are very rare (<1% of all cancers). Largely benign with a very high cure rate after surgical excision. Soft tissue tumours are a therapeutic challenge as there over 100 histological subtypes. ~30% of soft tissue tumours have disease specific rearrangements; the rest can often have random complex karyotypes.

Answer 253

G banding - Rarely used but is possible - Difficult on FFPE as poor quality FISH - Used as standard - Quick, can be done on small amounts of tissue with low number of abnormal cells - but itnerpretation is difficult, partner not identified and can miss some rearrangements RT-PCR - Cheap and quick - Need to know partner to have correct primers NGS - Often used as well as FISH - High throughput, can detect partners - Poor quality RNA leads to high failure rate and longer TaT

Answer 254

Group of tumours aising from different tissues (including sarcomas) characterised by small, round, relatively undifferentiated cells, which range from benign to incredibly aggressive Appear ‘blue’ when H&E stained due to the high nuclei to cytoplasm ratio Most commonly seen in children so often fall under the umbrella of ‘paediatric tumours’ (but can be seen in adults) 10% have germline predisposition

Answer 255

Typically very difficult to classify due to the similarities in histology (lack of differentiation), demographic prevalence, clinical history and disease site Includes: Ewing sarcoma Rhabdomyosarcoma Synovial sarcoma Neuroblastoma Medulloblastoma Desmoplastic small round cell tumours Rhabdoid tumours Liposarcoma Inflammatory myofibroblastic tumour

Answer 256

Ewing sarcoma Round cell sarcoma with EWSR1::non-ETS fusions CIC-rearranged sarcoma Sarcoma with BCOR genetic alterations

Answer 257

Ewing’s sarcoma is a malignant tumor that grows in the bones or the soft tissue, such as cartilage. 6-8% of primary bone tumours It is most common in children and young adults. In rare cases, Ewing sarcoma occurs in adults.

Answer 258

Palpable mass: Most often in the long bones of the arms and legs, the pelvis, or the chest. It can also develop in the skull or the flat bones of the trunk. Lesion shows 'onion skin' Fever, weight loss, swelling (metastatic) The tumour often metastasises to the lungs and other bones. At the time of diagnosis, spread is seen in about one third of children with Ewing sarcoma.

Answer 259

Five year survival is ~75% 25% if metastatic at diagnosis Favourable prognosis if complete pathological response Prognostic role of STAG2, CDKN2A, TP53 variants being validated- rare

Answer 260

Future: Potential for use of ctDNA to detect EWSR1::FLI1 Potential for circulating tumour cells to detect CD99+ cells Likely to emerge in the coming years

Answer 261

Core needle biopsy Essential diagnostic criteria: - diffuse infiltrate of small round cell morphology - CD99+ by IHC- strong diffuse membranous staining Desirable criteria: - identification of FET:ETS fusion usually EWSR1 - EWSR1 rearrangement by FISH and NGS Imaging - MRI to detect solid tumour mass

Answer 262

EWSR1-FLI1 (85%)- t(11;22)(q24;q12) EWSR1::ERG (10%), Other EWSR1/FUS fusions (<10%) Fusion partner may have prognostic value so usually detected by EWSR1 break apart FISH, followed by NGS Additional mutations at diagnosis are rare

Answer 263

Transcriptional activating domain of EWSR1 and DNA binding domain of FL1 Producing an aberrant transcription factor that drives oncogenesis by dysregulating gene expression and promoting uncontrolled cell proliferation and survival.

Answer 264

FISH: EWSR1 rearrangement WGS Structural: EWSR1, NTRK

Answer 265

Local surgery/resection And/or Radiotherapy And Intensive multi-agent chemotherapy (good repsonse) Currently no targeted therapies available- difficult to target as fusion protein lacks enzymatic activity and lack obvious pockets for small molecule binding

Answer 266

Relapse is mostly systemic (71-73%), followed by combined (12-18%) and local (11-15%) relapse 5 year post relapse survival rate of 15-25%, with local recurrence faring better than systemic

Answer 267

Small round cell tumour Mesenchymal tumours typically associated with the skeletal muscle, , and approximately 50% of cases are diagnosed in the first decade of life.

Answer 268

The most common soft-tissue sarcoma of childhood, annual incidence of 4.5/1 million children. Accounts for 5% of malignancies in children

Answer 269

Embryonal rhabdomyosarcoma (ERMS) – 80% , best prognosis Alveolar rhabdomyosarcoma (ARMS) – 20%, unfavourable prognosis. Two rare subgroups recognized by WHO: spindle cell and pleomoprhic

Answer 270

Alveolar type: PAX3::FOXO1 t(2;13)(q35;q14), PAX7::FOXO1 (more favourable outcome compared to PAX3). Spindle cell: MYOD1 L112R (very poor prognosis) Embryonal type: RAS variants common but no recurrent chromosomal abnormalities

Answer 271

Histology - Small round cell morphology - Some skeletal muscle differentiation - Desmin+ by IHC Molecular - FOXO1 rearrangement by FISH and NGS Imaging

Answer 272

4.5 per million per year Lump/swelling, painless mass

Answer 273

Low-risk RMS five-year survival ~80%; high-risk RMS five-year survival ~20-30%

Answer 274

Small round cell tumour Rare, highly aggressive 5-10% of all soft tissue tumours and10-20% in young adults Age range 5-85, median age 35 years. Small proportion caused by LFS or NF1

Answer 275

5-year survival rate is as low as 36%.

Answer 276

1/3 occur in <20 years 77% before 50y Females more commonly affected

Answer 277

Painful mass usually near joints of arm, leg or neck. Initial slow growth often delays Dx. Aggressive growth invade adjacent bone 50% patients exhibit metastatic disease, of which 74-81% are to the lungs.

Answer 278

SS18::SSX1 (approx. 60% case) - t(X;18)(p11.2;q11) SS18::SSX2 (30%), SS18::SSX4 (<10%) SYT-SSX1 fusions have poorer prognosis- controversial

Answer 279

Surgery Chemotherapy B-catenin inhibitors, MTOR inhibitors, RTKs inhibitors (inhibit PDGFR), BCL2 and EZH2 inhibitors

Answer 280

Affects immature nerve cells (neuroblasts), typically arising in the adrenal glands or along the sympathetic nervous system. Most often affects children <5 years and rarely adults, more common in boys

Answer 281

Familial neuroblastoma – germline mutations in the ALK and PHOX2B The PHOX2B gene is important for the formation and differentiation of nerve cells. Deletion of regions of chromosome 1 and chromosome 11 are associated with neuroblastoma. ~ 25 percent have MYCN amplification- unclear clinical relevance

Answer 282

Small round cell tumour Medulloblastoma (MB) is one of the most common childhood malignant brain tumours. Originates within the brainstem or the cerebellum Although many patients now survive, can develop chronic health complications due to treatments

Answer 283

5 cases per million per year Headaches, poor academic performance, hydrocephaly Associated with Turcot syndrome, Gorlin syndrome

Answer 284

WNT (10%) - Muations affecting WNT pathway e.g. CTNNB1, DDX3X and SMARCA4 - low risk SHH (30%) - Mutations in SHH pathway e.g. PTCH1, SMO, SUFU - further classified into TP53 mut (very high risk) and TP53 wt (intermediate risk) Group 3 (20%) - MYC amplification - Intermediate to high risk Group 4 (40%) - PRDM6 overexpression - Low to intermediate risk

Answer 285

Small round cell tumour Tumors that grow in the abdomen and pelvic area of the body. DSRCT is very rare. DSRCT occurs most often in young white males between the ages of 10 and 30.

Answer 286

Often asymptomatic When the tumors get larger, symptoms can include: pain, nausea and vomiting diarrhea, constipation, swelling in the abdomen.

Answer 287

5 year survival- 15%

Answer 288

Characterised by the EWSR1::WT1 t(11;22)(p13;q12)

Answer 289

Surgery Chemotherapy Hyperthermic intraperitoneal chemotherapy (HIPEC): This treatment washes the inside of the abdomen with warm chemotherapy drugs- kills the tumor cells in the abdomen without exposing the rest of the body to the drugs, which can cause side effects. Radiation Therapy

Answer 290

Small round cell tumour Rare, aggressive type of childhood cancer that can start in the kidneys, soft tissues or CNS. Primarily affects infants and young children

Answer 291

Poor prognosis with median survival 18 months, 5 year survival 30%

Answer 292

Majority of RTs arise as a consequence of biallelic inactivation of SMARCB1 Can be detected by IHC, PCR, NGS - not specific to diagnosis 25-30% with rhabdoid tumour on brain have a germline variant in SMARCB1

Answer 293

Surgery, radiotherapy and chemotherapy Current preclinical trials looking at targeting of epigenetic proteins e.g. HDAC inhibitors, DNMT inhibitors (azacitadine)

Answer 294

Lipomas are benign tumour's composed of fat cells. Most common adipocytic neoplasm (and also the most common soft tissue neoplasm). Commonly have rearrangements of HMGA2 and rarely HMGA1

Answer 295

Small round cell tumour Rare type of cancer that develops in the adipose tissue, which can be divided into four main types: Well-differentiated liposarcoma (most common, 50%) Dedifferentiated liposarcoma (progresses from well-differentiated liposarcoma) Myxoid liposarcoma (more frequently found in limbs) 15-20% Pleomorphic liposarcoma (rare, fast-growing)

Answer 296

Most common liposarcoma Also known as atypical lipomatous tumor as these tumours show no potential for metastasis Characterized by MDM2 amplification Low grade

Answer 297

Well differentiated and de-differentiated: MDM2 amplification Myxoid: FUS-DDIT3 t(12;16)(q13;p11) or EWS-DDIT3

Answer 298

CCS is a malignant neoplasm typically involving deep soft tissue of the extremities in close proximity to tendons and aponeurotic structures. Very rare tumor of young adults with melanocytic differentiation.

Answer 299

The exact incidence is largely unknown, although occasional case series mention CCS comprising less than 1% of all soft tissue sarcoma

Answer 300

Hallmark is t(12;22)(q13;q12): EWSR1::ATF1- 90% of cases. A related variant translocation t(2;22)(q32.2;q12) involves EWSR1-CREB1 (6%).

Answer 301

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue malignancy EMC is a malignant mesenchymal neoplasm of uncertain differentiation characterized by abundant myxoid matrix. Chondrosarcoma usually refers to a cancer derived from cells that produce cartilage, however despite its name there is no convincing evidence that EMC has cartilaginous differentiation. Aggressive but good prognosis

Answer 302

Characterised by t(9;22)(q22;q12.2)- EWSR1::NR4A3 Small proportion have BP56-NR4A3 NR4A3 fusions present in >90% of EMCs and are not present in any other sarcoma- diagnostic

Answer 303

Clear cell RCC (ccRCC) – most common 75%-80% of the cases Papillary RCC (pRCC) – 15% of the cases – previously has been subdivided to type 1 and 2, which has now been removed in the new WHO 5th edition (2022). Chromophobe RCC (chRCC) – 5% of the cases TFE3 rearranged RCC TFEB rearranged RCC SDH deficienct RCC hereditary leiomyomatosis

Answer 304

Different RCC histological subtypes were associated with specific survival outcomes. Patients with ccRCC had significantly poorer survival than those with pRCC or chRCC (P = 0.0001 and P = 0.0008, respectively) TP53 poor prognosis in ccRCC, pRCC CDKN2A loss or PTEN mutation poor prognosis in chRCC

Answer 305

Uses molecular classifications more than orevious additions Changed clear cell papillary renal cell carcinoma to clear cell papillary renal cell tumour as there has been no evidence of metastasis in this indolent tumour

Answer 306

Renal cell carcinoma (RCC) accounts for 2% of all cancers globally and is the cause of 2% of cancer deaths. Slight male prevalence – M:F = 1.58:1 (2017).

Answer 307

Obesity Cigarette smoking Hypertension Acute kidney- papillary RCC. Patients on long-term haemodialysis due to end-stage renal disease develop renal cysts and have an increased risk of renal cancer (3–7%) Most are sporadic but there are herediatary syndromes associated with RCC

Answer 308

Haematuria (blood in the urine), loin pain, malaise, weight loss, anaemia (from depression of EPO) hypertension (due to the excess secretion of renin by the tumour). Approximately 5% of patients will have polycythaemia.

Answer 309

Most cases of RCC are strongly suspected by imaging. Suspicion of RCC should prompt laboratory examinations of serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio, lactate dehydrogenase, C-reactive protein (CRP) and serum-corrected calcium.

Answer 310

Used to classify subtypes rather than targeted treatments SNV: FH, BRAF, MET, VHL, SDHA, SDHB, SDHC, SDHD, TCEB-1 (ELOC), TSC1, TSC2 Structural: TFEB, TFE3 and NTRK

Answer 311

Derived from renal tubular epithelial cells 80% of all RCC. The cells have clear and occasionally eosinophilic cytoplasm Associated with biallelic VHL inactivation.

Answer 312

Inactivation of the VHL complex is the defining signature event in ccRCC. Normally del3p affecting one allele and inactivating intragenic mutations or promoter region methylation of the second VHL allele Also frequent gain of 5q, loss of 14q

Answer 313

Multifocal and/or bilaterar Early age of onset Suggests a hereditary cancer syndrome such as von Hippel–Lindau syndrome. 5% of cases

Answer 314

Papillary adenomas usually occur in the renal cortex, particularly in the capsular or subcapsular area. Virtually all papillary adenomas are clinically silent and discovered as incidental findings.

Answer 315

MET, EGFR, KMT2C, trisomy 7 and 17 and loss of Y No relevant diagnostic abnormalities according to WHO

Answer 316

The main goal in diagnosis of chRCC, is the differential diagnosis with oncocytoma. Chromophobe RCCs have diffuse positivity for cytokeratin 7 (CK7), whereas oncocytomas are negative or present focal positivity for CK7.

Answer 317

Known pattern of single-copy chromosome losses of chromosomes 1, 2, 6, 10, 13 and 17 PTEN, TSC1, TSC2 and MTOR, TERT promoter

Answer 318

VHL: associated with clear cell renal cell carcinoma, aid diagnosis and response to VEGF treatment MET: associated with papillary RCC. Potential repsonse to MET inhibitors FH: Classify as FH deficient RCC, Germline mutations in the FH gene are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). SDHA-D: Variants allow classification of Succinate Dehydrogenase (SDH) Deficient Renal Cell Carcinoma ELOC: ELOC rearranged RCC

Answer 319

TFE3 rearrangements are characteristic of TFE3 rearranged RCC, which is a distinct subtype of RCC, formally MITF Xp11 translocation RCC). These tumors typically occur in children and young adults but can also be found in older patients. TFEB rearrangements are associated with a rare subtype of RCC known as TFEB rearranged RCC. These tumors are also known as TFEB-amplified RCC

Answer 320

Tumour located in the periphery of the second-order bile ducts, ranging from segmental bile ducts to smaller branches of the intrahepatic biliary tree.

Answer 321

Intrahepatic CCA (iCCA): located in the periphery of the second-order bile ducts, Perihilar CCA: arises at the junction where the right and left hepatic ducts meet, Distal CAA: common bile duct

Answer 322

CA19-0 elevated Clinical symptoms are dependent on where the lesions originate in the biliary tree and are typically absent in early stage tumours. Nonspecific symptoms (such as weight loss, abdominal discomfort, and malaise). Jaundice, pruritus, and pale stool when the tumour is large enough to obstruct the biliary flow.

Answer 323

Rare adult tumour with a global incidence of <6 in 100,000, although incidence in rising Intrahepatic CCA is second most common primary hepatic malignancy behind hepatocellular carcinoma and accounts for 10-15% of cases (2). Higher incidence in south-east Asia (Thailand >80 in 100,000).

Answer 324

Obesity Smoking Hypertension IBS Primary sclerosing cholangitis Chronic biliary stones Chronic liver disease Family history

Answer 325

Prognosis is poor (5-year OS of <20%) due to late diagnosis and high rate of relapse

Answer 326

Blood test - CA19-9 raised - Elevated liver function tests Imaging - Ultrasound, CT, MRI Histology

Answer 327

SNV: IDH1 Structural: FGFR2, NTRK MSI- lynch syndrome suspected

Answer 328

iCCA - IDH1/2 mutations (20%) - BAP1 mutations (10–20%) - FGFR2 fusions (15%). dCCA KRAS (20%) SMAD4 (10–20%). Mutations in TP53 are observed in either type (30%). Loss of MMR (could be indicative of lynch)

Answer 329

IDH1 R132 variant: Ivosidenib (second line) FGFR2 fusion: Pemigatinib (relapsed) MMR loss/ MSI-high: Pembrolizumab

Answer 330

Surgery is currently the only curative treatment option Due to tumour heterogeneity, chemotherapy has poor effectiveness Radiotherapy is rarely used against this tumour type. Stage I-II - Surgery of possible - Adjuvent chemotherapy if non curative resection Stage III-IV - Unresectable - Chemotherapy: Cisplatin - Immunotherapy /targeted treatments

Answer 331

Tumour recurrence occurs in ~70% of patients Long-term survival can rarely be expected once tumour recurrence occurs because the recurrence means ‘systematic disease’

Answer 332

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases.

Answer 333

Pre-cancerous cirrhotic nodules with low-grade dysplasia, called low-grade dysplastic nodules (LGDNs). LGDNs subsequently develop into high-grade dysplastic nodules (HGDNs) that can transform into early-stage HCC (stages 0 and A) and progress into more advanced HCC (stages B and C).

Answer 334

906 000 people were diagnosed with liver cancer globally. 5-year survival rate of approximately 18%. age between 60 and 70 predominantly affects men.

Answer 335

Over 90% of HCC cases occur in the setting of chronic liver disease as a consequence of chronic infections with the hepatitis B virus (HBV) or hepatitis C virus (HCV), alcohol abuse or alcoholic steatohepatitis (ASH), and nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Obesity, diabetes, and smoking Haemochromatosis or hereditary tyrosinaemia type 1. HIV

Answer 336

Solid hepatic nodules ≥1 cm, especially in patients with liver cirrhosis trigger investigation Imaging Biopsy - IHC for glypican 3, HSP70 and Glutamine synthetase - All 3 markers allows diagnosis

Answer 337

NTRK- for NTRK inhibitors

Answer 338

Currently no mutations are used to predict therapeutic response (other than NTRK) TERT promoter (60% of cases) TP53 (30%) CTNNB1 (30%) ARID1A (10%)

Answer 339

A1ATD is characterized by low levels of serum A1AT and affects 1:1800 to 1:2000 live births. It is the most common genetic cause of liver disease in children and increases risk for cirrhosis and HCC.

Answer 340

Liver resection or transplantation is the main curative option (5 year survival 75-80%) Thermal ablation- radiofrequency ablation to injure the tumour through EM energy Systemic disease - Sorafenib and Lenvatinib- first line TKI - Regorafenib- second line TKI - Pembrolizumab

Answer 341

Histopathological subtypes are: Oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC). ESCC is the predominant subtype that usually arises from squamous epithelial cells of the oesophagus, whereas EAC originates from glandular cells present near the stomach and is believed to be largely related to acid exposure of the lower oesophagus.

Answer 342

EC is a highly aggressive, malignancy with over 400,000 deaths annually, worldwide. Both ESCC and EAC carry poor outcomes with a five-year overall survival rates of 15%

Answer 343

Smoking Alcohol Hot beverage drinking Poor nutrition

Answer 344

HER2- only approved biomarker TP53 (72%), ELMO1 (25%), DOCK2 (12%), CDKN2A (12%), ARID1A (9%), SMAD4 (8%) and PIK3CA (6%). Gain of KRAS (21%), HER2 (19%), EGFR (16%), CND1 (10%) and MET (6%) Loss of SMAD4 (34%), CDKN2A (32%) and ARID1A (10%) are found.

Answer 345

HER2 testing – trastuzumab PD-L1 testing - found in 35% to 45% of oesophageal cancers. Pembrolizumab MMR and MSI testing -Pembrolizumab.

Answer 346

Annual 723,100 deaths Recurrence occurs in up to 30–40% of patients within 5 years

Answer 347

Diet Smoking Alcohol EBV infection Family history

Answer 348

The strongest association is found in hereditary diffuse gastric cancer (CDH1) syndrome, in which approximately 80% of patients will develop gastric cancer. Others with a much lower risk include: Lynch, Hereditary breast and ovarian cancer (BRCA), Li-Fraumeni, Familial adenomatous polyposis, and Peutz-Jegher syndromes.

Answer 349

Subtype 1 (ARID1A+ type) is characterized by high ARID1A and PIK3CA mutations and is associated with favorable prognosis Subtype 2 (TP53+ type) harbors a highly recurrent TP53 mutation, is associated with poor prognosis Subtype 3 (CDH1+ type) is accompanied by a high CHD1 mutation and is associated with a poor prognosis

Answer 350

Often present with an upper endoscopy report performed for symptoms, including dyspepsia and reflux, Also with symptoms or signs that may indicate advanced disease, such as dysphagia, weight loss, gastrointestinal bleeding, anemia, and emesis.

Answer 351

Stage 1-3 Resectable: gastrectomy - Triplet chemotherapy Stage IV - Palliative resections - Endoscopic stents - Palliative chemotherapy - HER2+ - trastuzumab - PD-L1/MSI - pembrolizumab

Answer 352

Rare malignancy with worse prognosis compared to other cancers of the gastrointestinal tract.

Answer 353

11,390 new cases of small bowel cancer were estimated, with 2100 cancer-related death.

Answer 354

HER2 BRAF V600E dMMR/TMB

Answer 355

3-4.5/million annual incidence; 1% of all head and neck cancer Most common of minor salivary glands

Answer 356

Mean age range 50-60. Indolent and slow growing, with few symptoms 1/3 patients present at with T4 tumour Symptoms, when eventually occurring, may include facial nerve paralysis, oroantral fistulas, and nasal obstruction.

Answer 357

Biopsy - histological subtypes tubular, cribriform, solid - MYB IHC used - often followed up by sequencing - MYB::NFIB most common (80%) Test directory - MYB, NTRK

Answer 358

MYB rearrangements - MYB::NFIB (80% of cases) and MYBL1::NFIB (5%) - Rearrangements lead to deletion of 3’ UTR regions, disabling the regulatory activity of miRNAs and resulting in overexpression of MYB genes. Copy number - KIT gain: poor prognosis

Answer 359

Curative surgery 5-FU + CAP (cisplatin, doxorubicin, and cyclophosphamide) Radiotherapy

Answer 360

In the UK, around 220 people are diagnosed with adrenal gland cancer every year (ACC and phaeochromocytoma). ACC found in 1-2/million people (1). Commonly detected in fifth/sixth decades of life, but also a secondary peak in children <10 years

Answer 361

Smoking Oral contraceptives Germline predisposition (10%): LFS, lynch, FAP, MEN1

Answer 362

Patients can present with Cushing’s syndrome- symptoms can include central obesity, muscle weakness, easy bruising, fatigue, and depression. Generic symptoms relating to presence of a mass- abdo pain, tiredness, weight loss, nausea, and vomiting. Female patients can be affected by increased androgens: excess facial and body hair (hirsutism), baldness, acne, deepening of the voice, increased muscularity, and an increased sex drive Metastatic disease 40-60%

Answer 363

p53/RB - TP53 (most common) - RB1 - MDM2 Wnt pathway - APC - CTNNB1 - MEN1 CNVs - CDK4 gain - RB1 loss

Answer 364

TP53 SNVs and CNVs NTRK

Answer 365

IHC - Ki67- prognostic biomarker. - SF1- diagnostic - BUB1B and PINK1 strong poor prognosis predictors

Answer 366

Low risk: no mutation in TP53 and Wnt pathways, do not display whole-genome doubling. High risk: frequent TP53 and Wnt pathway gene mutations, numerous non-recurrent alterations with potentially whole-genome doubling.

Answer 367

Currently CT/MRI Evidence supporting the use of ctDNA - high level of detectable mutations in ctDNA

Answer 368

Stage I-III Complete surgical resection Stage IV - Systemic treatments - Mitotane- acts specifically in the adrenal cortex, disrupts mitochondrial membranes and cytochrome enzymes leading to cell death - Anti-VEGF agents disrupt tumour angiogenesis. - IGF-I inhibitors - CDK4/6 inhibitors- targets CDK4 gains - Very limited evidence to suggest targeted therapies are affective

Answer 369

The 5-year overall survival rate is 60–80% for tumours confined to the adrenal space 35–50% for locally advanced disease37-47% Potentially curable disease if tumour is completely excised with no angioinvasion. Stage IV ACC unlikely to survive>5 years.

Answer 370

7th most common cancer globally, accounting for an estimated 890,000 new cases Roughly 4.5% of all cancer diagnoses around the world) 450,000 deaths per year (roughly 4.6% of global cancer deaths).

Answer 371

Smoking (leading risk factor) Alcohol HPV- cause of 72% cases EBV Areca nut Genetic: fanconi aneamia

Answer 372

Most present with advanced HNSCC small proportion present with pre mlaignant lesions Some symptoms: non-healing ulcer, palpable mass, issues speaking/eating et

Answer 373

SNVs: CDKN2A, EGFR, TP53 CNVs: TP53, CDKN2A Structural variants: RET, NTRK

Answer 374

Biopsy/ FNA - Histology to determine squamous differentiation IHC - HPV status (use p16 as a marker) - Squamous markers: CK5, CK6, p63 Genetics - TP53, CDKN2A

Answer 375

Local resection Systemic therapy: - Chemotherapy (cisplatin) +cetuximab - Pembrolizumab/nivolumab- liscensed for use with >1% anti-PD-L1 IHC companion diagnostic Other trials: - HRAS inhibitor tipifarnib

Answer 376

Poor, median OS 10-15 months

Answer 377

Urothelial carcinoma (80-90%) Squamous cell carcinoma (1-2%) Adenocarcinoma (1%)

Answer 378

Formally known as transitional cell carcinoma Most common form of bladder cancer and starts in the urothelial cells in the bladder walls inner layer

Answer 379

10,300 new bladder cancer cases in the UK every year, and is the 11th most common cancer in the UK. More common in males and most common >85 years

Answer 380

Smoking Chronic irritations Chronic inflamation

Answer 381

Often asumptomatic Haematuria (blood in urine) Dysuria Increased frequency, urgency

Answer 382

NMIBC and MIBC. MIBC has a high mutational burden Luminal - Better prognosis - FGFR2/3 mutations Basal - Poor prognosis - TP53 mutations and DNA repair pathways - Respond to better platinum based chemotherapy

Answer 383

Cystoscopy CT scan/MRI

Answer 384

70% NMIBC - 60-70% reoccur 25% MIBC - 5 year survival is 78% - median survival 18 months

Answer 385

Low stage - Transurethral resection of the bladder (TUR-BT) - Intravesival BCG - Chemotherapy High stage - Radical cystectomy - Radiation therapy Erdafitinib- FGFR inhibitors in NICE development currently

Answer 386

Malignant neoplasm of mesothelial differentiation that arises from mesothelial lining cells of the pleura

Answer 387

Up to 30 cases/million people/year An estimated 28,000 - 43,000 people die from malignant pleural mesothelioma worldwide every year.

Answer 388

Strong association with asbestos exposure- latency period of 20 to > 40 years Ionizing radiation for treatment of malignancy (Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer)

Answer 389

Parietal, visceral, mediastinal or diaphragmatic pleura Shortness of breath, Chest wall pain, pleurisy, Cough, Weight loss, Occasionally asymptomatic when discovered at early stage.

Answer 390

Loss of BAP1 Loss of MTAP Homozygous deletion of CDKN2A

Answer 391

CDKN2A CN loss (NGS and FISH) NTRK

Answer 392

Pleural thickening/ pleural effusion on X ray IHC - Loss of MTAP and BAP1 - Homozygous deletion of CDKN2A - When used in combination, 84% sensitive, 100% specific for mesothelioma diagnosis

Answer 393

Most common treatment is chemotherapy alone Also surgery and radiation therapy

Answer 394

Epithelioid subtype (best prognosis) > biphasic > sarcomatoid / desmoplastic subtype (worst prognosis)

Answer 395

MEC is the most common salivary gland malignancy in children and adults, and the most common malignancy of the major and minor salivary glands.

Answer 396

2.5 to 3.0 cases per 100,000 individuals a year, wide age range from childhood to elderly

Answer 397

Possible association with HPV and ionizing radiation.

Answer 398

33% of patients are asymptomatic Firm or fixed tumour, occasionally largely cystic.

Answer 399

CRTC1::MAML2 t(11;19)(q21;p13)-80% of MECs Also CRTC3:MAML2

Answer 400

MAML2 rearrangements by FISH or NGS NTRK

Answer 401

CT, MRI IHC - Positive: Pancytokeratin, CK5/6, p63, p40, - Negative: S100, HER2, DOG1

Answer 402

Excellent prognosis, with approximately 98.8% 5 year survival rate in low grade and 97.4% in intermediate grade tumors. About 67% 5 year survival rate for high grade tumors

Answer 403

Conservative excision with preservation of the facial nerve- low and intermediate-grade Radical neck dissection is performed in patients with cervical node metastasis and T3 lesion. Adjuvant radiotherapy and chemotherapy might be considered for higher grade tumors

Answer 404

Approximately 10,500 new cases of pancreatic cancer each year in the UK (statistics from (1)) Tenth most common cancer in the UK.

Answer 405

21% one-year survival, 3% five-year survival, 1% ten-year survival Fifth commonest cause of cancer death in the UK and accounts for 6% of all cancer deaths, but pancreatic cancer incidence in on the rise.

Answer 406

95% exocrine tumours Most commonly adenocarcinoma 5% are pancreatic neuroendocrine neoplasms

Answer 407

Non-specific symptoms leading to late stage disease Symptoms: - Abdominal and back pain - Unexplained weight loss - Jaundice and itchy skin - Indigestion - Loss of appetite - Change in bowel habits and fatty stools - Bloating and feeling full quickly - Tiredness

Answer 408

Blood test - CA19-9 established biomarker for pancreatic ductal adenocarcinoma Imaging - CT - Endoscopic ultrasound - MRI Biliary brushing for cytology Resection of pancreatic cysts

Answer 409

hereditary pancreatitis and a PRSS1 mutation BRCA1, BRCA2, PALB2 or CDKN2A (p16) mutations, and one or more first-degree relatives with pancreatic cancer Peutz–Jeghers syndrome. Lynch syndrome

Answer 410

KRAS, TP53, CDKN2A, GNAS, SMARCB1, SMAD4 and RB1

Answer 411

10% of pancreatic cancer is hereditary HBOC (breast and ovarian)- 7% - BRCA1/2 FAMMM (Familial atypical multiple mole melanoma) - CDKN2A PJS (Peutz-Jeghers syndrome) - STK11 LFS (Li-Fraumeni syndrome) - TP53 FAP (Familial adenomatous polyposis) - APC Hereditary pancreatitis - PRSS1 and SPINK1 Lynch syndrome - MLH1, MSH2, MSH6, PMS2

Answer 412

NGS +/MLPA BRCA1 BRCA2 CDKN2A PALB2 CDK4 MLH1 MSH2 MSH6 PMS2 PRSS1 RABL3 STK11

Answer 413

BRCA1/2 - PARP eligibility NTRK- NTRK inhibitors MSI- lynch pathway

Answer 414

No But evidence shows that pancreatic has high HRD and that these may respond to PARP inhibitors These tumours also respond well to platinum based chemotherapy

Answer 415

First line - FOLFIRINOX Second line - oxaliplatin-based chemotherapy Resection only curative option but more than 50% are not eligible PARP inhibitors if BRCA variant Immunotherapy if MSI/MMR deficient

Answer 416

There is no NHS national screening program due to the rarity of pancreatic cancer, the costs of screening and the fact that screening isn’t currently reliable and accurate enough. High risk (family history) received feedback. Screening begins around age 40 and involves CT scans or endoluminal ultrasound test, and sampling of pancreatic juices every three years. This pancreatic juice is subjected to mutational analysis for KRAS, TP53 and CDKN2A variants. If variants are discovered, screening frequency is increased to annual screening.

Answer 417

Rare neuroendocrine neoplasms Phaeochromocytomas originate from chromaffin cells of the adrenal medulla. Paragangliomas occur in the paraganglia outside the adrenal medulla and can migrate to the head, neck and pelvis

Answer 418

1: Mutations of genes that affect hypoxic signalling, usually germline affecting VHL (15-20% of PPGL’s) and TCA-cycle (SDHx genes, 10-15% PPGL’s). 2. Tyrosine kinase cluster’- mutations of RET, NF1, HRAS, TMEM127. These mutations are found in 50-60% of PCC/PPGL’s and can be germline or somatic mutations. Lower risk of mets 3. Somatic mutations in the WNT-altered pathway (MAML3 oncogene fusions and CSDE1 mutations). Likely aggressive. Found in 5-10% of PCC/PPGL’s.

Answer 419

Von Hippel-Lindau (VHL), syndrome, MEN2, NF1, FH - 1/3 casees Familial PPGL, SDHA-related autosomal-dominant syndromes

Answer 420

Ranges from 0.4-9.5 per million per year 50-60 years age 10-20% occur in children

Answer 421

RET, NF1, VHL, TMEM127, SDHA, SDHB, SDHC, SDHD, SDHAF2, FH,

Answer 422

Many present with few symptoms or can be asymptomatic (25% cases) but mostly present with catecholamine excess Hypertension Other symptoms may include abdominal pain, constipation, weight loss, tremor, facial pallor, panic attacks, fatigue and seizures

Answer 423

SNVs RET NTRK

Answer 424

Essential: Neuroendocrine neoplasm arising from the adrenal medulla with consistent morphology Desirable: CT/MRI IHC: + tyrsoine hydroxylase, GATA3, synaptophysin -ve for S200, SOX10 SDHx to guide subsequent genetic testing Routine assessment of cell proliferation (mitotic count, Ki67/MIB-1 labelling index); Mitoses are often very rare or absent Measurement of all 3 metabolites of parent catecholamines (including 3-methoxytyramine along with metanephrine and normetanephrine levels.

Answer 425

ESE guidelines recommend monitoring for 10 years. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be monitored for life Biochemical tests yearly including chromogranin-A Imaging every 1-2 years

Answer 426

Metanephrine blockade (alpha/beta blockers), phenoxybenzamine Resection cyclophosphamide, vincristine and dacarbazine (CVD) chemotherapy, the most widely used regimen Clinical trials using olaparib with temozolomide

Answer 427

Risk of metastasis ranges from ~5 to 15% . 5yr survival rate for adults was 40-95%, and 98% in children ( Germline SDHB mutations confer the highest risk of metastasis, 5yr survival rate drop s to 36-92% for adults and 76% for children

Answer 428

Thymic cancer is a rare epithelial type of cancer arises from the thymus gland. Thymic epithelial tumours represent a heterogeneous group of rare malignancies that include: * thymomas *thymic carcinoma (account for ~20% of all thymus tumours) *thymic neuroendocrine tumours

Answer 429

Thymic carcinomas are much less common than thymomas, accounting for 14–22% of all thymic epithelial tumours. They are more aggressive in terms of recurrence and metastasising than thymomas, and are more resistant to chemotherapy, they are not usually detected until it has become invasive.

Answer 430

Annual incidence ranging from 1.3 to 3.2 per million. Mean age at diagnosis is 50–60 years of age

Answer 431

No environmental or infectious factors have been demonstrated to play a role in the pathogenesis of thymic epithelial tumours. Genetic risk factors, such as multiple endocrine neoplasia 1 (MEN1), may influence the development of thymomas (but this is less common in thymic carcinoma)

Answer 432

1/3 are asymptomatic *Coughing * Chest pain * Shortness of breath * Difficulty swallowing * Fatigue * Weight loss

Answer 433

CT/MRI IHC - CD117/KIT and CD5+ determine thymic origin - EGFR/HER2 overexpression

Answer 434

Poorly understood Thymic squamous cell carcinoma - Loss of chromosome 16p Translocations: Thymic mucoepidermoid carcinoma (with MAML2 gene fusion) NUT carcinoma (with NUTM1 gene fusion) A subtype of clear cell carcinoma (hyalinizing clear cell carcinoma, with EWSR1 gene fusion) SNVs: TP53, CDKN2A, KIT and PTEN.

Answer 435

KIT - Common mutations are L576P, D820E - Predicts repsonse to imatinib

Answer 436

Chemotherapy: - better response for thymomas than carcinomas - Cisplatin based regimens Immunotherapy: - ICIs; normally high PD-L1 expression - clinical trial of pembrolizumab. Other options: - Imatinib- KIT mutated - Sunitinib is an option as 2nd line treatment (independent from KIT status) - Everolimus (mTOR inhibitor) may represent an option for refractory tumours

Answer 437

Recurrences of thymic epithelial tumours are not uncommon (∼10%–15% of all-stage resected tumours

Answer 438

Cancer of unknown primary CUP is defined as metastatic cancer in the absence of a clinically detectable anatomically defined primary tumour. Often challenging because it tends to be aggressive and has often spread to many parts of the body before it is found (often lymph nodes, liver, lung, peritoneum (lining of the bowel), or bone)

Answer 439

3-5% of all newly diagnosed cancers 1 year survival 10-20%

Answer 440

Smokers are at risk of developing CUP and this risk correlates with the level of tobacco exposure Type 2 diabetes autoimmune disorders (Human papillomavirus (HPV) High body mass index, waist circumference, low socioeconomic status and black ethnic background may be additional risk factors

Answer 441

Depends on which organs spread to. Can include: -Swollen, firm, non-tender lymph nodes - A mass in the abdomen -Shortness of breath -Bone pain

Answer 442

NTRK WGS- when standard of care is exhausted

Answer 443

Morphological pattern- differentiate between epithelial, round, spindle-shaped and anaplastic cancers to identify the pattern of tissue organisation regarding entity and tissue of origin. Immunohistochemistry (IHC)- markers to help determine tissue lineage MSI testing CT/MRI- locate primary tumour Genetics - Structural can aid diagnosis - gene expression profiles

Answer 444

Two common diagnostic difficulties in CUP work-up are poorly differentiated or undifferentiated cancer and better differentiated carcinoma, especially adenocarcinoma, without an obvious primary site. Can't offer a molecular panel if do not know the primary

Answer 445

NTRK inhibitiors MSI-H/TMB- Pembrolizumab If no druggable target, treated with empiric therapy

Answer 446

Immunotherapy is the utilisation of cellular immune responses to target cancer cells and ultimately trigger apoptosis of these cells

Answer 447

Tumour microenvironment consists of the environment surrounding cancer cells and the crosstalk and interplay between the tumour and surrounding cells. These surrounding cells can be cells of the innate and adaptive immune system as well as local cells of the affected organ. This is important for the use of immunotherapies as the presence of immune cells is required

Answer 448

1.Stroma 2. Carcinoma-Associated Fibroblasts (CAFs) 3. Tumour-Associated Macrophages (TAM) 4. Cytokines

Answer 449

The stroma comprises various non-cancerous cells, extracellular matrix (ECM), and signalling molecules surrounding the tumour cells. It provides structural support to the tumour. Increased collagen can create physical barriers that impede immune cell infiltration and drug delivery

Answer 450

They secrete growth factors, cytokines, and ECM components that support cancer cell survival, proliferation, and invasion

Answer 451

Can exhibit pro-tumour or anti-tumour functions depending on their activation state. In the TME, TAMs often adopt an immunosuppressive phenotype, promoting tumour growth and metastasis. They secrete cytokines, such as TGF-β and IL-10, which suppress the activity of cytotoxic T cells and natural killer (NK) cells, thereby facilitating immune evasion by cancer cells.

Answer 452

Certain cytokines, such as TGF-β, IL-10, and IL-6, have immunosuppressive properties and can inhibit the activity of immune cells within the TME. Cytokines like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) promote angiogenesis, facilitating the formation of new blood vessels to supply nutrients and oxygen to the growing tumour.

Answer 453

There is a significant infiltration of immune cells, particularly cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. These immune cells are actively engaged in recognizing and attacking cancer cells, contributing to an anti-tumour immune response. These tumours are more repsonsive to immunotherapies. However, even in hot TMEs, there may be immunosuppressive elements like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)

Answer 454

There is a limited infiltration of immune cells, particularly cytotoxic T lymphocytes and NK cells. Low levels of inflammatory cytokines and chemokines. Tumours often resistant to immunotherapies

Answer 455

Tumour Heterogeneity: varying molecular characteristics which respond differently to immunotherapy Resistance Mechanisms: upregulation of alternative immune checkpoints, alterations in antigen presentation, and recruitment of immunosuppressive cells. Physical Barriers: The dense extracellular matrix (ECM) and abnormal tumour vasculature within the TME can physically impede the infiltration of immune cells and the delivery of immunotherapeutic agents to the tumour site.

Answer 456

Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) are co-inhibitory receptors expressed on the surface of T cells to negatively regulate T cell-mediated immune responses. These receptors bind ligands expressed by host cells This is normal function of the immune system to prevent an inappropriately excessive immune response which may be harmful cancer cells can use checkpoint inhibitor proteins to inhibit immune surveillance

Answer 457

Drugs to attach to the co-inhibitory receptors on T cells/tumour cells, blocking the immune inhibition, thereby reactivating the immune response against tumour cells. Examples are anti-CTLA-4, anti-PD-1, and anti-PD-L1

Answer 458

Ipilimumab - Melanoma, RCC, colorectal, NSCLC etc CTLA-4 is constitutively expressed in regulatory T cells

Answer 459

Pembrolizumab - approved in 2014 - Melanoma, NSCLC, RCC, hodgkins lymphoma, endometrial Nivolumab - approved in 2014 - Melanoma, NSCLC, RCC, hodgkins lymphoma, colorectal etc

Answer 460

Atezolizumab - Bladder, NSCLC, breast

Answer 461

Cancer antigens produced as a result of mutations and presented by major histocompatibility complex (MHC) proteins on the surface of cancer cells This targets those cells for destruction by the immune system

Answer 462

PD-L1 IHC TMB MMR/MSI

Answer 463

Once immune checkpoints are blocked and T cells are able to target cancer cells, they still need to different the tumour cells from normal cells. The more neo-antigens present the easier this is The higher number of mutations present (both driver and passenger), the more likely mutant proteins will be expressed at the cell surface and are therefore more likely to repsond to immunotherapy Tumour mutational burden is a measure of the number of mutations present in a cell and correlates to response

Answer 464

TMB is expressed as the number of acquired mutations per megabase (mut/Mb) of sequenced DNA commonly assessed by next generation sequencing (NGS) in the tumour genome.

Answer 465

Gold standard TMB measurement is derived from WGS/WES- tissue availablity and long turnaround times means this is using routinely Smaller targeted panels that are already in widespread use have generally been used to measure TMB including, TSO500 from Illumina (1.33Mb, 523 genes) and Foundation One CDx from Foundation Medicine (0.8Mb, 324 genes), the latter which is FDA approved as a companion diagnostic for the ICI drug pembrolizumab (if (≥10 mut/Mb)

Answer 466

Sample issues - Low TC will underestimate TMB - Low quality of sample, particularly from FFPE samples may cause an overestimation of TMB Analytical - Using small panels reduces confidence in score - High variability in BI processes- what types of variants are included

Answer 467

TMB values vary widely between tumour types so it is difficult to set a cut off that suits all- likely each tumour type needs different TMB is not a sole predictor neo-antigenicity : The recognition of an antigen as a foreign entity will differ depending on the mutation profile present- indels and structural variants more likely than SNVs Doesn't consider TME- are there a high number of activated T cells (Hot TME)

Answer 468

Inactivation of this complex is associated with reduced DNA replication fidelity, leading to microsatellite instability (MSI) and the mutator phenotype often seen in colorectal and other cancers. Again likley to result in neo-antigens (correlates but is not an independent predictor as dependent upon mutation profile)

Answer 469

IHC - testing for loss of expression of the key mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 MSI - fragment analysis of microsatellite markers

Answer 470

To activate the immune system to recognize and combat cancer cells, prevent tumour growth, recurrence, or metastasis, and enhance the immune system’s capacity to eliminate cancer cells It involves eliciting an immune response by targeting specific tumour-associated antigens (TAAs), which are proteins expressed by cancer cells. A further aim of cancer vaccines is to induce a memory response, allowing for a more effective immune response upon subsequent encounters with tumour cells.

Answer 471

Prophylactic vaccines prevent cancer in high-risk populations, while therapeutic vaccines treat individuals already diagnosed with cancer

Answer 472

They use immune cells, such as dendritic cells, to stimulate an immune response against cancer cells by collecting from a patients blood or tumour, activating, and expanding these cells in a lab and reintroducing them into the patient’s body There are two approaches: Autologous vaccines utilize the patient’s own tumour cells, ensuring antigen compatibility but at the expense of increased costs and time requirements. Allogeneic vaccines, while lacking personalization, present a time-saving advantage.

Answer 473

Dendritic Cell Vaccines are collected from the patient’s blood or generated in the laboratory. They are then matured and activated using immune-stimulating molecules or tumour specific antigens (TSAS). The loaded DCs are administered back to the patient. These DCs migrate to lymphoid organs, where they interact with immune cells, such as T cells, B cells, and NK) cells. The DCs present the tumour antigens to CD4+ helper T cells and CD8+ cytotoxic T lymphocytes (CTLs), leading to their activation. The activated T cells provide help signals to other immune cells, enhancing the immune response against tumour cell, engaging both the innate and adaptive immunities and leading to the development of immunological memory in the case of tumour relapse.

Answer 474

Cancer cells are collected from the patient’s tumour or established cancer cell lines. These cells are inactivated or genetically modified to reduce their ability to grow and cause disease. When administered back to the patient, the whole cells are recognized by various immune cells, including DCs, macrophages, and NK cells, triggering an immediate non-specific inflammatory response. The activated immune cells, in turn, process the tumour antigens, present them to T cells, and initiate an immune response. CD4+ helper T cells provide help signals to other immune cells, while CD8+ CTLs recognize and eliminate tumour cells expressing the presented antigens. Whole-cell cancer vaccines also aim to induce a memory response for enhanced immune protection against tumour recurrence.

Answer 475

BCG became the first approved whole-cell vaccine for cancer therapy in 1990, specifically for bladder cancer, and was approved by the FDA in 1998

Answer 476

They involve the administration of peptides derived from TAAs, which are taken up by antigen-presenting cells (APCs) and presented to T cells, leading to an immune response

Answer 477

These vaccines deliver DNA or RNA encoding TAAs, which are taken up by cells to produce the antigens, then processed and presented by APCs to activate T cells.

Answer 478

iPSCs are differentiated into tumour microenvironment-specific cells expressing antigens, which activate immune cells and initiate a robust immune response upon administration.

Answer 479

The modified virus interacts with immune cells, including DCs, macrophages, and NK cells, triggering an inflammatory response and the release of pro-inflammatory cytokines and chemokines. The virus particles are phagocytosed by immune cells, and the TAAs expressed by the virus or delivered to infected cells are processed and presented to T cells. CD8+ CTLs recognize the presented TAAs, leading to their activation and expansion.

Answer 480

To enable a more effective immune response upon subsequent encounters with tumour cells

Answer 481

Viruses used as a vector to target and kill cancer cells, including natural and genetically modified viruses that reproduce in cancer cells without harming healthy cells Their ability to specifically bind and infect cells, replicate using cellular machinery, and lyse host cells, releasing new viruses to infect more cells

Answer 482

By provoking an inflammatory response and triggering an immune response against cancer cells, potentially turning the TME from a 'cold zone' to a 'hot zone'. When the cancer cells are lysed, they release tumour-associated antigens (TAAs), cytokines, and other molecules that promote an adaptive immune response and activate various immune cells.

Answer 483

Can pass the blood brain barrier

Answer 484

- ‘suicide gene’: Suicide gene therapy involves delivery of a gene which codes for a cytotoxic product or a gene which has the ability to correct mutated proapoptotic genes, inducing apoptosis - Cytokines: e.g. TGF-β are known to play a key role in the TME of tumour cells, and targeted delivery may alter the balance against tumour cells. Can be toxic - Genes that inhibit angiogenesis resulting in oxygen starvation in the tumour. - Sodium-iodide symporter (NIS) gene to the viral genome. When combined with radioiodine therapy it allows local radiotherapy of the tumour, as used to treat thyroid cancer.

Answer 485

The patient's immune system, which tries to deactivate the virus, especially after intravenous injection. It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy.

Answer 486

Using non-common human pathogens, coating the virus with polymers, or hiding the virus inside macrophages.

Answer 487

T-VEC, a genetically engineered oncolytic herpes simplex virus type 1, approved in 2015 for treating metastatic melanoma.

Answer 488

Monoclonal antibodies are identical clones of an antibody used to target a specific antigen epitope. Their use as a cancer therapeutic is in selectively identifying a specific cell as a target rather than a broad response which may affect all cells

Answer 489

Some cancer types are characterised by overexpression/inappropriate receptor signalling pathway activation which may cause uncontrolled growth. Use of monoclonal antibodies against these receptors or their ligands can bind and block these signalling pathways fuelling tumour growth. An example of receptor blocking is HER2 positive breast cancer which can be treated with Herceptin (trastuzumab).

Answer 490

The specific antigen binding fragment (Fab) of the monoclonal antibody identifies the region of interest, while the Fc domain binds NK cells which perforate and kill the target cell. An example of this is Rituximab, an anti CD-20 monoclonal antibody which is used in the treatment of CD-20 positive leukaemias. CD-20 is abundantly expressed on cell surface of mature B-NHL cancer cells while immature naïve B cells do not, theoretically allowing the maturation of normal functional B cells while targeting malignant B cells.

Answer 491

Mabs bearing cytotoxic drugs covalently bound via a chemical linker and can be defined as prodrugs Serves as targeted delivery system to the tumour expressing the antigen/target recognized by the antibody

Answer 492

CAR-T cells are engineered synthetic T cell receptors that redirect lymphocytes to recognize and eliminate cells expressing a specific target antigen, independent from the MHC receptor.

Answer 493

The four main components of a CAR are: Extracellular target antigen-binding domain. Hinge region. Transmembrane domain. Intracellular signalling domains.

Answer 494

The antigen-binding domain confers target antigen specificity and is derived from the variable heavy (VH) and light (VL) chains of monoclonal antibodies, forming a single-chain variable fragment (scFv) that targets extracellular surface cancer antigens.

Answer 495

The hinge region extends the binding units from the transmembrane domain, providing flexibility to overcome steric hindrance and allowing the antigen-binding domain to access the targeted epitope.

Answer 496

The transmembrane domain anchors the CAR to the T cell membrane and is usually derived from natural proteins like CD3ζ, CD4, CD8α, or CD28.

Answer 497

Intracellular signalling domains transmit activation signals. They determine the generation of the CAR, classified into first (CD3z only), second (one costimulatory domain + CD3z), or third generation (multiple costimulatory domains + CD3z).

Answer 498

The main challenges include: Antigen escape. On-target off-tumour effects. CAR-T cell trafficking and tumour infiltration. CAR-T cell-associated toxicities. CAR immunogenicity.

Answer 499

Antigen escape is the development of tumour resistance by the tumour downregulating the target antigen, preventing recognition by the T cells. Cancer cells may also show hetergoenity where not all cells express the same antigen, preventing all cells being targeted It can be countered by targeting multiple antigens using either dual CAR constructs or tandem CARs.

Answer 500

On-target off-tumour effects occur when CAR-T cells target antigens expressed on both tumour and normal tissues, leading to toxicity. This can be mitigated by targeting tumour-restricted post-translational modifications.

Answer 501

In solid tumours, it can be challenging for the CAR-T cells to access the tumour cells due to physical barriers e.g. stroma or the TME. Strategies to overcome this include: Local delivery of CAR-T cells. Expressing chemokine receptors on CAR-T cells. Removing physical barriers like tumour stroma. Combating the immunosuppressive tumour microenvironment.

Answer 502

CRS is a result of excessive cytokine release by activated CAR-T cells, managed primarily with IL-6 receptor blockade using tocilizumab and corticosteroids.

Answer 503

Strategies include combination immunotherapy, armored CARs, and engineering CAR-T cells to secrete pro-inflammatory cytokines or express cytokine receptors.

Answer 504

ICANS is characterized by elevated cerebrospinal fluid cytokine levels and blood-brain barrier disruption, managed with corticosteroids

Answer 505

Toxicities can be ameliorated by altering CAR structure, reducing antigen binding domain specificity, modifying hinge and transmembrane regions, and using different costimulatory domains

Answer 506

TCR-T cells are engineered T cells with exogenous T cell receptors directed towards specific tumour antigens, capable of targeting peptides from both intracellular and extracellular proteins

Answer 507

Advantages include less cytokine-induced toxicity and the ability to target intracellular and extracellular proteins presented by HLA molecules Disadvantages include the requirement for intact antigen processing and presentation machinery and potential suppression by immunomodulatory factors within the tumour microenvironment.

Solid Tumours Flashcards

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