08 - Stratified Medicine

Question 1

Name an approved drug for use in Breast Cancer

Answer 1

1) Herceptin - only used in HER2 positive cells (over expressing the HER2 receptor)
2) PARP inhibitors - one for BRCA1 / BRCA2 mutation positive BR/OC patients

Question 2

Name an approved drug for use in NSCLC

Answer 2

Gefitinib - a Tyrosine Kinase Inhibitor (TKI).

approved by NICE to treat patients positive for EGFR activating mutations in the EGFR kinase domain (axons 18,19,21)

Question 3

Name an approved drug for use in Malignant Melanoma

Answer 3

Vemurafenib - for BRAF V600E positive patients

Question 4

Name an approved drug for use in Cystic Fibrosis

Answer 4

1) Ivacaftor - for patients homozygous for G551D (or comp. het for other gating mutations)
2) Orkambi (Ivacaftor + Lumacafter) - licenced by recently rejected by NICE for treatment of patients with F508del homozygous

Question 5

Name an approved drug for use in CML

Answer 5

Imatinib. NICE recommends this ‘wonder drug’ for Ph+ CML.

TKI which inhibits the kinase activity of ABL1 in BCR-ABL

Question 6

Name an approved drug for use in APML (Acute promylocytic leukaemia)

Answer 6

ATRA - all trans retinoic acid.
APML associated with the t(15;17) PML-RARA translocation.
RARA - retinioic acid receptor alpha.
ATRA is a derivative of Vitamin A which can bind to the mutation RARA receptor - which encourages maturation of the pro myeloid cells into mature cells (which then die)

Question 7

what is ‘stratified medicine’

Answer 7

targeting treatment according to characteristics of a shared group (use of biomarkers to split patients into cohorts for treatment)

Question 8

What is HER2? What does it do? What is its relevance to breast cancer and why target it?

Answer 8

> HER2 - human epithelial growth factor receptor 2
tyrosine kinase encoded by ERBB2
amplification of the ERBB2 gene is found in 20-30% of early stage breast cancer
HER2 +ve breast cancer are associated with more aggressive phenotype

Question 9

How does Herceptin work?

Answer 9

Herceptin = monoclonal antibody binds to HER2 and inhibits its action (blocks liana binding site)

Question 10

What new drugs are in development for breast cancer

Answer 10

> TDM1 - combines Herceptin with DM1 (potent cytotoxic agent)
TDM1 binds to HER2 and blocks it.
when HER2 internalised and marked for degradation, the TDM1 is also degraded BUT importantly, the DM1 agent is then released (only in HER2 +ve cells) and effectively kills the cells from within (via microtubule arrest)

note: Herceptin is also known as Trastuzumab - which is the T in TDM1

Question 11

What drug is used in platinum sensitive ovarian cancer in patients with BRCA1/2 mutations

Answer 11

Olaparib - PARP inhibitor

Question 12

What is the significance of KRAS testing in regards to colorectal cancer?

Answer 12

> at time of diagnosis, 20-50% of CRC patients have metastatic disease. Even 50-60% of those with early stage CRC who have surgery, develop metastatic disease
KRAS activating mutations are found in 50-70% of metastatic CRC
Drugs are available for treatment [Panitumumab and Cetuximab] for patients with metastatic disease BUT they do NOT work well for patients with KRAS activating mutations.
NICE recommends use of these drugs ONLY if patient has wild type KRAS

Question 13

What is the relevance of the DPYD gene

Answer 13

DPYD encodes the DPD enzyme, which plays a role in the metabolisms of fluoropyrimidines.
DPD enzyme deficiency occurs in approx 5% population  and is associated with severe fluoropyrimidie related toxicity
Several variants (SNPS) are associated with absent of reduced DPD enzyme activity and thus confer risk of a severe and even fatal response to fluoropyrimidie

Question 14

Name 2 DYPD variants which are associated with severe response to fluoropyrimidie.

Answer 14

> DYPD2a (c.1905+1G>A)
DYPD13 (Ile560Ser)

both lead to absent DPD gene activity so het carriers = 50% activity