Breast cancer

Question 1

Groups of genetic derangement seen in breast carcinomas

Answer 1

Hormone receptor pathways: ER/PR/AR

Growth factors: HER2, FGFR1

Cell cycle regulators: Cyclin D1, CDK4, CDK6, RB1, TP53

PI3K pathway: PI3K/AKT/mTOR

Question 2

Mutations in breast carcinoma conferring secondary resistance of hormone therapy

Answer 2

ESR1 mutations involving the ligand-binding domain

ERBB2-activating mutations

NF1 loss of function mutations

Alterations in other MAPK pathway genes (EGFR, KRAS)

Alterations in ER transcriptional regulators (myc, CTCF, FOXA1, TBX3)

Question 3

The most common recurrent molecular alterations across all breast cancers involve. . .

Answer 3

TP53, PIK3CA and GATA3.

Question 4

Frequency of PIK3CA mutations in luminal type breast carcinomas

Answer 4

Luminal A: 45%

Luminal B: 29%

Question 5

Neoplasm-defining genetic features in breast carcinoma

Answer 5

1. CDH1 loss of function (lobular carcinoma)
2. ETV6-NTRK3 translocation / t(12;15) (secretory carcinoma)
3. MYB-NFIB translocation / t(6;9) (adenoid cystic carcinoma)

Question 6

Frequency of PIK3CA mutations in HER2-enriched tumors

Answer 6

39%

Question 7

Activating ESR1 mutations

Answer 7

Most commonly D538G and Y537S.

Can develop in the setting of estrogen deprivation therapy.

Seen in 35-40% of hormone-resistant ER-positive bresat cancer.

Question 8

Targeted CDK4/6 inhibitors

Answer 8

Palbociclib, ribociclib, abemaciclib

Act upstream of pRb. Now routinely in use in clincal practice for ER-positive breast carcinoma.

If the malignancy is RB1 mutated, there will be resistance fo these therapies.