Breast and Endometrial Cancer

Question 1

What are common mutations in breast cancer?

Answer 1

p53
PIK3CA (IP3 active subunit)
GATA3 (TF)
MAP3KI (JNK and ERK activated)
MLL3
BRCA1/2 (tumor suppressor)

Question 2

How much does mastectomy reduce BRCA2 risk?

Answer 2

90%

Question 3

When are GnRH modulators useful in breast cancer?

Answer 3

Prementopausal

No effect in postmenopausal: already low E

Question 4

When are aromatase inhibitors useful in breast cancer?

Answer 4

Postmenopausal

Not used in premenopausal

Question 5

What is a SERD?

Answer 5

Selective Estrogen Receptor Downregulator

Question 6

What is Fulvestrant MOA/AE?

Answer 6

MOA: SERD
ER+ breast cancer in postmenopausal women
pure estrogen antagonist: blocks!
prevents DIMERIZATION of E receptor

*Monthly IM injection

AE: 
   menopause caused: no more E
   NVD
   Hot flashes
   HA

Question 7

What are SERMs?

Answer 7

Selective Estrogen Receptor Modulators

Question 8

What is Tamoxifen MOA, AE?

Answer 8

MOA:
ER modulated: - breast, +endo/bone

*Daily PO

AE: 
   *endometrial cancer risk
   TERATOGENIC
   RETINAL degeneration
   DVT, stroke, PE

Question 9

What is Raloxifen MOA, AE?

Answer 9

MOA:
ER modulated: - breast, +bone

*Monthly IM

AE: 
    *no endometrial effect
   TERATOGENIC
   RETINAL degeneration
   DVT, stroke, PE

Question 10

What is Toremfene MOA, AE?

Answer 10

MOA: tamoxifen derivative
ER modulated: - breast, +bone +endo

*Daily PO

AE: 
   QT prolongation
   *endometrial cancer risk
   TERATOGENIC
   RETINAL degeneration
   DVT, stroke, PE

Question 11

What are aromatase inhibitor drugs?

Answer 11

ER+ women tx with:
Anastrozole: steroid
Letrozole: steroid
Exemestane: non-steroidal

Question 12

Aromatase inhibitor MOA?

Answer 12

Prevent conversion of T to E2 by blockcin CYP19A1 (aromatase)
Steroids: irreversible
Non-steroid: reversible

Question 13

What aromatse inhibitors cause cataracts?

Answer 13

Steroids:
Anastrazole
Letrozole

Question 14

What are aromatase inhibitor AEs?

Answer 14

Hot flashes
NVD
Hair thinning: adrenal and thyroid decreased
Arthralgia

Question 15

What is a genetic predictor of tamoxifen effectiveness?

Answer 15

CYP 2D6: tamoxifen is metabolized by CYP2D6, so if no CYP2D6 this prodrug will not work as well

Question 16

Tx summary for ER+ tumors?

Answer 16

Decrease Estrogen Fx with:
SERD
SERM
Aromatase Inhibitor

Question 17

What are HER2 antibody drugs?

Answer 17

Trastuzumab
Pertuzumab
Lapatinib: TK inhibitor

Question 18

Trastuzumab MOA and AE? (7 BBWs?)

Answer 18

MOA:
Ab to HER2 receptor

AE: 
   BBW:
        1. cardiomyopathy
        2. infusion reaction
        3. pregnancy
        4. ventricular dysfunction: QT prolongation
        5. ARDs HS Rx
        6. Respiratory
        7. liver dysfunction
   HS rx
   GI: NVD
   Blood dyscrasia
   Fatigue
   Edema
   Rash
   Wt gain
   Dizziness
    URTIs
   Pharyngitis

Question 19

Ado-trastuzumab emtansine MOA and AE?

Answer 19

MOA:
ab to HER2, cytotoxic drug attached (DM1)

AE:
Same as trastuzumab: no lung

Question 20

Pertuzumab MOA and AE?

Answer 20

MOA:
HER2 dimerization blocker (like ER/Fulvestrant for HER2)

AE: 
     BBW: PREGNANCY
     Leukopenia/Neutropenia
     HS
      GI: NVD
     Blood, fatigue, alopecia

Question 21

Lapatinib MOA and AE?

Answer 21

MOA:
HER 2 TK inhibitor (ERB1/ERB2 from HER1/2)

AE: 
    BBW: LIVER disease increases levels, no CYP
    LUNG: pneumonitis
    QT prolongation
    Hand-Foot syndrome
    normal other stuff: blood, leuko/GI

Question 22

Goserelin MOA and AE?

Answer 22

MOA:
GnRH agonist: castration

AE:
Bone thinning: low E
Normal stuff

Question 23

Everolimus MOA and AE?

Answer 23

MOA: ER+, HER2- tumors
mTOR inhibitor
binds FKBP-12 and complexes with mTOR
blocks protein synthesis, proliferation, angiogen.

AE: 
     CYP inhibitor
     BBW: opportunisitc infections
     BBW: secondary malignancy
     pneumonitis
      blood
      HYPERGLYCEMIA, lipidemia, TGs too
     Creatinine increased
      LFTs increased
      NVD, constipation
    *Monitor liver and kidneys