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1

anastrozole

aromatase inhibitor: REVERSIBLE (non-steroidal)
Tx: breast CA

2

exemestane

aromatase inhibitor: IRREVERSIBLE (steroid structure)
Tx: breast CA

3

letrozole

aromatase inhibitor: REVERSIBLE (non-steroidal)
Tx: breast CA

4

aromatase inhibitors

oral daily
block CYP19A1 mediated production of estrone and estradiol
Tx: ER+ breast CA in POST-menopausal (can't use in pre-menopausal women: E comes from other mechanisms)
AE: post menopausal (hot flash, hair thinning), teratogen, arthralgia, diarrhea

5

raloxifene

monthly IM
SERM
ER agonist: bone
ER antagonist: breast, uterus
Tx: ER+ breast CA
prevent: BRCA2 related breast CA

6

tamoxifen

daily PO
SERM
metabolized via CYP2D6 to more potent products: possible sub-optimal effect in poor metabolizers (no FDA requirement for testing)
ER agonist: bone, uterus
ER antagonist: breast
Tx: ER+ breast CA
prevent: BRCA2 related breast CA
BBW: endometrial CA/hypertrophy, vaginal bleeding

7

toremifene

PO daily
SERM (derivative of tamoxifen)
CYP3A4 metabolism
Tx: ER+ breast CA
BBW: QT PROLONGATION
lacks BBW of other SERM: but avoid with Hx of endometrial CA/hyperplasia and thromboembolic disease

8

fulvestrant

monthly IM
SERD: binds ER and prevents dimerization in the nucleus (pure antagonist)
Tx: ER+ breast CA
AE: post menopausal symptoms

9

SERM

selective estrogen receptor modifier
ER agonist MOA: recruits coactivators
ER antagonist MOA: recruits corepressors (HISTONE DEACETYLASE I stabilizes nucleosome and prevents mRNA production)
Tx: ER+ breast CA (more important in post menopause, but can use in pre)
prevent: BRCA2 breast CA (BRCA1 is ER-)
improves: lipid profile, increase bone mineralization
AE: teratogen, retinal degeneration
BBW: thromboembolic disease, stroke

10

goserelin

SC
GnRH agonist
Tx: breast CA, prostate CA

11

GnRH agonist in Tx of CA

use is CONTINUOUS: down regulates GnRH receptors causing fall of FSH and LH and therefore estrogen
FLARE UP of disease initially: bone pain (metastases), hypercalcemia, breast enlargement/tenderness
WEEKS to lower estrogen/androgen levels: use ANDROGEN RECEPTOR BLOCKERS until then
Tx: prostate CA, breast CA in PRE-menopausal women (not effective because ovaries aren't working anyway)
AE: post-menopausal (including done density); decrease bone density, elevated lipids, weight gain, DM, CV risk, sexual dysfunction/ loss of libido, gynecomastia, injection site reaction
CI: PREGNANCY

12

pertuzumab

Her-2/neu Ab: blocks heterodimerization of HER2 with HER3/4 (EGFRs)
Tx: breast CA
AE: decreased left ventricular ejection fraction, neutropenia, leukopenia

13

trastuzumab

Her-2/neu Ab: binds juxtraglomerular region of extracellular domain of HER2
Tx: breast CA
AE: cardiac, renal, hepatic, pulmonary
BBW: cardiomyopathy, infusion rxn (respiratory)

14

ado-trastuzumab/ emtasine (T-DM1)

Her-2/neu Ab: binds receptor causing it to be internalized allowing linked chemo agent to act on microtubules
Tx: breast CA
BBW: HF/ventricular dysfunction, hepatic

15

her-2/neu mAb

IV
Tx: breast CA
AE: hypersensitivity (asthenia, faitugue, GI), blood dyscrasia, INFUSION RXN (dyspnea, hypotension, rash)
BBW: pregnancy

16

lapatinib

oral
TKI: inhibits HER1/2: binds INTRACELLULAR ErbB1/2 at ATP binding site preventing phosphorylation/activation of receptor
metabolism: CYP3A4/5
Tx: breast CA
AE: GI toxicity, hand-foot syndrome, rash, anemia/thrombocytopenia, QT PROLONGATION, LUNG (interstitial lung disease/pneumonitis)
BBW: CI in LIVER DISEASE (increase drug levels)
monitor: LFT

17

everolimus

mTOR inhibitor: bind FKBP-12
substrate/inhibit: CYP3A4, P-gp
inhibits: CYP2D6
Tx: ER+ breast CA
AE: blood dyscrasia, hyperglycemia/lipidemia, elevated creatinine, diarrhea/constipation
monitor: blood glucose, CBC, LFTs, lipid-triglyceride-creatinine profiles
BBW: INFECTION, NEOPLASIA (lymphoma/SCC)
use with: EXEMESTANE

18

SERDs

selective estrogen receptor downregulator
Tx: ER+ breast CA (more important in post menopause, but can use in pre)
AE: post menopausal (hot flashes, asthenia, pain)

19

Why might the initial response to anti-estrogen treatment of breast CA not be sustained longterm?

SERM, SERD, aromatase inhibitors
CA finds alternative proliferation pathways

20

CYP3A4

tormifene
lapatinib (also 3A5)
everolimus

21

CYP2D6

tamoxien
everolimus

22

CYP19A1

aromatase inhibitors

23

What provides superior outcomes in postmenopausal women with breast CA compared to tamoxifen alone?

aromatase inhibitor for 5 years
or following tamoxifen up with aromatase inhibitors for 5 years total

24

P-gp

everolimus

25

How is triple neg. breast CA treated?

Sx (first for all breast CA)
drug therapy depends on tumor size, lymph involvement
adjuvant/neoadjuvant/metastatic: radiation, conventional chemo drugs

26

Besides determining drug choice for a patient, what is tumor genotyping used for?

determining prognosis: need for drug therapy after Sx?
good prognostic indicators: watch and wait
bad prognostic indicators: adjunctive therapy

27

standard adjuvant chemotherapy regimens for breast CA

ALL include cyclophosphamide and doxorubicin (with/out: taxol or fluorouracil)
exception: docetaxel and cyclophosphamide with or without doxorubicin

28

doxorubicin

anthracycline
MOA: intercalator, free radical generation, topo II inhibitor
Tx: triple neg. breast CA, ovarian CA, bladder CA
AE: CUMULATIVE CARDIOTOXICITY, secondary malignancy, myelosuppression, hepatic, extravasational necrosis

29

cyclophosphamide

Tx: triple neg. breast CA, ovarian CA
AE: renal, pulmonary fibrosis, secondary malignancy, blood dyscrasia

30

fluorouracil

Tx: triple neg. breast CA