Lecture 4 - Breast Cancer

Question 1

Tamoxifen

Answer 1

first generation SERM

application:
treat early stage or metastatic ER+ breast cancer in pre- or post-menopausal pts
decrease risk of cancer development

note that ER+/PR+/HER2- pts respond best to SERMs

MOA:
metabolized by CYP2D6 to active metabolites endoxifen and 4-hydroxyTAM that bind to ER-alpha, acting as antagonists in breast tissue to inhibit gene transcription, inhibit cell proliferation and promote apoptosis

acts as a partial agonist in endometrium to promote endometrial hyperplasia. there is a 4-6 fold increased incidence of endometrial cancer. Hence, not administered for more than 5-10 years.

SE:
menopausal sxs (hot flashes)
increased incidence of endometrial cancer
possible osteoporosis in pre-menopausal women (while being bone sparing in post-menopausal)

Contraindications:
hx of DVT or PE, pregnancy

Question 2

What is the MOA for tamoxifen?

Answer 2

metabolized by CYP2D6 to active metabolites endoxifen and 4-hydroxyTAM that bind to ER-alpha, acting as antagonists in breast tissue to inhibit gene transcription, inhibit cell proliferation and promote apoptosis

acts as a partial agonist in endometrium to promote endometrial hyperplasia. there is a 4-6 fold increased incidence of endometrial cancer. Hence, not administered for more than 5-10 years.

Question 3

What are the SE of tamoxifen?

Answer 3

menopausal sxs (hot flashes) 
increased incidence of endometrial cancer 

possible osteoporosis in pre-menopausal women (while being bone sparing in post-menopausal)

Question 4

What are the contraindications of tamoxifen?

Answer 4

hx of DVT or PE, pregnancy

Question 5

What drugs should NOT be given with tamoxifen and why?

Answer 5

SSRIs since they inhibit CYP2D6 converting tamoxifen to active metabolites

Question 6

How do pts become resistant to Tamoxifen?

Answer 6

down regulation of corepressors, ER alpha and beta

Question 7

Toremifene

Answer 7

first generation SERM

treat metastatic ER+ breast cancer in POST-menopausal pts

MOA:
active antagonist at ER-alpha/beta
does NOT require activation via CYP2D6

insufficient clinical data at this time, but may act as partial agonist in endometrium to promote endometrial cancer

SE:
menopausal sxs, may increase incidence of endometrial cancers

Contraindications:
hx of DVT, pregnancy

has equal efficacy to tamoxifen in treating breast cancer

bone sparing effects in post-menopausal women

Question 8

What is the MOA of toremifene?

Answer 8

active antagonist at ER-alpha/beta
does NOT require activation via CYP2D6

insufficient clinical data at this time, but may act as partial agonist in endometrium to promote endometrial cancer

Question 9

What are the SE of toremifene?

Answer 9

menopausal sxs, may increase incidence of endometrial cancers

Question 10

What are the contraindications of toremifene?

Answer 10

hx DVT

pregnancy

Question 11

Anastrozole

Answer 11

aromatase inhibitor

treat early stage or metastatic ER+ breast cancer in POST-menopausal pts

aromatase inhibitors more effective than tamoxifen (greater survival) in post-menopausal women

MOA: prevent conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissues
Anastrozole is reversible inhibitor (Exemestane is suicide inhibitor)

SE:
hot flashes
osteopenia
osteoporosis

not effective in pre-menopausal women d/t functional ovaries in HPG axis overriding

Question 12

What is the MOA of anastrozole and exemestane?

Answer 12

prevent conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissues
Anastrozole is reversible inhibitor (Exemestane is suicide inhibitor)

Question 13

What are the SEs of anastrozole and exemestane?

Answer 13

hot flashes
osteopenia
osteoporosis

Question 14

Leuprolide

Answer 14

GnRH agonist

treat metastatic or early stage ER+ breast cancer in PRE-menopausal women
may be combined with SERms
(ASCO considers Tamoxifen to be the best first treatment for early stage breast cancer)

MOA:
disrupts normal pulsatile stimulation of GnRH receptor by endogenous GnRH. this results in desensitization of GnRH receptors in the pituitary leading to decreased release of FSH and LH from the pituitary, which in turn decreases estrogen synthesis in the ovaries

SE:
hot flashes
osteoporosis
sexual dysfunction

contraindications:
pregnancy

may at first increase LH and FSH –worsening the cancer

Question 15

What is the best treatment for early stage breast cancer?

Answer 15

per the ASCO

tamoxifen

Question 16

What is the MOA of Leuprolide?

Answer 16

disrupts normal pulsatile stimulation of GnRH receptor by endogenous GnRH. this results in desensitization of GnRH receptors in the pituitary leading to decreased release of FSH and LH from the pituitary, which in turn decreases estrogen synthesis in the ovaries

may at first increase LH and FSH –worsening the cancer

Question 17

What are the SE and contraindications of leuprolide?

Answer 17

SE:
hot flashes
osteoporosis
sexual dysfunction

contraindications:
pregnancy

Question 18

Trastuzumab

Answer 18

biologic (cytotoxic drugs)
localized breast cancer with HER2 overexpression (HER2+)
metastatic HER2+ breast cancer

MOA: monoclonal Ab against HER2 extracellular domain IV to inhibit ligand-independent EGFR - HER2 dimerization and consequently inhibits RAS-MAPK signaling pathway; sensitizes cancer cells to cytotoxic chemotherapy; antibody-dependent cellular cytotoxicity

SE: hypersensitivity (infusion) reaction, nephrotic syndrome, interstitial lung disease; BBW - cardiomyopathy, fatal infusion rxn in the form of acute respiratory syndrome

Contraindication:
pregnancy

Question 19

What is the MOA of trastuzumab?

Answer 19

monoclonal Ab against HER2 extracellular domain IV to inhibit ligand-independent EGFR - HER2 dimerization and consequently inhibits RAS-MAPK signaling pathway; sensitizes cancer cells to cytotoxic chemotherapy; antibody-dependent cellular cytotoxicity

Question 20

What are the SE and contraindications of trastuzumab?

Answer 20

hypersensitivity (infusion) reaction, nephrotic syndrome, interstitial lung disease;
BBW - cardiomyopathy, fatal infusion rxn in the form of acute respiratory syndrome

Contraindication:
pregnancy

Question 21

Pertuzumab

Answer 21

metastatic ER2+ breast cancer; used in conjunction with trastuzumab and docetaxel

MOA: monoclonal antibody binds HER2 extracellular domain 2 to prevent ligand - dependent dimerization with EGFR

SE:
cardiotoxicity, severe hypersensitivity, including anaphylaxis
BBW: embryo-fetal toxicity

Question 22

What is the MOA for pertuzumab?

Answer 22

monoclonal antibody binds HER2 extracellular domain 2 to prevent ligand - dependent dimerization with EGFR

Question 23

What are the SE of pertuzumab?

Answer 23

cardiotoxicity, severe hypersensitivity, including anaphylaxis
BBW: embryo-fetal toxicity

Question 24

What are the subtypes of breast cancer?

Answer 24

ER+ (75% of all breast cancer, most likely to be PR+)
HER2+ (15-20%)
Triple negative (10-20%)

Question 25

Which subtype of breast cancer responds best to Tamoxifen therapy?

Answer 25

ER+/PR+/HER2-

Question 26

What is the treatment for triple negative breast cancer?

Answer 26

not hormonal
not trastuzumab

left with cytotoxic drugs

Question 27

Triple negative breast cancer

Answer 27

10-20%
majority of mutant BRACA-1 associated breast cancers are triple neg

worst prognosis

surgical and/or radiation therapy, plus cytotoxic chemo

Question 28

Tamoxifen vs Toremifiene

Answer 28

Tamoxifen for both pre and post menopausal ER+ breast cancer

Toremifiene for post menopausal breast cancer

Question 29

Leuprolide

Answer 29

GnRH agonist

PRE-menopausal ER+ breast cancer (also prostate cancer)

Question 30

AIs

Answer 30

Aromatase inhibitors

POST-menopausal ER+ breast cancer

adjuvant monotherapy for up to 5 years
sequential adjuvant therapy (10 years total) - ex. 5 years tamoxifen followed by 5 years AI

Question 31

Tamoxifen resistance

Answer 31

30-40% of pts become resistant to therapy after 5 years

d/t down regulation of co-repressors and/or ER- alpha/beta in breast tumor cells

Question 32

What is important to remember about CYP2D6?

Answer 32

this is used to metabolize the prodrug tamoxifen

this enzyme is highly polymorphic
CYP2D61 - normally active
CYP2D62xN - supre-active
CYP2D6*4 - inactive allele

Question 33

What drug of choice would you use for a pt with PM allele of CYP2D6?

Answer 33

this means their CYP2D6 is not working so they can’t break down the prodrug tamoxifen

so if they’re post-menopausal you can treat with Toremifene

although in 2010 the FDA no longer recommend genotyping pts for tamoxifen
but avoid SSRIs in these pts to prevent CYP2D6 competition

Question 34

MammaPrint

Answer 34

determining the risk of breast cancer recurrence
30% of pts will have distant recurrence (metastasis) in 5-10 years

independent of receptor (ER, PR or HER2, doesn’t matter)

test biopsy for 70 genes to determine if they are low or high risk chance of metastasis in 10 years

Question 35

Oncotype DX

Answer 35

21 gene breast cancer signature

test for pts with ER+/HER2- breast cancer who are on Tamoxifen for their breast cancer treatment

recurrence score from 0-100
the lower the better

these scores also help determine if Tamoxifen + a cytotoxic drug would be beneficial (those with recurrence score >18 would benefit from Tamoxifen and a cytotoxic drug, those with score <18 should just go on tamoxifen

Question 36

Genomic tests

Answer 36

MammaPrint
Oncotype Dx

both FDA approved to determine recurrence risk and if a cytotoxic drug would benefit these pts in addition to tamoxifen