PHRM 542 Breast Cancer Intro and Drugs

Describe luminal A breast cancer

ER +

PR +/-

HER2 -

Ki-67 < 14%

Describe luminal B breast cancer

ER +

PR +/-

HER2 +/-

Ki-67 ≥ 14%

Describe HER2+ breast cancer

ER -

PR -

HER2 +

Ki-67 ≥ 14%

Describe triple negative breast cancer (TNBC)

ER -

PR -

HER2 -

Ki-67 ≥ 14%

What is Ki-67?

An indicator of growth rate/proliferation

What does the activity of a partial agonist depend on?

What is currently going on in the tissue

System at full activity, partial agonist inhibits

System not at full activity, partial agonist activates

What is tamoxifen used for?

Treatment of early and advanced ER+ breast cancer

ALSO FDA approved for chemoprevention in women at high risk

Describe the metabolism of tamoxifen

PRODRUG activated by CYP2D6 in the liver

What is the active metabolite of tamoxifen?

4-OH-tamoxifen

Describe the MOA of the active metabolite of tamoxifen

Decreases/blocks transcription of estrogen-responsive genes

Describe the link between tamoxifen and endometrial cancer

Breast tissue antagonist, but partial agonist in the endometrium

How does tamoxifen affect bone tissue?

Has anti-osteoporotic effects from estrogenic activity in bone tissue

What is tamoxifen a substrate of?

P-gp = consider increasing dosing when given with other chemotherapeutic P-gp substrates

Describe the effects of raloxifene compared to tamoxifen

Raloxifene has similar effects to TAM, but does NOT stimulate the endometrium = no risk of endometrial cancer

What is raloxifene used for?

Prevention of post-menopausal osteoporosis

Prevention of breast cancer in women with high risk factors

What is raloxifene a substrate for?

P-gp

Fulvestrant

Faslodex

What is the MOA of fulvestrant?

ER competitive antagonist (in all tissues)

ALSO decreases ER expression both by decreased translation and INCREASED protein degradation (SERD)

Describe the metabolism of fulvestrant

CYP3A4 substrate

Alpelisib

Piqray

What is the MOA of alpelisib?

PI3K alpha inhibitor

INCREASES transcription of ER

What is alpelisib used in combination with?

Fulvestrant

Alpelisib "tricks" the cancer into thinking there is more ER available and then the fulvestrant takes it away since it degrades ER

Describe the metabolism of alpelisib

Hydrolysis and minor CYP3A4 metabolism

Elacestrant

Orserdu

What is the MOA of elacestrant?

ER competitive antagonist and SERD

Describe the metabolism of elacestrant

CYP3A4, 2A6, and 2C9

Describe the role of aromatase in the body

Aromatase is required for estrogen synthesis, converting testosterone and andrenedione into estrogens

Anastrozole

Arimidex

What is the MOA of anastrozole?

Inhibition of aromatase, reversible and competitive with endogenous androgens

Letrozole

Femara

What is the MOA of letrozole?

Competitively and reversibly binds to aromatase and blocks conversion of androgens to estrogens

What is a notable ADE of anastrozole and letrozole?

Osteoporosis

Exemestane

Aromasin

What is the MOA of exemestane?

Irreversible inhibitor of aromatase = suicide inhibition

Which aromatase inhibitor has the lowest bioavailability?

Exemestane

How can breast cancer therapies lead to hypercalcemia?

Breast cancer therapies that decrease estrogen lead to bone degradation/decreased bone deposition, which results in hypercalcemia

What are therapeutic options for hypercalcemia related to breast cancer treatment?

Zoledronic acid

Pamidronate

Denosumab

What is the MOA of zolendronic acid?

Inhibition of osteoclast activity/increased osteoclast apoptosis = decreased bone resorption

What are notable ADEs of zoledronic acid?

Renal toxicity leading to renal failure

Hypocalcemia

What benefit is associated with the use of zoledronic acid WITH aromatase inhibitors?

Increase in disease free survival (DFS)

What is the MOA of pamidronate?

Inhibition of bone resorption by adsorption into hydroxyapatite and inhibition of dissolution

May also directly inhibit osteoclast activity

What is the MOA of denosumab?

Humanized mAb targeting RANKL

Normally RANKL binds to RANK on osteoclasts to stimulate osteoclast differentiation, function, and survival

Inhibition of RANKL:RANK interaction prevents osteoclast activity, causes decreased bone resorption, and increased bone mass

Describe the metabolism of denosumab

Peptidytic degradation

Lapatinib

Tykerb

What is the MOA of lapatinib?

RTKi with activity against HER2 and EGFR over expressing tumors

Prevents phosphorylation and subsequent signaling cascades

Describe the metabolism of lapatinib

CYP3A4 substrate

Neratinib

Nerlynx

What is the MOA of neratinib?

Same MOA as lapatinib

What are notable ADEs of neratinib?

Life-threatening diarrhea

Severe liver damage

Describe the metabolism of neratinib

CYP3A4 substrate

Tucatinib

Tukysa

What is the MOA of tucatinib?

RTKi against HER2, inhibits P- of HER2 and HER3

Can be used in combination with HER2 targeted Ab

What are severe ADEs of tucatinib?

Diarrhea and liver damage

Describe the metabolism of tucatinib

CYP2C8 and CYP3A4 substrate

What is the MOA of trastuzumab?

h-mAb that binds extracellular domain of HER2

Inhibition through direct antibody binding

What is the MOA of pertuzumab?

h-mAb that binds the extracellular domain of HER2, but not same region as trastuzumab

BINDS DIMERIZATION DOMAIN

Inhibition through dimerization inhibition

What is the MOA of margetuxumab?

Chimeric mAb against HER2

Binds to SAME epitope as trastuzumab

How is margetuximab different from trastuzumab and how does that effect its MOA?

Different from trastuzumab in its design to alter receptor affinities, increasing affinity for a certain variant

This enhances innate immunity and targeted immunity

Describe the metabolism of margetuxumab

Catabolic breakdown

What are warnings for margetuximab?

Warnings for left ventricular dysfunction and embryonic lethality

What is the MOA of ado-trastuzumab emanstine?

HER2 targeting antibody conjugated to the cytotoxic drug DM1

DM1 binds tubulin, causing cell cycle arrest

ADC is internalized into cell, at which point DM1 is released and acts in HER2 overexpressing cells

What are rare ADEs of ado-trastuzumab emanstine?

Liver failure, interstitial lung disease, hepatic encephalopathy, peripheral neuropathy

What is the MOA of fam-trastuzumab deruxtecan?

HER2 targeting antibody conjugated to the topoisomerase I inhibitor, deruxtecan

ADC is internalized into the cell, where deruxtecan is released and acts in HER2 over expressing cells to cause DNA damage and apoptosis

What are notable ADEs of fam-trastuzumab deruxtecan?

Interstitial lung disease, neutropenia, left ventricular dysfunction

What is the MOA of sacituzumab govitecan?

Trop-2 targeted antibody conjugated with SN-38 (active metabolite of irinotecan, and a topo I inhibitor)

ADC is internalized into cell and then govitecan/SN-38 is released, causing cell damage and apoptosis

What is trop-2?

A transmembrane glycoprotein unregulated in all cancer types (TNBC particularly)

What are notable ADEs of sacituzumab govitecan?

Neutropenia is common and severe diarrhea may occur

May also see allergic reactions and severe CINV