Breast Cancer (Test 1)

- act on specific molecular targets that are associated with cancer

- designed to interact with a defined molecular target

- cytostatic (block tumor cell growth proliferation

- small molecules or biologics

Define targeted therapy

- act on all rapidly dividing normal and cancerous cells

- identified because they kill cells

- cytotoxic (kill tumor cells)

define standard chemotherapy

tumor markers from biopsies

What is selection of optimal treatment regimes based on?

- hormone receptors (HR)

- HER2 (Human Epidermal Growth Factor Receptor 2)

receptor status

- ER (estrogen receptor)

- PR (progesterone receptor)

- activation of these by steroid hormones drives cellular proliferation and tumor growth

- positive or negative

hormone receptors (HR)

- the nuclear protein is an established prognostic and predictive indicator; correlates with metastasis and the clinical stage of tumors

- a higher index suggests a more aggressive tumor with a greater risk of recurrence and spread

Ki-67 index

- progesterone receptor (PR) status

- Ki-67 index

What is the decision on further adjuvant hormonal therapy with additional chemotherapy in luminal A- and B-like breast cancers based on?

- a marker of cellular proliferation

- nuclear protein

- expressed in all active phases of the cell cycle

- absent in resting cells

- reflects the proportion of cells that are actively cycling

- reflects tumor proliferative activity

- how many tumor cells are actively cycling

Ki-67

- G1

- S

- G2

- M

active phases of the cell cycle

G0

resting phases of the cell cycle

- ER + and/or PR +

- HER2 -

- low Ki67

Luminal A gene expression

- most common

- low-Ki-67 and retains hormone sensitivity, so highly responsive to endocrine therapy

Luminal A

- ER + and/or PR +

- HER2 + or HER2- with high Ki67

Luminal B gene expression

- high Ki-67 and/or co-expression of HER2

- combo endocrine therapy, chemo, and anti-HER2 targeted agents

Luminal B

- ER -

- PR -

- HER2 +

HER2+ gene expression

- high HER2 in absence of hormone receptors

- highly aggressive, prognosis improved by anti-HER2 drugs

HER2+

- ER -

- PR -

- HER2 -

- cytokeratin 5/6+ and/or HER1 (EGFR) +

triple negative (TNBC) gene expression

- lacks all 3 receptor targets

- worst prognosis

triple negative (TNBC)

targeted endocrine therapy

Luminal A and B treatment

targeted anti-HER2 therapy

HER2+ treatment

chemotherapy

triple negative treatment

HR+

Is the response rate for hormone antagonists therapy more effective for HR+ or HR-?

- SERMs

- SERDs

- Aromatase Inhibitors

HR+ drug classes

- selective estrogen receptor modulators

- antagonize the action of estrogens in breast tissue

- acts as competitive antagonist directly at the estrogen receptor (ER) in breast tissue to shut down transcription

SERM's

- selective estrogen receptor degraders

- act as both ER antagonists and ER degraders

- bind the estrogen receptor, prevent nuclear translocation, and tag the ER complex with ubiquitin for destruction inside the cellular proteasome

SERD's

- block the de novo synthesis of estrogens

- block CYP19A1 aromatase enzyme, preventing the de novo synthesis of estrogen from androgen precursors in the body

aromatase inhibitors

Tamoxifen

SERM drug

- first target-directed anticancer drugs

- non-steroidal prodrug

Tamoxifen need to know

- adult patients with estrogen (hormone) receptor positive metastatic breast cancer

- adjuvant treatment of adult patients with early stage estrogen receptor positive breast cancer

reduce risk of invasive breast cancer following breast surgery and radiation in adult women with ductal carcinoma in situ (DCIS)

- to reduce the incidence of breast cancer in adult women at high risk

Tamoxifen indication

- estrogen antagonist in breast tissue

- estrogen antagonist in lung, liver, bone, and uterus

- the bound SERM receptor complex results in no transcription

Tamoxifen MOA

- uterine malignancies

- stroke

- pulmonary embolism

- benefits outweigh the risks

Tamoxifen BBW

reduces bone loss and fractures

Tamoxifen does what for post-menopausal women?

- sequential biotransformation of tamoxifen (TAM) to endoxifen in humans

- N-demethylated by the CYP3A4 enzyme to N-desmethyl tamoxifen

- undergoes 4-hydroxylation by CYP2D6 to endoxifen

Tamoxifen metabolism

active drug responsible for ER antagonism

endoxifen

- the ER complexed with estrogen become a nuclear transcription factor

- based on differential expression of ER subtype populations in these tissues (ER-a or ER-b)

- conformational changes to ER dimers and co-factors

What makes a SERM selective?

- Patients who are CYP2D6 poor metabolizers (Activity Score = 0) cannot efficiently convert the drug, resulting in significantly lower active endoxifen levels and a higher risk of breast cancer recurrence.

- CPIC guidelines recommend avoiding moderate/strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) which block this pathway

- use alternative therapy(like an aromatase inhibitor in poor metabolizers

CYP2D6 metabolism when taking tamoxifen

- fluvestrant (faslodex)

- elacestrant (orserdu)

SERD drugs

- first in class postmenopausal patients with HR+ breast cancer after progression on tamoxifen or AIs

- in combo with CDK inhibitors for metastatic breast cancer

fluvestrant (faslodex) indication

- poor pharmacodynamics

- painful intramuscular route of administration

- acquired resistance occurs via ESR1 mutation

first in class need to know

- encodes ER receptor

- resistant to tamoxifen and fulvestrant

- mainly in metastatic tumors

ESR1 mutation

- significant progression free-survival advantage over fluvestrant

- take with food

elacestrant (orserdu) need to know

postmenopausal women or adult men with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer with at least one disease progression following at least one line of endocrine therapy

elacestrant (orserdu) indication

- dyslimidemia

- embro-fetal toxicity

elacestrant (orserdu) warnings

- hypocholesterolemia and hypertriglyceridemia

- monitor lipid profile prior to starting treatment and periodically thereafter

dyslipidemia

- advise of potential risks to a fetus

- use effective contraception

embro-fetal toxicity

CYP3A4 inducers or inhibitors

elacestrant (orserdu) DDI

- key enzyme responsible for biosynthesis of estradiol and estrone from androgens

- leads to aromatization of steroid A-rings

aromatase

- CYP19A1

- frequently prescribes as adjuvant endocrine therapies

- third generation

aromatase inhibitors need to know

- letozole (Femara)

- Anastrozole (Arimidex)

aromatase inhibitors non-steroidal drugs

exemestane (Aromasin)

aromatase inhibitors steroidal drugs

aromatase inhibitor associated bone loss (AIBL)

aromatase inhibitors major concern

- IV zolendronic acid

- SC denosuma

aromatase inhibitor associated bone loss (AIBL) management

- palbociclib (Ibrance)

- ribociclib (Kisqali)

- abemaciclib (Verzenio)

CDK4/6 inhibitors drugs

- added to endocrine therapy for HR+, HER2- advanced or metastatic breast cancer

- combo with aromatase inhibitor as initial endocrine based therapy in postmenopausal women

- combo with fulvestrant in women with disease progression following endocrine therapy

CDK4/6 inhibitors indication

take with food

palbociclib (Ibrance) need to know

- QTC prolongation

- hepatotoxicity

ribociclib (Kisqali) AE

- BID

- diarrhea

- dysgeusia

abemaciclib (Verzenio) need to know and AE

- myelosupression

- interstitial lung disease/pneumoitis

- substrates of CYP3A4

CDK4/6 inhibitors AE

- poly-ADP ribose polymerase

- function through synthetic lethality

- oral

PARP inhibitors need to know

if two events are nonlethal when occur individually but Letha when they occur in combo

synthetic lethality

- tumor suppressor gene/protein

- defective HR repair pathway and can't repair double stranded breaks

BRCA

- synthetic lethality

- doesn't kill healthy cells

BRCA1/2 mutation with PARP inhibitors

- olaparib (lynparaza)

- rucaparib (rubraca)

- niraparib (zejula)

- talazoparib (talzenna)

PARP inhibitors drugs

- anemia

- neutropenia

- thrombocytopenia

- fatigue/HA

- N/V

PARP inhibitors AE

increase in Mean Corpuscular Volume (MCV)

Olaparib (Lynparza)

increased cholesterol and ALT/AST transaminitis

Rucaparib (Rubraca)

- hypertension

- palpitations

- anxiety

- dry mouth.

Niraparib (Zejula)

- hyperglycemia

- hypercalcemia

- alopecia

Talazoparib (Talzenna)

piqray (alpelisib)

PI3K inhibitors drugs

blocks PI3K/Akt signaling pathways and reduces tumor growth

piqray (alpelisib) MOA

- has been shown to induce increase in ER transcription in breast cancer cells

- only for PIK3CA-mutated breast cancer

piqray (alpelisib) combo with fulvestrant

- hyperglycemia

- severe allergic reactions

- severe skin reactions

- hyperglycemia

- lung problems (Penumoitis)

- diarrhea or colitis

piqray (alpelisib) AE

monitor blood sugar levels before start and during treatment with piqray (alpelisib)

hyperglycemia

- ligand binding causes receptor dimerization, activation, phosphorylation, and initiation of down-stream signaling

- preferential dimerization partner

- activation of HER2+ pathways enhances cell survival, proliferation and cell-cycle progression

HER2+

- work from outside (biologic-labs) of cell and inside (small molecule-kinase inhibitors)

Anti-HER2+ MOA

- trastuzumab (Herceptin)

- pertuzumab (perjeta)

monoclonal antibodies drugs

- first in class mab targeting HER2

- used in combo with pertizumab

- IV

trastuzumab (Herceptin) need to know

- indicated for metastatic breast cancer-combo

- neoadjuvant and adjuvant therapy for early stage disease

- IV

pertuzumab (perjeta) need to know

diarrhea

pertuzumab (perjeta) AE

- hydration

- avoid high-fat, greasy, spicy, gassy, or fried foods

- Loperamide, diphenocylate after each episode until subsides

pertuzumab (perjeta) diarrhea is managed with

- ado-trastuzumab emtansine

- fam- trastuzumab deruxtecan-nkxi (T-DxD)

antibody- drug conjugates (ADCs)

- demonstrate efficiency in HER2 non amplified breast cancers

- improves survival outcomes in patient with chemo-resistant advance breast cancer

- benefit for both HER2-low and HER2 untralow

antibody- drug conjugates (ADCs)

- Upon binding of trastuzumab emtansine (T-DM1) to HER2, TDM1 is is internalized in target tumor cell and undergoes lysosomal degradation.

- This results in the release of DM1, the active antimitotic agent which binds to tubulin, resulting in the prevention of microtubule polymerization. (destabilizer).

- T-DM1 has also been shown to retain mechanisms of action of trastuzumab.

ado-trastuzumab emtansine MOA

HER2-positive early breast cancer , and metastatic , with restrictions

ado-trastuzumab emtansine indication

- releases Dxd

- HER2 directed antibody and topoisomerase inhibitor I conjugate

fam- trastuzumab deruxtecan-nkxi (T-DxD) (ENHURTU) MOA

- early and metastatic breast cancer, in neoadjuvant and adjuvant settings as monotherapy or in combination

- across HER2 spectrum (positive, low, ultralow)

fam- trastuzumab deruxtecan-nkxi (T-DxD) (ENHURTU) indication

- interstitial Lund disease (ILD) and pneumonitis

- embryo-fetal toxicity

fam- trastuzumab deruxtecan-nkxi (T-DxD) (ENHURTU) BBW

- monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other worsening respiratory symptoms

- permanently discontinue in all patients with Grade 2 or higher IDL/ pneumonitis

interstitial Lund disease (ILD) and pneumonitis