Breast Cancer Treatment (Al-Mehdi)

Al-Mehdi

Estrogen receptor in adipose tissue effect

growth (breast development)

Estrogen receptor in uterus effect

Endometrial growth

Estrogen receptor in bone effect

inhibits osteoclasts (↑ osteoblast → epiphyseal closure → end of linear bone growth)

SERM drugs 

Tamoxifen 

Raloxifene  

(Fen, Fene, Phene endings) 

agonist at bone, antagonist at breast, agonist at uterus → ↑ endometrial cancer risk (Rx: ER+ breast cancer)

Tamoxifen

agonist at bone, antagonist at breast & uterus (no ↑ endometrial cancer): Osteoporosis &

breast cancer prevention

Raloxifene

Reducing estrogen synthesis or blocking estrogen receptor signaling decreases tumor progression.

SERM MOA

SERM MOA

Reducing estrogen synthesis or blocking estrogen receptor signaling decreases tumor progression.

A 55-year-old woman has estrogen receptor–positive breast cancer. She is treated with a medication that reduces estrogen synthesis in adipose tissue. The therapeutic effect is achieved by decreasing estrogen receptor–mediated transcription and proliferation.

What is the drug?

Anastrozole

(Aromatase inhibitor)

-ozole ending

Her2 is a cell ____ receptor, tyrosine kinase

surface

Human epidermal growth factor receptor 2

HER2

Does not require a ligand, always activate. Modulated through signaling domain 

HER2 

means agonistic and antagonistic depending on the receptor

Modulator

Aromatase inhibitors

Anastrozole
Letrozole

Anastrozole MOA

Aromatase inhibitor

________ response elements are in the ________ gene

Estrogen

Progesterone

Estrogen increased progesterone production

Progesterone brings in transcriptome and downregulates estrogen receptor

Increased endometrial cancer risk drug 

Tamoxifen 

Used for osteoporosis and breast cancer prevention (no increased risk of endometrial cancer)

Raloxifene

Mutations in the estrogen receptor ligand-binding domain enable estrogen-independent signaling.

_______ cause receptor internalization and destruction.

Used when tumors become resistant to estrogen-lowering therapy.

Selective estrogen receptor degraders (SERDs)

Used when tumors become resistant to estrogen-lowering therapy.

SERDs 

Selective estrogen receptor degraders (SERDs) 

cause estrogen receptor internalization and destruction.

Selective estrogen receptor degraders (SERDs)

SERDs MOA

cause estrogen receptor internalization and destruction.

A 56-year-old woman with metastatic breast cancer previously responded to an aromatase inhibitor plus palbociclib but now shows disease progression. Tumor sequencing reveals an Estrogen Receptor 1 ligand-binding domain mutation (activating). Which of the following is the most appropriate next therapy?

A. Tamoxifen

B. Letrozole

C. Elacestrant

D. Palbociclib monotherapy

E. Exemestane + everolimus

C. Elacestrant

SERD

ER1 mutations lead to ligand-________ ER activation causing resistance to _________ inhibitors

independent; aromatase inhibitors (anastrozole)

an oral SERD (selective estrogen receptor degrader), is specifically indicated in ER1-mutated, endocrine-resistant disease.

Elacestrant

Elacestrant MOA

Selective estrogen receptor degrader

is specifically indicated in ER1-mutated, endocrine-resistant disease

A 63-year-old woman with HR+/HER2− metastatic breast cancer tests positive for a PI3K mutation. She progressed on fulvestrant and abemaciclib. Which targeted agent is mechanistically most appropriate?

A. Trastuzumab

B. Inavolisib

C. Capecitabine

D. Tamoxifen

E. Doxorubicin

B. Inavolisib

PI3K mutations activate the PI3K-AKT pathway, driving endocrine resistance. INAVOLISIB (a selective PI3K inhibitor) + fulvestrant ± palbociclib improves outcomes in this molecular subset.

Inavolisib MOA

a selective PI3K inhibitor

PI3K mutations activate the PI3K-AKT pathway, driving endocrine resistance

Inavolisib (a selective PI3K inhibitor) + fulvestrant ± palbociclib improves outcomes in this molecular subset

A 47-year-old woman with HR+/HER2− metastatic breast cancer progresses after CDK4/6 inhibitor therapy. Genomic profiling reveals a PTEN loss-of-function mutation. Which of the following is the best drug to target this pathway?

A. Olaparib

B. Capivasertib

C. Trastuzumab deruxtecan

D. Sacituzumab govitecan

E. Docetaxel

B. Capivasertib

PTEN loss → increased AKT signaling.

Capivasertib = AKT inhibitor, effective in tumors with PI3K-AKT or PTEN mutation.

Loss of PTEN =

Increased AKT signaling

Capivasertib MOA

AKT inhibitor, effective in tumors with PI3K-AKT or PTEN mutation.

AKT inhibitor, effective in tumors with PI3K-AKT or PTEN mutation.

Capivasertib MOA

Trastuzumab deruxtecan is targeting the _____ ______ of HER2

signaling domain 

Sacituzumab govitecan is targeting the _________ of HER2

Dimerization

Deconjugated inside the cell and can travel via gap junctions to neighbors

Deruxtecan

(Tecan: topoisomerase 1 inhibitor)

Deruxtecan MOA

topoisomerase 1 inhibitor

Topoisomerase 1 inhibitor for cytotoxicity 

Deruxtecan 

Trastuzumab deruxtecan MOA

Trastuzumab brings deruxtecan to HER2+ cells and deruxtecan can travel to adjacent cancer cells with less HER2 expression to kill them while also killing the original cell by inhibiting topoisomerase 1

A 59-year-old woman with HER2+ metastatic breast cancer progresses after trastuzumab + pertuzumab + docetaxel. Which of the following medications is indicated next in the management of the patient?

Trastuzumab emtansine

Trastuzumab deruxtecan

Neratinib

Lapatinib

Tamoxifen

Trastuzumab deruxtecan

A 62-year-old woman with HER2+ metastatic breast cancer develops brain metastases. She has previously received TRASTUZUMAB DERUXTECAN. Which of the following regimens has been effective in brain metastatic disease?

Trastuzumab + pertuzumab

Docetaxel

Tucatinib + trastuzumab + capecitabine

Letrozole

Paclitaxel

Tucatinib + trastuzumab + capecitabine

Tucatinib (HER2-selective TKI) penetrates CNS and improves survival in HER2+ breast cancer with brain metastases.

HER2 selective tyrosine kinase inhibitor that penetrates the CNS

Tucatinib

Improves survival of HER2+ breast cancer with brain mets

Tucatinib MOA

HER2 selective tyrosine kinase inhibitor that penetrates the CNS

Improves survival of HER2+ breast cancer with brain mets

CDK4/6 inhibitors

Palbociclib

Abemaciclib

Ribociclib

A 52-year-old woman with HER2-low metastatic breast cancer previously treated with endocrine therapy is being considered for TRASTUZUMAB DERUXTECAN. Which of the following is the primary toxicity of this ADC that requires close monitoring?

A. Peripheral neuropathy

B. Severe diarrhea

C. Cardiotoxicity

D. Interstitial lung disease / pneumonitis

E. Thrombocytopenia

D. Interstitial lung disease / pneumonitis

requires early recognition and steroid treatment

fine crackles, ground glass opacities

A 41-year-old woman with stage III triple-negative breast cancer (TNBC) receives neoadjuvant pembrolizumab + chemotherapy. Following surgery, pembrolizumab is continued. Which of the following is the most likely effect of the continued therapy with this drug?

A. Prevent ER reactivation

B. Enhance tamoxifen sensitivity

C. Prolong survival

D. Reduce cardiotoxicity

E. Prevent HER2 upregulation

C. Prolong survival

In TNBC, peri-operative pembrolizumab (neoadjuvant + adjuvant) improves survival and recurrence outcomes.

In TNBC, peri-operative _________ (neoadjuvant + adjuvant) improves survival and recurrence outcomes.

pembrolizumab

Anti PdD-1

Pembrolizumab

Pembrolizumab MOA

Anti PD-1 inhibitor 

Blocks PD-1 ligands made by cancer cells

PD-1 co-inhibitory so needs to come off to activate immune response so cancer cells block it to keep naive T cells inactive

A patient with metastatic triple-negative breast cancer (TNBC) lacks PD-L1 expression. The patient progresses despite taxane therapy. Which of the following agents is next most appropriate?

Letrozole

Sacituzumab govitecan

Pembrolizumab monotherapy

Trastuzumab

Sacituzumab govitecan

Sacituzumab govitecan is standard post-chemo in PD-L1–negative TNBC.

standard post-chemo in PD-L1–negative TNBC

Sacituzumab govitecan

A 43-year-old woman with HER2-negative breast cancer has a germline BRCA1 mutation. Which of the following drugs kills tumor cells by adding another defect in the DNA repair mechanism?

A. Abemaciclib

B. Letrozole

C. Capecitabine

D. Olaparib

E. Trastuzumab

D. Olaparib

Poly(adenosine diphosphate-ribose) polymerase (PARP) is a DNA repair enzyme involved in fixing single-strand DNA breaks via the base excision repair pathway. When PARP is inhibited (PARP inhibitors OLAPARIB, TALAZOPARIB), single-strand breaks persist and become double-strand DNA breaks during replication. In normal cells, these double-strand breaks are repaired by homologous recombination repair by BRCA1/BRCA2.

Tumor cells with BRCA mutation use the PARP-mediated repair. OLAPARIB blocks that, and they die (Synthetic Lethality). Normal cells survive with intact homologous recombination repair.

PARP inhibitors

Olaparib

Talazoparib

Olaparib MOA

PARP inhibitor

single-strand breaks persist and become double-strand DNA breaks during replication. In normal cells, these double-strand breaks are repaired by homologous recombination repair by BRCA1/BRCA2.

Tumor cells with BRCA mutation use the PARP-mediated repair. OLAPARIB blocks that, and they die (Synthetic Lethality). Normal cells survive with intact homologous recombination repair.

Synthetic lethality 

Olaparib 

DNA repair enzyme involved in fixing single-strand DNA breaks via the base excision repair pathway.

Poly(adenosine diphosphate-ribose) polymerase (PARP)

A cancer cell line demonstrates dependence on phosphorylation of the retinoblastoma protein to pass the G1 to S checkpoint. Which therapy would inhibit this transition?

A. Aromatase inhibition

B. Inhibition of phosphoinositide 3-kinase

C. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibition

D. Inhibition of poly(adenosine diphosphate-ribose) polymerase

E. Monoclonal antibody immunotherapy

C. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibition

The -CICLIB drugs inhibit CDK4/6

Ciclib MOA

inhibit CDK4/6

Inhibits G1 to S checkpoint

A 62-year-old woman has metastatic breast cancer that expresses the estrogen receptor. She previously responded to estrogen deprivation but now shows tumor growth despite estrogen suppression. Sequencing demonstrates a mutation in the estrogen receptor ligand-binding domain. Which of the following is the most appropriate therapy?

A. Aromatase inhibition
B. Selective estrogen receptor degrader therapy
C. Estrogen receptor antagonism with partial agonist activity
D. Cytotoxic chemotherapy
E. Monoclonal antibody directed against Human Epidermal Growth Factor Receptor 2

B. Selective estrogen receptor degrader therapy

A cancer cell line needs to pass through the G1:S checkpoint. Which therapy would inhibit this transition?

A. Aromatase inhibition
B. Inhibition of phosphoinositide 3-kinase
C. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibition
D. Inhibition of poly(adenosine diphosphate-ribose) polymerase
E. Monoclonal antibody immunotherapy

C. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibition

A breast tumor shows activating mutation of phosphoinositide 3-kinase. Which therapy directly targets this resistance mechanism?

A. Selective estrogen receptor degrader
B. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor
C. Phosphoinositide 3-kinase inhibitor
D. Antibody-drug conjugate directed against Human Epidermal Growth Factor Receptor 2
E. Protein kinase B inhibitor

C. Phosphoinositide 3-kinase inhibitor

Loss of phosphatase and tensin homolog results in hyperactivation of which signaling molecule?

A. Protein kinase B
B. Cyclin D
C. Ras
D. Myc
E. Estrogen receptor

A. Protein kinase B

Which therapy is used to counteract the survival advantage resulting from phosphatase and tensin homolog loss?

A. Aromatase inhibition
B. Protein kinase B inhibitor therapy
C. Monoclonal antibody directed against Human Epidermal Growth Factor Receptor 2
D. Poly(adenosine diphosphate-ribose) polymerase inhibitor
E. Cytotoxic anthracycline therapy

B. Protein kinase B inhibitor therapy

A breast tumor overexpresses Human Epidermal Growth Factor Receptor 2. Which of the following mechanisms explains tumor suppression by TRASTUZUMAB?

A. Direct inhibition of DNA synthesis
B. Blockade of RTK signaling
C. Inhibition of microtubule assembly
D. Prevention of estrogen formation
E. Inhibition of topoisomerase I

Bonus question:  How does HER2 differ from other RTKs? (hint: constitutively active)

B. Blockade of RTK signaling

What is the functional purpose of the cytotoxic payload in an antibody-drug conjugate directed against Human Epidermal Growth Factor Receptor 2?

A. To increase immune cell recruitment
B. To promote apoptosis through targeted intracellular drug delivery
C. To directly inhibit estrogen receptor transcription
D. To inhibit ribosomal protein synthesis
E. To block microtubule polymerization systemically

B. To promote apoptosis through targeted intracellular drug delivery

A patient receiving antibody-drug conjugate therapy develops persistent dry cough and fine inspiratory crackles. Chest imaging reveals ground-glass opacities. Which complication is most likely?

A. Bacterial pneumonia
B. Noninfectious pneumonitis
C. Pulmonary embolism
D. Chronic obstructive pulmonary disease
E. Viral upper respiratory infection

B. Noninfectious pneumonitis

How does untreated pneumonitis progress to interstitial lung disease?

A. Inhibition of surfactant synthesis
B. Fibroblast activation
C. Hyperplasia of airway smooth muscle
D. Mucus gland hypertrophy
E. Loss of pulmonary macrophages

B. Fibroblast activation

A breast tumor lacks estrogen receptor, progesterone receptor, and Human Epidermal Growth Factor Receptor 2. Which of the following characteristics of the tumor predicts response to immune checkpoint blockade?

A. Low mitotic index
B. Strong desmoplastic stromal reaction
C. High density of tumor-infiltrating lymphocytes
D. Absence of lymphovascular invasion
E. High intracellular estrogen concentration

C. High density of tumor-infiltrating lymphocytes

Why is chemotherapy frequently combined with immune checkpoint blockade in tumors lacking hormone receptors and HER2 expression?

A. To increase tumor antigen presentation
B. To prevent immune overactivation
C. To block all DNA repair pathways
D. To decrease immune checkpoint protein expression
E. To restore estrogen signaling

A. To increase tumor antigen presentation

Germline BRCA1 mutation impairs which of the following DNA repair mechanisms?

A. Nucleotide excision repair
B. Base excision repair
C. Homologous recombination repair
D. Mismatch repair
E. Direct reversal of methylated bases

C. Homologous recombination repair

Poly(adenosine diphosphate-ribose) polymerase inhibitors block which cellular repair mechanism?

A. Homologous recombination
B. DNA replication fork assembly
C. Single-strand break repair
D. Nonhomologous end joining
E. Telomerase length maintenance

C. Single-strand break repair

What concept explains why tumors with germline BRCA1 mutation are highly susceptible to poly(adenosine diphosphate-ribose) polymerase inhibition?

A. Oncogenic addiction
B. Adaptive immunity
C. Synthetic lethality
D. Clonal evolution
E. Tumor heterogeneity

C. Synthetic lethality

Why do normal cells tolerate PARP inhibition better than tumor cells with germline BRCA1 mutation?

A. Lack of rapid cell division
B. Presence of homologous recombination repair
C. Absence of mitochondrial stress
D. Expression of drug efflux transporters
E. Avoidance of oxidative DNA damage

B. Presence of homologous recombination repair

Which therapy is first-line for ER+ metastatic breast cancer?

A. Monoclonal antibody for HER2

B. Endocrine therapy plus CDK4/6 inhibitor

C. Cytotoxic taxane chemotherapy

D. PARP inhibitor monotherapy

E. SERD monotherapy

B. Endocrine therapy plus CDK4/6 inhibitor

Which therapy is indicated after estrogen receptor mutation–mediated resistance to estrogen suppression develops?

A. Aromatase inhibition

B. Selective estrogen receptor degrader therapy

C. Cytotoxic chemotherapy

D. Phosphoinositide 3-kinase inhibition

E. Monoclonal antibody directed against Human Epidermal Growth Factor Receptor 2

B. Selective estrogen receptor degrader therapy

Which therapy is indicated after detection of activating mutation in phosphoinositide 3-kinase?

A. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor
B. Selective estrogen receptor degrader
C. Phosphoinositide 3-kinase inhibitor
D. Protein kinase B inhibitor
E. Poly(adenosine diphosphate-ribose) polymerase inhibitor

C. Phosphoinositide 3-kinase inhibitor

Which therapy is indicated after loss of phosphatase and tensin homolog is confirmed?

A. Protein kinase B inhibitor

B. Aromatase inhibitor

C. Cytotoxic microtubule inhibitor

D. Monoclonal antibody immunotherapy

E. Radiation therapy

A. Protein kinase B inhibitor

Which therapy is used in TNBC expressing PD-L1?

A. Aromatase inhibition

B. Immune checkpoint blockade plus chemotherapy

C. Monoclonal antibody directed against Human Epidermal Growth Factor Receptor 2

D. Protein kinase B inhibition

E. Poly(adenosine diphosphate-ribose) polymerase monotherapy

B. Immune checkpoint blockade plus chemotherapy

Big Picture Points to Ponder

Explain the role of ER signaling in breast cancer and describe how estrogen deprivation or ER blockade slows tumor progression.

Describe how G1→S transition promotes cancer cell proliferation and explain how CDK4/6 inhibitors block this process.

Identify how mutations in the ER ligand-binding domain promote resistance to therapy, and explain how SERDs (selective estrogen receptor degraders) overcome this resistance.

Explain how activating mutations in PI3K pathway promote tumor growth and resistance to hormone therapies, and how PI3K inhibitors work. (SERDS added by me)

Describe how loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) or activating mutations in PKB lead to cell survival and explain how PKB inhibitors restore sensitivity to therapy.

Explain the role of HER2 (Human Epidermal Growth Factor Receptor 2) signaling in breast cancer and describe how TRASTUZUMAB and ADC TRASTUZUMAB-DERUXTECAN interrupt these pathways.

Describe the clinical significance of low-level HER2 expression and explain how ADC TRASTUZUMAB-DERUXTECAN can be effective in tumors that are classified as HER2-low.

Differentiate between infectious pneumonia and noninfectious pneumonitis, and describe how ADC TRASTUZUMAB-DERUXTECAN can cause pneumonitis and interstitial lung disease.

Explain characteristics of triple-negative breast cancer (TNBC) and describe why it responds to immune checkpoint blockade combined with cytotoxic chemotherapy.

Define synthetic lethality and explain how tumors with germline BRCA1 or germline BRCA2 mutations are selectively vulnerable to poly(adenosine diphosphate-ribose) polymerase or PARP inhibitors.

A 62-year-old woman has metastatic breast cancer that expresses the estrogen receptor. She

previously responded to estrogen deprivation but now shows tumor growth despite estrogen

suppression. Sequencing demonstrates a mutation in the estrogen receptor ligand-binding domain.

Which therapy is most appropriate?

SERD

A cancer cell line demonstrates dependence on cyclin-dependent kinase-mediated phosphorylation of the retinoblastoma protein to pass the G1 to S checkpoint. Which therapy would inhibit this transition?

Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibition.

A breast tumor shows activating mutation of phosphoinositide 3-kinase. Which therapy directly targets this resistance mechanism?

Phosphoinositide 3-kinase inhibitor.

Loss of phosphatase and tensin homolog results in hyperactivation of which signaling molecule?

Protein kinase B.

Which therapy is used to counteract the survival advantage resulting from phosphatase and tensin homolog loss?

Protein kinase B inhibitor therapy.

A breast tumor overexpresses Human Epidermal Growth Factor Receptor 2. Which mechanism explains tumor suppression by monoclonal antibody directed against Human Epidermal Growth Factor Receptor 2?

Blockade of receptor signaling and immune-mediated tumor cell destruction.

What is the functional purpose of the cytotoxic payload in an antibody-drug conjugate directed against Human Epidermal Growth Factor Receptor 2?

Targeted intracellular delivery of cytotoxic drug promoting apoptosis.

A patient receiving antibody-drug conjugate therapy develops persistent dry cough and fine inspiratory crackles. Chest imaging reveals ground-glass opacities. Which complication is most likely?

Noninfectious pneumonitis.

How does untreated pneumonitis progress to interstitial lung disease?

Repeated alveolar epithelial injury leads to fibroblast activation and collagen deposition.

A breast tumor lacks estrogen receptor, progesterone receptor, and Human Epidermal Growth Factor Receptor 2. Which characteristic predicts response to immune checkpoint blockade?

High density of tumor-infiltrating lymphocytes.

Why is chemotherapy frequently combined with immune checkpoint blockade in tumors lacking hormone receptors and Human Epidermal Growth Factor Receptor 2 expression?

Chemotherapy increases tumor antigen presentation.

Which therapy is first-line for estrogen receptor–positive metastatic breast cancer?

Endocrine therapy plus cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor.

Which therapy is indicated after estrogen receptor mutation–mediated resistance to estrogen suppression develops?

Selective estrogen receptor degrader therapy.

Which therapy is used in triple-negative disease expressing Programmed Death-Ligand 1?

Immune checkpoint blockade plus chemotherapy.