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PHARM: Breast Cancer Flashcards

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1
Q

How does estrogen mediate non-genomic actions?

A

Membrane-bound ER ALSO mediates nongenomic action through its interaction with growth factor receptor tyrosine kinases or downstream molecules

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2
Q

What implications do non-genomic estrogen actions have on breast cancer treatment success?

A

explain treatment failure with drugs that target only estrogen’s classical genomic pathway

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3
Q

What is the source of estrogen in pre-menopausal women?

A

ovaries

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4
Q

What is the source of estrogen in post-menopausal women?

A

adrenal cortex

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5
Q

What are the two major treatment options for pre-menopausal women with breast cancer?

A 
Removal of ovaries
Chemical castration (GnRH agonists)
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6
Q

What is commonly seen with the use of GnRH agonists in breast cancer?

A

Because they are agonists, it will initially increase estrogen release so that things get worse (bone pain, hypercalcemia, breast tenderness) before getting better.

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7
Q

What are the three major treatment options for post-menopausal women with breast cancer?

A

SERMs, Aromatase inhibitors, SERDs

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8
Q

Why do SERMs, aromatase inhibitors, and SERDs have only a 6-12 month effect?

A

due to alternative estrogen (non-genomic) pathways

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9
Q

How do progesterone receptor negative cells spread?

A

can spread the “negativity” via a paracrine mechanism

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10
Q

What type of HRT has been show to increase risk of invasive breast cancer?

A

Estrogen + Progesterone can increase risk of breast cancer while estrogen alone shows a significant reduction in breast cancer

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11
Q

What types of drugs can target HER2 + tumors?

A

mAbs adn RTKIs

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12
Q

How are triple negative breast cancers managed?

A

conventional therapy/chemotherapy

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13
Q

What conventional chemotherapy is commonly used for triple negative breast cancer that often leads to cardiac issues in the years following treatment?

A

doxirubicin

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14
Q

What are the major consequences of BRCA1/2 mutations?

A

DNA strand breaks, dysfunctional break repair and uncontrolled cell cycling through abrogation of the normal checkpoint machinery

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15
Q

What clinical features warrent BRCA gene testing?

A
  • Breast cancer <45-50
  • Ovarian, fallopian tube or primary peritoneal cancer
  • 2+ primary breast cancer
  • Breast + ovarian cancer
  • Male breast cancer
  • 2+ family members with breast and/or ovarian cancer
  • Ashkenazi Jewish ancestry
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16
Q

What preventative treatment is available for women with BRCA mutations that decreases breast cancer risk by 90%?

A

prophylactic double mastectomy

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17
Q

What SERMs are used in BRCA carriers?

A

Tamoxifen
Raloxifene (post-menopausal only)
ONLY FOR BRCA2!!!!!

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18
Q

What percentage of BRCA1 carriers are ER+?

A

only 10-30%

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19
Q

What percentage of BRCA2 carriers are ER+?

A

60-75%

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20
Q

List the aromatase inhibitors. ROD?

A

Anastrozole
Exemestane
Letrozole
(all daily oral)

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21
Q

Which aromatase inhibitor is steroidal (irreversible)?

A

Exemestane

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22
Q

What are the indications for aromatase inhibitors?

A

ER+ metastatic BC in post-meno women for 5 years or swapping from AIs to tamoxifen, for a total period of 5 years

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23
Q

MOA of Aromatase inhibitors.

A

Aromatase inhibitors bind to heme center of CYP protein to block CYP19A1 mediated production of estrone and estradiol, thereby starving the tumor cell of continued proliferative signaling.

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24
Q

AEs of aromatase inhibitors.

A

Hot flashes, nausea, hair thinning (no effect on adrenal steroids, thyroid hormone and other hormones); more arthralgia and diarrhea but fewere gynecologic symptoms than SERMs

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25
List the SERMs.
Raloxifene (monthly IM) | Tamoxifen (daily PO)
26
List the 2nd generation SERM (derived from Tamoxifen).
Toreminfene (daily PO)
27
List the SERD used in breast cancer.
Fulvestrant (monthly IM)
28
List the GnRH agonist used in breast cancer.
Goserelin (SC q28d)
29
List the HER-2/neu Antibodies used in breast cancer.
Pertuzumab Trastuzumab Ado-Trastuzumab Emtasine all IV q28 days with taxane
30
What are the 3 components of Ado-Trastuzumab Emtasine?
trastuzumab, the cytotoxic agent DM1, and a linker that holds them together (emtansine is the linker-cytotoxic combination)
31
What is the TKI used in breast cancer?
Lapatinib (oral)
32
What is the mTOR inhibitor used in breast cancer?
everolimus
33
MOA: ER antagonist/agonist depending on the location of ER subtypes. When drug binds it recruits different sets of proteins called co-repressors (act through histone deacetylase I to stabilize nucleosome structure and prevent mRNA production in mammary tissue) OR co-activators (facilitate mRNA synthesis in bone to increase bone density). Lowers cholesterol, LDL, lipoproteins but increases Apo-A1
SERMs (Raloxifene, Tamoxifen, Toreminfene)
34
MOA: Leads to impaired receptor dimerization (via bulky substituent), increased turnover, disrupted nuclear localization, degradation.
SERD (Fulvestrant)
35
MOA: Providing continual drug stimulation of the GnRH receptors in the pituitary, the receptors down regulate and secretion of FSH and LH is attenuated (estrogen levels fall in 2-4 weeks)
Goserelin
36
MOA: Binds to the extracellular dimerization domain (Subdomain II). It blocks ligand-dependent hetero-dimerization of HER2 with other epidermal growth factor receptors, including HER3 and HER4.
Pertuzumab
37
MOA: Binds the juxtraglomerular region of the extracellular domain of HER2
Trastuzumab
38
MOA: Binds to the HER2 receptor which, upon internalization and breakdown in the lysosome, allows the thioester-linked chemotherapeutic (DM-1) to act on microtubules.
Ado-Trastuzumab Emtasine
39
MOA: Binds to the intracellular domain of the ErbB1 and ErbB2 receptors (HER1 and HER2) and competes with ATP. Inhibition of ATP binding prevents phosphorylation of the receptors and thus, prevents receptor activation.
Lapatinib
40
MOA: Binds to FKBP-12 and forms 3-way complex with mTOR that blocks protein action and downstream consequences such as angiogenesis, prolif, and cell metabolism.
Everolimus
41
What drugs require confirmation of overexpression of target (HER-2) by appropriate genetic tests (IHC 3+ or ISH+)? Test in every patient but also test in mets for stage IV patients.
Pertuzumab Trastuzumab Ado-Trastuzumab Emtasine
42
What drug is used in pre-menopausal women with breast cancer?
Goserelin
43
Using tamoxifen for how many years can half cancer mortality?
10 years
44
TOXICITY: BBW: DVT, PE, stroke; TERATOGEN; high dose retinal degeneration
Raloxifene
45
TOXICITY: BBW: endometrial hypertrophy, vaginal bleeding, endometrial cancer (agonist activity), DVT, PE, stroke; TERATOGEN; high dose retinal degeneration
Tamoxifen
46
TOXICITY: Long QT; no BBW; avoid with Hx of endometrial cancer/hyperplasia or thromboembolis disease; TERATOGEN
Toreminfene
47
TOXICITY: Nausea, HA, asthenia, pain, hot flashes
Fulvestrant
48
TOXICITY: amenorrhea, hot flashes, decreased libido, vaginal dryness, emotional lability, depression, sweating, gynecomastia, HA, N/V, edema, lethargy, anorexia, decrease bone density??
Goserelin
49
TOXICITY: BBW: TERATOGEN; Alopecia, loss of appetite; RARE: decrease LVEF, neutropenia, and leukopenia
Pertuzumab
50
TOXICITY: BBW: TERATOGEN, Infusion reactions, RDS, respiratory insufficiency, cardiomyopathy; Peripheral edema, rash, weight gain, URTIs, pharyngitis; RARE: HF, Renal failure, hepatotoxic, pneumonia
Trastuzumab
51
TOXICITY: BBW: TERATOGEN, hepatic disease, heart failure, ventricular dysfunction
Ado-Trastuzumab Emtasine
52
TOXICITY: BBW: Liver disease (increased levels and persistence of drug, elevates LFTs—routine monitoring); GI toxicity, anemia/thrombocytopenia, hand-foot syndrome, rash, HA, backache, ILD/ pneumonitis, long QT
Lapatinib
53
TOXICITY: IMMUNOSUPPRESSANT so increased risk of opportunistic infections, neoplasia (lymphoma/SCC), non-infectious pneumonitis, blood dyscrasias, hyper-glycemia, -lipidemia, -TGemia, elevated creatinine and liver enzymes; N/V, diarrhea, pain, constipation
Everolimus
54
What do you have to monitor when taking everolimus?
glucose, CBC, LFTs, etc.
55
When do you use everolimus?
Used in advanced ER+, HER2- tumors with Exemestane
56
How do you manage a "low grade" prognostic tumor?
vigilance is more appropriate than treatment
57
How do you manage a "high grade" prognostic tumor?
tumors with a genetic signature of highly invasive and rapidly proliferating disease are excellent candidates for immediate adjuvant therapy.
58
Endometrial cancer is treated by what two drugs?
medroxyprogesterone and megestrol
59
What is the similar effect that medroxyprogesterone and megestrol have on the HPA axis?
suppress it (reduce hypothalamic stimulation of hormonally responsive tissue)
60
MOA: Bind to progestin receptors and block GnRH release
Medroxyprogesterone (IM weekly) | progestin contraceptive
61
MOA: Suppresses pituitary LH release and enhances estrogen degradation. Promotes differentation and maintenance of endometrial tissue.
Megestrol (oral) | synthetic oral progestin used in anorexia
62
Toxicity of Medroxyprogesterone?
Amenorrhea, edema, anorexia, weakness
63
Toxicity of Megestrol?
Weight gain (increased appetite), hot flashes, malaise, asthenia, lethargy, sweating, rash; tumor flare and hypercalcemia in BC patients with bony mets; thrombophlebitis and emboli

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