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Reproduction Pharmacology > Treatment of Breast & Endometrial Cancer > Flashcards

Treatment of Breast & Endometrial Cancer Flashcards

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1
Q

Aromatase Inhibitors Drugs:

A

Anastrozole
Letrozole
Exemestane

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2
Q

SERDs & SERMs Drugs:

A

Raloxifene
Tamoxifen
Toremifene
Fulvestrant

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3
Q

HER-2/neu Antibodies Drugs:

A

Pertuzumab
Trastuzumab
Ado-Trastuzumab Emtasine

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4
Q

TKI Drugs:

A

Lapatinib

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5
Q

GnRH Agonist Drugs:

A

Goserelin

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6
Q

mTOR Inhibitor Drugs:

A

Everolimus

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7
Q

BRCA1 & BRCA2 Function:

A

Tumor suppressors involved in repair of double strand breaks.

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8
Q

PIK3CA Function:

A

Catalytic subunit of PI3 kinase; key signal transduction enzyme involved in cellular growth, survival and insulin signaling.

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9
Q

TP53 Function:

A

Tumor suppressor; key regulator of cell cycle, DNA repair, apoptosis.

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10
Q

GATA3 Function:

A

Transcription factor which regulates luminal epithelial cell differentiation in the mammary gland.

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11
Q

MAP3K1 Function:

A

Kinase that activates ERK and JNK kinase pathways.

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12
Q

MLL3 Function:

A

Histone-lysine N-methyltransferase involved in transcriptional co-activation.

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13
Q

Options for Mutant BRCA1/2 Carriers Prophylactic

A

Mastectomy and bilateral salpingo-oophorectomy (BSO) in order to decrease the risk of breast and ovarian cancer.

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14
Q

Bilateral mastectomy decreases breast cancer risk by?

A

90%

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15
Q

Options for Mutant BRCA1/2 Carriers Chemoprevention?

A

tamoxifen or raloxifene

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16
Q

Prospective study indicates 50% reduction in risk for BRCA2 mutation carriers but no effect for BRCA1 carriers. Why?

A
  • 60-75% BRCA2-tumors are ER+

* 70-90% of BRCA1-tumors are ER-

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17
Q

Clinical features that warrant referral for genetic

testing for BRCA1/2 mutations?

A
  • Early-onset breast cancer, (< age 50 or 45)
  • Ovarian, fallopian tube or primary peritoneal cancer
  • Individuals with 2 or more primary breast cancers, or breast & ovarian cancer in the same individual
  • Male breast cancer
  • 2 or more individuals in the family with breast and/or ovarian cancer
  • Ashkenazi Jewish ancestry
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18
Q

A significant number of patients with ER- or PR-positive tumors

A

Respond to hormonal therapy. Clinically response in 8 to 12 weeks to detect.

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19
Q

Anti-estrogen therapy includes:

A

Selective Estrogen Receptor Downregulators (SERDs)
Selective Estrogen Receptor Modulators (SERMs)
Aromatase Inhibitors (AI)

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20
Q

Fulvestrant Mechanism:

A

Pure antagonist; no estrogenic actions.

Impaired dimerization, increased turnover, disrupted nuclear localization, degradation leading to decrease ER levels.

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21
Q

Fulvestrant used in treatment for?

A

For ER+ metastatic BC in PM women with disease

progression following anti-estrogen therapy.

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22
Q

Fulvestrant
Administer:
Metabolism:
Side Effects:

A 
Monthly IM: sustained plasma levels
Hepatic metabolism; no drug interactions
Adverse effects – PM symptoms
– Nausea, asthenia, pain, vasodilation (hot flashes),
& headache
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23
Q

Fulvestrant Failure of therapy

A

Estrogen-independent cell growth

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24
Q

Tamoxifen & Raloxifene Mechanism:

A

ER agonist/antagonist
– Location of ER subtypes (α and β)
– Estrogen effect on bone
– Anti-estrogen effect on mammary tissue

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25
Tamoxifen Dosage:
Daily PO [Tam]
26
Raloxifene Doseage:
Monthly IM [Ral]
27
Tamoxifen & Raloxifene Effects:
– Decrease bone metabolism (Increase bone mineral density) | – Decrease serum cholesterol, LDL, lipoproteins, and Increase apolipoprotein-A1
28
Tamoxifen & Raloxifene High dosage causes?
– Retinal degeneration at high doses | – Teratogens
29
Tamoxifen BBW:
``` Endometrial hypertrophy, vaginal bleeding, endometrial cancer. Thromboembolic disease (DVT or PE), Stroke. ```
30
Raloxifene BBW
Thromboembolic disease (DVT or PE), Stroke.
31
Toremifene Mechanism:
Derivative of tamoxifen with antiestrogenic properties.
32
Toremifene Dosage:
PO Daily; CYP3A4 metabolism (no active products)
33
Toremifene Side effects & CI:
* Teratogen * Similar adverse effects – except prolongs QT interval. Avoid in pre-existing condition & with 3A4 inhibitors * NO other BBWs BUT recommended avoid with Hx of: Endometrial cancer/hyperplasia, Thromboembolic disease
34
AIs: Mechanism: Anastrozole & Letrozole
Non-steroidal – reversible inhibitor
35
AIs: Mechanism: Exemestan
Steroidal - irreversible inhibitor
36
AI: Anastrozole, Letrozole, & Exemestan Dosage:
Daily oral: hepatic metabolism
37
AI: Anastrozole, Letrozole, & Exemestan | Side Effects:
• Hot flashes, nausea, hair thinning No effect on adrenal steroids, thyroid & other hormones. • More arthralgia & diarrhea but fewer gynecologic symptoms than tamoxifen
38
The American Society of Clinical Oncology recommends that all postmenopausal women with hormone receptor positive early breast cancer?
Receive adjuvant aromatase inhibitor therapy.
39
Aromatase Therapy Options include:
5 years of an aromatase inhibitor or sequential therapy with 2—3 years or 5 years of tamoxifen followed by 2—3 years or 5 years of an aromatase inhibitor.
40
Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial Findings?
Benefit of reduced breast cancer recurrence & mortality with 10 yrs of adjuvant tamoxifen vs. 5 yrs out weighs increase risk of endometrial cancer (in PM women).
41
Testing Guides for HER2 Therapy Which tests?
Immunohistochemistry (IHC) or in situ hybridization (ISH) assay.
42
Testing Guides for HER2 Therapy Test Results:
A positive test is IHC 3+ or ISH positive, equivocal is IHC 2+ or ISH equivocal, and negative is IHC 1+ or IHC 0 or ISH negative
43
Testing Guides for HER2 Therapy When to test?
Must request testing for every primary invasive cancer (and on the metastatic site if stage IV) – Should recommend targeted therapy if the test is positive • Must delay treatment decision if initial test result is equivocal – Must not recommend targeted therapy after negative tests • May consider HER2-targeted therapy if a test result remains equivocal, even after reflex testing with an alternative assay.
44
Her-2/neu: Drugs
Pertuzumab, Trastuzumab, & Ado-Trastuzumab
45
Pertuzumab Mechanism:
A monoclonal antibody "HER dimerization inhibitors" by binding to HER2, it inhibits the dimerization of HER2 with other HER receptors.
46
Trastuzumab Mechanism:
is a monoclonal antibody that interferes with the HER2/neu receptor.
47
Ado-Trastuzumab Mechanism:
An antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the toxin specifically to tumor cells.
48
Pertuzumab, Trastuzumab | Dosage:
IV Q21D: long half-lives
49
Pertuzumab, Trastuzumab | Reaction:
Caution; hypersensitivity reactions with initial dose
50
Pertuzumab, Trastuzumab | Common Adverse Effects:
GI upset, asthenia, blood dyscrasias, fatigue
51
Pertuzumab | Unique AE:
Alopecia, loss of appetite | Increase LVEF, neutropenia & leukopenia.
52
Trastuzumab | Unique AE:
Peripheral edema, rash, weight gain, dizziness, URTIs, pharyngitis, fatigue Cardiomyopathy & HF, renal failure, hepatotoxicity, pneumonia & respiratory failure
53
Pertuzumab BBWs
Pregnancy
54
Trastuzumab BBWs
``` Cardiomyopathy Infusion reactions Pregnancy Respiratory distress syndrome* Respiratory insufficiency* *Sequelae of infusion reactions ```
55
Ado-Trastuzumab BBWs
Heart failure Hepatic disease Pregnancy Ventricular dysfunction
56
Lapatinib Mechanism:
Dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways.
57
Lapatinib Metabolism:
Extensive hepatic metabolism; CYP3A4 & 5 • Liver disease or dysfunction will lead to increase levels & persistence • Elevates LFTs; routine monitoring required
58
Lapatinib Common AE:
GI issues toxicity, anemia & thrombocytopenia, hand-foot syndrome, rash pain, headache, backache.
59
Lapatinib Serious AE:
Interstitial lung disease/pneumonitis; QT prolongation.
60
Hormonally-responsive tumors Mechanism:
Down-regulation of the GnRH receptor on the pituitary gland and ultimately decreased production of FSH and LH. Serum levels of estradiol consequently fall to post-menopausal levels in 2-4 weeks.
61
Goserelin Mechanism:
GnRH agonist
62
Goserelin Administered:
SC injection q 28d in upper abdominal wall
63
Goserelin Side Effects:
(hypo-estrogenic action) Amenorrhea, hot flashes, decrease libido , vaginal dryness, emotional lability, depression, sweating, and gynecomastia. Also headache, N/V, peripheral edema, lethargy & anorexia
64
Goserelin Bone effects:
Decrease bone density, osteopenia/osteoporosis.
65
Everolimus Mechanis:
mTOR regulates cell proliferation, angiogenesis, and cell metabolism by activating or inhibiting protein synthesis upon receipt of appropriate biochemical signals. Drug binds to FKBP-12 & forms a 3-way complex with mTOR that blocks protein action & downstream consequences.
66
Everolimus Used in advanced:
ER +ve, HER-2 –ve tumors, with exemestane
67
Everolimus Inhibitor:
CYP3A4 & P-gp substrate; 3A4, 2D6 inhibitor & P-gp inhibitor
68
Everolimus Side Effects
• Non-infectious pneumonitis – sometimes fatal • Blood dyscrasias, hyperglycemia, hyperlipidemia, hypertriglyceridemia, & elevated creatinine - liver enzymes • N/V, diarrhea, pain, constipation
69
Everolimus BBW:
Risk of opportunistic infections – neoplasia; lymphoma/SCC
70
Triple Negative Breast Ca Excision of primary tumor & lymph nodes is standard practice for?
Early stage disease
71
Triple Negative Breast Ca Drugs and/or radiation are utilized in an?
Adjuvant role to prevent recurrence of disease or a neoadjuvant role prior to excision
72
Advanced tumor - metastatic disease - triple negative breast cancer (TNBC; estrogen receptor –ve, progesterone receptor –ve & HER-2/neu –ve) TREATMENT:
Systemic treatment with conventional chemotherapeutic agents is the norm
73
PR+ in primary breast cancers =
Favorable prognosis More differentiated, less invasive phenotype PR+ is also predictive of better overall survival
74
Loss of PR in ER+ tumors is associated with?
A more aggressive tumor phenotype, reduced responsiveness to endocrine therapies, & a shorter overall survival.
75
Menopausal hormone therapy: A combination of estrogen and progestin [Prempro] was associated with?
A 28% increased risk of invasive breast cancer.
76
Menopausal hormone therapy: Estrogen alone was associated with a significant?
(21%) reduction in breast cancer.
77
Drugs for Endometrial Cancer
Medroxyprogesterone | Megestrol
78
Medroxyprogesterone Mechanism:
A progestin contraceptive: Bind to progestin receptors & block GnRH release.
79
Medroxyprogesterone Side Effects:
Amenorrhea, edema, anorexia, weakness
80
Megestrol Mechanism:
Synthetic oral progestin: Suppresses pituitary LH release & enhances estrogen degradation. Promotes differentiation/maintenance of endometrial tissue.
81
Megestrol Side Effects:
Weight gain (increased appetite), hot flashes, malaise, asthenia, lethargy, sweating (diaphoresis) & rash (unspecified)
82
Megestrol Adverse Effects:
Thrombophlebitis, thrombo- or pulmonary-embolism

Reproduction Pharmacology (9 decks)

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