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Flashcards in Breast & Endometrial Ca Deck (40)
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1
Q

What are some of the common mutations in breast cancer?

A

Heterogenous dz. MOST COMMON: loss of TP53 function & PIK3CA function. Others: GATA3, MAP3K1, MLL3, BRCA1/BRCA2

2
Q

What do BRCA1/2 do?

A

Mediates homologous recombination & cell cycle regulation (S & G2 phases) when bound to different macro complexes. Consequence of BRCA1/2 are DNA strand breaks, dysfunctional break repair & uncontrolled cell cycling through abrogation of normal checkpoint machinery –> incr division of cells carrying DNA damage & process of carcinogenesis.

3
Q

What are some options for carriers of BRCA1/2 mutations?

A

1) Surgery–mastectomy & BSO
2) SERMs (selective estrogen receptor modulators)–tamoxifen or raloxifene (for PM women) if mutation in BRCA2 since these drugs are ineffective for BRCA1 mutation due to absence of estrogen signaling.

4
Q

Why/when do genetic testing for BRCA1/2 mutations?

A

1) early onset breast ca (<50 or 45)
2) ovarian, fallopian tube or peritoneal ca
3) 2 or more primary breast ca, or breast + ovarian ca in same individual
3) male breast ca
4) 2 or more ppl in fam hx w/ breast &/or ovarian ca
5) Ashkenazi Jewish ancestry

5
Q

What are the 3 important cell surface receptors that could be targeted in breast ca tx?

A

estrogen, progesterone and human epidermal growth factor-2 (HER-2/neu) receptors
*Tx HER2/neu+ w/ Mabs or RTKIs.

6
Q

Tx options for premenopausal women w/ ER+ tumors?

A

Surgical removal of ovaries or chemical castration w/ GnRH agonists or antagonists that down regulate HP axis control.
SERMs can be used to block estrogen receptor in tumor (but generally reserved for PM women)
*No drugs for peripheral aromatization

7
Q

Tx options for postmenopausal women w/ ER+ tumors?

A

There is peripheral aromatization of steroids in PM women. USE: aromatase inhibitors, SERMS, selective estrogen receptor down regulators (SERDS)

8
Q

Cellular MOA of estrogen?

A

Binding leads to activation & dimerization of ER, which translocates to nucleus & activates target gene expression via interaction w/ ERE, coactivators or other TFs.
Membrane bound ERs can interact w/ growth factor receptor tyrosine kinase or downstream molecules.
Need drugs that target: MAPK, PI3K, AKT, Src

9
Q

What are some anti-estrogenic approaches to tx?

A

SERMs, SERDs, and AIs.
Initial response not sustained for long since alternative prolif pathways take over
PR+ & ES- tumors respond to HT
Response in 8-12 wks. Avg remission 6-12 months but sometimes yrs.

10
Q

SERDs: Fulvestrant

A

Only SERD currently used to tx BC. Binds to ER but carries bulky substituent that prevents dimerization of ERs in the nucleus => sustained down regulation in ER expression. NO estrogenic actions of this drug.
ADVERSE effects: PM symptoms (N/headache/pain/vasodilation or hot flashes/ asthenia)
Hepatic metabolism, no drug interactions
Monthy IM, sustained plasma levels

11
Q

SERMs: Tamoxifen & Raloxifen

A

ER agonist/antagonist. Location of ER subtypes (alpha & beta). ESTROGEN EFFECT ON BONE. ANTI-ESTROGEN EFFECT ON MAMMARY TISSUE.
PO–Tam, and IM–Ral
Decr bone metabolism (incr bone mineral density). Decr serum cholesterol, LDL, lipoproteins, and incr Apolipoprotein-A1. Retinal degradation @ high doses. TERATOGENS
AE: endometrial hypertrophy, vaginal bleeding, stroke, thromboembolic dz (DVT or PE)
TAMOXIFEN also can cause ENDOMETRIAL CA.

12
Q

SERMs: Toremifene

A

Derivative of tamoxifen w/ antiestrogenic properties. PO. CYP3A4 metabolism. TERATOGEN.
AE: prolongs QT interval. Avoid w/ preexisting conditions or w/ 3A4 inhibitors.
Avoid if hx of endometrial ca/hyperplasia or thromboembolic dz.

13
Q

How does a drug posses both agonistic & antagonistic effects?

A

When ER bound by an antagonist like tamoxifene, it dimerizes and recruits set a proteins called co-repressors that act through histone deacetylase I to stabilize nucleosome structure & prevent mRNA production.
Expression of ancillary proteins & of estrogen receptor itself can give rise to agonistic actions in some tissues & antagonistic actions in others.
Tamoxifen represses estrogen activity in breast but acts as an agonist in endometrium.

14
Q

What are some products of Tamoxifen metabolism by CYP2D6?

A

4-0H-Tamoxifen & Enoxifen => more potent than parental agent

15
Q

What do aromatase inhibitors block?

A

CYP19A1 mediated production of estrone & estradiol. Drug binds to heme center of CYP protein.

16
Q

AIs: Anastrozole, Letrozole, Exemestane

A

Non-steroidal–reversible inhibitors. Steroidal ones (Exemestane) are irreversible inhibitors. PO. Hepatic metabolism.
AE: hot flashes, nausea, hair thinning. No effect on adrenal steroids, thyroid or other hormones. More arthralgia & diarrhea but fewer gyn symptoms than tamoxifen

17
Q

When is aromatase therapy indicated?

A

In PM women w/ hormone ER+ early BC. Adjuvant to tamoxifen. Use AI for 5 yrs or swapping from AIs to tamoxifen again for a total period of 5 yrs is better than the use of tamoxifen alone.

18
Q

What is the optimal duration of tamoxifen or AI tx?

A

ATLAS trial showed that 10 yrs of tamoxifen benefits outweighs risk of endometrial ca.

19
Q

What are some testing guides for HER2 therapy?

A

IHC or ISH assay. Must request testing for every primary invasive ca (& on the metastatic site if stage IV). Delay tx decision if test is equivocal. Consider targeted tx if a test remains equivocal even after reflex testing w/ alternative assay

20
Q

Cellular MOA of Trastuzumab, Pertuzumab, Trastuzumab emtansine and Lapatinib?

A

Binds to juxtraglomerular region of extracell domain of HER2.
*Pertuzumab binds to extracell dimerization domain (Subdomain II).
Both block ligand-dependent heterodimerization of HER2 w/ other EGFR like HER3/4.
*Trastuzumab emtansine (T-DM1) binds to receptor, which upon internalization, allows thioester-linked chemotherapeutic to act on microtubules.
These 3 are based on IgG1 kappa immunoglobulin.
*Lapatinib is small molecule TKI that inhibits HER1/2. Binds to intracell domain of ErbB1/2 receptors & competes w ATP. Prevents phosphorylation of receptors and receptor activation.

21
Q

Ado-Trastuzumab

A

Trastuzumab emtansine = Ab-drug conjugate that selectively binds to HER2-overexpressing tumor cells.
Components of drug: monoclonal Ab, cytotoxic agent DM1, linker that holds them together. Linker + cytotoxic agent = emtansine
Inside cell, molecule breaks apart in lysosome & DM1 interferes w/ microtubules, preventing cell division.

22
Q

Adverse effects of both Trastuzumab & Pertuzumab?

A

hypersensitivity rxn & their sequelae like asthenia, fatigue, GI upset, blood dyscrasias.
*Both drugs taken w/ taxane

23
Q

Common AE of Pertuzumab

A

Alopecia, loss of appetite. TERATOGEN.

24
Q

Common AE of Trastuzumab

A

Peripheral edema, rash, weight gain, dizziness, URTIs, pharyngitis

25
Q

Rare AE of Pertuzumab

A

decr LVEF, neutropenia, leukopenia

26
Q

Rare AE of Trastuzumab

A

Cardiomyopathy, HF, renal failure, hepatotoxicity, pneumonia, resp failure. Pregnancy contraindication.
Sequelae to infusion rxn: resp distress syndrome + resp insufficiency

27
Q

BBW for Ado-Trastuzumab

A

Heart failure, hepatic dz, pregnancy, ventricular dysfunction

28
Q

The only RTKI approved for tx of BC?

A

Lapatinib. Extensive hepatic metabolism: CYP3A4 & 5.
LIVER DZ or dysfunction => incr levels & persistence
Common AE: GI issues toxicity, anemia & thrombocytopenia, HAND FOOT SYNDROME, rash pain, headache, back ache.
Serious AE: interstitial lung dz/pneumonitis; QT prolongation.

29
Q

What’s a GnRH agonist used to tx BC?

A

Goserelin. SC injection in upper and wall. Common side effects related to hypo-estrogenic actions: amenorrhea, hot flashes, decr libido, vaginal dryness, emotional lability, depression, sweating, gynecomastia, headache, N/V, peripheral edema, lethargy, anorexia
AE: decr bone density, osteopenia/osteoporosis, may be irreversible
Risk factors: chronic alc/tobacco abuse, fam hx of osteoporosis, chronic drugs that decr bone mineralization

30
Q

What does mTOR do?

A

Regulates cell prolif, angiogenesis, cell metabolism by activating or inhibiting protein synthesis upon receipt of appropriate biochem signals.
Binds to FKBP-12 & forms a 3-way complex w/ mTOR that blocks protein action & downstream consequences.

31
Q

Name an mTOR inhibitor used in BC tx?

A

Everolimus = macrolide immunosuppressant & analog of serolimus. Used in advanced ER +ve, HER-2 -ve tumors w/ A1 exemestane.
CYP3A4 & P-gp substrate; 3A4, 2D6 inhibitor & P-gp inhibitor.
**RISK OF OPPORTUNISTIC INFECTIONS–NEOPLASIA, LYMPHOMA/SCC.
Non-infectious pneumonitis. Blood dyscrasias, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated creatine–liver enzymes. N/V. Diarrhea, pain, constipation.
TESTS: blood glucose, CBC w/ differential, LFTs, serum bilirubin-creatinine-lipid profile-phosphate-triglycerides.

32
Q

How do you treat triple negative BC?

A

Excision of primary tumor + lymph nodes is standard for early stage dz.
Drugs + radiation used as adjuvant to prevent recurrence or neoadjuvant role prior to excision.
For triple neg = systemic tx w/ conventional chemo

33
Q

Triple Negative BC management

A

If lymph nodes + => adjuvant anthracycline/taxane-based chemo
If lymph nodes - => T1a ( T1b (0.6-1cm) = consider chemo
If lymph nodes - => T1c (>1cm) = adjuvant chemo

34
Q

What are some standard adjuvant chemo regimens?

A

Cyclophosphamide, doxorubicin, taxol, fluorouracil, docetaxel
*Most women on doxorubicin go on to have cardiac issues in yrs following successful survival of BC

35
Q

What about progesterone and its role in BC?

A

It directly regulates gene transcription through 2 specific progesterone receptor proteins, A & B in target tissues such as breast, uterus, brain, CNS, heart. These proteins arise from a single gene & act as ligand-inducible TFs, regulating expression of genes by binding specific progesterone responsive elements on DNA. PR activity controlled by SUMOylation (form of ubiquitination) & post-translational phosphorylation. PR can have repressive control over ER activity.
-P promotes pre-neoplastic progression by stimulating cyclic prolif of mature breast epithelium & activate mammary stem cell pools or occult tumor initiating cells. Switch from paracrine to autocrine regulation of prolif contributes to progression.

36
Q

PR+ BC is favorable or unfavorable?

A

Favorable! More differentiated & less invasive phenotype. Loss of PR in ER+ tumors is associated w/ more aggressive tumors, reduced responsiveness to endocrine therapies & shorter overall survival.

37
Q

What about HRT?

A

WHI trials do not support use for chronic dz prevention, although it’s appropriate for symptom management in some women.

  • E+P - 28% incr risk of invasive BC
  • Estrogen alone was associated w/ 21% reduction in breast ca
38
Q

What are some drugs for endometrial ca?

A

1) Medroxyprogesterone = progestin contraceptive

2) Megestrol = synthetic oral progestin

39
Q

Medroxyprogesterone

A

Binds to progestin receptors & blocks GnRH release.

AE: amenorrhea, edema, anorexia, weakness

40
Q

Megestrol

A

Sometimes used for breast ca
Suppresses pit release of LH & enhances estrogen degradation
Promotes differentiation/maintenance of endometrial tissue (wieght gain, hot flashes, malaise, asthenia, lethargy, sweating, rash, tumor flare & hypercalcemia in BC pts w/ bony mets, thrombophlebitis, thrombo- or PE)