What are some of the common mutations in breast cancer?
Heterogenous dz. MOST COMMON: loss of TP53 function & PIK3CA function. Others: GATA3, MAP3K1, MLL3, BRCA1/BRCA2
What do BRCA1/2 do?
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.
What are some options for carriers of BRCA1/2 mutations?
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.
Why/when do genetic testing for BRCA1/2 mutations?
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
What are the 3 important cell surface receptors that could be targeted in breast ca tx?
estrogen, progesterone and human epidermal growth factor-2 (HER-2/neu) receptors
*Tx HER2/neu+ w/ Mabs or RTKIs.
Tx options for premenopausal women w/ ER+ tumors?
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
Tx options for postmenopausal women w/ ER+ tumors?
There is peripheral aromatization of steroids in PM women. USE: aromatase inhibitors, SERMS, selective estrogen receptor down regulators (SERDS)
Cellular MOA of estrogen?
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
What are some anti-estrogenic approaches to tx?
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.
SERDs: Fulvestrant
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
SERMs: Tamoxifen & Raloxifen
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.
SERMs: Toremifene
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.
How does a drug posses both agonistic & antagonistic effects?
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.
What are some products of Tamoxifen metabolism by CYP2D6?
4-0H-Tamoxifen & Enoxifen => more potent than parental agent
What do aromatase inhibitors block?
CYP19A1 mediated production of estrone & estradiol. Drug binds to heme center of CYP protein.
AIs: Anastrozole, Letrozole, Exemestane
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
When is aromatase therapy indicated?
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.
What is the optimal duration of tamoxifen or AI tx?
ATLAS trial showed that 10 yrs of tamoxifen benefits outweighs risk of endometrial ca.
What are some testing guides for HER2 therapy?
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
Cellular MOA of Trastuzumab, Pertuzumab, Trastuzumab emtansine and Lapatinib?
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.
Ado-Trastuzumab
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.
Adverse effects of both Trastuzumab & Pertuzumab?
hypersensitivity rxn & their sequelae like asthenia, fatigue, GI upset, blood dyscrasias.
*Both drugs taken w/ taxane
Common AE of Pertuzumab
Alopecia, loss of appetite. TERATOGEN.
Common AE of Trastuzumab
Peripheral edema, rash, weight gain, dizziness, URTIs, pharyngitis
Rare AE of Pertuzumab
decr LVEF, neutropenia, leukopenia
Rare AE of Trastuzumab
Cardiomyopathy, HF, renal failure, hepatotoxicity, pneumonia, resp failure. Pregnancy contraindication.
Sequelae to infusion rxn: resp distress syndrome + resp insufficiency
BBW for Ado-Trastuzumab
Heart failure, hepatic dz, pregnancy, ventricular dysfunction
The only RTKI approved for tx of BC?
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.
What’s a GnRH agonist used to tx BC?
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
What does mTOR do?
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.
Name an mTOR inhibitor used in BC tx?
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.
How do you treat triple negative BC?
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
Triple Negative BC management
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
What are some standard adjuvant chemo regimens?
Cyclophosphamide, doxorubicin, taxol, fluorouracil, docetaxel
*Most women on doxorubicin go on to have cardiac issues in yrs following successful survival of BC
What about progesterone and its role in BC?
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.
PR+ BC is favorable or unfavorable?
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.
What about HRT?
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
What are some drugs for endometrial ca?
1) Medroxyprogesterone = progestin contraceptive
2) Megestrol = synthetic oral progestin
Medroxyprogesterone
Binds to progestin receptors & blocks GnRH release.
AE: amenorrhea, edema, anorexia, weakness
Megestrol
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)