Breast and Cervical Cancers Flashcards
Common Site of Metastatic Disease in Breast Cancer (3)
- BONE and soft tissue (skin, peritoneal): typically respond to endocrine therapy
- Visceral (lung, liver): requires chemotherapy
- Brain: commonly seen with HER2 positive disease
Treatment Principles of Breast Cancers in Stages I and II (3)
- Goal of therapy: Cure
- Surgical management: Lumpectomy or mastectomy + axillary lymph node dissection (?)
- Radiation: Lumpectomy, tumor > 5cm, positive surgical margins + lymph nodes
Treatment Principles of Breast Cancers in Stage III (4)
- Goal: Cure
- Surgical management: Lumpectomy or mastectomy + axillary lymph node dissection, breast conserving surgery an option
- Chemotherapy
- Radiation
Treatment Principles of Breast Cancers in Stage IV (2)
- Goal of therapy= palliation: Maintain quality of life, potentially prolong survival
- Median survival: 3 years
Breast Cancer Receptors (3)
- Growth of breast tissue is dependent on hormones: Estrogen, progesterone, androgens, prolactin, insulin-like growth factors
- Tumor expressing receptors retain hormonal sensitivities of normal breast tissue:
- Estrogen Receptor (ER)
- Progesterone Receptor (PR)
- Human Epidermal Growth Factor Receptor (HER2) - First neoplasm responded to hormonal manipulation
Breast Cancer Adjuvant Therapies (4)
AC→TH (A=Anthracyclines, C=Cyclophosphamide, T=Taxane, H=Herceptin)
- Anthracyclines (doxorubicin) MOA: DNA strand breakage mediated by anthracycline effects on topoisomerase II; DNA intercalation; DNA polymerase inhibition
- Cyclophosphamide MOA: Metabolism of cyclophosphamide by hepatic enzymes produces active alkylating metabolite which alkylates DNA and inhibits DNA synthesis
- Taxane (paclitaxel, docetaxel) MOA: Enhanced formation and stabilization of microtubules. Mitotic arrest is seen with accumulated polymerized microtubules
- Herceptin
Anthracyclines (Doxorubicin) MOA and ADRs
MOA: Intercalation into DNA. Inhibition of topoisomerase II. Generation of semiquinone free radicals and oxygen free radicals.
ADRs:
1. CARDIOTOXICITY - Cardiac tissue lacks catalase. The only route for hydrogen peroxide is through Fenton pathway to form hydroxy radical)
1A. Irreversible congestive heart failure: Get baseline of left ventricular ejection fraction before starting therapy, check after treatment – impacted patient show a decrease in left ventricular ejection fraction (~10-20% decrease from baseline), related to generation free radicals, treat with CHEMOPROTECTIVE AGENT (iron chelator – dexrazoxane). Signs of ACUTE toxicity: arrhythmias and conduction abnormalities. Signs of CHRONIC toxicity: dose-dependent, dilated cardiomyopathy associated with heart failure.
2. Alopecia
3. Mucositis
4. Stomatitis
Cyclophosphamide (Acrolein) MOA and ADRs
MOA: Cyclophosphamide is a prodrug. Converted to aziridinium ion. During activation form acrolein (UROTOXIC).
ADRs:
1. Hemorrhagic cystitis - Can be seen after start of treatment; patient presents with blood in urine. The nucleophilic -SH group of the bladder cell cysteine residues are alkylated by acrolein. Severe hemorrhage, sclerosis, and possible induction of bladder cancer. MINIMIZE EFFECT of acrolein- Hydration and Mesna (CHEMOPROTECTIVE AGENT).
Taxanes (Docetaxel and Paclitaxel) MOA and ADRs
MOA: Promote microtubule formation by inhibiting the disassembly of tubulin. Taxanes bind to the intermedia surface of the beta-tubulin to decrease depolymerization. Antagonizes the disassembly of tubulin. Promotes the micro tubular polymerization and elongation. Cell cycle arrest in mitosis.
ADRs:
- Alopecia
- Peripheral neuropathy
Other Breast Cancer Therapies (3)
- Epidermal Growth Factor Receptor (HER2 positive)
- Herceptin
- Lapatinib - Treatment of estrogen receptor positive tumors
- Estrogen receptor antagonist (Fulvestrant, Tamoxifen)
- Estrogen synthesis inhibitor (Aromatase Inhibitor - Anastrolzole, Letrozole, Exemestane) - PI3K Inhibitor (Hormone receptor positive & HER2 negative)
- Alpelisib – FDA approved 6/3/19—35% of breast cancers have a mutation in PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha)
Trastuzumab (Herceptin) MOA and ADRs (4)
MOA: Recombinant humanized antibody.
– Selectively binds to HER-2
– Down regulation of HER-2 receptors
– Decrease cellular proliferation
– Inhibits cell cycle progression by decreasing cells entering S phase
– ADCC, CDC and apoptosis of cells overexpressing HER-2
ADRs:
– Cardiomyopathy (HER-2 receptors in heart tissue)
– Infusion-related reactions (fever, chills)
– Hypersensitivity reactions (including anaphylaxis)
– Myelosuppression
Lapatinib (Tykerb) MOA and ADRs (4)
MOA:
- Inhibits the kinase components of the EGFR and HER2
- Inhibits autophosphorylation by EGFR-TK
- Blockage of downstream EGFR signal transduction pathway and arrest of tumor growth
ADRs: – Anemia – Diarrhea, nausea, vomiting – Elevated hepatic enzymes – Hand and foot syndrome
Estrogen Inhibitors (SERMs vs. SERDs)
- Selective estrogen-receptor modulators (SERMs):
- Multifunctional drugs
- Not pure estrogen-receptor antagonists
- Act as estrogenic antagonists in some tissues, while being estrogenic agonists in other tissues - Selective estrogen-receptor downregulators (SERDs):
- Pure estrogen-receptor antagonists
Aromatase Inhibitors (Anastrolzole, Letrozole, Exemestane) MOA and ADRs
MOA: Aromatase converts androgens to estrogens. Blocking the aromatase enzyme can effectively inhibit the estrogen formation
ADRs:
1. Osteoporotic fractures
PI3K Inhibitor (Alepisib) MOA and ADRs (3)
MOA: 35% of breast cancers have a mutation in PIK3CA. Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors. In breast cancer cell lines, alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth. PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased antitumor activity compared to either treatment.
ADRs:
- Increases in glucose, creatinine, ALT, hemoglobin, lipase
- Diarrhea, rash, nausea, fatigue, alopecia, activated partial thromboplastin time (aPTT) prolonged
- Decreases in lymphocyte count, appetite, calcium weight
