Done by: Heba Jaamour May 2022. Treatment Approaches in Breast Cancer Curative intent: Treatment with a curative intent is advised for clinical stage I, II, and III disease. Palliative intent: Treatment with palliative intent is appropriate for all patients with stage IV (metastatic) disease and for patients with unresectable local cancers. Class Anthracyclines Alkylating agent Drug MOA Side Effects Doxorubicin Intercelates with the DNA ⇒ Inhibits topoisomerase II Prevents the DNA double helix from being resealed ⇒ stopping replication. Also produces free radicals ⇒ DNA damage Cardiotoxicity: Most dangerous SE (The rate of cardiomyopathy is dependent on its cumulative dose) Typhlitis: inflammation of cecum Myelosuppression Alopecia ● Doxorubicin interacts with DNA by intercalation. ● Topoisomerase II is an enzyme which relaxes supercoils in DNA for transcription ● Cardiomyopathy may be prevented with dexrazoxane. The effect is due to its metabolite phosphoramide mustard Forms DNA crosslinks both between & within DNA strands at guanine N-7 positions ⇒ leads to cell apoptosis Specific: Hemorrhagic cystitis (Bleeding from the bladder) Nonspecific SE: Bone marrow suppression, Vomiting, Alopecia, Infertility Hemorrhagic cystitis is due to acrolein (a metabolite), which is toxic to the bladder epithelium. Risks of hemorrhagic cystitis can be minimized with adequate hydration and of mesna, a sulfhydryl donor which binds & detoxifies acrolein Most active in S phase Cyclophosphamide No specific phase Methotrexate S phase Antimetabolite 5-Fluorouracil S phase Taxanes Curative approach can be don thru ● Surgical Resection: Breast-conserving therapy/ Mastectomy/ Radiotherapy ● Adjuvant Systemic Therapy: Chemotherapy/ Targeted therapy/ Endocrine therapy/ Bisphosphonates/ Adjuvant therapy in older women ● Neoadjuvant Therapy Paclitaxel/ Docetaxel M phase ● ● ○ ● ● Presents itself as a structure similar to folic acid. Inhibits dihydrofolate reductase ⇒ inhibiting the synthesis of dihydrofolic acid and tetrahydrofolic acid ⇒ prevent synthesis of purines, thymidine, methionine, which are responsible for DNA replication Inhibits DNA synthesis during S phase by inhibition of thymidylate synthetase and incorporation of its metabolites into RNA and DNA. This drug targets tubulin. It inhibits depolymerization of microtubules thus leads to failure in chromosome segregation and cell division Myelosuppression Hepatotoxicity Ulcerative stomatitis Leukopenia Megaloblastic anemia Neurological damage Methotrexate is teratogenic. Notes What’s an anti-metabolite? A drug that structurally resembles a substrate. It enters the metabolic pathway and results in the formation of a wrong product. ● Folic acid regeneration is achieved by administering Folinic acid- Leucovorin (structurally similar to tetrahydrofolate) – without affecting the therapeutic effect of methotrexate ● Folinic acid enters the cycle in a later stage and is immune to inhibition by methotrexate ● Normal cells are quick to take up folinic acid, compared to the malignant cells Mucositis, nausea, vomiting, myelosuppression, hand-foot syndrome Vomiting, Neuropathy (tingling in the hands or toes), Myelosuppression Targeted therapy Targeted therapy refers to agents that are directed specifically against a protein or molecule expressed uniquely on tumor cells or in the tumor microenvironment. HER2 overexpression: ~ 20% of breast cancers are characterized by amplification of the HER2 oncogene leading to overexpression of the HER2 oncoprotein. Associated with poor prognosis. However, prognosis improved with the development of HER2-targeted therapy. Herceptin [H] Trastuzumab Monoclonal antibody that binds to HER2 tyrosine kinase receptor. Inhibits growth of tumor cells that overexpress HER2 Cardiomyopathy develops in 0.4–4% of patients who receive trastuzumab-based regimens. Hence, anthracyclines and trastuzumab are rarely given concurrently and cardiac function is monitored periodically throughout therapy. ● Targets HER2/neu (c-erbB2) tyrosine kinase receptor ⇒ ↓ of HER2 initiated cellular signaling and ↑ antibody-dependent cytotoxicity ⇒ ↓ tumor growth ● It’s not used alone, usually with combinations ● Indicated in all HER2-positive tumors No details about Pertuzumab, Neratinib and Trastuzumab-Emtansine as it was indicated that they won't ask about them in the exams Everolimus Endocrine/Hormone Therapy ● Adjuvant hormone modulation therapy is highly effective in decreasing relative risk of recurrence by 40–50% and mortality by 25% in women with hormone receptor–positive (ER/PR-positive) tumors regardless of menopausal status. ● The benefits of endocrine therapy for hormone receptor–positive disease appear to be independent of age. SERM: A receptor modulator can be an agonist or an antagonist depending on the tissue. SERM Selective Estrogen Receptor Modulator Tamoxifen Acts as a competitive antagonist on the estrogen receptors of the breast to prevent receptor activation by endogenous estrogens ⇒ ↓ breast cancer cell growth. It also has cytostatic effect rather than cytocidal effects (cells accumulate in Go and G1 phase of the cell cycle) Anastrozole Reduce estrogen production. Effective in the adjuvant setting for postmenopausal women. SERD Selective Estrogen Receptor Down-regulator Fulvestrant SERD Binds to estrogen receptor monomers ⇒ inhibits receptor dimerization ⇒ reduces translocation of receptor to the nucleus, and accelerates degradation of the estrogen receptor ⇒ pure antiestrogenic effects and inhibition of breast tumor growth. CDK inhibitors Ribociclib Aromatase inhibitors Nausea, skin rash, and hot flushes (an antagonist effect) . Increases the risk of endometrial hyperplasia & cancer (an agonist effect) Risk for Venous thromboembolic events. Rarely, induces hypercalcemia in patients with bony metastases. AIs have fewer associated serious side effects (such as endometrial cancers and thromboembolic events) than tamoxifen. However, they are associated with accelerated bone loss and an increased risk of fractures as well as a musculoskeletal syndrome (arthralgias &/or myalgias). Indicated in ● Early stage estrogen receptor-positive breast cancer, as adjuvant therapy. ● Estrogen receptor-positive metastatic breast cancer. ● DCIS (following surgery & radiation, as chemoprevention) ● LCIS (as chemoprevention along with surveillance) ● Ovulation induction (off-label) AIs should not be used in a patient with functioning (premenopausal) ovaries since they do not block ovarian production of estrogen. Indicated in advanced breast cancer (ER positive) Hormonally driven breast cancer may be particularly sensitive to inhibition of cell cycle regulatory proteins, called cyclin dependent kinases (CDK). CDK inhibitors can be combined with an endocrine agent (AI or fulvestrant) Clinical trials support the use of a CDK4/6 inhibitor plus AI as the gold standard treatment in the first-line setting. Adverse effects of CDK4/6 inhibitors: neutropenia, diarrhea. The use of adjuvant bisphosphonates in addition to standard local and systemic therapy for early-stage breast cancer and have shown a consistent reduction in the risk of metastatic recurrence in postmenopausal patients, in addition to improvement in bone density. Bisphosphonates Side effects associated with bisphosphonate therapy include bone pain, fever, osteonecrosis of the jaw (rare, less than 1%), esophagitis or ulcers (for oral bisphosphonates), and kidney injury. ● ● ● ● The following therapies have all been shown to be effective in hormone receptor–positive metastatic breast cancer: Administration of medications that block or downregulate estrogen receptors (such as tamoxifen or fulvestrant, respectively) Medications that block the synthesis of hormones (such as AIs) Ablation of the ovaries, adrenals, or pituitary Administration of hormones Targeting HER2-positive tumors; ● Trastuzumab plus chemotherapy ● Combination of pertuzumab, trastuzumab, and docetaxel is the first-line gold standard for HER2-positive metastatic breast cancer Single-agent hormonally targeted therapy options include: ● Pure estrogen receptor antagonist fulvestrant, ● Tamoxifen ● Anastrozole Targeting “triple-negative” breast cancer ● Role of immune modulation in the treatment of breast cancer ● Cancer cells can evade the immune system so these drugs inhibit the evading mechanisms. They do not kill the cancer cells, only affect the evading mechanisms. These are known as immune modulators. ● Recent studies have shown effectiveness of immune modulation therapy in breast cancer and have been practicing changing. ● Atezolizumab: an anti-PD-L1 antibody, is FDA-approved for metastatic triple-negative breast cancer that is positive for PD-L1 expression.
