Chemo and Hormonal Therapy for Breast Cancer

• The course material covers chemo and hormonal therapy for breast cancer
• The learning objectives include classifying medications, explaining mechanisms of action, listing uses/side effects/interactions, and selecting proper treatments for breast cancer cases

Lines of Treatment for Breast Cancer

• Surgery is a line of treatment
• Adjuvant radiation therapy is a line of treatment
• Chemotherapy (neoadjuvant and adjuvant) is a line of treatment
• Hormone therapy is a line of treatment
• Biological and targeted therapy is a line of treatment
• Preoperative treatment aims to decrease tumor volume and allow less extensive surgery
• It is a guide for selection of adjuvant therapy in triple-negative or HER2-positive diseases
• Postoperative adjuvant therapy targets micrometastasis and should be started early to reduce resistance in newly growing, susceptible cells
• Aromatase inhibitors and SERMS are hormone therapies
• Monoclonal antibodies and ADC, TK inhibitors, CDK 4/6 inhibitors, and PRAP inhibitors are biological/targeted therapies

Chemotherapy

• Chemotherapy involves the use of medications to treat breast cancer.
• Types of drugs used in Chemotherapy:
  • Alkylating agents - Cyclophosphamide, Cisplatin
  • Cytotoxic antibiotics - Doxorubicin
  • Anti-metabolites - Methotrexate, Capecitabine
  • Natural products - Vinblastine, Docetaxel
• Alkylating agents mechanism of action involves alkylation of DNA which lethally affects tumor cells by DNA cross-linking; it can cause hemorrhagic cystitis and nephron-toxicity
• Cytotoxic antibiotics produce oxygen-free radicals to bind and cause DNA breaks; can cause cardiotoxicity
• Anti-metabolites interfere with folate or DNA synthesis; can cause megaloblastic anemia or hand-foot syndrome
• Natural products are microtubule inhibitors, which inhibit mitosis; can cause bone marrow depression or neurotoxicity

Indications for Chemotherapy

• High-risk hormone receptor-positive (HR+) breast cancer
• Triple-negative breast cancer (TNBC)
• HER2-positive breast cancer (often combined with HER2-targeted therapy)
• Common regimens include anthracycline-based (doxorubicin + cyclophosphamide), taxane-based (paclitaxel, docetaxel), and combination regimens (docetaxel + doxorubicin + cyclophosphamide)
• Chemotherapy typically lasts 4–6 months, adjusted per regimen and patient tolerance

General Adverse Effects of Anticancer Drugs

• Bone marrow depression (leucopenia, thrombocytopenia, or pancytopenia)
• Immunosuppression (infections and delayed wound healing)
• GIT disturbances (vomiting, diarrhea, and GIT ulcers)
• Hair loss
• Gonadal damage (sterility, amenorrhea, and azospermia)
• Teratogenicity and mutagenicity
• Secondary malignancy
• Hyperuricemia

Hormonal Therapy

• Selective estrogen receptor modulators (SERMs) like Tamoxifen work by decreasing the number of estrogen receptors in the breast, increasing them in bone and endometrium to prevent osteoporosis and potentially causing endometrial cancer
• Aromatase inhibitors (AIs) like Anastrozole, Letrazole, and exemestane are potent, selective, non-steroidal, and decrease the conversion of androstenedione and testosterone to estrone or estradiol, reducing tumor mass or delaying progression

Hormonal Therapy (SERMs) Use & Adverse Effects

• SERMs are primarily for premenopausal women
• Adjuvant treatment in early HR-positive breast cancer lasts 5-10 years, orally, with or without Leuprolide
• SERMs are used for HR-positive advanced and metastatic breast cancer and for the prevention of breast cancer in high-risk patients
• Fluvestrant (selective estrogen receptor degrader/SERD) is used in advanced or metastatic breast cancer and combined with CDK 4/6 or PI3K inhibitors
• Adverse effects can include hypercalcemia, osteoporosis, hot flashes, vaginal dryness, menstrual irregularities, endometrial hyperplasia, malignancies, thrombotic complications, and drug interactions via CYP 3A4/5 and CYP2D6, which can reduce the activation and efficacy of tamoxifen

Hormonal Therapy: Aromatase Inhibitors (AIs) Use & Adverse Effects

• AIs are for postmenopausal women.
• Used for adjuvant treatment in early HR-positive breast cancer and should be combined with ovarian suppression if the woman is premenopausal
• AIs are used first-line for HR-positive or unknown locally advanced or metastatic breast cancer, and for advanced breast cancer with disease progression following tamoxifen
• Adverse effects include hypercalcemia, osteoporosis, bone and joint pain, muscle pain, hot flashes, vaginal dryness, and drug interactions with tamoxifen (decreasing the serum concentration of Anastrozole)

Hormonal Therapy: Schedules (Examples)

• Premenopausal schedules include Tamoxifen with or without ovarian suppression for 5-10 years
• Tamoxifen with ovarian suppression for 5 years followed by an Al for 5 years if in menopause
• An Al with ovarian suppression for 5-10 years
• An Al with ovarian suppression along with ribociclib for 3 years, followed by Al alone to complete 5 years
• Postmenopausal schedules include an Al for 5-10 years
• An Al for 2-3 years followed by tamoxifen for 2-3 years otherwise (5 years total treatment)
• Postmenopausal schedules include an Al with ribociclib for 3 years followed by Al alone to complete 5 years

Biological and Targeted Therapy - Trastuzumab

• Trastuzumab is a monoclonal antibody against Human Epidermal Growth Factor Receptor 2 (HER2/neu)
• Action is antibody-dependent cellular cytotoxicity by inhibiting proliferation of HER2-positive cells
• Used in early stage (6 months - 1 year) or advanced stage (long period) with or without chemotherapy in IV and SCs
• Adverse effects include acute infusion reactions, nausea, dyspnea, rashes, and heart failure, which can enhance the cardiotoxic effect of Anthracyclines

Biological and Targeted Therapy - Other medications

• Pertuzumab and Margetuximab, similar to trastuzumab, are used for early stage, advanced, and metastatic HER2-positive breast cancer
• Antibody-drug conjugates combine antibodies with chemotherapy for targeted cell homing, including ado-trastuzumab emtansine and fam-trastuzumab deruxtecan
• Tyrosine Kinase inhibitors like Labatinib and Neratinib are used
• CDK4/6 inhibitors like Palbociclib, ribociclib, and abemaciclib are used for HR-positive, HER2-negative breast cancer

Special Considerations

• Poly ADP ribose polymerase (PARP) inhibitors (e.g., Olaparib) may be considered for BRCA mutation carriers, especially in high-risk triple-negative breast cancer
• Chemotherapy is the primary adjuvant treatment for triple-negative breast cancer (TNBC)
• Capecitabine (oral) may be considered for patients with residual disease after neoadjuvant chemotherapy
• Immunotherapy using pembrolizumab (immune checkpoint inhibitor) is utilized, especially in PD-L1-positive tumors, in both neoadjuvant and adjuvant settings