Breast Cancer and Antineoplastic Agents

Comprehensive vocabulary flashcards covering the anatomy, classification, risk factors, biomarkers, and various antineoplastic agents used in the treatment and prevention of breast cancer based on NCCN guidelines.

Oncotype DX®

A 21-gene RT-PCR assay that provides a quantitative assessment of distant recurrence risk and assesses the benefit of chemotherapy in HR-positive, HER2-negative patients.

Oncotype DX Recurrence Score (RS) threshold

An assessment where a score of $RS \text{ < } 26$ suggests no chemotherapy benefit and $RS \text{ } \boldsymbol{\beta} \text{ } 26$ indicates chemotherapy benefits.

Tamoxifen

A Selective Estrogen Receptor Modulator (SERM) used for the treatment of ER+ breast cancer and for reducing incidence in high-risk women; notable boxed warnings include thromboembolism and endometrial cancer.

Aromatase Inhibitors (AIs)

A class of drugs including Anastrozole, Letrozole, and Exemestane that inhibit the conversion of adrenal androgens to estrogen; they are used only in post-menopausal women or pre-menopausal women with ovarian suppression.

Fulvestrant

A Selective Estrogen Receptor Degrader (SERD) administered via IM injection for post-menopausal women, often in combination with CDK4/6 inhibitors.

CDK4/6 Inhibitors

Antineoplastic agents such as Palbociclib, Ribociclib, and Abemaciclib that reduce cell proliferation by preventing progression from the G1 phase to the S phase of the cell cycle.

GnRH Agonists

Drugs like Leuprolide and Goserelin used to suppress ovarian function in premenopausal women, effectively decreasing estrogen levels to a post-menopausal state.

ESR1 Mutation

A mutation in the estrogen receptor 1 gene that makes the receptor constitutively active (independent of estrogen), rendering traditional aromatase inhibitors ineffective.

Trastuzumab (Herceptin)

A monoclonal antibody targeting HER2/neu that inhibits the proliferation of cells overexpressing the HER2 protein; it has a boxed warning for cardiomyopathy (decrease in LVEF).

Antibody-Drug Conjugates (ADCs)

Targeted agents like Ado-trastuzumab emtansine (T-DM1) and Fam-trastuzumab deruxtecan (T-DXd) that combine a HER2-targeting antibody with a cytotoxic payload like a microtubule or topoisomerase inhibitor.

Pembrolizumab (Keytruda)

A PD-1 checkpoint inhibitor used for TNBC or cancers with high MSI, dMMR, or TMB-H ($\text{ } \boldsymbol{\beta} \text{ } 10 \text{ mutations/megabase}$).

PARP Inhibitors

Agents like Olaparib and Talazoparib that induce cell death in BRCA1/2 deficient tumor cells by forming double-stranded DNA breaks during mitosis.

Paclitaxel (Taxol)

A taxane (antimitotic) that promotes microtubule assembly and interferes with disassembly; it requires premedication with steroids and antihistamines to prevent hypersensitivity reactions caused by its Cremophor EL vehicle.

Hand-Foot Syndrome (HFS)

Also known as palmar-plantar erythrodysesthesia (PPE); a dose-limiting cutaneous toxicity characterized by painful erythema and swelling of hands or feet, common with 5-FU and Capecitabine.

Calvert Equation

The formula used to calculate the dose of Carboplatin: $\text{Dose(mg) = AUC} \times \text{(GFR + 25)}$, where the GFR is capped at $125 \text{ } mL/min$.

Doxorubicin (Adriamycin)

An anthracycline anti-tumor antibiotic that inhibits topoisomerase II; it is known for causing cardiotoxicity and has a maximum lifetime cumulative dose of $300-550 \text{ } mg/m^2$.

Hemorrhagic Cystitis

A serious side effect of Cyclophosphamide and Ifosfamide caused by the toxic metabolite acrolein; it is prevented with aggressive hydration and sometimes Mesna.

Methotrexate (MTX)

An antimetabolite S-phase specific drug that inhibits dihydrofolate reductase (DHFR); toxicities like myelosuppression and mucositis may be managed with Leucovorin rescue.

Capecitabine (Xeloda)

An oral prodrug of 5-FU that is converted to the active drug within the tumor; it should be taken with food or within 30 minutes of a meal to decrease absorption-related toxicity.

PD-L1 Combined Positive Score (CPS)

A biomarker measurement used to determine eligibility for pembrolizumab in TNBC, where a score of $\text{CPS } \boldsymbol{\beta} \text{ } 10$ is typically required.

Risk Factors For Breast Cancer

•Gender: Female >>>>> Male

•Age: Increased risk in women > 40 y.o.

•Early start of menses: before 12 y.o.

•No children or late first childbirth (> 30 y.o.)

•Late menopause: after 55 y.o.

•Post-menopausal combined HRT 5-10 yrs or more

•Long-term OC use at high estrogen dose

•First-degree relative with breast cancer before 45 y.o.

•Defective or mutated BRCA 1 or 2, PTEN genes, p53, (i.e., Ashkenazi Jewish female for BRCA 1)

Screening and Prevention

•For average risk group, Age≥ 40 y.o—> Annual screening mammogram

•For average risk group, Age≥ 25 y.o—>Clinical encounter every 1-3 years [clinical breast exam, risk assessment, and risk reduction counseling (if needed)]

•Breast awareness

Pap smear is recommended for average risk group, ≥ 21 y.o. cervical cancer

Classification

·       Lobular carcinoma in Situ (LCIS) ·       Ductal carcinoma in Situ (DCIS) o   Early-stage breast cancer (stage 0) ·       Invasive or infiltrating lobular carcinoma o   2nd most common type of breast cancer ·       Invasive or infiltrating ductal carcinoma (IDC) o   Most common and more progressive ·       Based on hormone receptor pos and Her2/neu amplification o   ER+/PR+ (hormone receptor pos) BC: §  Antiestrogens, aromatase inhibitors +/- CDK4/6 inhibitors o   Her2/neu (Her2) +BC §  Her2 targeting agents or Her2 targeting agent-containing meds: Trastuzumab, Pertuzumab, Lapatinib o   TNBC (Triple neg breast cancer) §  No her2 targeting agent/no hormone tx §  Traditional chemo or other targeted tx

Worst prognosis of breast cancer

Gene testing for Check-point inhibitors

•PD-L1 expression testing +: Check-point inhibitors—>PD-L1 CPS (Combined Positive Score ≥ 10)

•MSI-H or dMMR (VS MSI-L or pMMR): Check-point inhibitors

Other gene testing

•BRCA1/2 Testing+: PARP inhibitors (Olaparib, Talazoparib)

•ESR1 (Estrogen Receptor 1) Mutation Testing+: Elacestrant, Imlunestrant

•The estrogen receptor becomes constitutively active: it no longer needs estrogen to stimulate tumor growth, making estrogen-lowering drugs (e.g., aromatase inhibitors) ineffective.

•PIK3CA Mutation Testing+: PIK3CA inhibitor (Alpelisib+fulvestrant)

NTRK (Neurotrophic Tyrosine Kinase Receptor) fusion positivity: NTRK inhibitors (Larotrectinib, Entrectinib)

ER+ and/or PR endocrine tx

•Major Endocrine Agents: (5-10 years)

•Aromatase Inhibitors

•Post-menopausal woman

•Pre-menopausal women with ovarian ablation/suppression

•Anastrozole/ Letrozole/ Exemestane

•Antiestrogens: SERM: Tamoxifen

•Selective ER modulator (or SERM): Tamoxifen

•SERD (Selective Estrogen Receptor Degrader)

•Fulvestrant, Elacestrant, Imlunestrant

•GnRH agonists (e.g. Leuprolide, Goserelin)

•Only for premenopausal ovarian ablation and suppression

•Used to protect ovarian function in premenopausal women receiving chemotherapy for fertility preservation

•CDK4/6 Inhibitor (e.g., abemaciclib, ribociclib)

•In combination with endocrine therapy (aromatase inhibitor or tamoxifen)

•Use with GnRH inhibitor if combining with aromatase inhibitor in premenopausal women

ER+ and/or PR+ recurrent unresectable or M1

•Major Endocrine Agents

•CDK4/6 inhibitor (+ Aromatase Inhibitors or Fulvestrant)

•CDK4/6 inhibitor: Palbociclib/ Ribociclib/ Abemaciclib

•Aromatase Inhibitors: Anastrozole/ Letrozole/ Exemestane

•GnRH agonists (e.g. Leuprolide, Goserelin): only for premenopausal ovarian ablation/suppression

•Specific Genetic Biomarkers

•PIK3CA activation mutation+ Her2(-): Alpelisib

ESR1 mutation+ Her2(-): Elacestrant, Imlunestrant +/- Abemaciclib