Breast Cancer

Breast Cancer Gauri Sabnis, PhD Reading: Katzung et al, Basic and Clinical Pharmacology, Chapter 54 Dipiro et al, Pharmacotherapy: A pathophysiologic Approach, Chapter 105 Risk Factors ✥Age 2 ✥Gender (F>M) ✥3Race/Socioeconomic status ✥yEnvironmental factors S ❊ Radiation exposure 6 ❊ Diet/obesity (postmenopausal) ❊ Alcohol consumption ❊ Smoking (?) 8 Western culture a❊ Physical activity 5 teenpregnancy Risk Factors prevent from breast coder CI 10Family history/genetics ✥ ❊ Previous diagnosis of breast cancer or benign breast disease ❊ First degree maternal relatives > 2nd degree paternal ❊ BRCA1 mutations ✥Endocrine and reproductive risk factors period ❊ Early menarche – late menopause ❊ First pregnancy after age 30 or being nulliparous ❊ Not breast-feeding after giving birth ❊ Postmenopausal hormone replacement therapy (OC use >10y?) ❊ Mammographically dense breasts ✥Not all risk factors are equal ✥Risk assessment models ❊ Algorithms to calculate risk – Gail model (1.66 or higher) ❊ Risks based on genetic testing h"ps://bcrisktool.cancer.gov 6 Breast – Anatomy and Development comesfrom glad ✥Modified sudoriferous glands that produce milk ✥15-20 lobes separated by adipose tissue Intercostal muscles Suspensory ligament of the breast (Cooper’s ligament) Pectoralis major muscle Lobule containing alveoli ❊Smaller lobules in each lobe – cluster ❊Alveoli convey milk into secondary tubules ❊Passes into mammary duct ✥As the duct approaches nipple, they expand to form lactiferous sinus where milk may be stored Mammary duct Rib Lactiferous sinus Lactiferous duct Nipple Areola Adipose tissue in subcutaneous layer Sagittal section 7 Breast – Anatomy and Development ✥Breast tissue develops at different stages in life ✥During puberty, the breast tissue develops into a mature system of lobules and ducts ❊ In response to estrogens and progesterone, milk ducts stretch and branch out ❊ Develop into a system of ducts and lobes – ductal tree 8 Hormonal Regulation of Breast Development ✥Final maturation of breast tissue happens during pregnancy in response to prolactin ❊ Terminal differentiation Hypothalamus ❊ Synthesis of milk protein ✥Increased estrogen levels during photoPRL Anterior pituitary pregnancy (late pregnancy significantly higher than a normal cycle) stimulate release of prolactin from AP (>20 times higher than menstrual cycle) ❊ Increase in # of alveoli and change in lobule type 05 6 ✥Antagonizes the action of prolactin – to prevent milk release placentaEstrogen Con ❊ Rapidly declining levels of E and P lead to milk letdown after delivery release 9 Maturation of Breast Tissue Don't have kids 10 Breast Tissue After Menopause ✥Number of lobules decreases, and the remaining ones shrink in size ✥As estrogen production from the ovaries declines, glandular tissue from the breast is replaced with adipose tissue – changes in breast density ❊ Less glandular tissue ❊ More fat ⇥ Easier to read mammogram • Breast density and mammogram ✥Connective tissue looses its strength ❊ Breasts may increase in size and sag ✥At a molecular level, in response to declining levels of E, expression of ERα increases ❊ Breasts become more sensitive to levels of circulating estrogens 11 Types of Breast Cancers 63 ✥Benign growth ❊Ductal hyperplasia ✥Types of breast cancers ❊Non-invasive ⇥ DCIS and LCIS ❊Invasive ⇥ Infiltrating ductal carcinoma (and subtypes) ⇥ Infiltrating lobular carcinoma (and subtypes) ⇥ Other less common • Male breast cancer, Paget’s disease, inflammatory breast cancer 12 Types of Breast Cancers DCIS LCIS 13 Symptoms ✥Symptoms: ❊Lump in the breast ± swollen lymph nodes ⇥ A lump in the underarm area ❊Swelling of all or part of the breast ❊Skin irritation or dimpling ❊Breast pain ❊Nipple pain or the nipple turning inward ❊Redness, scaliness, or thickening of the nipple or breast skin ❊A nipple discharge other than breast milk ✥Screening: ❊Breast exam (self or Gyn) e so ❊Mammograms (yearly after age 40) 14 Mammography ✥Breast density as a risk factor ❊ ~4X increase in breast cancer incidence ❊ Masking effect ⇥ Digital versus film mammogram ✥Reporting requirements (CA – 2013) ❊ Breast density ✥Breast density changes ❊ Age, menopausal status ❊ Lifestyle, weight, diet Highrisk 15 Diagnosis ✥Imaging: ultrasound, MRI or CT ✥Biopsy: ❊To diagnose malignancy ❊Primary tumor, sentinel lymph node ❊Staging: TNM ✥Type of breast cancer ❊Classification based on receptor expression ✥Decision about therapeutic modality ✥Further tests to tailor therapies ($$) 16 Classification Based on Receptor Expression p.es 8gprogestrnpaHEEIIeB ✥ER/PR + (or) HR+ ❊ ER+/PR+ Best Prognosis ❊ ER+/PR❊ ER-/PR+ ❊ ER-/PR- ✥Her-2+ ❊ HR+/Her-2+ Poorer Prognosis Aggressive disease ✥ER/PR – (or) HR- ❊ HR-/Her-2+ ✥TNBC To Triplenegative bragstonorld 17 AlsocalledHer Ineu g Family Receptors ErbB EGF, TGFα Epiregulin etc. No Ligands Neuregulins P P P P Her-1 EGFR ErbB-1 P P P P P P Her-2 ErbB-2 6 Neuregulin signaling (NRG-1) poinitiate Extracellular: Ligand Binding Domain Her-3 ErbB-3 P P Her-4 ErbB-4 Intracellular: Tyrosine Kinase Domain Chthonsits signals via phosphorylation Doshthaveongtaghoogetsacticatedby togetatiated another Hertthen getsphosphorylated 18 worst Higherthe ofThe Her-2/neu also called as erbB-2 thecancer 19 HR Positive Her-2 Positive Triple Negative 21 Tumor Grade ✥Tumor grade stated from estimated rate of cell proliferation <10% 10-19% ❊ S-phase fraction ⇥ Percentage of cells present in S-phase (actively replicating DNA) ❊ Ki67 antigen ⇥ Half-life of 1-1.5 hours; only present in active phases of cell cycle (G1, S, G2 and M) ⇥ Absent in resting phase - G0 20-50% >50% ✥Prognostic marker Tat 23 ℞ Based on Stage ✥Stage 0 (cis) ❊ Only Local (surgery, radiation) ❊ May add endocrine therapy (HR+) ✥Stage I, IIA and IIB ❊ Surgery, radiation ❊ Consider neoadjuvant Rx (if T2 or T3) ❊ Systemic adjuvant Rx based on receptor ✥Stage IIIA, IIIB and IIIC ❊ Neo-adjuvant Rx based on receptor ❊ Loco-regional Rx - surgery, radiation ❊ Systemic adjuvant Rx I stage IV ✥Systemic/ de novo ❊ If bone involvement – add zoledronic acid, pamindronate or denosumab ❊ If no bone disease – Rx as per receptor expression ⇥ HR+ disease - CDK 4/6 + AI or Fulvestrant ❊ Visceral crisis: initiate chemotherapy 25 Dose Intensity ✥Dose intensity is defined as the amount of drug delivered per unit of time (i.e., mg/m2/week) ✥Variables include dose per cycle of chemotherapy, the interval between cycles, and the total cumulative dose of chemotherapy delivered. ❊ Doxorubicin 60mg/m2 IV on Day 1 ❊ Cyclophosphamide 600mg/m2 IV on Day 1 ❊ Given q3 weeks x 4 cycles ✥Maintaining dose intensity is vital to survival outcomes resulting from chemotherapy treatment Foote M. The importance of planned dose chemotherapy on time: do we need to change our clinical Practice? The Oncologist 1998; 3:365-368 Chemotherapy Cycles and “Chemo Days” ✥In the treatment of solid tumors, each dose of a defined chemotherapeutic regimen is called a cycle. ✥Cycles can be repeated at varying frequencies: weekly, q 3 weeks, etc. ✥One cycle may include multiple days of chemotherapy, referred to as Chemo Day 1, Day 2, etc. ❊Remember, the Day is not the date! ✥Key factor in choosing ℞ is receptor Choice of Pharmacotherapy expression ❊ 75% have tumors that express ERα (w/ or w/o PR) ❊ 67% of the patients with breast cancer are postmenopausal ❊ 25% have Her-2 positive disease ❊ 10-20% are TNBC ✥Multi-gene assays for consideration of addition of adjuvant systemic chemotherapy vs endocrine therapy ❊ OncotypeDx - 21 gene signature ⇥ pN0 cancers ⇥ Preferred ❊ MammaPrint - 70 gene ❊ PAM50 ✥Hormone therapy for HR+ve cancers ❊ Significantly lower ADRs ❊ Taken for 5-10 years, out-patient ✥Anthracycline-based chemotherapy ❊ Improved outcomes 34 Chemotherapy regimens ✥AC ❊ Doxorubicin (Adriamycin®) 60 mg/m2 IV on day 1 ❊ Cyclophosphamide 600 mg/m2 IV on day 1 For Her-2 negative disease ⇥Cycled every 21 days for 4 cycles ✥Dose dense AC (preferred) ❊ Cycled every 14 days for 4 cycles ✥TC ❊ Docetaxel 75 mg/m2 IV on day 1 ❊ Cyclophosphamide 500 mg/m2 IV on day 1 Do NOT try to memorize details of all these regimens ⇥Cycled every 21 days for 6 cycles ✥AC→ T ❊ AC therapy followed by a taxane (weekly or Q2w paclitaxel) ❊ Also dose dense ✥CMF ❊ Cyclophosphamide 100 mg/m2 PO days 1-14 ❊ Methotrexate 40 mg/m2 days 1 and 8 ❊ 5-FU 600 mg/m2 IV days 1 and 8 ⇥Cycled every 28 days for 6 cycles 35 From week 1 2 Alkylating Agents ✥Produce highly reactive ion intermediates which transfer alkyl groups to cellular macromolecules ❊ N7 or O6 of guanine is highly susceptible ✥Alkylated DNA can undergo ❊ Cross-linking of bases, with other strand of DNA, cross-linking of DNA with proteins I ❊ Excision of guanine from the DNA backbone ⇥ BER or NER pathway ❊ Abnormal base pairing ⇥ MMR pathway ❊ Unfixed errors can lead to mutations ⇥ Oncogenes and secondary malignancies ✥Anticancer actions of alkylating agents ❊ Cytotoxic effect – cell death ⇥ Not dependent on multiplying DNA - not cell cycle specific ❊ Radiomimetic actions 36 From Week 1 Nitrogen Mustards ✥Cyclophosphamide ❊ Prodrug that requires activation by P450s (CYP2B6>CYP3A4) ❊ Carbinolamine - which will enter the cell ❊ Phosphoramide mustard - pKa of 4.6 — tramped in the cell ❊ Mustard cyclizes forms aziridinium ion - alkylates DNA ✥ Requires activation in the liver, mustard does not form until its inside the cell ❊ Can be given PO, lower GI toxicity, less non-specific activity ✥Acrolein formed during activation highly toxic ❊ Extensive damage to cells of kidney and bladder ✥Chloroacetaldehyde formed during CYP3A4 metabolism — neurotoxic ❊ 10% of the dose gets converted - glutathione scavengers in the liver 37 ow ✥Acrolein scavenged by glutathione Cyclophosphamide (GSH) in the liver ❊ In the bladder cleaves from GSH ❊ Attacked by nucleophilic SH of cysteine 6 51 residues of proteins in bladder cells ❊ Severe hemorrhage, sclerosis and ⇥ (rarely) bladder cancer ✥Can also damage nephrons ❊ esp. is combined with other nephrotoxic drugs ❊ Push fluids, irrigate bladder ✥Mesna — chemoprotectant ❊ Inactive mesna carried in blood, excreted and collected in the bladder ❊ Competes with acrolein to react for HS on cysteine Mechanism of action of Mesna From Week 1 ❊ Not effective for nephron — concentrated in bladder 39 ✥Called antibiotics because — obtained from microorganisms 6 ❊ Anthracyclines Anti-cancer Antibiotics ⇥Doxorubicin (Adriamycin) ⇥Daunorubicin ⇥Epirubicin ⇥Idarubicin ⇥Mitoxantrone ❊ Actinomycin D (dactinomycin) ❊ Mitomycin ❊ Bleomycin 40 Anthracyclines ✥Highly effective anticancer drugs ✥Isolated from Streptomyces — natural or semisynthetic ✥Closely related to tetracyclines ❊ A sugar (L-daunosamine) ❊ A non-sugar —anthracycline aglycone ⇥ Photosensitive phenolic group (protect from light) ⇥ Chromophore —imparts orange-red color to the compound - retained when excreted - turning urine orange-red • Patients should be warned - this is color - not blood sugar ✥Vesicants - IV ONLY ❊ Never IM, SQ or IT ❊ Tissue necrosis upon extravasation ✥Secondary malignancies - highest risk ✥Myelosuppression and alopecia, TLS (rapidly growing), N/V, fertility impairment 41 Anthracyclines ✥4 distinct mechanisms of action for anthracyclines a ❊Have planar ring structure - due to aromaticity of the rings, they 011 0 intercalate of the DNA helix ⇥ By inserting between base pairs ⇥ Forming strong non-covalent interactions with DNA bases ⇥ The highly stabilized complex deforms the DNA, uncoiling it and prohibiting proper replication • Even small number of DSBs caused by anthracyclines are very lethal to the cells • Due to the site of cleavage ➙ T-A dinucleotide • L-Daunosamine sugar moiety orchestrates the DNA sequence specificity interaction ❊Functions as2topoisomerase inhibitors (Topo-II) 3 ❊Generation of semiquinone free radicals and oxygen free radicals am through iron-dependent enzyme mediated reductive process ❊Binding to 4 cellular membranes to alter fluidity and iron transport 43 Anthracycline Metabolism Aldoketoreductase a Anthracycline Conjugation Sulfate conjugate poshthoethat 5499 C13-alcohol (Rubicinol) metabolite activity much buthone toxicity O-dealkylation Anthracycline aglycone 46 Anthracyclines Induced Free Radical Generation Cytotoxic • NADPH/CYP450 reductase Moo (Toxic) •• + Superoxide radical anion Ei T.FI 2H+/e Superoxide dismutase Cu2+ + Catalase Jason Absentin cardiomyocytes t Fe2+ • OH + + Fe3+ Fenton Reac4on Grresponsiblefortle toxicitytoatwesecint Anthrocydines 47 Anthracyclines and Free Radical Generation limiting Dose toxicity ✥One of the biggest or DLT of anthracyclines is cardiotoxicity (2 types) ✥Acute toxicity due to rubicinol metabolite generated ⇥ Within 2-3 days ⇥ Reversible 08814 ❊ Prolonged calcium loading, inhibition of Ca and Mg ATPase ❊ Increased Ca2+ levels in cytoplasm ❊ Conduction abnormalities - arrhythmia ❊ Also contributes to chronic toxicity m2 ✥zChronic orABB delayed 45 5 omg ⇥ Can manifest suddenly years after completing anthracycline treatment ⇥ Irreversible and non-responsive to medications ❊ Cardiomyopathy and heart failure 48 Anthracycline Induced Cardiotoxicity ✥Chronic/delayed - dilated cardiomyopathy and severe congestive heart failure ❊ Dose dependent - cumulative life-time doses approaching 450-550 mg/m2 ❊ Systolic and diastolic failure - non-responsive to treatment ❊ Females and AA patients more at risk ✥Dexrazoxane — given with anthracyclines ❊ Antioxidant ❊ Prodrug iron chelating agent ❊ Affinity for iron greater than anthracyclines ❊ Useful to prevent tissue damage after accidental extravasation injury ⇥ Can reduce efficacy of anthracyclines —used after cumulative doses accumulated high enough 50 Anthracyclins Doxorubicin (Adriamycin) Epirubicin Daunorubicin mogadtivatythonoll that A Idarubicin otros Mitoxantrone Blue-green color 51 cardio toxicity radical chronic frog Antidote LoBusutfanD.gg eIIngagent V pigstiesis Tanones Nyropathy Do I I Myloyppression Tumseverythingin me Mitoxantrone blues ✥Semisynthetic anthracycline ❊ Chemically - anthracenedione ❊ Sugar moiety missing ⇥ But the cationic side chain binds to DNA backbone in the same fashion ❊ Can still bind to Topo-II ❊ Unable to bind to NADPH/CYP reductase ⇥ Limits the free radical generation ⇥ No cardiotoxic metabolite ❊ Significantly less cardiotoxicity (but still present) ⇥ Patients who received other anthracyclines still at risk ❊ Other AE - alopecia, mucositis, N/V etc. significantly less ❊ Risk of ulceration and necrosis after extravasation is low ❊ Myelosuppression still significant ✥Blue-green color of drug can cause bodily fluids including sclera to turn blue-green 53 Liposomal doxorubicin (Doxil) ✥Liposomal formulation to increase tumor penetration and reduce cardiac toxicity ❊ Still cardiotoxic - less than conventional formulation ✥DO NOT substitute ✥Only compounded in D5W 54 Actinomycin D/dactinomycin ✥Chromopeptides contain same chromophore, planar phenoxazone actinosin – red orange color ❊Planar ring intercalates the DNA between adjacent G-C pair ❊Polypeptide chains extend along the minor groves ⇥ Inhibits RNA polymerase (transcription) ⇥ Causes SSBs ✥Toxicity; alopecia, Sar = Sarcosine MeVal = N-Methyl Valine extravasation leads to marked inflammation ❊Erythema leading to necrosis (areas exposed to X-rays, before during or after), desquamation, pigmentation OHWIND ❊Anorexia, N/V 55 Bleomycin ✥Small peptide that has DNA binding region and iron binding region at the opposite ends of the molecule ❊Oxygen free radicals, ds and ss breaks and inhibition of DNA synthesis ❊Cell cycle specific that causes accumulation of cells in G2 phase ✥Can be given IV, SC or IM ✥Eliminated renally, reduce dose in renal impairment ✥DLT: pulmonary – pneumonitis, cough, dyspnea, go dry inspiratory crackles and infiltrates on X-ray (higher >70 yr old) 56 mostlyas catheter the insectinto Mitomycinno C bladder ✥Undergoes metabolic activation to generate alkylating agent that cross-links DNA. EAT tumor stem cells are conducive to reductive ✥Hypoxic reaction and sensitive to mitomycin than normal cells and oxygenated tumor cells ✥Intravesicle treatment of superficial bladder cancer ❊Does not get absorbed, no systemic toxicity ✥Toxicity: hemolytic uremic syndrome (microangiopathic hemolytic anemia, thrombocytopenia), renal failure 57 5 Microtubule damaging agents ✥Cell cycle specific ❊M- phase ❊Chromosomes fail to move apart ❊Cell cycle arrest and apoptosis ✥Vinca alkaloids ❊Vincristine ❊Vinblastine ❊Vinorelbine ✥Taxanes ❊Paclitaxel ❊Docetaxel 58 ✥Isolated from the bark of pacific yew tree Taxanes (Taxus brevifolia); now semi-synthetically from European yew (renewable resource) ✥Taxanes bind to polymerized β tubulin at a specific hydrophobic receptor site located deep within the tubular lumen ✥Promotes a stable tubulin conformation similar to that of GTP-bound β-tubulin IN❊ Renders microtubules resistant to depolymerization and prone to excessive polymerization ⇥ Inhibits disassembly of microtubules in the mitotic spindle ⇥ Polymerization occurs in absence of microtubule associated proteins and GTP ❊ Promotes elongation phase of dynamic instability at the expense of shortening phase ❊ Extensive polymerization leads to formation of large dense aberrant structures ⇥ Asters - contain stabilized microtubule bundles ✥Taxanes are substrates for P-gp - cellular as efflux pump - expression associated with resistance to taxanes Taxol-induced microtubule aster ✥Low aqueous solubility (solubalizers) ❊ Paclitaxel more lipophilic than docetaxel 59 used anymore Alsoknownas tool int me Paclitaxel premed Abraff ✥Low solubility requires use of Kolliphor EL as vehicle ❊ 50%alcohol and 50% polyethoxylated castor oil ❊ High risk of hypersensitivity reactions due to Kolliphor ⇥ Anaphylaxis — dyspnea, hypotension, angioedema, urticaria (BBW) Dok late para copy ⇥ Pretreatment with GC, H1RA and H2RA required ✥DLT: myelosuppression - neutropenia (BBW) g ❊ Do not administer if ANC <1500/mm3 ✥Irritant with vesicant like properties: extravasation reactions milder skin discoloration, tenderness, erythema, swelling, recall skin reactions ✥Metabolized >80% by P450s (CYP2C8 and 3A4) excreted via hepatobiliary route ✥Ability to up regulate capecitabine activating enzyme - combination ℞ 60 Abraxane ✥Abraxane: Albumin-bound paclitaxel (nab-paclitaxel) ❊ Significantly reduced hypersensitivity (Polysorbate 80) – pre℞ still required ❊ Significantly reduced myelosuppressive effect, ❊ Reversible sensory neurotoxicity ✥DO NOT substitute (BBW) ✥Stored refrigerated - <24 hours (<4 hours ambient) ❊ Protect from bright light 61 Taxanes ✥Docetaxel: More potent than paclitaxel; same MOA ✥Also, more soluble than paclitaxel ❊ Does not need Cremophor - uses Polysorbate 80 - preRx still required ✥DLT: neutropenia (more than paclitaxel), ❊ Fuid retention with repeated doses - 2 kg weight gain ❊ Skin – alopecia, rash, stomatitis, edema etc. ❊ Arrhythmia, fall in BP ❊ Neuropathy (less frequent than Abraxane) ✥Metabolized by CYP3A4 - DDI ✥Cabazitaxel: Lower affinity for P-gp ❊ Sustained retention in tumors ⇥ Effective in docetaxel resistant P-gp expressing tumors ❊ Higher BBB penetration ✥DLT: neutropenia,, peripheral motor and/or central neuropathy ❊ High incidence of diarrhea ❊ Similar H2O solubility as docetaxel - same vehicle - same hypersensitivity ✥CYP2C8 and CYP3A4 (major) metabolism 62 ✥Only HR+ patients Hormonal Therapy ❊ Selective estrogen receptor modulators ⇥ Tamoxifen, toremifene (Fareston) ❊ Ovarian ablation Hypothalamus 1 GnRH (pulsatile) ⇥ Oophorectomy, luteinizing hormone- 2 5 Elevated estrogen Anterior inhibits release of pituitary FSH and LH t FSH/LH 3 FSH released into blood stimulates ovarian follicles Ovaries (F) 4 (negative feedback) GnRH stimulates the release of FSH by AP gonadotrophs releasing hormone (LHRH) analogs, chemotherapy drugs Post-menopausal Low blood levels of estrogens (F) stimulates release of ❊ Estrogen receptor downregulator ⇥ Fulvestrant (Faslodex) ❊ Aromatase Inhibitors (AIs) ⇥ Letrozole (Femara), Anastrozole (Arimidex), Exemestane (Aromasin) ❊ Less commonly used hormonal therapy Estrogen released into blood by follicular cells ⇥ Progestin agents – Megestrol acetate (Megace) ⇥ Androgens PHAR-742 ⇥ High doses of estrogen 63 ✥Menopause is generally the Menopause permanent cessation of menses or permanent decrease in ovarian estrogen synthesis. ❊ Prior bilateral oophorectomy ❊ Age ≥60 y ❊ Age <60 y and amenorrhoeic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and ❊ Follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range ⇥ If taking tamoxifen or toremifene, and age <60 y, then FSH and plasma estradiol level in postmenopausal ranges ✥Women receiving LHRH agonist ✥Women premenopausal at the beginning of chemo and with chemo induced amenorrhea removingovaries Aromatase Androstenedione ❊ Oophorectomy, serial measurement of Estrone FSH and/or E2 64 Adrenal Glands Sec$on through adrenal gland Capsule Adrenal cortex: Angiotensin II, K+ Capsule Zona glomerulosa Mineralocorticoids, mainly aldosterone Aldosterone synthase Adrenal Cortex Zona fasciculata Glucocor=coids, mainly cor=sol ACTH 20, 22 Lyase 11β hydroxylase, 17α hydroxylase Zona re1cularis androgens Adrenal medulla Chromaffin cells Epinephrine and Norepinephrine (NE) Adrenal Medulla PHAR-742 LM 50x Subdivisions of adrenal gland 65 PHAR-742 66 SERMs ✥ Tamoxifen (generic - tab, Soltamox – soln.) ✥ Toremifene (Fareston) ✥ Raloxifen (Evista) PO ❊ Prevention in women with osteoporosis ❊ Similar efficacy as tamoxifen – STAR trial ✥ PO - Q daily for 5 years (switch to AI after 2-3 years preferable) ✥ AE: ↑ risk of thromboembolism (PE, DVT),hot flashes, arthralgia, bone loss Premenopausal (monitor BMD) ❊ Possible: tamoxifen - tumor flare, endometrial hyperplasia in women w/ intact uterus 67 Tamoxifen ✥Antagonism of actions of estrogens at the estrogen receptor (ERα) ❊ Selective antagonism in the breast tissue ✥Agonistic in the uterus ❊ Endometrial hyperplasia ➔Cancer ✥Minimally toxic, administered PO ✥Up to 5 years continuous; switch over to AI following 2-3 years of tamoxifen ❊ AI as first line Rx for new diagnosis (if post-menopausal) ✥Other AEs: Thromboembolism (BBW in DCIS prevention setting) ✥Monitoring: Gynecologic exam Q1yr, BMD (premenopausal), serum lipids, signs and symptoms of DVT, PE 68 Metabolic Activation of Tamoxifen ✥Tamoxifen metabolized by ❊ CYP3A4 to N-desmethyl tamoxifen ❊ CYP2D6 to 4-OHT ⇥ Active form of the drug ⇥ Endoxifen (also active) formed from 4-OHT ✥CYP2D6 pharmacogenomics ❊ CYP2D6-/- significantly low concentration of 4-OHT and endoxifen ❊ DDI w/ CYP2D6 substrates ⇥ SSRIs/SNRIs ⇥ Grapefruit ❊ Genetic testing may be considered 69 Moitinsection Antiestrogen - fulvestrant ✥Pure antiestrogen and estrogen receptor down-regulator ❊ AEs: loss of BMD, arthralgia, injection site pain ❊ Pregnancy test required for women of reproductive potential postmenopausal only 70 ooh n NI AB ✥Estrogen synthesis in postmenopausal women Estrogen Biosynthesis ❊Not under pituitary control Androstenedione Estrone Aromatase ❊Extra-gonadal tissues ⇥ Adipose ⇥ Muscles ⇥ Breast tissue itself 17β HSD 17β HSD Testosterone Estradiol Aromatase 5-α-reductase Most Potent Estrogen DHT Binds to AR ✥Aromatization reaction involves 3 hydroxylation reactions with NADPH as electron donor ❊Single enzyme responsible - P450arom ❊NADPH reductase ✥No other steroid downstream that is affected 71 Aromatase inhibitors ✥Post-menopausal hormone receptor positive breast cancer ✥Steroidal analog of the substrate ❊ Exemestane (Aromasin) Androstenedione Formestane Exemestane ✥Irreversible inhibitor of aromatase ✥Reduce estrogen production by 35-70% ✥Metabolized by CYP3A4 ✥Rx of gynecomastia, water retention induced by testosterone doping ❊ Banned by WADA 72 Aromatase inhibitors ✥Non-steroidal ❊ Letrozole (Femara) ❊ Anastrozole (Arimidex) ✥Reversible, inhibit estrogen production by >95% Letrozole ✥AEs: Hyperlipidemia, hot flashes, arthralgia, osteoporosis, weight gain ✥1st line for HR+ cancer ❊ Neo-adjuvant 4-6 months ❊ Adjuvant 5 years (10 years?) Anastrozole 73 Aromatase inhibitors Letrozole BIG 1-98 group N Engl J Med 2005; 353:2747-2757 74 month follow-up showing improved OS 74 Fertility after ℞ ✥Women under the age of 35 may resume menses Lessof me ❊Amenorrhea does not mean loss of fertility aid ❊Resuming of menstruation does not mean fertility ✥Pregnancy during and/or after Rx ✥Fertility and amenorrhea ❊Preserving fertility before Rx— refer to fertility specialists ⇥Use of GnRH analogs to preserve fertility ❊Contraception needed during treatment ❊Hormonal contraceptives and hormonal therapy in adjuvant setting 75 Prevention ✥Surgical interventions High risk patients ❊ Oophorectomy ❊ Mastectomy ✥Pharmacotherapeutic interventions ❊ Tamoxifen ❊ Raloxifene ❊ Exemestane 76 pineedlobe postmenopausal concernendometrial thromboembolism goodfor hypoxia g Tamoxifen/Raloxifene/Exemestane? ✥For each of the following at-risk patients, please identify which chemo-preventive agent will be ideal. ❊60-year-old woman with history of Boot thromboembolism Exemestane metomestine ❊65-year-old woman with uterine leiomyoma Bonedensity pist ❊61-year-old woman with osteopenia so Mordred ❊ 45-year-old B Roxane woman with prior hysterectomy ❊49-year-old with DCIS Tangier tamoxifen stageoincencer 77 Targeted Therapy ✥Monoclonal antibodies targeting Her-2 ❊ Trastuzumab (Herceptin) ❊ Pertuzumab (Perjeta) ✥Tyrosine kinase inhibitors ❊ Lapatinib (Tykerb) ❊ Neratinib (Nerlynx) ✥mTOR inhibitor ❊ Everolimus (Afinitor) ✥CDK4/6 inhibitor ❊ Palbociclib (Ibrance) ❊ Ribociclib (Kisqali) ❊ Abemaciclib (Verzenio) ⇥ 1st line with letrozole in HR+, 2nd line with fulvestrant in HR+ progressing on AI 79 combat Chemotherapy regimens e ✥AC→ T + H For Her-2 positive disease ❊ AC therapy followed by ❊ Paclitaxel with trastuzumab (Herceptin®) 4mg/kg IV with first dose of paclitaxel ❊ H - 2 mg/kg IV weekly for 1 year (6 mg/kg every 6 weeks after paclitaxel cycles finished) or until progression ✥AC→ T + trastuzumab + pertuzumab ✥TCH ✥TCH + pertuzumab ✥Paclitaxel + trastuzumab 80 ✥Antibodies against extracellular domain Her-2 targeted therapy of the receptors - IV ✥Indicated for Her-2+ cancers with/after chemotherapy ✥Trastuzumab (Herceptin®) ❊ Humanized monoclonal antibody against Trastuzumab EGF, TGFα Epiregulin etc. extracellular domain of Her-2; mediates antibody dependent cellular toxicity Pertuzumab Neuregulin No Ligands NRG-1 (NRG-1) Extracellular: Ligand Binding Domain ⇥ Cardiomyopathy – ↓ LVEF, HF - highest with anthracycline containing regimen ⇥ Infusion site reactions ⇥ Pulmonary toxicity ⇥ Pregnancy – oligohydramnios (7-month washout period) Intracellular: P P P P Her-1 EGFR ErbB-1 P P Her-2 ErbB-2 Lapatinib P P P P Her-3 ErbB-3 Neratinib P P Her-4 ErbB-4 Tyrosine Kinase Domain ✥Pertuzumab (Perjeta®) ❊ Humanized monoclonal antibody that prevents Her-2/Her-3 dimerization ⇥ Same toxicity as H ⇥ Compounded in NS only ✥Ado-trastuzumab emtansine (Kadcyla®) ✥Antibody drug conjugate (T-DM1) ❊ Trastuzumab targets Her-2 ❊ Emtansine is a microtubule targeting agent that inhibits 81 Growth Factor Receptor PI(4,5)P2 PI(3,4,5)P3 PI3-K Shc Grb2 SHP-2 Akt PTEN SHP-2 P P P P SOS RAS-GDP RAS-GTP mTOR RAF 4E-BP1 S6K elF-4E p90RSK Ribosomal Synthesis mRNA Transla:on Nucleus DNA Polymerase MAPK MEK Cyclin D1 Cell prolifera:on Suppress apoptosis TRANSCRIPTION 82 ✥Small molecule tyrosine kinase Tyrosine Kinase Inhibitors inhibitors binding to the intracellular kinase domain of the receptors ✥TKIs contain 4-anilinoquinazoline pharmacophore ❊ Metabolized by CYP enzymes to aniline  CYP (R ≠ H) p-hydroxyaniline  quinoneimine (hepatotoxic) Aniline moiety CYP Tyrosine kinase inhibitor ✥Most TKIs exhibit ❊ Hepatotoxicity ⇥ Baseline LFT ⇥ Monitoring of LFTs routine CYP Quinoneimine ⇥ dose adjustment p-hydroxyaniline moiety ❊ DDI/DFI requiring dosage adjustments w/ CYP3A4 inhibitors/inducers 0 ❊ Interstitial lung disease (ILD), NeraGnib pneumonitis ❊ Diarrhea ✥Other ADRs related to EGFR pathway inhibition Lapatinib ❊ Rash ❊ Cardiotoxicity 83 Tyrosine Kinase Inhibitors Neratinib ✥TKIs containing 4anilinoquinazoline pharmacophore ❊ Hepatotoxic Lapatinib ❊ DD/DF interactions – CYP3A4 ❊ Diarrhea Erlotinib Gefitinib 84 Her-2 targeted therapy ✥Small molecule tyrosine kinase inhibitors binding to the intracellular kinase domain of the receptors - PO ✥Lapatinib (Tykerb®) ❊ Tyrosine kinase inhibitor targeting EGFR and Her-2 ⇥ Approved for 2nd line after H LapaGnib ⇥ ↓ LVEF, pulmonary toxicity, pregnancy, infusion site reactions, dermatologic tox ⇥ QT prolongation, hepatotoxicity (fatal - BBW), diarrhea (3-4) ✥Neratinib (Nerlynx®) ❊ Extended Her-2 targeted treatment (after TRZ) for early-stage breast cancer ⇥ AE: diarrhea (prophylaxis needed), hepatotoxicity, separate from PPI by 2+ hours ❊ Hepatotoxicity Neratinib ❊ DDIs – CYP3A4 85 Recurrence and Metastasis ✥ Regional recurrence ❊ Lump or swelling under arm or collarbone ❊ Loss of feeling or pain in the area of previous lesion ✥ Distant recurrence ❊ Constant back, bone, or joint pain ❊ Difficulty with urinating (either incontinence or not being able to go) ❊ numbness or weakness anywhere in your body ❊ a constant dry cough ❊ difficulty breathing, shortness of breath, chest pain ❊ loss of appetite or weight loss ❊ abdominal bloating, pain, or tenderness, constant nausea, vomiting, jaundice ❊ severe headaches, confusion, loss of balance ❊ seizures ❊ vision problems (blurry vision, double vision, loss of vision) 86 Recurrence and metastasis ✥ Blood tests (including tumor markers in some patients) ✥ Whole-body bone scan, with or without X-rays of specific bones MRI of the spine or brain ❊ CT scan of the chest, abdomen, pelvis, and/or brain ❊ PET scan ❊ X-ray or ultrasound of the abdomen or chest ❊ ✥ Bronchoscopy if you have a constant cough or trouble breathing ✥ Biopsy of any suspicious area ✥ Tap: a pleural tap or a spinal tap 87 Recurrent or stage IV disease ✥ Chemotherapy ❊ Doxorubicin (or pegylated doxo) ❊ Paclitaxel Single agent ❊ Capecitabine ❊ Gemcitabine ❊ CAF ❊ FEC ❊ AC Combination ❊ CMF ✥ Endocrine therapy ❊ Non-steroidal AIs (letrozole, anastrozole) or steroidal AIs (exemestane) ❊ Antiestrogen fulvestrant ❊ Exemestane + everolimus ❊ Palbociclib + letrozole* ❊ Palbociclib + fulvestrant* 88 Cdk 4/6 inhibitors Estrogen ✥Palbociclib (Ibrance®) ✥Ribociclib (Kisqali ®) ❊ 3 weeks on and 1 week off ❊ +Hormonal therapy (non-steroidal AI or fulvestrant) ✥Abemaciclib (Verzenio ®) ❊ Q daily w/ NSAI or fulvestrant ✥AEs: ❊ Neutropenia, pneumonitis, diarrhea, hepatotoxicity (all 3) ❊ CYP3A4 metabolism & DD/FI (all 3) ❊ QT prolongation (ribo, palbo), VTE (abe) ✥Indication: Metastatic breast cancer in combination with non-steroidal AI or Fulvestrant 89 CDK 4/6 inhibitors Ribociclib Palbociclib PI3K inhibitor Abemaciclib Alpelisib 90 Alepelisib ✥PIQRAY® - Inhibitor of PI3K pathway ✥Advanced metastatic HR+ve/Her-2 negative PIK3CA mutated Br Ca with fulvestrant ❊ Males and females ✥ADRs and warnings: ❊ Severe hypersensitivity (SJS, EM) so ❊ Hyperglycemia including DKA ❊ Pneumonitis ❊ Diarrhea André F et al. N Engl J Med 2019;380:1929-1940 91 92 TNBC ✥Absence of all receptors that make tumors sensitive to targeted/hormonal agents ⇥ ER negative, PR negative and Her-2 negative (Triple Negative) ❊ Poorer prognosis ❊ High grade and undifferentiated tumors ❊ More responsive to cytotoxic chemotherapy – pCR likely ✥Cytotoxic agents preferred ❊ Nitrogen mustard - cyclophosphamide ❊ Anthracycline - doxorubicin ❊ Platinum compounds - carboplatin ✥Targeted treatment choices besides cytotoxic chemotherapy – specific indicn ❊ PARP inhibitors ⇥ Olaparib, talazoparib ❊ Immune checkpoint inhibitor ⇥ Atezolizumab 93 PARP Inhibitors Synthe5c Lethality ✥℞ of deleterious or suspected germline BRCA-mutated, Her-2negative metastatic breast cancer (gBRCAm) ❊ Targeted therapy for TNBC ✥PARP - nuclear enzyme that participates in DNA SSB repair via base excision repair pathway. ✥SS breaks when not repaired get converted to ds breaks. ✥BRCA mutant cells (cancer cells) not able to repair  cell death ✥Olaparib (Lynparza ®) ✥Talazoparib (Talzenna ®) 94 Olaparib Robson M et al. N Engl J Med 2017;377:523-533. ✥Mimic the nicotinamide component of NAD+ substrate ✥Potential teratogens and reproductive toxins ✥PO; absorption delayed with high fat meal ✥Biotransformed by CYP3A4 – DD /DF interactions ✥AE: ❊Myelosuppression ❊Secondary malignancies ❊NV, rash, pneumonitis 95 Atezolizumab ✥Tecentriq ® ✥Immune checkpoint inhibitors ❊Antibody against PD-L1 ✥Activate immune system to attack cancer cells ✥DLT: Immune-related adverse effects (irAEs) 96 Robson M et al. N Engl J Med 2017;377:523-533 To be covered Later Bone metastases ✥Breast cancers preferentially metastasize to bone, lung, liver and brain ✥Bone metastases of breast cancer tend to be osteolytic ✥℞ of bone mets: ❊ Zoledronic acid (Zometa) -IV ⇥ 4 mg Q12W vs. 5 mg Q1Y (Reclast - OP) ❊ Denosumab (Xgeva) - SQ ⇥ 120 mg Q4W vs 60 mg Q6Mo (Prolia - OP) ❊ Pamindronate – IV ⇥ 90 mg Q4W ✥Hypercalcemia of malignancy 97 ✥Breaks cancer risk factors ✥Development of breast tissue and hormonal control ❊ Why lactation has protective effect on future breast cancer risk ❊ Impact of breast density on breast cancer risk and how it affects screening ✥Classification of breast cancers based on receptor expression ❊ Treatment based on receptor expression ⇥ Hormone receptors and Her-2 ❊ Comparing various endocrine treatment options of breast cancer ⇥ Advantages and disadvantages (ADRs, DDIs) of each of them ❊ Use of CDK 4/6 inhibitors in stage IV disease ⇥ Recurrent or de novo (treatment naive) - combine w/ nsAI/Ful ✥Treatment regimens ❊ Names of drugs from the regimen ❊ Administration precautions including DDI ❊ ADRs and DLTs for the ℞ ❊ Supportive care and rescue agents Summary ✥Hormonal and targeted therapy ❊ Specificity of indication ⇥ Receptor expression (ER/PR/Her-2) ⇥ Mutations and other markers ❊ Sequence in regimen 99