Risk Factors for Breast Cancer

Breast Cancer Dr. Leiva Risk Factors for Breast Cancer Family History and Genetic Mutations Nonmodifiable Factors • • • • • • • Female • Advancing age Lifestyle Factors • Increased BMI • Alcohol consumption • Current or prior estrogen and progesterone hormone therapy • Oral contraceptives Protective Factors Personal history of BC and certain breast conditions Reproductive History • Early menarche • Nulliparity/lower parity • Older age at 1st live childbirth 1st degree relative BC Two 1st degree relatives with BC 2nd degree relative with BC gBRCA1 mutation gBRCA2 mutation Ashkenazi Jewish ancestry i • • • • • • Past history of breast cancer LCIS DCIS Hyperplasia with atypia Proliferation with atypia Radiation exposure • Late menopause be somuch estrogen *Having many pregnancies and becoming pregnant at an early age reduces breast cancer risk overall. BC = breast cancer; BMI = body mass index; DCIS = ductal carcinoma in situ; BRCAm = BReast CAncer gene mutation; gBRCAm = germline BRCA mutation; LCIS = lobular carcinoma in situ. Screening For Average At Risk Persons • Routine mammogram screening • Offered for average at risk cisgender woman or transmasculine person (who has not had top surgery) starting at 40 y/o and encouraged for starting at 45 y/o e • From 55-74 y/o can change to every other year if they prefer. Screening can be continued as long as a person is expected to live for 10 years (>74 y/o) • Recommended in transwomen 50+ y/o receiving hormonal therapy (estrogen and/or progesterone) for 5 years or more Breast Cancer Screening for Average Risk Individuals NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) 25y ≤ Age ≤ 39y Age > 40y • Clinical encounter every 1y3y • Breast awareness • Annual clinical encounter • Annual mammogram with consideration of tomosynthesis • Breast awareness American Cancer Society 40y ≤ Age ≤ 44y Optional annual mammograms 45y ≤ Age ≤ 54y Annual mammograms Age ≥ 55y Biennial or optional annual mammograms Breast Cancer Screening for High-Risk Individuals American Cancer Society > 30y Who is High Risk? • Annual mammogram and annual breast MRI • Lifetime risk of breast cancer of about 20% to 25% or greater, • Have a known BRCA1 or BRACA2 mutation • Have a 1st degree relative (parent, brother, sister, or child) with a BRCA1 or BRCA2 mutation, and have not had genetic testing themselves • Had XRT to the chest between 10 -30 y/ of age • Have Li-Fraumeni syndrome, or related genetic disorder or who have first-degree relatives with one of these syndromes Types of Breast Cancer I 1. Ductal carcinoma in situ (DCIS) – 25% of cisgender women will be dx with pre-invasive BCAs 2. Invasive Ductal carcinoma (IDC)– 80% 3. Invasive Lobular carcinoma (ILC) – 10% i 4. Inflammatory (IBC) – ~1% Grsometimes involvestheskid It Pathophysiology Receptors Involved 523 Clinical Presentation • New lump or mass • Swelling • Skin irritation or dimpling • Breast or nipple pain III • Nipple retraction • Redness, scaling, or thickening • Nipple discharge • Metastatic symptoms depend on location gym dd toesonesideslostered conceronkeftbreastbat hnode gourngalump countylatend General Sequence of Administering Treatment Modalities in Non-Metastatic Breast Cancer 69091 administered • • • • • concertitthatis primaytrt before thesestepson forstages Neoadjuvant Chemotherapy (if indicated) adapt Surgery Adjuvant Chemotherapy Radiation Therapy Endocrine Therapy (may be given concurrently with radiation) Treatment of Early Stage Breast Cancer • Treatment of breast cancer dependent on tumor size, lymph node involvement, and hormone receptor and HER2 status • Goals of treatment for Stage IA, IB, IIA, or IIB breast cancer is cure, prevent recurrences, and eradicate micrometastases AH Early Stage Breast Cancers • Early stage 5 – May receive adjuvant systemic therapy (chemo) – Hormone (+) – receive adjuvant endocrine therapy – Hormone (+) • Oncotype DX  genetic testing to see likelihood of recurrence. – Scored 0-100; lower scores more favorable » Risk stratification is based on age (> 50 y/o or <50 y/o) – Useful for women to determine benefits vs. risk of chemotherapy or XRT Stage III/Advanced BCA 86 • Operable ji – Preoperative chemo – Often followed up with adjuvant chemo – May have XRT – (+/-) Adjuvant endocrine therapy • Inoperable – Systemic therapy – May have XRT – (+/-) Adjuvant endocrine therapy Stage IV - Metastatic of phasty life • Mastectomy not recommended unless QOL issue for Patient – multiple trials have not shown OS or PFS benefit 05 • Treatment Modalities Bfualityof life refrain no – – – – thenrift Systemic therapy (palliative) oUnsentrolledformore XRT for palliation (bones, brain, etc) (+/-) Adjuvant endocrine therapy Bone modulating agents (75% of women have bone mets  pain, spinal cord compression, HCM, etc • Zometa, Aredia, Xgeva – Comfort care/Hospice GDon'tgivetreatments Stage IV - Metastatic exist natived lo ofthe outside area Moa General Treatment Modalities • Surgical Options: – Breast Conserving Therapy (BCT) – Mastectomyt Removingallorpartofabratto • Radiation Therapy (RT) • Hormonal Therapies – SERMS, AI’s, etc • Targeted therapies – CDK4/6 Inhibitors – HER2 blockers • Immunotherapy* – Pembrolizumab • Chemotherapy – Neoadjuvant – Preoperative – Adjuvant – Postoperative – Palliative 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. ow • One cycle may include multiple days of chemotherapy, referred to as Chemo Day 1, Day 2, etc. • Remember, the Day is not the date! Calculating BSA • Body Surface Area (BSA) Mosteller dosing formula • Dose= units (e.g., milligrams) per meter squared (i.e., 200mg/m2) BSA (m2) = √{(height in cm)(weight in kg) } 3600 • BSA is an estimate of cardiac output, and subsequent blood flow to liver and kidneys Cancer care for transgender and gender nonconforming persons Body Weight • >6 months of continuous gender affirming hormone therapy • Weight based formulas identical to gender affirmed identity • Creatinine Clearance use gender affirmed identity calculations Lab Reference Range • Somewhat controversial • Proposed standard for Transgender women (TGW) and Transgender men (TGM) • TGW and TGM on hormonal therapy have similar Hgb and HCT as Cisgender counterparts • Problematic for Prostate Specific Antigen (PSA) values in TGW Gupta S, Imb orek KL, Krasowski MD. Challenges in Transgender Healthcare: The Pathology Perspective. La b Med. 2016;47(3):180-188. doi:10.1093/labmed/lmw020 Webb AJ, McManus D, Rouse GE, Vonderheyde R, Topal JE. Implications for medication dosing for transgender patien ts: A review of the literature and recommen dations for pharmacis ts. Am J Health Syst Pharm. 2020;77(6):427-433. doi:10.1093/ajhp/zxz355 NCCN Definition of Menopause goperjod toremoveovaries any no Suns Non-Invasive DCIS Gs Invasive Hormone (+) Breast Cancer cease Monitor ADRs Hotflushes Utrinesarcoma cardiacevents LFti BC Epidponal eventsADR thrombotic gynetomarmonth osett bonepain Hepatotoxicity neutropenia 8880 Tifton BEE Lion charge Lotrozolctemgal thinkin Systemic Piverenum Endocrine osteopr tosses Therapy Armida pesotomaNERIPRelicauseartificaemergos Selective Estrogen Receptor Modulators • Tamoxifen, Toremifene Aromatase inhibitors MAromasin UP A • Anastrozole, Letrozole, Exemestane ArthralgiasNFatigee 8 14Luteinizing Hormone Releasing Hormone INI insomanhot flash wloveronsuppress Agonists Oberon • Leuprolide yesardievan any oblation notFDA approve no• Goserelinsonde fedapproved'overonablation p zmonthpmonpagueforbon • Triptorelin arthlogies CDK4/6 Inhibitor Ratropena Abdoralpain Facts Acceconsevaetrayes Tamoxifen Diarrhea t CUeniol s notcompatible majordose codoseddiy wights Limiting OAopterann infection contraceptives LeultpiBeeksafterlast fatigue tapeti thrompopeia tigidf8nnio9 go.insystem • Palbociclib • Ribociclibskistalil • Abemaciclib icontakelopenemidel OH Moggprolongation dose langdigensecchecklftereyzmonth Estrogen Receptor Antagonist • Fulvestrant mTOR Inhibitor • Everolimus I category2b Adjuvant Endocrine Therapy – Invasive BCA must doit 248 so should You doit must haveoverexpressiond play *Baseline bone density assessment needed in persons at risk (>65 y, chronic steroids, FHx) Principles of Adjuvant Endocrine Therapy CDK4/6 Inhibitors • Evolving discussion about place in therapy • MonarchE Study – addition of Abemaciclib + endocrine therapy reduced absolute risk of recurrence at 4 years by 6.4% in high-risk HR+/HER2- patients • Palbociclib – failed to show benefit as adjuvant therapy in early BCA • NATALEE trial showed 3.3% benefit in DFS for stage II and Stage III HR+/HER2- BCA • Now adding 2 years of adjuvant CDK4/6 is Category 1 Abemaciclib (Verzenio) • May be used in combo w/ fulvestrant, Tamoxifen, or an aromatase inhibitor or on its own • Dosed 150 mg BID or 200 mg BID – w/wout food • CYP3A4 – caution with strong inhibitors or inducers • ADRs – Diarrhea – major dose limiting issue; 81% - 90% of patients experienced • Usually during the first month • Median time to onset of the first diarrhea event ranged from 6 – 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectivelyLaHospital • Up to 26% of patients with diarrhea required dose interruption and up to 23% a dose reduction – Instruct patients to start antidiarrheal therapy such as loperamide at the first sign of loose stools, increase oral fluids, and notify their provider Abemaciclib (Verzenio) • Most COMMON ADRS (>20%) – neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia – FN <1% • Major warnings and precautions – Interstitial lung disease and fatal pneumonitis – Hepatoxicity – Check LFTs before initiating • Monitor LFTs every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated (generally monthly) – Likely fetal harm – advise contraception during treatment and for 3 weeks after last dose Ribociclib (Kisqali) • May be used in combo w/ fulvestrant, or an aromatase inhibitor • Dosed 21 days on, 7 days off • Caution with CYP3A/4 inducers and inhibitors • ADRs: (>20%) – neutropenia, nausea, infections, constipation, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia Ribociclib (Kisqali) • Major warnings and precautions – Interstitial Lung Disease WE – Severe cutaneous Adverse events: SJS, TEN – QT prolongation • Monitor ECGs and electrolytes prior to initiation of treatment with KISQALI. • Repeat ECGs at Day 14 of the first cycle, and as clinically indicated. • Monitor electrolytes at the beginning of each cycle for 6 cycles, and as clinically indicated. • Avoid using KISQALI with drugs known to prolong QT interval and/or strong CYP3A inhibitors – DO NOT USE WITH TAMOXIFEN – Hepatotoxicity: LFTs before starting • Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated – Neutropenia:sCBCes before starting • Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. – Embryo-Fetal Toxicity: may cause harm; not compatible with lactation Adjuvant Endocrine Therapy • Tamoxifen (Soltamox) - (ER/PR+) – Pre and Postmenopausal – Dosing: • 20mg/day in daily for 5 – 10 years • Given with food – Drug Interactions: • CYP3A4, CYP1A2, CYP2C9, and CYP2D6 substrate; CYP3A4 inhibitor – Monitoring: • LFTs, CBC, pregnancy testing, lipid profile, gyn exam Q 12 months if patient still has uterus. – ADRs: *Hot flashes, uterine sarcoma, cardiac events, thrombotic events, hepatoxicity, neutropenia, vision changes News Flash on Hot Flashes Contraindicated in persons taking tamoxifen no ___ Oxybutinin 2.5-5mg BID 70-86% reduction in HF or 15 mg ER QD better efficacy with lower doses Contraindicated in persons taking tamoxifen Contraindicated in persons taking tamoxifen Dry mouth reported as the most significant ADR. Caution in elderly persons. 981fortotfashes Adjuvant Endocrine Therapy • Leuprolide (Lupron) – Not FDA indicated for BCA – “Ovarian ablation” in premenopausal – Studied w/ 11.25 mg SQ every 3 months for 2 years vs. 6 cycles of CMF (cyclophosphamide/MTX/5-FU) • Goserelin (Zoladex) – FDA approved for BCA ovarian ablation in pre or perimenopausal – 3.6 mg SQ every 28 days • Triptorelin (Trelstar) Adjuvant Endocrine Therapy • Anastrozole (Arimidex) - (ER/PR+) – Premenopausal w/ ovarian suppression – Postmenopausal – Dosing: • 1 mg PO daily for 5 years total of hormonal therapy • Same time every day regardless of food – Monitoring: WEATscreening • Osteoporosis/penia – ADRs: Hot flashes, osteoporosis, thrombotic events, bone pain, myalgias, serious skin reactions É D Adjuvant Endocrine Therapy • Letrozole (Femara) - (ER/PR+) – Premenopausal w/ ovarian suppression – Postmenopausal – Dosing: • 2.5 mg PO daily for 5 years total of hormonal therapy • May be continued for 24 months past Tamoxifen • Regardless of food – Monitoring: • LFTs (baseline and periodically) – ADRs: Hot flashes, cardiac events, thrombotic events, osteoporosis, elevated liver enzymes, nausea, arthralgias, and headaches joint pain Adjuvant Endocrine Therapy • Exemestane (Aromasin) - (ER/PR+) – Premenopausal w/ ovarian suppression – Postmenopausal w/ advanced BCA failed tamoxifen or already on tamoxifen for 2-3 years and are switched – Dosing: • 25 mg PO Daily; increase to 50 mg w/ strong CYP3A4 inducers • Taken after meals – Drug Interactions: • CYP3A4 substrate – ADRs: Arthralgias, Nausea, fatigue, insomnia, hot flashes, Headache, VTE Goblooddotformsinalgin Endocrine Therapies in Stage IV Hormone Receptor (+)/HER2(-) BCA issue Arthralgiasjointpaint or major w iArmateintin Endocrine Therapies in Stage IV Hormone Receptor (+)BCA Stage IV - Endocrine Therapy • Palbociclib (Ibrance) –(ER+/PR+/HER2-) with Fulvestrant or AI – Premenopausal w/ovarian suppression – Postmenopausal – Administration: • 100-125 mg PO Daily for 21 Days then OFF FOR 7 DAYS; repeat Cycle Q 28 days • Best with high fat food • We only dose reduce for hematological toxicity of Grade 3 or higher – Drug Interactions: • CYP3A4 substrate (avoid w/ CYP3A4 inhibitors) – Monitoring: • CBC/with diff Q 2 weeks during the first 2 months of therapy and monthly thereafter. – ADRs: myelosuppression – neutropenia, anemia, and thrombocytopenia, fatigue, N/V/D, PE risk, alopecia, URI I End Stage IV - Endocrine Therapy ceded • Fulvestrant (Faslodex) – given w/ everolimus or a CDK4/6 Inhibitor – Advanced Premenopausal w/ ovarian suppression or postmenopausal (ER+/PR+/HER2-) – Advanced postmenopausal (ER+/PR+/HER2+) given w/wo trastuzumab – Administration: 5 mL each injection = !!Ouch!! • 500 mg IM (one 250 mg injection in each buttock) on Days 1, 15, 29, and once monthly thereafter – ADRs: Nausea, injection site reaction, bone pain, hot flashes, peripheral edema, Goo flu-like syndrome the Smallingof e nest Stage IV - Endocrine Therapy • Everolimus (Afinitor) - (ER+/PR+/HER2-) – Premenopausal w/ovarian suppression – Postmenopausal w/ exemastane or fulvestrant or tamoxifen who failed aromatase inhibitors – Administration: • 10 mg PO daily w/ exemastane • Same time every day, best without food – high fat reduces availability • Oral suspension not interchangeable with tablets – Drug Interactions: • CYP3A4 substrate (avoid w/ CYP3A4 inhibitors) – Monitoring: • Blood glucose, LFTs, CBC w/diff, SrCr, lipid profile – ADRs: Opportunistic infections, pneumonitis, cardiac events (hypotension, CP), N/V, mucositis, myleosuppression i i Early Stage BCA • Eradicate, Conserve breast tissue, and improve prognosis – Neoadjuvant therapy: Curative • Chemotherapy • Biologic therapy • Immunotherapy • Hormonal therapy • Surgery • Radiation – Adjuvant therapy: Curative • Chemotherapy • Biologic therapy • Immunotherapy • Hormonal therapy • Surgery • Radiation Preoperative/Adjuvant Chemo for HER2 (-) Anthracyclines • • • • • • • Daunorubicin Daunorubicin liposomal Doxorubicin Doxorubicin liposomal Idarubicin Epirubicin Mitoxantrone (synthetic anthracenedione) Anthracycline Toxicities • • • • Myelosuppression Nausea/vomiting Alopecia Discoloration of body fluids –Doxorubicin, daunorubicin, idarubicin, epirubicin – red secretions –Mitoxantrone – blue-green secretions • Vesicant • Secondary leukemia Anthracycline Cardiotoxicity • Reactions observed: – Early transient EKG changes • Uncommon • Not related to cumulative dose patient received • Arrhythmias • Pericarditis Anthracycline Cardiotoxicity • Late Onset – More common, requires careful monitoring – May develop several years or even decades after therapy. – Manifests as ventricular dysfunction, CHF, conductile disturbances and arrhythmias. – Occurs more often in childhood / adolescence cancer survivors who received anthracyclines. – Common and life threatening. – Related to cumulative dose patient received Lifetime Doses of Anthracyclines • Lifetime doses • Doxorubicin (450 mg/m2) • Daunorubicin (900 mg/m2) • Idarubicin (225 mg/m2) • Mitoxantrone (200 mg/m2) • Epirubicin (900 mg/m2) • Lifetime doses of anthracycline are always expressed in mg/m2, not the actual dose. • Must have an ECHO or MUGA before treatment (measurement of ejection fraction, ideally should be >55%) ECHO=Echocardiogram; MUGA=Multigated Acquisition Scan Relative Cardiotoxicity of Anthracyclines Drug Lifetime Maximum Dose (mg/m2) Doxorubicin Conversion Factor* Doxorubicin 450mg/m2 1 Daunorubicin 900mg/m2 0.5 Idarubicin 225mg/m2 2 Epirubicin 900mg/m2 0.5 Mitoxantrone 200mg/m2 2.2 *Dose equivalencies for 5% incidence of cardiotoxicity Anthracyclines • Doxorubicin (Adriamycin) – Moderate (<60 mg/m2) to Highly emetogenic especially when combined with Cytoxan – Administration • • • • Vesicant  Dexraxozane Can cause mucositis  Ice chips Alopecia – cooling caps (controversial) May discolor urine – Dose: • Depending on your institution, the LIFETIME CUMMULATIVE DOSE could 550 MG/M 2 and if XRT to the chest 450 MG/M 2 OR 450 MG/M2 regardless of XRT to the chest. You were taught 450 in calculations, so this is the number I will test on. – Nadir: • 10-14 days, recovery by Day 21  Need growth support if dose dense – Monitoring: • Baseline ECHO/MUGA, CBC w/diff, LFTs, periodic ECHO if high risk of cardiac toxicity – ADRS: radiation recall, mucositis, alopecia, N/V/D, LFT elevation, bone marrow suppression, CARDIOTOXICITY - cardiomyopathy, VESICANT; secondary malignancies  MDS/AML, etc • Liposomal Doxorubicin (Doxil) – – – – Not interchangeable with Doxorubicin Reformulated to reduce vesicant and cardiotoxicity potential (less but still possible) A lot Less nausea – Low emetic risk Infusion reactions – premedicate with Benadryl first time and slower infusion; most patients do fine and don’t require further premedication. – MAJOR ADR • Hand and foot syndrome can be severe in patients. Usually mild and starts about 5 -6 weeks but often requires a dose reduction or treatment break. Dexrazoxane - A rescue agent • Acts as an intracellular metal chelating agent • Proposed mechanism of action is via metal-chelation (free iron and iron bound in anthracycline complexes)  leads to decrease of anthracycline induced free radical damage • dexrazoxane likely changes topoisomerase II configuration to a closed-clamp form and prevents anthracyclines from binding to the topoisomerase II complex Nitrogen Mustards • Cyclophosphamide (Cytoxan) – Moderate (lower doses) or Highly emetogenic especially when combined with Doxorubicin – Administration: • Never infuse <30 min: “Wasabi nose syndrome” • Encourage hydration – Dosing modifications: • Caution in renal dysfunction – increased risk of hemorrhagic cystitis – Nadir: • 10-14 days, recovery day 21 – Monitoring: • CBC w/diff, SrCr, BUN, electrolytes – ADRs: bone marrow suppression, alopecia, N/V, SIADH (rare), secondary malignancies  MDS/AML, etc Taxanes • Taxane class – ‘spindle poisons’ – – – – Also known as anti-mitotics Paclitaxel Docetaxel (Taxotere®) Cabazitaxel (Jevtana®)-not indicated in breast CA • Mechanism of action – Promote microtubule assembly (enhances tubulin polymerization) and interfere with microtubule disassembly  form stable but nonfunctional microtubules – Prevents mitosis and leads to cell death Taxane Toxicity Profile • Paclitaxel • • • • • • • • Myelosuppression Hypersensitivity Peripheral neuropathy Bradycardia Diarrhea/Mucositis Alopecia Hepatotoxicity Onycholyis • Docetaxel • • • • Myelosuppression Hypersensitivity Fluid retention Skin changes • Onycholyis • • • • • Alopecia Diarrhea/Mucositis Peripheral neuropathy Arthralgias/myalgias Hepatotoxicity Taxane Induced Neuropathy • Neuropathy-due to disruption of neuronal microtubules, resulting in axonal degeneration and demyelination. • Primarily manifests as numbness and paresthesias. • More frequent with longer infusions of paclitaxel Taxanes – Paclitaxel (Taxol) • Administration: (Irritant) – Premedication: Diphenhydramine 25-50 mg IV, Dexamethasone 10-20 mg IV/PO, and H2 Blocker (famotidine, ranitidine, etc) IV 30-60 min • Must be in NON-PCV bag and tubing w/ in-line filter • <100mg/m2 over 1 hr >100 mg/m2 over 3 hrs • Formulated with Cremophor El (castor oil) – Dose Modifications: • Hepatic impairment – Low Emetogenic risk (10-30%) – Monitoring: • CBC w/diff, LFTs, • Nadir: 10-12 Days • ADRs: anaphylaxis, BMS – Neutropenia grade 4 up to 75%, alopecia, Radiation recall, peripheral neuropathy (~70% grades 1-2/3-4 ~7%), myalgia/arthralgia 60% Taxanes – Nab-PACLitaxel (Abraxane) • Albumin-bound paclitaxel (Abraxane) – Metastatic breast after failure of combination chemotherapy or ALL RXN to paclitaxel – Administration: • No premedication necessary =) • PVC bags okay – Dose Modifications: • Adjust for hepatic impairment – Monitoring: • EKG (Baseline + periodically) • CBC w/ diff, LFTs, Electrolytes – ADRs: Severe BM suppression, rash, myalgia, cardiovascular toxicity (edema, hypotension), peripheral neuropathy (71% of patients), alopecia • Cannot directly substitute for paclitaxel in terms of mg per mg Albumin-Bound Paclitaxel (Abraxane®) Taxanes – Docetaxel (Taxotere) • Administration: (Irritant) • PI says must premed Dex 8 mg PO Q 12 hrs x 3 days starting 1 day before chemo • Most infusion centers give single dose Dexamethasone 20 mg IV as a premedication • Non-PVC bag and in-line filter • Infuse over 1 hour • Polysorbate 80 can cause HSR • Some formulations made with alcohol – made patients feel “drunk” or woozy • Monitoring: • Baseline and every cycle CBC w/ diff, LFTs • ADRs: Anaphylaxis, fluid retention (edema and effusion up to 60%), BMS Neutropenia up to 86%, rash, alopecia, peripheral neurotoxicity up to 58% Platinum Analogs – Carboplatin (Paraplatin) • Administration • Generally infused over 30-60 minutes; • Irritant • Reaction around 6-8th dose • Calvert formula – Generally cap GFR at 125 • Moderately or Highly Emetogenic depending on dose; delayed 2-5 days • Monitoring: • CBC w/diff, Electrolytes, SrCr BUN • Nadir ~21 Days, recovery around 28 days • ADRs: BMS ~60-85% grades 1-2/grades 3-4 15-35%, N/V, pain, renal toxicity ~27% Calvert Formula- Carboplatin • What’s Mike D’s Dose? – He is 61 y/o, 6’1” and weighs 172 lbs – CrCL = 123 mL/min – AUC is 5 5• x (123 + 25) = 740 mg Carboplatin *>10% Change in Body Weight or CrCL requires dose recalculation Anti-Metabolites- Capecitabine (Xeloda) • PO prodrug of 5-FU – Administration: • Multiple doses depending on regimen • Often given on Days 1-14 of 21 day cycle • Taken with food – Drug Interactions: Strong CYP2C9 Inhibitor  Avoid Warfarin – Dosing Modifications: • CrCl <30 mL/min contraindicated – Monitoring: • CBC w/diff, LFTs, SrCr, BUN – ADRs: paresthesias, HA, peripheral neuropathy, Hand-foot syndrome (~60%), cardiac events, BMS, diarrhea – median time to first occurrence was 34 days Anti-PD1 - Pembrolizumab (Keytruda) • Administration – – – – IV over 30 min Infuse with an inline filter – 0.2-1.2 microns Infusion reactions like CRS rare - ~1% Dosing Modifications: • Never dose reduce; hold for toxicities – Monitoring: • Baselines and throughout; LFTs, Renal function, Thyroid function (~Q 6 weeks), blood sugar, cortisol (periodically), neuro checks – ADRs: hypothyroidism, colitis, hepatitis, peripheral edema, hypophysitis, pneumonitis, encephalitis, adrenal insufficiency, diabetes, rash Immune Checkpoint (ICP) Inhibitors • Immunomodulatory agents targeting immune checkpoints – Block pathways called “checkpoints” • Key regulators of immune system with stimulatory and inhibitory actions • Utilized by tumor cells cells to evade cytotoxic T-cell mediated death • Checkpoints may be positive or negative regulators of T-cell immune function • Currently ICP inhibitors block inhibitory checkpoints, disrupt signaling • Restoration of the immune system – ICP proteins and associated ligands: • CTLA-4  CD80/CD86 • PD-1  PD-L1 ICP Inhibitor Toxicities • Mechanism of AEs: – Infusion-related reaction – irAEs • Driven by same immunologic mechanisms responsible for the drugs’ therapeutic effects • Blockage of inhibitory mechanisms that suppress the immune system and protect body tissues from an unrestrained acute or chronic immune response Possible irAEs in Patients Treated With ICP inhibitors • Skin • Rash • Severe cutaneous ADRs • Bullous dermatoses Possible irAEs in Patients Treated With ICP inhibitors • GI • Colitis • Hepatitis • Lung • Pneumonitis • Endocrine • Hypothyroidism • Hyperthyroidism • Adrenal insufficiency • Hypophysitis • Diabetes • Musculoskeletal • Renal • Nervous System • Hematologic • Cardiovascular • Myocarditis, arrhythmias, heart failure, vasculitis, Venous thromboembolism • Ocular Preoperative/Adjuvant Chemo for HER2 (+) HER-2/neu Overexpression • HER-2/neu gene is overexpressed in 25% to 30% of breast cancer patients • There is a significant decrease in 5-year survival for breast cancer patients who overexpress HER-2/neu • Significant for both node-positive and node-negative patients who overexpress HER-2/neu • HER-2/neu overexpression increased the following cell activities in malignant breast epithelial cells in vitro: • DNA synthesis • Cell growth • Tumorigencity • Metastatic potential Slamon DJ. Chemotherapy Foundation Symposium. 1999;46. Abstract 39. Goldenberg MM. Clinical Therapeutics. 1999;21(2):309-318. Implications of HER2/neu Overexpression • Late-stage disease • Chemotherapy resistance • Hormone-therapy resistance • Increased risk of recurrence • Decreased progression free survival and overall survival • Poor outcome Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999; 82(2): 241-250. HER2(+) BCA • Trastuzumab (Herceptin) – Different dosing schedules based on chemo combo, metastatic disease, or high risk early BCA • 4 mg/kg IV over 90 min week 1week 2; 2 mg/kg IV over 30 min for 12 weeks1 week later 6 mg/kg IV over 30-90 min every 3 weeks for total of 52 weeks • 8 mg/kg IV over 90 min week 13 weeks later 6 mg/kg IV over 30 min every 21 days for total of 52 weeks HER2(+) BCA • Trastuzumab (Herceptin) – Administration: • Compatible in NS only!! • Premedicate: Diphenhydramine 25-50 mg PO + acetaminophen 500650 mg PO 30 min first dose; optional after – Dosing modifications: • Withhold for 4 weeks if: – >16% absolute decrease in LVEF from baseline – Permanently discontinue Herceptin for a persistent (>8 weeks) LVEF decline or on >3 occasions of cardiomyopathy – Monitoring: • Echocardiogram (baseline and every 3 months) – ADRs: Cardiomyopathy, infusion reactions, pulmonary hypertension or fibrosis, rash, neutropenia – BBW: Cardiomyopathy, Infusion rxns, ARDs, and fetal toxicity HER2(+) BCA • Ado-trastuzumab emtansine (Kadcyla) – Cannot BE SUBSTITUTED FOR or WITH Herceptin – Administration: • IV – Dosing modifications: • Withhold for LVEF <40% OR IS BETWEEN 40-45% and should not be restarted if LVEF has not improved or declined further – Monitoring: • Echocardiogram (baseline and every 3 months), CBC w/diff, LFTs – ADRs: Cardiomyopathy, infusion reactions, pulmonary hypertension or fibrosis, pyrexia, myelosuppression w/ thrombocytopenia, peripheral neuropathies – BBW: Cardiomyopathy, Infusion rxns, ARDs, and fetal toxicity HER2(+) BCA • Pertuzumab (Perjeta) – Administration: • Compatible in NS only!! • Premedicate: Already doing with Trastuzumab – Dosing schedule: • 840 mg IV over 60 min3 weeks later 420 mg IV over 30 min every 3 weeks for 6 cycles – Dosing modifications: • Withhold trastuzumab + pertuzumab at least 3 weeks if: – LVEF <45% or LVEF 45-49% with a 10% or greater decrease below baseline – Monitoring: • Echocardiogram (baseline and every 3 months) – ADRs: DIARRHEA, Cardiomyopathy, infusion reactions, peripheral edema, rash, neutropenia, insomnia – BBW: Cardiomyopathy and fetal toxicity HER2(+) BCA • Fam-Trastuzumab (Enhertu) – Administration: • Compatible in D5W only!! • Premedicate: moderate/high emetogenicity (79%) • Dosing schedule: – First dose IV over 90 min3 weeks later subsequent doses IV over 30 min if tolerated – Dosing modifications: • Multiple – Monitoring: • Echocardiogram (baseline and regularly), baseline PFTs and potentially Chest CT scans periodically – ADRs:NAUSEA, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, alopecia, increased blood alkaline phosphatase, constipation, musculoskeletal pain, decreased appetite, hypokalemia, diarrhea, and respiratory infection. – BBW: Interstitial lung disease (ILD) and fetal toxicity Stage IV – HER2(-) **In an effort to not overwhelm you with drugs – we will cover Vinorelbine and gemcitabine in greater detail when we discuss Lung cancer. I put these agents here so that you could see the various treatment options for stage IV PARP Inhibitors • Mechanism: Inhibits poly (ADP-ribose) polymerase (PARP) – PARP enzymes are involved in DNA transcription, cell cycle regulation, and DNA repair • Four PARP Inhibitors available in the United States: – Olaparib (Lynparza®)* – Talazoparib (Talzenna®)* – Rucaparib (Rubraca®) – Niraparib (Zejula®) • * FDA approved for treatment of breast cancer BRCA+/HER2• Olaparib (Lynparza) – High/Moderate Emetogen – HER2(-) patients with germline BRCA mutations (may be used in early disease – brand new indication) – Dosing: • 300 mg PO BID • W/without food – Drug Interactions: • CYP3A4 substrate – Monitoring: • CBC w/diff baseline and periodically, s/s pneumonitis – ADRs: fatigue, pneumonitis, arthralgias, myelosuppression – can result in MDS and AML Metastatic BCA HER2(-) • Eribulin (Halaven) – Metastatic breast treated with at least 2 chemo regimens – Administration: • IVPush over 2-5 minutes on Days 1 and 8 every 21 days – Dose Modifications: • Adjust for hepatic and renal impairment – Monitoring: • EKG (Baseline + periodically) • CBC w/ diff, LFTs, SrCr, BUN, Electrolytes – ADRs: QT prolongation, neutropenia, peripheral neuropathy Stage IV – HER2(+) Stage IV – HER2(+) • Lapatinib (Tykerb) – HER2(+) W/ an AI (ER/PR+) OR W/ capecitabine or trastuzumab – Dosing: • 1250 mg PO Daily on Days 1 – 21 (continuously) • Empty stomach is best – Drug Interactions: • CYP3A4 substrate, No grapefruit juicecan inhibit CYP2C19 – caution with Warfarin – Monitoring: • Baseline ECHO/MUGA, and ~3-6 months, LFTs, CBC w/diff, – ADRs: DIARRHEA, QT prolongation, Cardiac toxicity, Myelosuppression – anemia more common, fatigue, hand-foot syndrome/rash, Stage IV – HER2(+) • Tucatinib (Tukysa) – PFS 7.8 months vs 5.6 months – HER2(+) + capecitabine + trastuzumab – Dosing: • 300 mg PO BID (continuously) • w or w/out food – Drug Interactions: • CYP3A4, CYP2C8, P-gp substrate – Monitoring: • LFTs, CBC w/diff, – ADRs: diarrhea, hand food syndrome, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash Immunotherapy in Advanced BCA • Emerging – Pembrolizumab still has FDA approval (early stage and advanced/met TNBC) • Keynote 522 – Atezolizumab had its accelerated approval removed in mTNBC – Concerns about efficacy as salvage therapy Bone Health and Breast Cancer • The evidence is mixed regarding efficacy to support one bone modifying therapy over another. • BMA should be continued until evidence of a substantial decline in a patient’s general performance status. • All BMA therapy should be accompanied by calcium and Vitamin D supplements to prevent hypocalcemia. Bisphosphonates • Inhibit osteoclast maturation and function • Use of bisphosphonates for patients with MBC to bone reduces the risk of skeletal related events (SREs) by 15%. – a pathologic fracture – spinal cord compression – necessity for radiation to bone (for pain or impending fracture) – surgery to bone • Optimal duration of therapy unknown • Zoledronic Acid 4mg IV q 12 weeks • Pamidronate 90mg IV q 4weeks Denosumab (Prolia®, Xgeva®) • Denosumab fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL) protein, which acts as the primary signal to promote bone removal. • By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density. Denosumab • FDA approved as a treatment to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer. – administered as a single subcutaneous injection of 60 mg once every 6 months. (Prolia®) for this indication. • Also indicated for prevention of skeletal related events in bone metastases from solid tumors – administered as a single subcutaneous injection of 120 mg once every 4 weeks (Xgeva®) for this indication Bone Metastasis Treatment and Prevention Denosumab (Xgeva) Bisphosphonates • QOL > than with Zometa • Non-inferiority w/ Zometa; significantly improved time to SRE (skeletal related event) compared to Zometa • Pamidronate (Aredia) • Zoledronic Acid (Zometa) Q 3 months • More cost effective vs. Xgeva Supportive Care for Metastatic Disease RT for skeletal lesions and pathologic fractures RT for brain, lung, visceral metastasis Pamidronate, Zoledronic acid, or denosumab for bony metastasis Palliative chemotherapy (low dose or single agents to reduce disease burden) Palliative care and/or Hospice Wrap Up Epidemiology • Median age of dx 61, significant portion of cancer patients have breast cancer Adjuvant Endocrine Therapy in early vs. met • Definition of menopause and menopausal status Early BCA Txt • Goal is cure • Surgery, XRT, chemo Stage IV Txt Goals • Goal is control, relief, QOL • Chemo, xrt for palliation