Breast Lectures PT3 2023 (1).pptx

Breast Cancer Breast Cancer • Most frequently diagnosed solid tumor in women – Over 297,790 new cases estimated in 2023 – 2nd most common cause of cancer death • 42,500 deaths estimated for 2023 • Deaths due to breast cancer continue to decline • 1 in 8 lifetime risk of developing • 1 in 37 risk o...

Breast Cancer Breast Cancer • Most frequently diagnosed solid tumor in women – Over 297,790 new cases estimated in 2023 – 2nd most common cause of cancer death • 42,500 deaths estimated for 2023 • Deaths due to breast cancer continue to decline • 1 in 8 lifetime risk of developing • 1 in 37 risk of death • Majority of women present with early-stage breast cancer. Staging (TNM system) Tis Carcinoma in situ T1 Tumor ≤2 cm T2 Tumor >2cm but ≤5 cm T3 Tumor >5 cm T4 Tumor of any size with extension in chest wall/skin N0 No regional lymph node metastasis N1 Metastasis to movable ipsilateral axillary lymph nodes N2 Metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures N3 Metastasis to ipsilateral internal mammary lymph nodes M0 No distant metastasis M1 Distant metastasis Woodward WA, et al. J Clin Onc. 2003. Breast Cancer TNM Staging Stage 0 Tis N0 M0 Stage I T1 N0 M0 T0, T1 N1 M0 T2 N0 T2 N1 M0 T3 N0 M0 T0, T1, T2 N2 M0 Stage IIA Stage IIB M0 Stage IIIA T3 N1, N2 Any T N3 M0 T4 Any N M0 Stage IIIB Stage IV M0 Any T Any N M1 • If all signs of the tumor are surgically removed then patient will receive adjuvant therapy for a pre-defined period of time to reduce the risk of tumor recurrence. • Patients who have tumor lesions (Stage IV) will stay on treatment until treatment failure or intolerance. Tumor Subtypes and Biomarkers • Using the primary tumor, we determine expression of Estrogen Receptor (ER), Progesterone Receptor (PR) and/or Human Epidermal Growth Factor Receptor 2 (HER2). • The expression of these receptors allows us to determine the breast cancer molecular subtype. Luminal (ER+/PR+) HER2 amplified Triple Negative (ER-/PR-/HER2-) • If any of these receptors are present, they likely stimulate tumor growth. Thus, treatments aimed at inhibiting their activity will have anti-tumor effects. This is termed “targeted therapy” in Overall Breast Cancer Treatment Options Pre/Post Menopausal/ Hormone receptor (ER/PR) ER+/PR+ ER-/PRNegative (25% +/-) Chemotherapy Positive (75% +/-) Hormonal Therapy HER2 HER2 (+ ~ 25%) (+) Endocrine +/-Chemo + HERtargeted therapy (-) (+(-) Endocrine Tx +/) Chemo +/-targeted (+ ~ 25%) (+) Chemo + HER2-targeted therapy therapy Note: For each category for younger (<50yo), aggressive, extensive or symptomatic visceral disease, chemotherapy is warranted (-) (-) Chemo http://www.pathophys.org/wp-content/uploads/2012/12/breastcancer-copy.png Outline Breast Cancer Subtypes 1. Hormone Receptor Positive (ER+/PR+) – Endocrine therapy (SERMs, AIs and SERD) – CDK 4/6 inhibitors – chemotherapy for high-risk patients 2. HER2 overexpressing/amplified – HER inhibitors – chemotherapy for high-risk patients 3. Triple negative (ER-/PR-/HER2-) – Chemotherapy +/- anti-PD1 (immune therapy-see lung cancer and melanoma lecture) – PARP inhibitor for BRCA mutant tumors Breast Cancer Case • 45 YO pre-menopausal lady, with 2 children, has growing breast mass first noticed 6 months ago and now painful to touch. Mammogram shows a 4cm mass in left breast. Ultrasound reveals an ipsilateral axillary lymph node. Biopsy reveals an invasive ductal carcinoma, grade 3, ER -, and HER2+ (by FISH). Biopsy of lymph node (+) for adenocarcinoma. LVEF = 53%. Pt has no family history and refuses genetic testing (eg., BRCA). • She is staged as a IIB (T2N1M0) • Plan: This is a high-risk patient. Because of her younger age, ER (-), aggressive tumor, and poor grade, she will receive neo-adjuvant chemotherapy (before surgery). Then adjuvant therapy after surgery. • It is decided to give her 6 cycles of TCH-P before surgery Targeted Drug TherapyMechanism of Action • Endocrine therapy – Interferes with estrogen or androgen signaling in the tumor or their production in the body • Tyrosine Kinase Inhibitors – Interfere with phosphorylation(activity) of intracellular kinases that stimulate cell proliferation • Monoclonal Antibodies – Target extracellular protein on cancer or immune cells Monoclonal Antibodies, TKIs and Endocrine Therapies Monoclonal Antibodies RAS Raf MEK MAPK/ Erk Hormone receptor Endocrine therapy c Drugs used for ER+/PR+ disease Endocrine Therapy for ER+ (luminal) Breast Cancer •Most breast cancers are hormone receptorpositive esp. pos-menopausal— they contain receptors for the hormones, estrogen (ER+ cancers) and/or progesterone (PR+ cancers). •Endocrine therapy for breast cancer either lowers estrogen levels or stops estrogen from acting on breast cancer cells through ER. Endocrine Therapy for Breast Cancer First-line treatment • SERMs- Selective Estrogen Receptor Modulators • AIs- aromatase inhibitors Others – SERDs- Selective Estrogen Receptor Degrader – LHRH analogs (for pre-menopausal women, see prostate cancer lecture) ER+/PR+ Disease 1. Premenopau sal women Covered in Prostate Cancer Lecture https://www.intechopen.com/books/estrogen/challenges-in-treating-estrogen-receptor-positive-br ER+/PR+ Selective Estrogen Receptor Disease Modulators (SERMs) ER+/PR+ SERM Disease • Tamoxifen (Tam, Nolvedex™️) – Competes with estrogen for binding to ER. Blocks ER action in breast cancer cells. – Acts like an anti-estrogen in breast cells – Acts like estrogen in the uterus, blood, and bones. – Some patients with bone metastases experience "tumor flare" with pain and swelling in muscles and bones. – Tam increases the risk of endometrial cancer in postmenopausal women. – Blood clots in the form of DVTs, PEs, strokes or heart attacks can occur. Decreases levels of protein C and the anticoagulant ATIII – Other common side effects include fatigue, hot flashes, ER+/PR+ Disease FDA APPROVED SERMS Blood clot + + + + Shang Nature Reviews Cancer 6, 360–368 (May 2006) | doi:10.1038/nrc1879 Available as oral agents Raloxifene- FDA approved for breast cancer prevention in postmenopausal women. ER+/PR+ Disease 2. https://www.intechopen.com/books/estrogen/challenges-in-treating-estrogen-receptor-positive-br ER+/PR+ Disease Estrogen Production in Postmenopausal Women * * Tumor Growth Aromatase expressed in various tissues esp. adipose and tum ER+/PR+ Aromatase Inhibitors (AI) Disease • Aromatase can synthesize sufficient estrogens to fuel ER+ breast tumor growth. • AIs prevent tissue associated estrogen production in post-menopausal women • Available as oral agents AROMASIN™ ARIMIDEX™ FEMARA™ ER+/PR+ Disease Aromatase Inhibitors (AI) – Exemestane: irreversibly inactivates aromatase. – Anastrozole, letrozole, and vorozole: reversibly inhibit aromatase Different from Tamoxifen • AIs do NOT increase risk of uterine cancer or venous thromboembolism. • AIs lack the beneficial effect of tamoxifen to maintain bone density Similar to Tamoxifen • AIs reduce circulating estrogens, patients often experience hot flashes and other menopausal ER+/PR+ Disease 3. https://www.intechopen.com/books/estrogen/challenges-in-treating-estrogen-receptor-positive-br ER+/PR+ Selective Estrogen Receptor Disease Degrader (or downregulator) • Fulvestrant (Faslodex) – Approved for post-menopausal women with metastatic breast cancer no longer responding to tamoxifen. – Causes the ER protein to be degraded (acts as a PURE Antagonist) – Given by injection into the buttocks. – Common side effects include hot flashes, night sweats, mild nausea, fatigue and osteoporosis (if taken for a long time) – “Off-label” in pre-menopausal women to turn off ovary production of estrogens. – Update: PI3 Kinase inhibitor (Piqray (alpelisib)) was FDA ER+/PR+ DiseaseTherapy Endocrine SERM or AI therapy – Adjuvant therapy (typically Stage 1-3) • Given for 5-10 years to prevent tumor recurrence. – Metastatic disease (Stage 4) • Given for as long as tumor responds to drug or intolerable side effects. – Primary prevention in high-risk patients • While interfering with estrogen signaling in ER+ cancers is highly effective in most patients, additional therapies can improve patient outcomes. • Interfering with cell cycle progression in addition to endocrine therapy ER+/PR+ Cell Cycle Inhibitors Disease ER+/PR+ Disease Kinase Inhibitors (used in addition to endocrine therapy) • Intracellular kinase targets (CDKs, Cyclin Dependent Kinases) • Kinase inhibitors are available as oral agents • Some kinase inhibitors are competitive ATP inhibitors (reversible) and others covalently bind to the kinase (irreversible) • In general, kinase inhibitors have high non-specificity that contribute to their side effects (ATPase inhibitors especially) • Resistance often develops through mutations (ATPase inhibitors especially) ER+/PR+ Disease CDK 4/6 Inhibitors • Approved for first line treatment in combination with AIs for postmenopausal women with ER+, advanced or metastatic breast tumors • Prevent cell cycle progression from G1 to S phase • Given orally • ATP competitive inhibitor 30 ER+/PR+ Disease CDK 4/6 Inhibitors Palbociclib (Ibrance) • Side effects include neutropenia (54%), leukopenia (19%), and fatigue (4%) 2. Abemaciclib (Verzenio) • Side effects include diarrhea (~80%) , fatigue and nausea 3. Ribociclib (Kisqali) • Side effects include change in heart rhythm called QT prolongation (~6%), neutropenia (~70%), nausea (45%) 1. ER+/PR+ Disease Summary of Treatments Post-menopausal First-line therapy – Tamoxifen or AI – High risk: AI + CDK inhibitor – Add chemo if high risk Second- or third-line therapy - Tamoxifen or AI, whichever wasn’t used first - Fulvestrant (SERD) Treatment of HER2+ Breast Cancer Human epidermal growth factor receptors (HER) ~20-25% of breast cancer has HER2 amplification Extracellular ligand-binding domain HER1/EGFR HER2 (ErbB2) HER3 (ErbB3) HER4 (ErbB4) (ErbB1) Transmembrane domain Intracellular tyrosine kinase domain 34 Rowinsky. Oncologist. 2003;8(suppl 3):5-17. Yarden et al. Nature Rev Mol Cell Biol. 2001;2:127-137. HER (erbB) related cell signaling 35 HER dimers cause mitogenic effects Homodimers HER2:HER2 HER3:HER3 Heterodimers HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER1:HER1 HER3:HER4 + + + + + + + + + + + + + Signaling activity 15 Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397. + + + Monoclonal Antibodies for HER2+ Breast Cancer HER2+ Disease Trastuzumab (Herceptin®) • Mechanism of Action: (Part of the HER pathway) – A humanized MoAb (IgG1) – Targets the HER2/neu (erb-b2) receptor embedded in cell membrane (Human Epidermal growth factor Receptor 2) • Indicated in patients that over-express HER2 – HER2 gene over-expressed in 20+% of breast cancers • Used as adjuvant treatment and in metastatic breast cancer (MBC) – Testing by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) • HER2+ Disease Trastuzumab (Herceptin®) • Trastuzumab is first drug for HER2+ disease. It binds to the extracellular domain of HER2. It is still first line therapy. • Monoclonal antibodies are highly selective for their target but HER2 is also expressed in other tissues (like the heart), leading to side effects. • Antibodies stimulate an immune response. It mediates ADCC (antibody-dependent cell-mediated cytotoxicity). • It has TWO mechanisms of action: inhibiting HER2 signaling and ADCC. HER2+ Disease Trastuzumab (Herceptin®) Adverse Effects (black box warning) Infusion related reactions (fever, rigors, chills) Cardiotoxicity (CHF) (up to 7%) ↑ risk with concurrent or previous anthracycline use, pre-existing cardiac disease, age, XRT to chest (10%). HER2+ Pertuzumab Disease(Perjecta®) (used in addition to trastuzumab) • Humanized monoclonal antibody • Targets extracellular dimerization domain (Subdomain II) of HER2. Different binding site than trastuzumab so they are used together. • Blocks HER 1, 3, 4 from heterodimerizing with HER2. • Thus, blocks ligand-initiated intracellular signaling through the MAP (mitogen-activated protein) and PI3K (phosphoinositide 3-kinase) pathways • Leads to cell growth arrest and apoptosis • Also mediates ADCC (antibody-dependent cell- HER2+ Pertuzumab (Perjecta®) Disease • Indication: – Is indicated in combination with trastuzumab and chemotherapy for the treatment of HER2+ who have not received prior therapy HER2+ Disease FDA Phase III ‘CLEOPATRA’ Trial • HER2+, Met BC with no prior treatment • 808 pts. - Trastuzumab + pertuzumab + docetaxel vs trastuzumab + docetaxel – PFS: 18.7 mo vs 12.4 mo ~ 6.3 mo – OS: 56.5 vs 40.8 mo (15.7 mo advantage) • Toxicity: (>30%) – Diarrhea, neutropenia, hair loss, fatigue, rash, peripheral neuropathy, pruritus, mucosal inflammation, dry skin HER2+ Disease(Perjeta®) Pertuzumab • Adverse Effects (black box warning) – Embryo-fetal toxicity -verify pregnancy status prior to tx – Left ventricular dysfunction (4.4%) -assess LVEF prior to initiation of tx -withhold if LVEF < 40% (can resume when >45%) – Infusion-related reactions (11%) – HER2 testing using an FDA-approved test – Should be withheld if trastuzumab discontinued, but not chemo HER2+ Disease Pertuzumab (Perjeta®) • Other toxicities: – Fatigue & Asthenia – Diarrhea – Neutropenia & febrile neutropenia – Neuropathy • Cost: Single dose cost ~ Perjeta - $5,200 + Herceptin - $4,800 ($10,000) – Yearly cost (Q3wk dosing) ~ $180,000 HER2+ Disease NCCN Guidelines-Early Stage (Simplified) ER-/HER2+ • T1-3 – N0 or N1mic • Consider adjuvant chemo w/ Trastuzumab esp if tumor > 1 cm – N+ • Consider adjuvant chemo w/ Trastuzumab +/- pertuzumab HER2+ Disease Lapatinib (Tykerb) – Second line therapy – Dual EGFR and ErbB2 Inhibitor – A competitive ATP inhibitor (small molecule kinase inhibitor) – Inhibits both EGFR and ErbB2 (HER2) – Approved for metastatic breast cancer treatment given in combination with Xeloda™ (capecitabine) or with an aromatase inhibitor for ER+HER+ tumors – Toxicities: rash, fatigue and diarrhea – the most common treatment-related adverse events to be reported 47 Pan-HER inhibition Neratinib (Nerlynx) HER2+ Disease Pan-HER inhibition Neratinib (Nerlynx) – Indicated as adjuvant therapy or metastatic HER2+ breast cancer, where trastuzumab has failed or is contraindicated. – Irreversibly (covalently) binds to HER receptors. – Small molecule kinase inhibitor given orally. – Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, elevated liver enzymes, nail disorder, dry skin, abdominal distention, weight loss and urinary tract HER2+ Disease Ado Trastuzumab Emtansine (Kadcyla®) • Mechanism: – Is a HER2-targeted antibody and microtubule inhibitor conjugate – Trastuzumab is a humanized HER2 IgG1 MoAb that directs the chemotherapy preferentially to tumor cells. – DM1, a cytotoxic microtubule inhibitor derived from maytasine (chemotherapy drug). • 3.5 DM1 molecules per antibody – stable thio-ether covalent linker HER2+ Disease Ado Trastuzumab (Kadcyla®) HER2+ Disease Ado Trastuzumab (Kadcyla®) • Indication: – For HER2 metastatic breast cancer pts who have previously received trastuzumab and/or a taxane. – Does not substitute for trastuzumab – Adverse Events: (black box warning) • Hepatotoxicity, cardiac toxicity, embryo-fetal toxicity – Other toxicities: • Pulmonary, hypersensitivity, thrombocytopenia, neurotoxicity, extravasation HER2+ Disease Ado Trastuzumab (Kadcyla®) • FDA-approved trial: (EMILIA) – Phase III randomized trial (991 pts) • Ado Trastuzumab 3.6 mg/kg q3wk vs lapatinib + capecitabine • PFS: 9.6 mo vs 6.4 mo ~ 3.2 months • OS: 30.9 mon vs 25.1 mo ~ 5.8 months • Cost: $94,000 per treatment course HER2+ Disease Summary of Treatments First-line therapy Trastuzumab + chemotherapy High risk patients prastuzumab + pertuzumab + chemotherapy Second- or third-line therapy Lapatinib + chemotherapy Neratinib Ado Trastuzumab Emtansine NCCN Guidelines - Early Stage NCCN: Breast Cancer. V.3.2018 Targeted Therapy for ER-/PR-/HER2(Triple Negative) Breast Cancer Recommend to test for BRCA status (predict sensitivity to PARP inhibitor and PDL1 expression (predict sensitivity to Immune therapy) NCCN Guidelines-Early Stage (Simplified) ER-/HER- (PR-) • T1-3 – N0 or N1mic • N0- no adjuvant chemotherapy • T> 1 cm-Adjuvant chemo – N+ • Adjuvant chemo • T4 – Chemo Two things could change this treatment plan, presence of a BRCA mutation or high expression of PD-L1. TNBC poly (ADP-ribose) Disease polymerase (PARP) Inhibition https://medium.com/@CRUKresearch/olaparib-realising-the-promise-of-syntheticlethality-f5f61d84ad99 TNBC Disease PARP Inhibitor • Olaparib (Lynparza) – Used in combination with DNA damaging agents for metastatic disease in tumors with germline BRCA1 mutation – Given orally twice daily – Metabolized by the liver (CYP3A). Potential for drug interactions and grapefruit juice. – Side effects include anemia (~80%), neutropenia (~25%), nausea (~60%), vomiting (~30%) and fatigue (~40%). More serious include pneumonitis, Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). TNBC Disease Summary of Treatment First-line treatments – BRCA wildtype, low PD-L1 expression • Chemo - BRCA mutant, low PD-L1 expression • Chemo + PARP inhibitor – BRCA wildtype, high PD-L1 expression (~1 in 5 patients) • Immune therapy (see lung cancer lecture) Second- and third-line treatments – Different chemo or clinical trial Back to the Breast Cancer Case.. • 45 YO pre-menopausal lady, with 2 children, has growing breast mass first noticed 6 months ago and now painful to touch. Mammogram shows a 4cm mass in left breast. Ultra sound reveals an ipsilateral axillary lymph node. Biopsy reveals an invasive ductal carcinoma, grade 3, ER -, and HER2+ (by FISH). Biopsy of lymph note + for adenocarcinoma. LVEF = 53%. Pt has no family history and refuses genetic testing (eg., BRCA). • She is stages as a IIB (T2N1M0); • Plan: Because of her younger age, ER -, aggressive tumor, and poor grade, she will receive neoadjuvant chemotherapy (before surgery). Then adjuvant therapy after surgery. • Treatment Option ~ pre-surgery - TCH+P X 6 cycles, followed by T+P for 1 year Follow-Up on 45 yo Patient • During her 6 cycles of treatment, the patient received aggressive 3-drug antiemetic regimen (5hT-3/NK-1/Dex) = neulasta for neutropenia. Patient did have some intermittent diarrhea, nausea, mucositis, and rash and a few instances of infusion reactions. Prognosis for this Lady • Stage II Disease: – >40 yo – <40 yo Estimated 5-year Survival 90% 70% - 80% • Stage III Disease: – >40 yo – <40 yo 58% 40% - 48% • Stage IV Disease: – >40 yo 23% - 25% – <40 yo 15% - 18% • Looking at Age Only: – Patients >40 yo 85% – Patients <40 yo 75% Other Breast Cancer Patient Types • The majority of women with breast cancer are over 60 yo, post-menopausal, ER/PR + and HER2 – • What would the treatment options be for a patient like this if it was adjuvant therapy? • How about for metastatic disease? NCCN Guidelines-Early Stage (Simplified) • ER+/HER2• T1-3 – N0 or N1mic • Adjuvant endocrine + chemo if high risk (based on tumor size or 21 gene expression assay) – N+ • Adjuvant endocrine + chemo NCCN Guidelines-Early Stage (Simplified) • ER+/HER2+ • T1-3 – N0 or N1mic • Adjuvant chemo + trastuzumab +/endocrine – N+ • Adjuvant chemo + trastuzumab (+/pertuzumab) +/- endocrine NCCN Guidelines- Recurrent or Stage IV Disease (Simplified) • ER+/HER2– Endo Rx < 1 yr • Premenopausal-ovarian ablation + endocrine +/- CDK4/6 inhibitor • Post-menopausal- different endocrine +/- CDK4/6 inhibitor • Visceral crisis- consider chemo – Endo Rx> 1 yr • Premenopausal- same as above • Post-menopausal- AI (+/- CDK 4/6 inhibitor), SERM, SERD (+/- CDK 4/6 inhibitor) • Visceral crisis- consider chemo NCCN Guidelines- Recurrent or Stage IV Disease (Simplified) • ER+/HER2+ – Endo Rx < 1 yr • Premenopausal-ovarian ablation + HER2 target Rx + Taxane • Post-menopausal- different endocrine + HER2 target Rx + Taxane – Endo > 1 yr • Premenopausal- ovarian ablation + SERM + HER2 target Rx + Taxane • Post-menopausal- AI , SERM, SERD +/- HER2 target Rx or chemo + HER2 target Rx Other Breast Cancer Types • What is the general approach for a breast cancer lady with metastatic disease ER/PR – Recurrence is not uncommon the higher stage of cancer seen – Once with metastatic disease, OS ~ 15% - 25% • What type of chemotherapy is given? – HER+ - Trastuzumab + pertuzumab + taxane – HER2- -chemo (+/- PARP inhibitor is BRCA1 mutant) NCCN Guidelines - Early Stage NCCN: Breast Cancer. V.3.2018