Breast Cancer. UpToDate:

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Crystal Wells
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1 Breast Cancer UpToDate: - For patients with HER2-positive breast cancer, HER2-directed agent trastuzumab with or without pertuzumab should be added to the chemotherapy regimen as neoadjuvant or systemic therapy. Pertuzumab is NOT indicated in adjuvant setting at this time. Introduction: Sporadic (>90%), familial (< 10%) Risk Factors: Biology: - Genetics/heraditary: * BRCA1/BRCA2: high risk * Others: Li-Fraumeni syndrome (p53), Cowden's syndrome (PTEN), Peutz-Jegher's syndrome (STK11), Ataxia-telangiectasia (ATM). - High-risk lesions: Relative risk >4 * Atypical ductal hyperplasia (ADH), LCIS, - Hormones: OCP low risk (HR=1.24), abnl mammo after 1y risk of nodal involvement or distant metastasis at diagnosis (for post-menopausal woman). - Radiation exposure before age 40y A. ER/PR: PR downstream to ER - ER(+)/PR(+): grow slowly, better differentiated. better prognosis. - ER(+)/PR(-): women > 50y, larger tumors, nodal involvement B. HER2- positive: 20% in breast cancers. C. BRCA1: ER/PR(-), higher grade, risk of both breast and ovarian cancers. BRCA2: ER/PR(+), luminal-like, risk of breast ca, less so of ovarian cancer D. Histology: - Luminal A: ER(+) best prognosis - Luminal B: ER(-), variable expression of Her2 poor prognosis - Her3-enriched: Her2(+)/ER(-) poor prognosis, respond to anti-her2. - Basal-like: triple negative worst prognosis Symptoms: Diagnosis: Breast mass 1) Gail model: assess woman's risk for developing breast cancer - Includes: age at menarche, age at first live birth, number of previous biopsies and presence of atypia, number of first-degree female relatives with breast cancer. 2) Screening Mamo (40-74 yrs): screening for breast cancer mortality. - MRI indicated for high-risk patients (known BRCA mutations, untested first-degree relative BRCA mutation carrier, radiation exposure to chest between age 10 and 30, Li- Fraumeni syndrome, Cowden syndrome). 3) Biopsy Pathology Pathology: A. DCIS: Comedo (high-grade) Page 1 of 8

2 * Cribriform, Papillary, Solid (low or intermediate grade) B. Invasive breast cancer: - Infiltrating ductal carcinoma (70-80%) - Infiltrating lobular carcinoma (5-10%): multicentric, bilateral, ER-positive, metastasize late (to unusual locations). - Others types: * Favorable: Tubular, Mucinous (colloid), Adenoid cystic (even larger size) * Intermediate: Medullary, Metaplastic. * Aggressive: Micropapillary (early nodal mets), Mixed (tubulolobular) C. Staging T0, Tis, T1: <2cm T1mic: <0.1cm T1a: cm T1b: cm T1c: 1-2 cm T2: 2-5 cm T3: >5cm T4: any size with direct invastion to chest wall and/or skin T4a: Chest wall (but not to pectoralis muscle) T4b: Skin (same side) T4c: Both chest wall and skin T4d: Inflammatory ca N1: Movable Axillary LN, Ipsilateral N2: Unmovable LN N2a: fixed/matted, ipsilateral axillary LN N2b: palpable ipsilateral internal mammary LN wihout palpable axillary LN N3: N3a: ipsilateral infraclavicular LN N3b: ipsilateral internal mammary + axillary LN N3c: ipsilateral supraclavicular LN Stage Tumor work-up : Tis, N0, M0 DCIS H&P,lab I: T1 (include T1mic), N0, M0 Early H&P, lab IIA: T0-T1, N1, M0 local Bone scan and CT T2, N0, M0 invasive as clin indicated IIB: T2, N1, M0 BC Page 2 of 8

3 T3, N0, M IIIA: T3, N1, M0 Bone scan, CT T0-T3, N2, M0 Bone scan, CT IIIB: T4, N0-N2, M0 staging, IIIC: anyt, N3,M0 PET-CT (opt) IV: anyt, anyn, M Prognosis: A. DCIS Recurrence Score: - Grade: high-grade (comedo subtype) local recurrence poorly differentiated if recur worse prognosis - Margin: negative margin (<10mm) in breast recurrence. B. Prognostic factors for local invasive breast cancer: Prognostic Factors Predictive Factors Nodal status Steroid receptors Tumor size Her2 Steroid receptors Multigene assay Her2 Histologic grade Histologic subtype Proliferative rate Age C. Molecular Prognosis: - ER (+) tumor: persistent risk of tumor relapse even after many years. - ER (-) tumor: respond better to chmo. - HER over expression: relative resistance to tamoxifen and sensitivity to anthracyclines. Tx Principle: A. Carcinoma In-Situ: 1) LCIS: No palpable mass, diffuse, high ER/PR expression. - Dx: Incidental finding on biopsy. bilateral mamo r/o any invasive - Tx: Wide excision, plus chemoprevention (No RT) * Tamoxifen 5 years (56% risk reduction in P1). Or Raloxifen (postmenopausal women - STAR trial). AI has NO preventative role in this setting. - Special: for pleomorpic LCIS, managed as DCIS (controversial?). 2) DCIS: - Dx: bilateral mamo. ER/PR status. NO need to test Her2! - Tx: Lumpectomy, + whole breast RT (cat 1) Tamoxifen x 5yrs (prevention) *AI or chemo has no role in this setting. * Sentinel lymph node (SNB) indicated only for high-risk DCIS: microinvasion, Page 3 of 8

4 extensive, size >5cm, or high-grade. * Contraindication of lumpectomy: pregnancy, more than one primaries in different quadrants, previous RT to breast, persist margin. - Recurrent DCIS: either mastectomy or recision plus RT B. Microinvasive Breast Cancer: T1mic, a/w DCIS (larger size, multicentric, high-grade). - Dx: Palpable mass (common) biopsy ER/PR, Her2 - Tx: Lumpectomy SLN biopsy * For tumor ER/PR (+), node (-) or microscopic invasion node (<2mm, pn1mic) adj Tamoxifen or AI (NO chemo) * For tunmor ER/PR (-), node (+) including pn1mic (<2mm) adj chemo +/- anti- Her2 therapy C. Invasive Breast Cancer (stage I to IIIA): 1) Local Tx: Surgery plus radiation principle - Lumpectomy + adj RT to whole breast (category 1). * (+) SLBN node dissection - Mastectomy SLNB adj RT based on SLNB: * (-) axillary nodes: NO RT, except T >5cm, or margin (+) or close margin (<1mm) * > 4 (+) axillary nodes adj RT to chest wall (category1). * 1-3 (+) axillary nodes controvertial. 2) Adj Chemo: effective regardless of ER/PR status, start 4-6 wks after sugery. - CALGB 947: Dose dense is superior. - Less-aggressive regimen: AC x 4 cycles, CMF x 6 months, TC=AC, DC? - Aggressive chemo: AC-T, AC-TH-H, TCH, FAC or FEC (superior to AC). 3) Adj Endocrine: indicated for all ER/PR-positive tumors, except for patients > 60y, node (-), T<1cm. - Do NOT give hormone and chemo together (hormone after chemo and RT). - Pre-menopausal: Taxmixifen x 5 yrs ± ovarian suppression (OA) or ablation switch to AI for another 5 yrs (cat1) after post-menopausal * Tamoxifen recurrence by 39% and death by 31%, second primary BC - Post-menopausal: AI x 5ys; or Taxmoxifen x 2-3 ys AI x 5ys; or AI x 2-3 ys Tamoxifen x 5 ys. * ATAC (Anastrozole, Tamoxifen Alone or in Combination): Anastrozole vs Tamoxifen superior DFS, but no OS difference in post-menopausal woman. * BIG 1-98 trial: Letrozol vs Tamoxifen (also no OS benefit) * MA 17 trial: "tamoxifen x 5ys letrozole" vs tamoxifen alone ( DFS, not OS) * IES (Intergroup Exemstane Study): tamoxifen 2-3 yrs exemstane vs tamoxifen 5 ys ( DFS, trend to OS). * META: "tamoxifen 2-3 ys anastrozole" vs tamoxifen 5 ys ( DFS, OS) 4) Adj Anti-Her2 Therapy (Trastuzumab): indicated for all node-positive and node negative tumor >1cm (category 1). - Concurrent chemo and trastuzumab followed by maintenance trastuzumab x total of 12 mos DFS (HR=0.52), OS (HR=0.61) * AC-TH-H (NSABP B-31, NCCTG-9831). * FinHER: 9 wk of trastuzumab no improvement in DFS, OS * HERA: assess longer (>1 yr) duration of trastuzumab (ongoing) Page 4 of 8

5 * BCIRG-006: non-trastuzumab regimen AC-TH-H TCH (lowest cardiac side effect). Avoid CMF for anti-her2 therapy. - Laptinib: DO NOT use in adj setting. 5) Bone loss prevention: VitD/Ca, prolia every 6 months while on AI. - DEXA annually - Premenopausal: tamoxifen bone loss. Postmenopausal: tamoxifen bone loss - Postmenopausal: AI bone loss. 6) Algorithm (Board Review) - Node (-) BC of pure tubular or colloid histogy excellent prognosis after surgery NO adj chemo regardless of tumor SIZE - Node (+) BC (>2mm node involvement): adj chemo - Node (-), ER (-): if T >1cm adj chemo if T cm prefer adj chemo > observation if T <0.5cm observe (NO chemo) - Node (-), ER (+): if T < 0.5 cm observe (NO chemo) if T > 0.6 cm, Oncotype DX (21-gene -RS Score) RS <18 low risk No chemo RS=18-30 intermediate-risk TailorOx Trial? RS > 31 high-risk adj chemo ( DFS by 22%) - Node (-), ER (+), age >70, very small and well-differentiated BC: Lumpectomy alone with wide negative margin (>10mm) NO RT post surgery (RCT - small difference in local recurrence but no OS difference). - Old woman: if life span <5 yrs no hormonal tx. - Male BC: prognosis and treatment are the same as woman BC. - Breast cancer in pregnancy: chemo can be given after 1st trimester. - Obese woman BC: standard weight based drug dose should be administered to all patients. DO NOT use ideal body weight. D. Locally Advanced Breast Cancer: neoadj therapy 1) Rationale: - Debulky, chance of BCT (for T>3 cm or palpable nodes BC or inflammatory BC) - In vivo drug testing - However, no survival and PFS benefit compared to adj chemo. 2) Regimen: the same as those of adj chemo - Add trastuzumab to neoadj chemo recommended for Her2+ tumor (similar to adj chemo) improve response rate complete trastuzumab for a total of 52 wks after surgery. (Trials: *Neoadj Herceptin Trial (NOAH), * GeparQuattro, * NeoALTTO, etc). - Important: complete all neoadj chemo in pre-op setting, rather than deviding it between pre- and post-op. - Assess response before surgery: For non-responder (rare) no proven benefit to switch chemo (GeparTrio trial) consider neoadj XRT or hormonal therapy. - When neoadj therapy is indicated, neoadj chemo is preferred. Neoadj endocrine Page 5 of 8

6 therapy is an option for ER/PR (+) tumor. AI (preferred) as neoadj setting for postmenopausal woman. E. Metastatic Breast Cancer (MBC): 1) Dx: re-biopsy is essential at metastasis because discordance in ER/PR expression (14%) and Her2 expresson (5%). 2) ER/PR-positive and Her2-negative tumors: - Premenopausal: * Ovarian ablation or suppression * Endocrine therapy as for post-menopausal women. - Post-menopausal: * 1st line: Ibrance/Femara * 2nd line: Falsodex/Femara Aromasin/Affinitor - Visceral crisis: initiate chemotherapy. 3) Her2-positive tumors: - ER/PR-positive endocrine therapy +/- Her2-targeted chemotherapy - ER/PR-negative Pertuzumab + trastuzumab + taxane or T-DM1 or trastuzumab + chemo. 4) Trastuzumab-refractory tumors: continue Her2 blockade - If interval between adj tx and relapse > 12 mos, repeat "trasutuzumab + taxane" - If interval between adj tx and relapse <12 mos or progress while receiving trastuzumab: * laptinib + xeloda * "Lapatinib + Trastuzumab" DFS, trend to OS * "Pertuzumab + Trastuzumab" DFS, trend to OS * "T-DM1 (Trastuzumab emtansine)" DFS, OS (HR 0.62) - EMILIA. 5) Triple negative metastatic breast cancer - Basal-like moleuclar subtype, BRCA1(+) - Symptoms: aggressive behavior, high risk of visual and brain metastasis than soft tissue, bone mets, early relapse - Chemotherapy: AC-T or single agent. "Bev + Taxel" is good for Her2- neg tumor (do not use Bev in Her2 positive BC). 6) CNS mets: a/w age<40, pulomonary mets, AAF, Her(+), or triple negative. - Tx: Multiple brain mets: "Lapatinib + Capecitabine" before WBRT (LANDSCAPE phase II trial) CNS RR 67%, DFS, OS. * Solitary Met: surgical resection or radiosurgery (SRS), followed by WBRT - Leptomeningeal mets: uncommon (numb chick syndrome) 7) Inflammatory breast cancer (IBC): Median OS < 1yr - Sx: erythema, warmth, and edema (peau d'orange), no breast mass in > 50% of pts - Path: ER-negative, high E-cadherin, TP53 mutation. Page 6 of 8

7 - Dx: Punch biopsy - Tx: Mastectomy (rather than BCT), plus adj XRT. Adj chemo and hormonal therapy similar to other breast cancer. 8) Locoregional Relapse: - In-breast tumor recurrence (IBTR) (occur early within 5-yr): mastectomy - Chest wall recurrence: worse prognosis, surgical resection, f/u by either XRT or chemo - Regional nodal recurrence: full LN dissection followed by adj chemo 9) Special Consideration: 9.1. Phyllodes Tumor: - Path: similar to fibroadenoma, but large size (>2cm), rapid growth. * Benign, Borderline, malignant; * LN metastasis rare, even for malignant tumor. * Distant metastasis does occur. - Dx: US, Core need biopsy. - Tx: Wide local excision (margin >1cm) or lumpectomy. NO SNB is needed. * Benign observe after wide excision. * Bordline or malignant adj RT after wide excision, plus adj chemo reserved for large and recurrent tumor. - Follow-up (sarcoma guideline): H&P, CXR, q 6 mos x 2 yrs, then annually. For high risk (T>5cm) tumor, CT scan q 6 mos x 2 yrs, then annually Breast Cancer in Pregnancy: ER/PR (-), Her2 (+), poorly differentiated - Dx: US (breast densed during pregnancy), MRI not safe - Sx: large tumor, positive nodes or mets - Tx: mastectomy + axillary node dissection (SNB is contraindicated in pregnancy). * 1st trimester: no chemo * After 1st trimester: OK for chemo, - Pregnancy does risk of recurrence. Wait for 2 yrs before conceiving. Follow-Up: A. Follow-up: H&P, annual mamo. NO lab or imaging needed. B. Symptom Management: - Vasomotor Tx: Gabapentin, Venlafaxine or SSR; avoid Estrogen. For woman taking tamoxifen avoid Paroxetine, Fluoxetine - DEXA for osteoporosis. Rx bisphosphonate for osteopenia. Pharmacology: A Tamoxifen: for both pre- and post menopausal women, but the greater benefit for premenopausal woman. - SSRI inhibits CYP2D6 metabolism of tamoxifen to endoxifen (active). However, BIG 1-98 trial no association between CYP2D6 genotype and clinical outcome. So, testing for CYP2D6 genotype is NOT recommended! But avoid CYP2D6 inhibitors (paroxetine, fluoxetine) when taking tamoxifen. - SE: Serious uterine cancer, thromboembolic events Others hot flash, endometrial hyperplasia, polyps fibroid Page 7 of 8

8 B. Raloxifen: for postmenopausal woman only, potential teratogenic - SE: fewer uterine cancer, thromboembolic events, but more musculoskeletal pain, dyspareunia, and weight gain C. Aromatase Inhibitors (AI): - Non-steroidal Letrozol (Femara), Anastrozole (Arimidex); - Steroidal: Exemestrane (Aromasin) - SE: Bone loss, osteoporosis, joint pain, stiffness, risk of ischemic cardiovascular diseases, lower risk of VTE compared to Tamoxifen. D. Perjeta (Pertuzumab): Her2/neu receptor dimerization inhibitor. Front-line Tx in combination with transtuzumab and docetaxel for Her2-positive metastatic breast cancer. * CLEOPATRA study very positive - SE: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. LVF (similar to trastuzumab) * Echo q 3months, hold Perjeta if ef <40% or ef 40-45% with >10% absolute decrease before pre-treatment value. Repeat echo in 3-weeks, resume Perjeta if ef>45%. Page 8 of 8

Breast Cancer. Dr. Andres Wiernik 2017

Breast Cancer. Dr. Andres Wiernik 2017 Breast Cancer Dr. Andres Wiernik 2017 Agenda: The Facts! (Epidemiology/Risk Factors) Biological Classification/Phenotypes of Breast Cancer Treatment approach Local Systemic Agenda: The Facts! (Epidemiology/Risk