Aki Morikawa and Andrew D. Seidman
Estimated survival at 5-y OS 24%: AA has worse survival compare to Caucasian (15 vs. 25%) (CA 2013;63;1)
PS, site of disease (worse w/viscera or CNS), no. of sites of disease, subtypes (worse HR− & HER2+), disease-free interval (>2 vs. <2), prior tx exposure
H&P (KPS, disease-related sx); labs (CBC, CMP, consider tumor markers: CEA, CA15–3, CA 27.79); imaging (CT CAP & BS or PET/CT), consider additional imaging (x-ray, brain MRI) if specific concern such as fracture, brain met
Bx: Strongly consider for the first site of met/recurrence to document met & ER/PR/HER2 status. Discordance in receptor status between 1° & met in approx. 20–30% (due to sampling bias, proliferation of different clone, lab error, etc.)
General Management Principle
Goal of tx: ↑ survival, ↓ sx, ↑ QoL
1° tx: Systemic (endocrine, chemo, target/biologic)
Choice of Rx: Factors to consider—extent of disease, age, PS, receptor status (ER/PR/HER2), prior tx (type & time from), tempo of progression, tox, comorbidities, pt preference
Hormonal tx: Initial Rx usu for ER/PR + disease; if significant visceral disease, rapid POD, aggressive disease or hormone refractory, then consider chemotherapy as induction
Ovarian suppression/ablation (surgical or medical) if premenopausal.
Sequential use of single agents > combination
Combination tx → ↑ RR but ↑ tox. Consider if significant burden & rapid progression.
No specific standard sequence of agents
↑ lines of Rx → ↓ RR
Consider clinical trial
Local intervention (such as surgery & RT) for symptomatic control & imminent organ threat (eg, bone pain, cord compression, ascites, pleural effusion, & brain mets)
For HER2 disease – see HER2 section
AI: (Steroidal) anastrozole, letrozole; (nonsteroidal)
Exemestane. For post-meno, AI → small but ↑ efficacy vs. tamoxifen.
Exemestane + Everolimus (mTOR inhibitor) > exemestane: ↑ PFS (10.6 mos vs. 4.1 mos, p < 0.05) for progressed on nonsteroidal AI (BOLERO-2, NEJM 2012;366:520)
SERM: Tamoxifen, toremifene
500 mg IM > 250 mg IM for ↑ PFS (CONFIRM, JCO 2010;28:4594) & ↑ OS
(SABC oral presentation 2012). Fulvestrant vs. AI → SWOG study: Fulvestrant + AI > AI for ↑ PFS (13.5 mos vs. 15 mos, HR = 0.8 p < 0.05) The subgroup analysis → greater benefit in w/o previous tamoxifen (NEJM2012;367:435); FACT study: Fulvestrant + AI = AI for TTP (FACT, JCO 2012;30:1919)
Others: Megestrol acetate, androgens, estradiol
Ovarian suppression/ablation: Surgical (oophorectomy) or medical (LHRH agonists); commonly use w/other endocrine Rx. A meta-analysis of trials (N = 506) tamoxifen + LHRH agonist > LHRH agonist HR ↓ 22% for D & PFS 30% ↓ (JCO 2001;19:343).
Anthracyclines: Doxorubicin, epirubicin, pegylated liposomal doxorubicin; single agent or in combination; if previous anthracycline use, consider addition of dexrazoxane if > 300 mg/m2 of doxorubicin exposure (JCO1999;17:3333); pegylated liposomal doxorubicin- less cardiotoxic
Taxanes: Paclitaxel, Docetaxel, albumin-bound paclitaxel. Paclitaxel weekly > q3w for RR, TTP, OS (JCO 2008;26:1642).
Other antimicrotubule agents: Vinorelbine, Eribulin. Eribulin > “Physician tx of choice” ↑OS (13.1 mos vs. 10.6 mos HR = 0.81, p < 0.05) in pretreated MBC (EMBRACE, Lancet 2011;277:914)
Antimetabolite: Cap, GEM. Single agent or combination
Less commonly used: Infusional 5-FU, ixabepilone, vinblastine, etoposide, CIS, cyclophosphamide, mitoxantrone, irinotecan
Combination: CAF/FAC, FEC, AC, EC, AT, CMF, docetaxel/Cap, GEM/paclitaxel, Cap w/ixabepilone
NCCN guideline rec: BSC when failure to achieve response to 3 sequential chemotherapy regimens or ECOG PS ≥3.
Anti-VEGF: Bev (Avastin)– recombinant humanized monoclonal IgG Ab, initially FDA approved but later revoked. E2100, AVADO, & RIBBON-1 trials → Bev+ chemo > chemo ↑ PFS but no OS benefit (E2100, NEJM2007;357:2666; AVADO, JCO 2010;28:3239; RIBBON-1, JCO 2011;29:1252)
m-TOR inhibitor: mTOR signaling pathway important in endocrine resistance. Everolimus: Approved: Combo with AI (see above BOLERO-2).
Bisphosphonates: Zoledronic acid (4 mg IV q3–4w) & pamidronate (90 mg IV q3–4w). ↓ SRE but not OS benefit.
Anti-RANK Ligand Ab: Denosumab (120 mg SQ q4w) ↓ SRE & time to SRE, but not OS. Denosumab 120 mg SQ given q4w > zoledronic acid 4 mg IV q4w, ↓ time to first SRE HR = 0.82, p < 0.05 (JCO2010;28:5132)
ASCO guideline: BMA ->recommended for MBC with bone destruction; monitor serum Cr (bisphosphonates), preventive dentistry for ONJ, calcium monitoring (sev. hypocalcaemia reported for denosumab); no specific dose recommendation for CA & Vit D supplement but if no contraindication recommended same dose as used in clinical trials (Denosumab study rec: Calcium ≥ 500 mg & vitamin D ≥ 400 IU daily) (JCO 2011;29:1221).
H&P, labs, consider tumor markers; Imaging CT CAP w/BS or PET/CT (optional per NCCN guideline) every 2–4 cycles on chemotherapy on average or clinically indicated