Advances In Adjuvant Systemic Therapy Of Breast Cancer
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Advances In Adjuvant Systemic Therapy Of Breast Cancer Advances In Adjuvant Systemic Therapy Of Breast Cancer Presentation Transcript

  • Advances in Adjuvant Systemic Therapy of Breast Cancer Anne F. Schott, MD University of Michigan
  • Who to Treat With What? Current struggles in the real world…
  • When all you have is a hammer…
    • Chemotherapy
    • Endocrine therapy
    • Targeted therapy (ie trastuzumab)
    • Radiotherapy
  • Patient Example
    • A 44 year old healthy premenopausal woman has the following pathologic diagnosis:
      • Left breast lumpectomy: Invasive ductal carcinoma (1.8 cm), Bloom-Richardson grade 2. No angiolymphatic invasion.
      • Sentinel lymph node biopsy: 2/4 lymph nodes positive, ALND no more nodes +
      • ER positive (96%), PR positive (84%), Her-2/neu 2+, FISH negative (ratio 1.37)
  • Adjuvant! 8.0 10-Year Prognosis
  • NCCN Guidelines 2008
  • Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4 Sir Richard Peto, SABCS, 2007 0.81 (0.05) 0.78 ( 0.08) 60-69 0.75 (0.05) 0.65 (0.07) 50-59 0.51 (0.06) 0.57 (0.07) <50 ER+ ER-poor Age
  • Common Adjuvant Regimens 20% 20% TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation
  • Worldwide Overview: Taxane vs no chemo: Age <50 Sir Richard Peto, SABCS, 2007 0.86 (0.05) 0.84 ( 0.04) Taxane vs Anthr. 0.46 (0.08) 2p>0.00001 Taxan vs no chem 0.38 (0.07) Multiplying 3 RR 2p<0.00001 0.81 (0.05) 0.84 (0.05) Anthr. Vs CMF 0.68 (0.05) 0.56 (0.05) CMF vs no chem BREAST CANCER MORTALITY rate ratio RECURRENCE rate ratio years 0-4 only
  • What is “standard treatment”?
    • Trastuzumab-containing regimen
    • Oncotype Dx, treat if intermediate or high risk
    • No chemotherapy
    • 2 nd Generation chemotherapy (TC, FEC)
    • 3 rd Generation chemotherapy (TAC, FEC-D, ddAC-Taxol)
    X X X
  • 2 nd Versus 3 rd Generation Regimen: Differences in Relapse at 10 years (Adjuvant! 8.0) 2 nd Generation Regimen 3rd Generation Regimen
  • ER Neg ER Pos HER2 NEG HER2 POS HER2 is Predictive of Paclitaxel Benefit By Estrogen Receptor Disease Free Survival n = 1322 paclitaxel No paclitaxel paclitaxel No paclitaxel paclitaxel No paclitaxel paclitaxel No paclitaxel Years Hayes D.F., et al. N Engl J Med. 357:1496-506, 2007 n=390 (29%) n=144 (11%) n=703 (53%) n=79 (6%)
  • Common Adjuvant Regimens 20% 20% TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation
  • US Oncology: TC vs AC RANDOMIZE Doxorubicin 60 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 cycles Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 cycles
  •  
  •  
  • 2 nd Generation Adjuvant Chemo Trials CALGB 40101 ddAC versus ddTaxol TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation
  • 3rd Generation Adjuvant Chemo Trials Anthracycline regimen and trastuzumab FEC-docetaxel AC-weekly Taxol Dose dense AC-Taxol Control Arm Adds/substitutes new agent lapatinib Her-2 positive ALTTO Substitutes new agent ixabepilone Triple Negative PACS08 Adds new agent bevacizumab Her-2 negative E5103 Optimal scheduling metronomic AC-Taxol High Risk S0221 Concept Experimental Therapy Patient Population Trial Name
  • Can Bisphosphonates Prevent Bone Metastasis?
  • Effects of Bisphosphonates on Antitumor Activity in Preclinical Models Tumor-induced osteolysis Tumor cell proliferation and viability Metastatic behavior of tumor cells Activity of cytostatic drugs Angiogenesis Tumor burden in vivo
  • Comparison of Adjuvant Breast Cancer Trials of Clodronate vs. Placebo/Control
    • Diel/Jaschke Powles Saarto
    • No. of patients 290 1069 299
    • Treatment site single multi-center single institution institution
    • Selection BM+ Stage I-III LN+
    • Treatment length (y) 2 2 3
    • Control arm observation placebo observation
    • Follow-up time (y) 8.5 10 10
    • Skeletal effect + (5 yrs) + NS
    • Overall survival + + NS
    Jaschke et al. Proc ASCO, 2004 Powles et al. Breast Cancer Res, 2006 Saarto et al. Acta Oncol 43:80-82, 2004
  • Adjuvant Clodronate vs Placebo: Survival Powles TJ et al, Br Cancer Res, 2006
  • Phase III Studies of Bisphosphonates Vs. Placebo/Control as Adjuvant Therapy for Breast Cancer with DFS Endpoint
    • NSABP B-34 : (3 years) n=3,200 stage I-II
      • Placebo
      • vs.
      • Clodronate 1,600 mg po qd
    • BIG/AZURE : (5 years) n=3,300 stage II-III
    • Control
    • vs.
    • Zoledronic acid 4 mg IV q mo x 6, followed by q3 mo x 2 yrs, followed by q6 mo
    Closed Closed
    • German/GAIN : (2 years) LN positive
    • ETC vs. EC-TX
    • x
    • Ibandronate 50 mg po qd vs observation
    Open
  • ABCSG-12 Trial Design
    • 1,803 premenopausal breast cancer patients
    • Endocrine-responsive
    • Stage I&II, <10 positive nodes
    • No chemotherapy except neoadjuvant
    • Treatment duration: 3 years
    Surgery (+RT) Goserelin 3.6 mg q28d Randomize 1:1:1:1 Tamoxifen 20 mg/d Tamoxifen 20 mg/d + Zoledronic Acid 4 mg q 6 mo Anastrozole 1 mg/d Anastrozole 1 mg/d + Zoledronic Acid 4 mg q 6 mo
  • First DFS Events (ITT Population) ASCO 2008 meeting, Gnant 60 months HR=0.64 P=.011
  • SWOG 0307
    • Drug Dose Route Interval
    • Arm 1
    • Zoledronic acid 4 mg* IV q4 wks x 6, then q3 mo x 2.5 yrs
    • Arm 2
    • Clodronate 1,600 mg oral daily x 3 yrs
    • Arm 3
    • Ibandronate 50 mg oral daily x 3 yrs
    *Zoledronic acid dose adjusted for baseline renal function Current accrual 1958/4500
  • First DFS Events (ITT Population) ASCO 2008 meeting, Gnant 60 months HR=1.096 P=.593
  • What Endocrine Therapy?
    • Aromatase inhibitors are indicated in the adjuvant treatment of postmenopausal women, either alone or following tamoxifen
    • Early data does not support superiority of aromatase inhibitors in premenopausal women
    • Many women become menopausal with chemotherapy
  • Petrek et al JCO 2006 Bleeding after Chemotherapy by Patient Age
  • Bleeding after Chemotherapy by Type of Regimen Petrek et al JCO 2006
  •  
  • Schema HR+ patients with postmenopausal E2, amenorrhea > 8 weeks Start AI therapy Monitor E2 levels at 2, 4, 6, 8, 10, 12 wks Measure other hormone levels less often E2<10 E2 10-20 E2>20 Continue AI therapy, monitoring (18 mo) Off study Recheck E2 levels in 1 week E2<10 E2>10
  • Patient Example: Adjuvant Systemic Therapy Recommendations
    • 2 nd or 3 rd generation chemotherapy
      • Chemotherapy trial
      • Bisphosphonate trial – S0307
    • Tamoxifen
      • SOFT clinical trial
    • If menopausal, switch to AI after 2-5 years of tamoxifen
      • “ Early switch” endocrine therapy trial APPEL
  • Neoadjuvant Chemotherapy: Issues and Controversies
  • Patient Example
    • BL is a 58 year old postmenopausal woman who was discovered to have a 3.0 cm breast mass on imaging
    • ER 89%, PR 7%, H2N 1+
    • Surgeon feels breast conservation possible but better cosmesis after neoadjuvant therapy
  • NSABP B-18 Stratification • Age • Clinical Tumor Size • Clinical Nodal Status + TAM if > 50 y AC x 4 + TAM if > 50 yrs. AC x 4 Operable Breast Cancer Operation Operation
  • B-18 Lumpectomy Rate P < 0.01 Preop Chemo Postop Chemo 60% 68% 80% 60% 40% 20% 0
  • Local Therapy
    • Pros
    • Downstaging of primary tumor and lymph nodes
    • Less radical local-regional therapy needed
    • Breast conservation possible more often
    • Cons
    • Pathologic nodal staging requires additional procedure
      • FNA of nodes
      • up-front SLNB
    • Local treatment delayed for nonresponders
    • Decisions for XRT complicated
  • Systemic Therapy
    • Pros
    • In vivo assessment of response, could potentially improve treatment by “tailoring” based on response
    • Good biologic model to evaluate effects of chemotherapy tumors
      • Predicitve factor development
      • Acceleration of adjuvant regimen development
    • Cons
    • Potential for overtreatment in some subsets of patients
    • Unclear what to do in ER positive, node negative disease
  • Which tumors > 1, <5 cm definitely get chemotherapy (pre or post)? ++ ++ Node positive ++ ?? Node negative ER/PR both negative ER or PR positive
  • Which tumors > 1, <5 cm definitely get endocrine therapy (pre or post)? - ++ Node positive - ++ Node negative ER/PR both negative ER or PR positive
  • Patient Recommendations
    • Sentinel Lymph Node Biopsy
      • 0/1 lymph node positive
  • Patient Example: OncotypeDX Results
  • Probability of pathologic complete response (pCR) as a function of Recurrence Score Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005 Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005 doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) every 3 weeks x 3, followed by weekly paclitaxel (80 mg/m2) x 12.
  • Recurrence Score Predicts CR to Neoadjuvant Docetaxel (Chang, BCRT 2008)
  • Patient Recommendations (Level 3 evidence)
    • Sentinel Lymph Node Biopsy
      • 0/1 lymph node positive
    • Begin neoadjuvant hormonal therapy
    • Send Recurrence Score
      • Low risk, no chemotherapy
      • Intermediate risk, consider chemotherapy if poor response
      • High risk, chemotherapy
  • Using the Neoadjuvant Model To Develop New Systemic Therapies
  • Common Adjuvant Regimens 20% 20% TC*4 -> AC*4 Dose Dense (CA*4 -> Txl*4 q2wk) -> AC*4 -> Txl*4 q3wk -> AC*4 FEC*3 ->D*3 -> CE(100)F*6 -> CE(50)F*6 TAC*6 -> FAC*6 -> CMF*6 CAF*6, CEF*6 -> CMF*6 Third Generation -> Second Generation -> First Generation
  • pCR as Surrogate Marker for DFS Bear, et al. JCO. May 1, 2006
  • pCR in The Neoadjuvant Model Would Have Predicted Trastuzumab Efficacy Journal of Clinical Oncology , Vol 23, No 16 (June 1), 2005: pp. 3676-3685
  • National Neoadjuvant Chemo Trials Nab-paclitaxel then AC Anthracycline then taxane-trastuzumab Docetaxel then AC FEC-75 then paclitaxel-trastuzumab Control Arm Adds new agent, support schedule “equivalence” Add sunitinib or not, AC first or second Locally advanced, Her-2 negative S0800 Adds and/or substitutes new agent Add carbo or not, add or substitute lapatinib Her-2 positive CALGB 40601 Adds new agents, data mines for predictive factors Add gemcitabine or capecitabine, add bevacizumab or not Palpable and operable cancer NSABP B40 Optimal scheduling, toxicity Paclitaxel-trastuzumab then FEC-75-trastuzumab Her-2 positive ACOSOG-Z1041 Concept Experimental Therapy Patient Population Trial Name
  • Diffusion MRI: Functional Diffusion Mapping Red – increase ADC Green – stable ADC Blue – decrease ADC
  • Schema Pre-Treatment Evaluation Baseline MRI Repeat Baseline MRI Chemotherapy A Post-Chemo A MRI Chemotherapy B Surgery Chemotherapy A Post-Chemo A MRI Chemotherapy B Post-Chemo B MRI Part One Part Two Pre-Chemo B MRI 10 patients 14 patients
  • Diffusion MRI, Interim Results cSD -2.40 -1.62 7 cSD -0.33 -0.23 5 cPR 1.40 1.04 4 cPR 1.75 1.14 2 cPR 1.61 1.02 1 after Part A only ±.05 null thresh ±.025 null thresh Case # Response % vol inc > 2.5%
  • Diffusion MRI Interim Results cPR, pPR cPR, pPR cPR, pPR cPR, pCR cCR, pCR after Parts A & B cSD -2.40 -1.62 7 cSD -0.33 -0.23 5 cPR 1.40 1.04 4 cPR 1.75 1.14 3 cPR 1.61 1.02 1 after Part A only ±.05 null thresh ±.025 null thresh Case # Response % vol inc > 2.5%
  • What’s the Goal?
    • Select patients who will require systemic therapy for neoadjuvant treatment
    • Find predictive factors (either before or early in treatment) that allow for accurate tailoring of therapy