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  • Several important conclusions were drawn from the randomised trials. All the studies confirmed the high clinical response to neoadjuvant systemic therapy of breast tumours, which led to an increase in breast conservation rate in most studies. Neoadjuvant therapy had a good safety profile, with limited toxicity and without interfering with subsequent surgery or radiation therapy, therefore not compromising the use of locoregional therapy for the patient. The long-term results of these studies demonstrated similar disease-free survival (DFS) and overall survival (OS) rates for patients receiving neoadjuvant therapy vs. the same regimen given as adjuvant treatment1, demonstrating convincingly the equivalence of the two treatment strategies. A consistent finding among different studies is that the subgroup of patients who achieve pathological complete response (pCR) following neoadjuvant therapy chemotherapy, have significantly higher DFS and OS2.In most neoadjuvant studies, various histological and biological parameters were analysed, to identify predictive markers of response. Several factors demonstrated their value in predicting response to neoadjuvant chemotherapy. The following parameters were consistently associated with higher rates of pCR: smaller tumoursvs. larger tumours, higher grade vs. well differentiated tumours, hormone receptor (HR) negative tumoursvs. those with positive receptors, ductal histology vs. lobular, and higher proliferation rate vs. slow growing tumours1. The triple negative phenotype (oestrogen receptors [ER], progesterone receptors [PR] and ErbB2 receptors absent), which include the basal-like molecular subtype, and the ErbB2+ subtype (ErbB2+ with HR-negative), were shown to have higher pCR rates than the luminal subtypes3, consistent with the already reported data for HR-negative tumours.Several studies proposed molecular signatures as predictors of response to specific primary chemotherapy regimens4. Although promising, these results need to be validated prospectively before being accepted for clinical use.Hanrahan EO, et al. Neoadjuvant systemic therapy for breast cancer: an overview and review of recent clinical trials. Expert OpinPharmacother2005;6:1477–91Guarneri V, et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J ClinOncol2006;24:1037–44 Rouzier R, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005;11:5678–85Ayers M, et al. Gene expression profiles predict complete pathologic response to neoadjuvantpaclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J ClinOncol2004;22:2284–93
  • Recently a meta-analysis of all co-operative neoadjuvant trials conducted in Germany between 1998 and 2006, and which included an anthracycline and a taxane, was presented. The strengths of this analysis include the fact that it was an integrated meta-analysis based on individual data, and the homogeneous definition of pathological complete response (pCR) (no invasive residuals in the excised tissue of breast and axillary lymph nodes [ypT0/is, ypN0]). 6634 patients included in seven prospective neoadjuvant trials containing doxorubicin or epirubicin, docetaxel or paclitaxel, with or without trastuzumab were analysed. Among those, 1407 patients were ErbB2+, 671 received chemotherapy with trastuzumab while the remaining 736 received no trastuzumab. The pathological complete response rate was significantly higher for the group of patients who received trastuzumab: 41% vs. 22.7%. This study thus confirmed, on a larger scale, the results of the smaller randomised clinical trials.Although the results of neoadjuvant treatment with trastuzumab plus chemotherapy are encouraging, this use of trastuzumab has not yet been approved by the regulatory authorities. However, it is recommended by the National Comprehensive Cancer Network guidelines2.Von Minckwitz G, et al. Integrated meta-analysis on 6634 patients with early breast cancer receiving neoadjuvantanthracycline-taxane +/- trastuzumab-containing chemotherapy. SABCS 2008; Abstract 79 and presentationNCCN (National Comprehensive Cancer Network) Clinical Practice Guidelines in Oncology. Breast Cancer. V1. 2009. Availableat: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdfAccessed March 2009 
  • To define pCR and total pCRPrimaryPathological Complete Response (pCR) defined according to the NSABP guidelines, as no invasive cancer in the breast or only non-invasive in-situ cancer in the breast specimen SecondarypCR rate in breast AND lymph nodes [total pCR (tpCR)]
  • The German Breast Group is performing an extensive phase III trials programme exploring the integration of new therapies (e.g. lapatinib, bevacizumab, everolimus) into neoadjuvant chemotherapy regimens for primary breast cancer. One of these is the GeparQuinto, in which ErbB2+ patients will receive four cycles of EC chemotherapy (epirubicin and cyclophosphamide), followed by four cycles of docetaxel, concomitant with either trastuzumab (loading dose: 8 mg/kg, maintenance dose: 6 mg/kg, day 1 q day 21) or lapatinib: 1250 mg (five tablets) orally once daily1. Following surgery, patients continue to receive trastuzumabto complete 52 weeks of ErbB2 blockade.ENDPOINTSPrimary:pCR rates of neoadjuvant EC-Doc with either trastuzumab or lapatinib in HER2-positive, untreated primary breast cancerSecondary:compliance and toxicity other pCR definitionsbreast conservation rateefficacy in stratified subgroups clinical response rates of breast and lymph-nodesdisease-free and overall survival prediction by pre-defined molecular markersGeparQuinto-Trial. Available at:http://www.germanbreastgroup.de/geparquinto/english.html. Accessed Mar 2009

BALKAN MCO 2011 - A. Eniu - How to optimize systemic therapy in LABC BALKAN MCO 2011 - A. Eniu - How to optimize systemic therapy in LABC Presentation Transcript

  • How to optimize systemic therapy for locally advanced breast cancer
    Alexandru ENIU, MD, PhD
    Medical Oncologist
    Department of Breast Tumors
    Head, Day Hospital Unit
    Cancer Institute Ion Chiricuţă
    Cluj-Napoca, Romania
  • Heterogeneity of Locally Advanced Breast Cancer (LABC)
    N2
    N2
    T4
    Stage IIIB
    N0
    N1
    N1
    T4
    T4
    Stage IIIC
    N3
  • Heterogeneity of Locally Advanced Breast Cancer (LABC)
    N2
    N1
    N1
    T3
    T1-3
    N0
    T3
    Stage IIB
    Stage IIIA
  • Mortality of breast cancer in Europe
    Coleman, M, et al Responding to the challenge of cancer in Europe
    www.euro.who.int/Observatory accesed August14, 2009
  • Breast cancer stage at presentation, 2004
    Institutional cancer registry
    Cancer Institute “I. Chiricuta”, Cluj-Napoca, 2004
  • Primary chemotherapy for LABCWhat we know?
    Initially used to shrink inoperable cancers
    Not formally compared to local therapy alone…
    Improvements in survival with combined modality established it as STANDARD OF CARE
    Few studies specifically in LABC
    Heterogeneity (definition, regimens, endpoints)
    Standard regimens are Anthracycline-based
    Taxanes were evaluated in newer studies
  • Neoadjuvantsystemic therapy – what do we know?
    • Safety profile:
    • Limited toxicity
    • Does not interfere with subsequent surgery/radiation therapy
    • Offers similar DFS and OS, vs. the same regimen given as adjuvant treatment
    • Patients who achieve pCR have significantly higher DFS and OS
    • Predictive factors for pCR:
    • Smaller tumours
    • Higher grade
    • Ductal histology
    • Higher proliferation rate
    • Hormone receptor (HR) negative tumours
    • The triple negative phenotype (ER-, PR-, ErbB2-) and the ErbB2+ subtype(ErbB2+, HR-) have higher pCR rates than the luminal subtypes
    DFS, disease-free survival; OS, overall survival; pCR, pathological complete response
  • The NSABP data OPERABLE breast cancer
    cCRpCR
    B-1836%13%
    4 x AC
    n=1506
    B-2760%26%
    4 x AC
    +
    4x Docetaxel
    n=2411
    Wolmark, J Nat Cancer Inst Monogr. 2001, 30:96; Bear, J Clin Oncol 2006,24:2019
  • The MD Anderson experience- LABC
    pCR Predictive
    Kuerer 12% ER-, G3
    4 x FAC
    n=372
    Green (n=258)
    4x q3wP
    + 15,7% ER-, PR-
    4 x FAC
    12 x wP
    + 28,2%
    4 x FAC
    Kuerer, J Clin Oncol,1999; Green, J Clin Oncol 2005; Hennessy, J Clin Oncol 2005
  • Evaluation prior to primary systemic therapy for LABC
    Clinical examination:
    Clinical size of tumor
    Skin changes: erythema, edema, ulceration, and dimpling
    Lymph node status
    Photo documentation (inflammatory, T4’s…)
    Elicitation of symptoms suggestive for distant metastasis
    Natural history of the disease (rapid growing <6 months versus neglected tumor to differentiate T4d from T4b)
  • Evaluation prior to primary systemic therapy for LABC (2)
    Pathology: CORE BIOPSY !
    FNA cytology is not acceptable anymore!
    Full assessment of grade, invasion, RE, RP and Her2
    Adequate breast imaging: extent of disease
    Mammography
    Ultrasound for T and N
    MRI- may add, but still controversial
    Clip placement at dg (for surgery & pathology!)
    Staging: X-ray, blood tests (CBC, liver, AP)
    optional: bone scan, abdominal CT
  • Response assessment
    Clinical exam at each cycle (T, N)-> to identify progression
    Post therapy: 2 weeks after last cycle of chemo
    Clinical exam: notoriously inaccurate!
    Mammography / ultrasound ( Chagpar, Ann Surg, 2006)
    MRI if performed at dg
    better anatomic staging
    limitations: false +, false - !
    Functional Imaging (Dynamic Contrast Enhanced MRI, PET)- still investigational
    Clinical
    utility?
  • Surgery after primary chemotherapy
    Surgery: 3 w or later after chemo
    WBC nadir : 1,5-2 weeks
    N>1500, Plt >50 000
    Type of surgery
    MRM for all LABC ?!
    Criteria for breast conservation ( Singletary, Cancer Treat Res 1997)
    Resolution of skin edema
    Residual tumor size <5 cm
    Absence of extensive breast lymphatic invasion
    Absence of extensive suspicious microcalcifications ->MRM
    No evidence of multicentricity-> MRM
  • Systemic treatment after surgery
    Hormone receptor positive -> hormone therapy
    Her2 positive -> adjuvant trastuzumab
    Further chemotherapy ?
    Many (all?) patients had anthra+alkylator and taxanes
    No data to suggest further benefit from chemo
    In the absence of trial data, further chemotherapy should not be administered if anthra and taxanes have been already used
    Would more chemotherapy be better?
    Yes, tumor is really sensitive to chemo
    No, prognosis is already very good
    Would more chemotherapy be better?
    Yes, high risk imposes further treatment
    No, tumor does not respond to chemo
  • (R)Evolution of classificationin oncology
    Anatomical
    classification
    Genomic
    analysis
    Molecular
    profiling
    Individual
    carracteristics
    Histologic
    classification
    “Therapy A”
    “TherapyB”
    Ductal
    Invasive
    carcinoma
    “RE positiveor
    Her2 positive”
    “Triple negative
    orLuminal A”
    “”Breast cancer”
  • HR NEGATIVE
    HR POSITIVE
    Her2+
    Her2 -
    Her2+
    Her2 -
    G2-3 or Ki67 
    G1 or Ki67 
    CC. Her2 POSITIVE
    CC. TRIPLE NEGATIVE
    CC. LUMINAL A
    CC. LUMINAL B
    CHEMOTHERAPY
    +
    ANTI HER 2 THERAPY
    HORMONE THERAPY
    +
    CHEMOTHERAPY
    • CHEMOTHERAPY
    • CLINCAL TRIALS
    HORMONE THERAPY
    Molecular subtypes or clinical subtypes?(or SHORT HANDS?)
    BREAST CANCER
  • “Luminal A”Optimal neoadjuvant systemic therapy- hormone therapy?
    ER + (+++) PR + (+++)
    Her2 negative
    Low Grade - grade 1
    Low Ki-67
  • Primary hormonal therapy for LABC(luminal ?)
  • Preoperative Endocrine Therapy:Conclusions
    Aromatase inhibitors more effective than TAM
    30-50% clinical response…but <5% pCR
    Breast conserv. in >40% initially proposed MRM
    Optimal duration: at least 4 mth (…12-18mths?)
    Not a substitute for surgery on the long term
    Good alternative for chemotherapy in older patients with high ER/PR
    How to select?
  • Individualized therapy“Triple negative cc.”
    ER - PR - Her2 -
    High grade ( 3)
    High Ki-67
  • Triple Negative Breast CancerHETEROGENEITY
    Basal - like
    Infiltrating
    ductal
    carcinoma
    ER, PR, Her2 Negative
    “3-”
    Non Basal - like
    Other histologies (medullary,
    squamous, apocrine
    Used as a surrogate to represent the basal-like category ( ~80% of “3-” are basal-like)
  • Response, Survival with Neoadjuvant Chemotherapy: “3-”
    1118 pts. who received neoadjuvant PCT for stage I-III breast cancer at MD Anderson
    255 (23%) with “3-” disease
    Pts with “3-” had
    Higher pCR rates ( 22% vs 11%, p=0.34)
    Increased risk for visceral mets
    Decreased 3 yr progression-free survival and overall surviva, p<0.0001
    Shortened post recurrence survival
    Liedtke C et al, Ann Oncol, 2008, 26:1275
  • Overall survival as a function of response to neoadjuvant PCT
    Liedtke C et al, J Clin Oncol, 2008, 26:1275
  • Individualized therapy“Her2 positive cc.”
    Her2 positive, ER - or +, PR – or +,
    High grade ( 3)
    High Ki-67
  • NOAH Study DesignLABC including Inflammatory
    pCR= 43%
    IBC= 55%
    pCR= 23%
    IBC= 19%
    Baselga J, et al. Oral presentation at ECCO 2007 (Abstract 2030) Gianni L, et al. Poster presented at ASCO 2007 (Abstract 144)
  • T
    OP
    EC
    TX
    R
    OP
    T  X
    OP
    Epirubicin
    90 mg/m²
    Cyclophosphamide
    600 mg/m²
    Docetaxel
    100 mg/m² (A)
    75 mg/m² (B,C)
    Capecitabine
    1800 mg/m²
    If endocrine
    responsive
    Tam/AIs
    If Her2 pos:
    Trastuzumab
    6 mg/kg q3w 1y
    A G O
    GEPARQUATTRO Study Design
    pCR= 45,5% vs 20,6%
    No CHF grade IV
    No LVEF< 45%
  • German meta-analysis of neoadjuvant chemotherapy and trastuzumab: effect in ErbB2+ patients
    yp
    T
    is N0
    yp
    T
    0 N0
    Pathological complete response (%)
    45
    p<0.001
    40
    13.4
    35
    30
    25
    5.6
    20
    15
    27.7
    10
    17.1
    5
    0
    Without trastuzumab
    With trastuzumab
    n=736
    n=671
    Von Minckwitz et al. SABCS 2008;Abstract 79 and presentation. Reproduced with permission
  • Lapatinib and/or trastuzumab in the neo-adjuvant setting: NEO-ALTTO study design
    6 wks 12 wks 9 wks 34 wks
    Eligibility
    Baseline
    Surgery
    FEC ×3 courses
    T >2 cm
    Nx
    M0
    FISH+
    IHC3+
    n=450
    Lapatinib
    1500 mg/day + paclitaxel
    80 mg/m2 q wk
    Lapatinib
    1500 mg/day
    Lapatinib
    1500 mg/day
    Trastuzumab
    6 mg/kg q 3 wk
    Trastuzumab
    2 mg/kg q wk
    +
    paclitaxel
    80 mg/m2 q wk
    Trastuzumab
    2 mg/kg q wk
    Lapatinib
    1000 mg/day +
    Trastuzumab
    6 mg/kg q 3 wk
    Lapatinib
    750 mg/day
    + trastuzumab
    2 mg/kg q wk
    +paclitaxel
    80 mg/m2 q wk
    Lapatinib
    1000 mg/day +
    Trastuzumab
    2 mg/kg q wk
    Wk 2
    Wk 6
    Tumour biopsy, blood
    Tumour biopsy,
    blood, PET
    PET
    PET, positron emission tomography
  • Efficacy – pCR and tpCR
    L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
    pCR pathologic complete response
  • NeoSphere: study design
    FEC q3w x 3
    trastuzumab q3w cycles 5–17
    FEC q3w x 3
    trastuzumab q3w cycles 5–17
    docetaxel q3w x 4->FEC q3w x 3
    trastuzumab q3w cycles 5–17
    FEC q3w x 3
    trastuzumab q3w cycles 5–21
    TH (n=107)docetaxel + trastuzumab
    S
    U
    R
    G
    E
    R
    Y
    Patients with operable or locally advanced /inflammatory* HER2-positive BC
    Chemo-naïve & primary tumors >2cm (N=417)
    THP (n=107)docetaxel + trastuzumab +pertuzumab
    HP (n=107)trastuzumab + pertuzumab
    TP (n=96)docetaxel + pertuzumab
    Study dosing: q3w x 4
    BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0H, trastuzumab; P, pertuzumab; T, docetaxel
    3
  • p = 0.0198
    p = 0.0141
    p = 0.003
    NeoSpherepCR rates: ITT population summary
    50
    40
    pCR, %  95% CI
    45.8
    30
    20
    29.0
    24.0
    10
    16.8
    0
    H, trastuzumab; P, pertuzumab; T, docetaxel
    TH
    THP
    HP
    TP
    6
  • Lapatinib and/or trastuzumab in the neo-adjuvant setting: GeparQuinto study design
    EC +
    T
    D +
    T
    Trastuzumab 1 year overall (including therapy)
    Core biopsy
    Trastuzumab
    R
    n=2547
    EC +
    L
    D +
    L
    Trastuzumab 1 year
    Lapatinib
    Epirubicin
    Cyclophosphamide
    Docetaxel
  • pCR Rates According to Other Definitions
    no invasive residual in breast & nodes
    no invasive residual
    in breast
    P<0.05
    P<0.05
  • Intrinsic molecular classification: (neoadjuvant?) therapeutic implications
  • Conclusions
    Standard primary chemotherapy for LABC should include an anthracycline (FEC, AC, EC…) AND taxanes
    Optimal duration is unknown –(6-8 cycles ?)
    Dose-intense anthracycline regimen does not improve outcome (metronomic schedule may)
    Addition of taxanes improved outcomes but not DFS or S ( sequential, not concurrent ?)
    4 cycles of Anthra (metro?) plus 4 cycles of docetaxel or 12 w of weekly paclitaxel, before surgery
  • Conclusions (2)
    Achieving pCR is prognostic !
    most useful for Her2 + and “3-”
    some pCR patients still relapse
    some non-pCR patients do not relapse
    we need better surrogate endpoints than pCR
    HR- (3-) have substantially higher rates of pCR
    Anti-Her2 primary therapy- very effective but not reimbursed??!
    Endocrine: alternative for chemotherapy in older patients with high ER/PR
    Limited info fortailoring chemo according to
    tumor biology
    tumor response
  • www.ictwcluj.org