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


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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: 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: Accessed Mar 2009
  • BALKAN MCO 2011 - A. Eniu - How to optimize systemic therapy in LABC

    1. 1. How to optimize systemic therapy for locally advanced breast cancer<br />Alexandru ENIU, MD, PhD<br />Medical Oncologist<br />Department of Breast Tumors<br />Head, Day Hospital Unit<br />Cancer Institute Ion Chiricuţă<br />Cluj-Napoca, Romania<br />
    2. 2. Heterogeneity of Locally Advanced Breast Cancer (LABC)<br />N2<br />N2<br />T4<br />Stage IIIB<br />N0<br />N1<br />N1<br />T4<br />T4<br />Stage IIIC<br />N3<br />
    3. 3. Heterogeneity of Locally Advanced Breast Cancer (LABC)<br />N2<br />N1<br />N1<br />T3<br />T1-3<br />N0<br />T3<br />Stage IIB<br />Stage IIIA<br />
    4. 4. Mortality of breast cancer in Europe<br />Coleman, M, et al Responding to the challenge of cancer in Europe<br /> accesed August14, 2009<br />
    5. 5. Breast cancer stage at presentation, 2004<br />Institutional cancer registry <br />Cancer Institute “I. Chiricuta”, Cluj-Napoca, 2004<br />
    6. 6. Primary chemotherapy for LABCWhat we know?<br />Initially used to shrink inoperable cancers<br />Not formally compared to local therapy alone…<br />Improvements in survival with combined modality established it as STANDARD OF CARE<br />Few studies specifically in LABC<br /> Heterogeneity (definition, regimens, endpoints)<br />Standard regimens are Anthracycline-based <br />Taxanes were evaluated in newer studies<br />
    7. 7. Neoadjuvantsystemic therapy – what do we know?<br /><ul><li>Safety profile:
    8. 8. Limited toxicity
    9. 9. Does not interfere with subsequent surgery/radiation therapy
    10. 10. Offers similar DFS and OS, vs. the same regimen given as adjuvant treatment
    11. 11. Patients who achieve pCR have significantly higher DFS and OS
    12. 12. Predictive factors for pCR:
    13. 13. Smaller tumours
    14. 14. Higher grade
    15. 15. Ductal histology
    16. 16. Higher proliferation rate
    17. 17. Hormone receptor (HR) negative tumours
    18. 18. The triple negative phenotype (ER-, PR-, ErbB2-) and the ErbB2+ subtype(ErbB2+, HR-) have higher pCR rates than the luminal subtypes</li></ul>DFS, disease-free survival; OS, overall survival; pCR, pathological complete response<br />
    19. 19. The NSABP data OPERABLE breast cancer<br />cCRpCR<br />B-1836%13%<br />4 x AC<br />n=1506<br />B-2760%26%<br />4 x AC<br /> +<br />4x Docetaxel<br />n=2411<br />Wolmark, J Nat Cancer Inst Monogr. 2001, 30:96; Bear, J Clin Oncol 2006,24:2019<br />
    20. 20. The MD Anderson experience- LABC<br />pCR Predictive<br />Kuerer 12% ER-, G3<br />4 x FAC<br />n=372<br />Green (n=258)<br />4x q3wP<br /> + 15,7% ER-, PR-<br />4 x FAC<br />12 x wP<br /> + 28,2%<br />4 x FAC<br />Kuerer, J Clin Oncol,1999; Green, J Clin Oncol 2005; Hennessy, J Clin Oncol 2005<br />
    21. 21. Evaluation prior to primary systemic therapy for LABC<br />Clinical examination:<br />Clinical size of tumor<br />Skin changes: erythema, edema, ulceration, and dimpling<br />Lymph node status<br />Photo documentation (inflammatory, T4’s…)<br />Elicitation of symptoms suggestive for distant metastasis<br />Natural history of the disease (rapid growing <6 months versus neglected tumor to differentiate T4d from T4b)<br />
    22. 22. Evaluation prior to primary systemic therapy for LABC (2)<br />Pathology: CORE BIOPSY !<br />FNA cytology is not acceptable anymore!<br />Full assessment of grade, invasion, RE, RP and Her2<br />Adequate breast imaging: extent of disease<br />Mammography<br />Ultrasound for T and N<br />MRI- may add, but still controversial<br />Clip placement at dg (for surgery & pathology!)<br />Staging: X-ray, blood tests (CBC, liver, AP) <br />optional: bone scan, abdominal CT<br />
    23. 23. Response assessment<br />Clinical exam at each cycle (T, N)-> to identify progression<br />Post therapy: 2 weeks after last cycle of chemo<br />Clinical exam: notoriously inaccurate!<br />Mammography / ultrasound ( Chagpar, Ann Surg, 2006)<br />MRI if performed at dg<br />better anatomic staging<br />limitations: false +, false - !<br />Functional Imaging (Dynamic Contrast Enhanced MRI, PET)- still investigational<br />Clinical <br />utility?<br />
    24. 24. Surgery after primary chemotherapy<br />Surgery: 3 w or later after chemo <br />WBC nadir : 1,5-2 weeks<br />N>1500, Plt >50 000<br />Type of surgery<br />MRM for all LABC ?!<br />Criteria for breast conservation ( Singletary, Cancer Treat Res 1997)<br />Resolution of skin edema<br />Residual tumor size <5 cm<br />Absence of extensive breast lymphatic invasion<br />Absence of extensive suspicious microcalcifications ->MRM<br />No evidence of multicentricity-> MRM<br />
    25. 25. Systemic treatment after surgery<br />Hormone receptor positive -> hormone therapy<br />Her2 positive -> adjuvant trastuzumab<br />Further chemotherapy ? <br />Many (all?) patients had anthra+alkylator and taxanes<br />No data to suggest further benefit from chemo<br />In the absence of trial data, further chemotherapy should not be administered if anthra and taxanes have been already used<br />Would more chemotherapy be better?<br />Yes, tumor is really sensitive to chemo<br />No, prognosis is already very good<br />Would more chemotherapy be better?<br />Yes, high risk imposes further treatment<br />No, tumor does not respond to chemo<br />
    26. 26. (R)Evolution of classificationin oncology<br />Anatomical<br />classification<br />Genomic <br />analysis<br />Molecular<br />profiling<br />Individual <br />carracteristics<br />Histologic<br />classification<br />“Therapy A”<br />“TherapyB”<br />Ductal<br />Invasive <br />carcinoma<br />“RE positiveor<br />Her2 positive”<br />“Triple negative<br />orLuminal A”<br />“”Breast cancer”<br />
    27. 27. HR NEGATIVE<br />HR POSITIVE<br />Her2+<br />Her2 -<br />Her2+<br />Her2 -<br />G2-3 or Ki67 <br />G1 or Ki67 <br />CC. Her2 POSITIVE<br />CC. TRIPLE NEGATIVE<br />CC. LUMINAL A<br />CC. LUMINAL B<br />CHEMOTHERAPY<br />+<br />ANTI HER 2 THERAPY<br />HORMONE THERAPY<br />+<br />CHEMOTHERAPY<br /><ul><li>CHEMOTHERAPY
    28. 28. CLINCAL TRIALS</li></ul>HORMONE THERAPY<br />Molecular subtypes or clinical subtypes?(or SHORT HANDS?)<br />BREAST CANCER<br />
    29. 29. “Luminal A”Optimal neoadjuvant systemic therapy- hormone therapy?<br />ER + (+++) PR + (+++)<br />Her2 negative<br />Low Grade - grade 1<br />Low Ki-67<br />
    30. 30. Primary hormonal therapy for LABC(luminal ?)<br />
    31. 31. Preoperative Endocrine Therapy:Conclusions<br />Aromatase inhibitors more effective than TAM<br />30-50% clinical response…but <5% pCR<br />Breast conserv. in >40% initially proposed MRM<br />Optimal duration: at least 4 mth (…12-18mths?)<br />Not a substitute for surgery on the long term<br />Good alternative for chemotherapy in older patients with high ER/PR<br />How to select?<br />
    32. 32. Individualized therapy“Triple negative cc.”<br />ER - PR - Her2 -<br />High grade ( 3)<br />High Ki-67<br />
    33. 33. Triple Negative Breast CancerHETEROGENEITY<br />Basal - like<br />Infiltrating <br />ductal<br />carcinoma<br />ER, PR, Her2 Negative<br />“3-”<br />Non Basal - like<br />Other histologies (medullary, <br />squamous, apocrine<br />Used as a surrogate to represent the basal-like category ( ~80% of “3-” are basal-like)<br />
    34. 34. Response, Survival with Neoadjuvant Chemotherapy: “3-”<br />1118 pts. who received neoadjuvant PCT for stage I-III breast cancer at MD Anderson<br />255 (23%) with “3-” disease<br />Pts with “3-” had<br />Higher pCR rates ( 22% vs 11%, p=0.34)<br />Increased risk for visceral mets<br />Decreased 3 yr progression-free survival and overall surviva, p<0.0001<br />Shortened post recurrence survival<br />Liedtke C et al, Ann Oncol, 2008, 26:1275<br />
    35. 35. Overall survival as a function of response to neoadjuvant PCT<br />Liedtke C et al, J Clin Oncol, 2008, 26:1275<br />
    36. 36. Individualized therapy“Her2 positive cc.”<br />Her2 positive, ER - or +, PR – or +, <br />High grade ( 3)<br />High Ki-67<br />
    37. 37. NOAH Study DesignLABC including Inflammatory<br />pCR= 43%<br />IBC= 55%<br />pCR= 23%<br />IBC= 19%<br />Baselga J, et al. Oral presentation at ECCO 2007 (Abstract 2030) Gianni L, et al. Poster presented at ASCO 2007 (Abstract 144) <br />
    38. 38. T<br />OP<br />EC<br />TX<br />R<br />OP<br />T  X<br />OP<br />Epirubicin<br />90 mg/m²<br />Cyclophosphamide<br />600 mg/m²<br />Docetaxel<br />100 mg/m² (A)<br />75 mg/m² (B,C)<br />Capecitabine<br />1800 mg/m²<br />If endocrine<br />responsive<br />Tam/AIs<br />If Her2 pos:<br />Trastuzumab<br />6 mg/kg q3w 1y<br />A G O<br />GEPARQUATTRO Study Design<br />pCR= 45,5% vs 20,6%<br />No CHF grade IV<br />No LVEF< 45%<br />
    39. 39. German meta-analysis of neoadjuvant chemotherapy and trastuzumab: effect in ErbB2+ patients<br />yp<br />T<br />is N0<br />yp<br />T<br />0 N0<br />Pathological complete response (%)<br />45<br />p<0.001<br />40<br />13.4<br />35<br />30<br />25<br />5.6<br />20<br />15<br />27.7<br />10<br />17.1<br />5<br />0<br />Without trastuzumab <br />With trastuzumab <br />n=736<br />n=671<br />Von Minckwitz et al. SABCS 2008;Abstract 79 and presentation. Reproduced with permission<br />
    40. 40.
    41. 41.
    42. 42. Lapatinib and/or trastuzumab in the neo-adjuvant setting: NEO-ALTTO study design<br /> 6 wks 12 wks 9 wks 34 wks<br />Eligibility<br />Baseline<br />Surgery<br />FEC ×3 courses<br />T >2 cm<br />Nx<br />M0<br />FISH+<br />IHC3+<br />n=450<br />Lapatinib<br />1500 mg/day + paclitaxel<br />80 mg/m2 q wk<br />Lapatinib<br />1500 mg/day<br />Lapatinib<br />1500 mg/day <br />Trastuzumab<br />6 mg/kg q 3 wk<br />Trastuzumab <br />2 mg/kg q wk<br />+ <br />paclitaxel<br />80 mg/m2 q wk<br />Trastuzumab<br />2 mg/kg q wk<br />Lapatinib<br />1000 mg/day +<br />Trastuzumab<br />6 mg/kg q 3 wk<br />Lapatinib <br />750 mg/day<br />+ trastuzumab<br />2 mg/kg q wk<br />+paclitaxel<br />80 mg/m2 q wk<br />Lapatinib<br />1000 mg/day +<br />Trastuzumab<br />2 mg/kg q wk<br />Wk 2<br />Wk 6<br />Tumour biopsy, blood <br />Tumour biopsy, <br />blood, PET<br />PET<br />PET, positron emission tomography<br />
    43. 43. Efficacy – pCR and tpCR<br />L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab<br />pCR pathologic complete response<br />
    44. 44. NeoSphere: study design<br />FEC q3w x 3<br />trastuzumab q3w cycles 5–17<br />FEC q3w x 3<br />trastuzumab q3w cycles 5–17<br />docetaxel q3w x 4->FEC q3w x 3 <br />trastuzumab q3w cycles 5–17<br />FEC q3w x 3<br />trastuzumab q3w cycles 5–21<br />TH (n=107)docetaxel + trastuzumab <br />S<br />U<br />R<br />G<br />E<br />R<br />Y<br />Patients with operable or locally advanced /inflammatory* HER2-positive BC<br />Chemo-naïve & primary tumors >2cm (N=417)<br />THP (n=107)docetaxel + trastuzumab +pertuzumab <br />HP (n=107)trastuzumab + pertuzumab <br />TP (n=96)docetaxel + pertuzumab <br />Study dosing: q3w x 4<br />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<br />3<br />
    45. 45. p = 0.0198<br />p = 0.0141<br />p = 0.003<br />NeoSpherepCR rates: ITT population summary<br />50<br />40<br />pCR, %  95% CI<br />45.8<br />30<br />20<br />29.0<br />24.0<br />10<br />16.8<br />0<br />H, trastuzumab; P, pertuzumab; T, docetaxel<br />TH<br />THP<br />HP<br />TP<br />6<br />
    46. 46. Lapatinib and/or trastuzumab in the neo-adjuvant setting: GeparQuinto study design <br />EC +<br /> T<br />D +<br /> T<br />Trastuzumab 1 year overall (including therapy)<br />Core biopsy<br />Trastuzumab<br />R<br />n=2547<br />EC + <br />L<br />D + <br />L<br />Trastuzumab 1 year<br />Lapatinib<br />Epirubicin<br />Cyclophosphamide<br />Docetaxel<br />
    47. 47. pCR Rates According to Other Definitions<br />no invasive residual in breast & nodes<br />no invasive residual <br />in breast<br />P<0.05<br />P<0.05<br />
    48. 48. Intrinsic molecular classification: (neoadjuvant?) therapeutic implications<br />
    49. 49. Conclusions<br />Standard primary chemotherapy for LABC should include an anthracycline (FEC, AC, EC…) AND taxanes<br />Optimal duration is unknown –(6-8 cycles ?)<br />Dose-intense anthracycline regimen does not improve outcome (metronomic schedule may)<br />Addition of taxanes improved outcomes but not DFS or S ( sequential, not concurrent ?)<br />4 cycles of Anthra (metro?) plus 4 cycles of docetaxel or 12 w of weekly paclitaxel, before surgery<br />
    50. 50. Conclusions (2)<br />Achieving pCR is prognostic ! <br />most useful for Her2 + and “3-”<br />some pCR patients still relapse<br />some non-pCR patients do not relapse<br />we need better surrogate endpoints than pCR<br />HR- (3-) have substantially higher rates of pCR<br />Anti-Her2 primary therapy- very effective but not reimbursed??!<br />Endocrine: alternative for chemotherapy in older patients with high ER/PR<br />Limited info fortailoring chemo according to <br />tumor biology<br />tumor response <br />
    51. 51.<br />