1. 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

2. Heterogeneity of Locally Advanced Breast Cancer (LABC) N2 N2 T4 Stage IIIB N0 N1 N1 T4 T4 Stage IIIC N3

3. Heterogeneity of Locally Advanced Breast Cancer (LABC) N2 N1 N1 T3 T1-3 N0 T3 Stage IIB Stage IIIA

4. 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

5. Breast cancer stage at presentation, 2004 Institutional cancer registry Cancer Institute “I. Chiricuta”, Cluj-Napoca, 2004

6. 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

8. Limited toxicity

9. Does not interfere with subsequent surgery/radiation therapy

10. Offers similar DFS and OS, vs. the same regimen given as adjuvant treatment

11. Patients who achieve pCR have significantly higher DFS and OS

12. Predictive factors for pCR:

13. Smaller tumours

14. Higher grade

15. Ductal histology

16. Higher proliferation rate

17. Hormone receptor (HR) negative tumours

18. The triple negative phenotype (ER-, PR-, ErbB2-) and the ErbB2+ subtype(ErbB2+, HR-) have higher pCR rates than the luminal subtypesDFS, disease-free survival; OS, overall survival; pCR, pathological complete response

19. 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

20. 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

21. 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)

22. 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

23. 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?

24. 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

25. 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

26. (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”

28. CLINCAL TRIALSHORMONE THERAPY Molecular subtypes or clinical subtypes?(or SHORT HANDS?) BREAST CANCER

29. “Luminal A”Optimal neoadjuvant systemic therapy- hormone therapy? ER + (+++) PR + (+++) Her2 negative Low Grade - grade 1 Low Ki-67

30. Primary hormonal therapy for LABC(luminal ?)

31. 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?

32. Individualized therapy“Triple negative cc.” ER - PR - Her2 - High grade ( 3) High Ki-67

33. 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)

34. 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

35. Overall survival as a function of response to neoadjuvant PCT Liedtke C et al, J Clin Oncol, 2008, 26:1275

36. Individualized therapy“Her2 positive cc.” Her2 positive, ER - or +, PR – or +, High grade ( 3) High Ki-67

37. 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)

38. 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%

39. 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

42. 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

43. Efficacy – pCR and tpCR L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response

44. 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

45. 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

46. 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

47. pCR Rates According to Other Definitions no invasive residual in breast & nodes no invasive residual in breast P<0.05 P<0.05

48. Intrinsic molecular classification: (neoadjuvant?) therapeutic implications

49. 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

50. 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

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