Adjuvant and Neoadjuvant Chemotherapy

Transcription

1 Adjuvant and Neoadjuvant Chemotherapy 2014 Situation Dr Alexandre Bodmer Centre du Sein HUG Genève

2 Encouraging.

3 2014 challenge Breast Cancer - Survival Kaplan-Meier Survival Curves We need to: Identify which patients would benefit from chemotherapy. Identify which patient would not. Which Breast Cancers Return? Have reliable prognostic factors Have clinically applicable predictive factors

4 Tumor size Risk assessment Prognostic and predictive factors Lymph node involvement Grade Proliferation Markers : Ki 67 Hormone receptors HER2 status Gene expression profiles

5 Stage : prognostic factor 91% at 5 years 98% at 5 years 80 %at 84% at 5 5 years years 63% at 5 years 58% at 5 years

6 Molecular subtypes and prognosis

7 How can we do better? Better selection of patients for adjuvant chemotherapy Treat only those patients who are most likely to recur and who will therefore benefit most from the addition of chemotherapy Take advantage of genomics

8 The PAM 50 risk of recurrence score risk of recurrence score (ROR) ABCSG-8 trial 2 ATAC trial 1 1 Dowsett M et al. Comparison of PAM50 risk recurrence (ROR) with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy JCO 2013;31: Chia SK et al. A 50 gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen. Clin Caner Res 2012M18:4465

9 21 gene recurrence score Oncotype DX N = 675 patients ER+, N0, ttt Tamoxifen (NASBP-B14) Risk of distant recurrence at 10yr, according to recurrence-score categories. 7% 31% 14% HR 3.21 p <0.001 Paik et al, NEJM 2004

10 21 gene recurrence score predictive factor 91% All RS :< 18 90% NSABP B20 N= 651, ER+ N0 227 : TAM 424 : CT + TAM Outcome : time to distant recurrence 88% RS : RS > 30 60% Paik et al. JCO 2006

11 21 gene recurrence score predictive factor Retrospective analysis, 1447 patients, menopausal, N+ (1-3/>4), RE+ Tamoxifen vs CAF-Tamoxifen 60% 64% P=0.97 HR % 43% P=0.033 HR 0.59 Albain K et al. Lancet oncol 2010

12 21 gene recurrence score issues unresolved in 2014 Not clear at which RS cut off chemotherapy should or should not be administrated? Recently completed TAILORx trial will provide better data In this trial women with RS between 11 et 25 were randomly assigned treatment either endocrin therapy vs chemotherapy followed by endocrine therapy Data from SWOG study suggest role for RS in patients with involved lymph nodes? We wait results from prospective study RxPONDER.

13 Adjvuant chemotherapy for HR+/- & HER2- BC

14 Adjvuant chemotherapy for HR+/-,HER2- BC Anthracycline better than CMF EBCTCG Comparison between different polychimiotherapy regimens for early breast cancer: metaanalysis of long term outcome among women in 123 randomised trial. Lancet 2012;379:432

15 Adjvuant chemotherapy for HR+ /-,HER2- BC Anthracycline + taxane better than anthracycline alone EBCTCG Comparison between different polychimiotherapy regimens for early breast cancer: metaanalysis of long term outcome among women in 123 randomised trial. Lancet 2012;379:432

16 Adjvuant chemotherapy for HR+/-, HER2- BC No single standard regimen Intermediate risk ER+/PR- or low ER/PR or T>2cm or Grade 2-3 orki67% >20% TC x 4 ( docetaxel 75mg/2 + Cyclophosphamide 600mg/m2) High risk N+ 3xFEC 3x docetaxel Alternative chemotherapy AC /EC x 4 AC/EC x 4 docetaxel x 4 AC / EC x 4-paclitaxel weekly x 12 weeks 4x AC( every 14 days) -paclitaxel dose dense FEC 100 x 6 CMF x6

17 Adjvuant chemotherapy for HR+/-, HER2- BC schedule / every 2 weeks treatment Improvement of DFS and OS mainly seen for ER / PR negative BC Bonilla L et al. Dose dense chemotherapy in non metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials: J Natl Cancer Inst 2010;102:1845)

18 Adjvuant therapy for HR+/- & HER2+ BC

19 Adjvuant chemotherapy for HER2+ BC benefit of adjuvant trastuzumab All trials establishing the benefit (DFS and OS) of adjuvant trastuzumab 1 pt1a? Trastuzumab is, still in 2014, the only HER2 directed agent to result in survival benefit when administered with chemotherapy in the adjuvant setting Subcutaneous formulation? On the basis of pertuzumab in neoadjuvant and metastatic setting, NCCN guidelines added: pertuzumab can be incorporated into adjuvant treatment of HER2+, alongside trastuzumab and chemotherapy. However the benefit of this strategy for overall survival is not known Randomized trial evaluating th role of pertuzumab are ongoing. Other HER directed agent including trastuzumab-emtansine and lapatinib remain area of clinical investigation. 1 Moja L et al. Trastuzumab containing regimens for early breast cancer Cochrane Database Syst Rev 2012;4:CD006243

20 Adjvuant therapy for HER2+ BC trastuzumab duration, HERA study Women with locally determined HER2- positive invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF 55% Randomization OBSERVATION n=1698 After ASCO 2005, option of switch to Trastuzumab 1 year Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n= years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n=1701

21 HERA trial DFS for 2 years vs 1 year trastuzumab at 8 yrs FU Disease-free su urvival (%) % 81.6% 86.7% 75.8% 81.0% 76.0% Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) year Years from randomization No. at risk Trastuzumab 2 years Trastuzumab 1 year

22 DFS

23 Adjuvant therapy for HER2+ BC Choice of chemotherapy Several chimiotherapy regimens have been evaluated with trastuzumab Anthracycline followd by taxane&trastuzumab regimen is prefered: greater experience and limited data to suggest greater efficacy for non-anthracycline based regimen No anthracycline based regimen: docetaxel+ carboplatine +trastuzumab (TCH) (D. Slamon) = appropriate and effective alternative Lower congestive heart failure (0.4% vs 2%)

24 Adjuvant therapy for HER2+ BC Lapatinib? Should not be administered in adjuvant setting Lack of benefit for the combined HER2 directed therapy trastuzumab + lapatinib ALTTO study, 4.5 years follow up: combination lapatinib + trastuzumab non impact on DFS Piccart-Gebhart MJ et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC) American Society of Clinical Oncology Annual Meeting; Abstract LBA4.

25 Role of Neoadjuvant chemotherapy

26 Role of Neoadjuvant Chemotherapy Originally neoadjuvant chemotherapy was considered for women with large toumors or inflammatory disease Actually commonly used for high risk (ER-/PR-) (HER2+), operable, stage II and III, primary breast cancer. Associated with identical DFS and OS compared to same treatment in the adjuvant setting 1 Additionnal benefit: Improvement surgical options Enhancement of breast conservation Attractive model for new drug investigation 1 Mauri D et al. Neoadjuvant verus adjuvant systemic treatment in breast cancer: meta-analysis. J Natl Cancer Inst 2005;97:188-94

27 Role of Neoadjuvant Chemotherapy Impact of pcr Assess clinical response of the primary tumor. Minimal response to pathological complet response (pcr) Definition of pcr/fda 1 Absence of any residual invasive cancer Absence of invasive and non invasive cancer on hematoxylin and eosin evaluation on the resected breast specimen, and all sampled ipsilateral lymph nodes following completion of Neoadjuvant chemotherapy pcr correlated with improved survival 2 1 Cortazar P et al. Pathological complete response and long term clinical benefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13 2 Von Minckwitz G et al. Impact of treatment charachterisitcs on response of different breast cancer phenotypes:pooled analysis of the German neoadjuvant chemotherapy trials Breast cencer Treat 2011;125:

28 Prognostic value of pcr Cortazar P et al. Pathological complete response and long term clinical benefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13

29 Prognostic value of pcr by breast subtypes Cortazar P et al. Pathological complete response and long term clinical benefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13

30 Factors associated with pcr Adequate cumulative dose of anthracycline and taxane Concurrent use of trastuzumab ER-/PR-, G3, HER2+ : pcr rate up to 40% Von Minckwitz G et al. Impact of treatment charachterisitcs on response of different breast cancer phenotypes:pooled analysis of the German neoadjuvant chemotherapy trials Breast cencer Treat 2011;125:

31 Patients selection Locally advanced breast cancer, stage 2-3 Inflammatory breast cancer Large operable tumor (> 5cm)1 According tumor biology, likelihood of achieving a pcr HER2+/non luminal TNBC Luminal B 1Fisher B et al. Effect of preoperative chemotherapy on locoregional disease in women with operable breast cancer: findings from the NSABP B18. JCO 1997:15:2483

32 Patients selection Invasive lobular carcinoma: Better clinical behaviour compared with other histological types Lower pcr rates after neoadjuvant chemotherapy Offer neoadjuvant chemotherapy mainly to ILC patients with ER/PR negative and high grade tumor Loibl S et al. Response and prognosis after neoadjuvant chemotherapy in 1051 patients with infiltrating lobular breast carcinoma. Berast Cancer Res Treat,2014;144:

33 Systemic therapy Optimal regimen and duration of neoadjuvant chemotherapy have not been established. General concensus: third generation regimen that contain anthracycline and taxanes. NSABP B267 trial: AC x4 followed by docetaxel x4 was associated with a higher clinical complete response rate (63% vs 40.1% p< 0.001) compare to AC alone, and a higher pcr rate (26.1% vs 13.7%p< ) Bear HD et al. JCO 2003;21:4165

34 What we have learned? Early switch to a non-cross resistant regimen: GeparTrio study Specific treatment strategies for patients with or without response to 2 cycles of TAC ( docetaxel, doxorubicine, cyclophosphamide) Response guided ( switch to another chemotherapy in case of no early response) Patient with response guided chemotherapy had a signigificant longer DFS and OS. Regimen: TAC x 6 vs TAC x 8 /responder vs TAC-NX ( navelbine, xeloda) Von Minckwitz G et al. Neoadjuvant chemotherapy adapted by interim response improves overall survival of primary breast cancer patients: result of the Gepar Trio trial. Cancer Res 2011;72 (24suppl)53-2

35 What we have learned? NSABP B-40 : addition of bevacizumab to neoadjuvant chemotherapy Addition of capecitabin and gemictabine to docetaxiel.

36 What we have learned? EC (90/600mg/m2) with or without use bevacizumab 15mg/kg GeparQuinto trial pcr rate breast and axilla 15.9%in chimiotherapie alone vs 18.4% in bevacizumab group. With bevacizumab improvement of pcr rates but higher incidence of toxicity Until results of other study ( biomarkers of response), bevacizumab is not recommended to use in neoadjuvant setting

37 What we have learned? Conclusion-I Incorporation of additional cytotoxic agent or antiangiogenic agent to anthracycline-taxane based regimens: Has not offered significant additional benefit to breast conservation or pcr rate

38 What we have learned? Dual blockade of HER2 signaling Dual blockade of the HER2 receptor with trastuzumab and lapatinib NeoALTTO study pcr : Combination of trastuzumab and lapatinib increase pcr rate and pcr is associated with improved survival. Piccart-Gebhart M et al. JCO 2014 Not confirmed in adjuvant ALTTO trial1 1 Abstract LBA4

39 What we have learned? Dual blockade of HER2 signaling Pertuzumab, monoclonal antibody inhibiting dimerization of HER2 with other HER receptors NeoSPHERE phase II trial: evaluated efficacy of trastuzumab + pertuzumab + docetaxel FDA granted accelerated approval to pertuzumab for the use in combination with deocetaxel for neoadjuvant treatment of patients HER2+, locally advanced, inflammatory, early stage greater than2cm, or with N+ Gianni L et al. Lancet Oncol 2012,13:25

40 What we have learned? Gepar Sixto Evaluate efficacy of carboplatin in combination with paclitaxel for HER2+ and TNBC Results : increase of the pcr rate (37.2 to 46.7%) by addition to carboplatin Absolute increase by > 20% oberved in patients with TNBC (37.9% vs 58.7%) but not increase in HER2+ Large biomarker program, including BRCA mutation in aim to identify subgroup of TNBC that derive higher benefit from carboplatin We have to wait until result of correlative studies before to decide carboplatin as part of standard neoadjuvant therapy for stage 2-3 TNBC

41 Future perspective Patients who have no achieving pcr, currently no clear role for adjuvant chemotherapy. Novel compounds are being investigated in post neoadjuvant

42 Future perspective Trastuzumab-emtansine (T-DM1) Post neoadjuvant without pcr: treatment with T-DM1 compared with continuation of trastuzumab in HER2+ patients (Katherine Study) Novel cyclin D kinase 4/6 inhibitor: palbociclib Cyclin D kinase inhibitor explored in addition to endocrine therapy in patients without pcr after neoadjuvant treatment (PENELOPE study) Olaparib: Phase III evaluating efficacy and safety of PARP ihibitors as adjuvant treatment in patients with germline BRCA1/2 mutations and high risk HER2- primary breast cancer.have completed surgery and (neo)adjuvant chemotherapy

43 CONCLUSIONS Current consensus opinion for use of neoadjuvant chemotherapy recommends anthracycline and taxane based therapy Several data suggest that neoadjuvant anthracycline and taxane based therapy is associated with the highest response rate. As similar survival benefits have been demonstrated for the administration of chemotherapy before or after surgery. More frequently recommended for women with primary operable stage 2-3 disease Neoadjuvant chemotherapy is an attractive area for research by identifying new effective treatment strategies As we enter in an era of «personalized» therapy, the identification of surrogate predictive and prognostic biomarkers are essential in order to aid treatment decisions.

44 Thank you for your attention