Update on neoadjuvant treatment of breast cancer

Update on neoadjuvant treatment of breast cancer

«IS PATHOLOGIC COMPLETE RESPONSE STILL A GOOD SURROGATE OF SURVIVAL?»

Complete histological response varies according to tumoral type pcr (%) 40 35 30 25 20 15 10 5 0 Luminal A (N=572) Luminal B (HER2-) (N=211) Luminal B (HER2+) (N=281) HER2+ (non-luminal) (N=178) Triple-negative N=362) Untch M, et al J Clin Oncol. 2010, Apr 20;28(12):2024-31

Prognostic impact of pathologic complete response (pcr) on disease-free survival (DFS) in 4,193 patients according to breast cancer intrinsic subtype. with luminal A luminal B, HER2 neg luminal B, HER2 pos pcr rate after neoadjuvant chemotherapy is associated with better outcome only for patients with: HER2-positive/hormone receptor negative or triple-negative and some more aggressive HER2-negative/hormone HER2-positive (nonluminal luminal B, HER2 neg receptor positive tumours. TN von Minckwitz G et al. JCO 2012;30:1796-1804

Update HER2+++ breast cancers What s new?

Unresolved questions Noah study (and other phase II studies) have shown that Traztuzumab should be added to chemotherapy in neoadjuvant setting Questions : Traztuzumab and Anthracyclins combination? Precocity of Traztuzumab use?

Trastuzumab and anthracyclin Joint use of anthracyclin and Trastuzumab in neoadjuvant studies in HER2+++ patients, acceptable toxicity This combination is doubtfull as for its innocuousness Retrospective analysis of 583 patients who received anthracyclins and Traztuzumab (3 neoadjuvant trials) Cardiac toxicity rate (linear variable ) Increase cardiac toxicity (OR = 1,95, 95% CI 1,16-3,29) 44 cardiac events in the group with T vs 28 in the group without T Bozovic-Spasojevic ILancet Oncol. 2011 Mar;12(3):209-11

What is the optimal time for Traztuzumab initiation? There are no direct data answering to this question as there are no studies comparing Traztuzumab in neoadjuvant vs adjuvant setting (except Remagus study.) In metastatic setting, arguments in favor of an early use (1) In adjuvant setting (NCCTG) in favor of an early use With a 6 years follow up DFS (2) AC-P (12 weeks) = 71,9 % AC-P (12 weeks then )-T = 80,1 % AC-PT (concommitant) = 84,2 % HR : 0,69 [0,57-0,85], p = 0,0005 HR : 0,75 [0,60-1,11], p = 0,02 (1) Marty et al, J clin oncol, 2005, (23) (2) Perez EA J Clin Oncol. 2011, 29(34):4491-7.

The interest of double blockage?

Lapatinib in neoadjuvant Tyrosine Kinase inhibitor of EGFR and HER2 Efficacy in metastatic breast cancers HER2 +++ combined with capecitabine or to Traztuzumab Geyer CE N Engl J Med. 2007 Apr 5;356(14):1487. Blackwell KL, et al: J Clin Oncol. 2012 Jul 20;30(21):2585-92.

HER2 signaling pathway Trastuzumab HER2/HER3 PTEN TORC2 Lapatinib PI3K PIP 3 Akt PDK1 Ras Raf MEK Anti HER2 treatment are monoclonal antibodies against extracellular portion (traztuzumab) and small molecules which inhibit tyrosin kinase (lapatinib). Tuberin Erk Rheb TORC1 Rsk Baselga J et al. SABCS 2010

Two randomised trials

Neo-ALTTO Breast cancer HER2+, T > 2 cm (no inflammatory ) FEVG > 50 % n = 450 Stratification : S 5 cm vs. S > 5 cm RE ou RP + vs. RE & RP n 0-1 vs. n 2 Surgery or not Conservative or no R A N D O M I S A T IO N lapatinib trastuzumab paclitaxel lapatinib trastuzumab paclitaxel 6 sem paclitaxel + 12 week s u r g e r y lapatinib trastuzumab lapatinib trastuzumab 34 week 52 semaines de traitement anti-her2 Baselga J et al. Lancet. 2012 Feb 18;379(9816):633-40. F E C X 3

Neo-ALTTO Efficacy pcr et tpcr p = 0.0001 p = 0.001 p = 0.34 p = 0.13 24.7 % 29.5 % 51.3 % 20.0 % 27.6 % 46.9 % L T L + T n = 154 n = 149 n = 152 pcr L T L + T n = 150* n = 145* n = 145* tpcr Loco regional pcr L : lapatinib; T : trastuzumab; L+T : lapatinib plus trastuzumab pcr : pathologic complete response Baselga J et al. Lancet. 2012 Feb 18;379(9816):633-40.

Neo-ALTTO Efficacy % of conservative surgery and % N- p = 0.14 p = 0.03 p > 0.5 p > 0.5 42.9 % 38.9 % 41.4 % 48.0 % 56.6 % 69.0 % L T L + T n = 154 n = 149 n = 152 Conservative surgery L T L + T n = 150* n = 143* n = 147* Negative lymph nodes status L : lapatinib; T : trastuzumab; L+T : lapatinib plus trastuzumab Baselga J et al. Lancet. 2012 Feb 18;379(9816):633-40.

GeparQuinto-HER2+ EC Doc Trastuzumab (T) T 6 months R EC Doc* 620 Pts 309 ECTH, 311 ECTL Lapatinib (L) T 12 months C : Cyclophosphamide 600 mg/m² E : Epirubicine 90 mg/m² T : Trastuzumab 6 (8) mg/kg * + G-CSF Doc : Docetaxel 100 mg/m² L : 1000-1250 mg/j p.o. (cycles de 3 semaines) Untch M et al. Lancet Oncol. 2012 Feb;13(2):135-44

GeparQuinto pcr (non invasive / no invasive carcinoma in breast and lymph nodes by central review ) 50,0% 45,0% 40,0% 35,0% 30,0% 25,0% 20,0% 15,0% 10,0% 5,0% 0,0% EC-Doc + T p < 0.03 EC-Doc + L Untch M et al. Lancet Oncol. 2012 Feb;13(2):135-44

GeparQuinto pcr according to subgroups (pre dfined and stratified 50% 45% 40% Negative RE/RP Positive RE/RP T1-3 and N0-2 T4 or N3 35% 30% 25% 20% 15% 10% 5% 39 % 28 % 26 % 16 % 31 % 20 % 31 % 30 % 0% EC-Doc + H EC-Doc + L EC-Doc + H EC-Doc + L EC-Doc + H EC-Doc + L EC-Doc + H EC-Doc + L Untch M et al. Lancet Oncol. 2012 Feb;13(2):135-44

NSABP B-41 : lapatinib evaluation in neoadjuvant treatment in HER2 +++ breast cancer (1) Operable HER 2 +++ breast cancer 529 ptes R AC - wp + T AC -wp + L Trastuzumab for one year AC- wp + T + L T = trastuzumab ; L = lapatinib ; wp = paclitaxel hebdomadaire Criteria : pcr, cardiac events, progresssion free survival, overall survival ASCO 2012 - D après Robidoux A et al., LBA506 actualisé

NSABP B-41 : lapatinib evaluation in neoadjuvant treatment in HER2 +++ breast cancer (2) Pricipal criteria pcr rate in the breast (non statistically significant ) Secondary criteria pcr rate in the breast and lymph nodes : limit for significativity 100 80 60 40 Taux de réponse histologique p = 0,056 p = 0,78 49,4 47,4 60,2 20 0 AC wp + T (n = 176) wp = paclitaxel hebdomadaire AC wp + L (n = 171) AC wp + T + L (n = 117) ASCO 2012 - D après Robidoux A et al., LBA506 actualisé

Pertuzumab :inhibits HER2 dimerisation Monoclonal anti body against a different target of HER2- HER3 Pertuzumab is a humanised monoclonal antibody, first of a new class : HER2 dimerisation inhibitor With the inhibition of HER2 dimerisation, pertuzumab inhibits HER 2 signaling patways spark off proliferation and survival of cellular cells. Pertuzumab prevent HER2-3 formation Franklin et al. Cancer Cell 2004;5:317-328 Augus et al. Cancer Cell 2002;2:127-137

surgery NeoSphere Design of the study TH (n = 107) docetaxel + trastuzumab FEC /3 w x 3 trastuzumab /3 w cycles 5 17 HER2 +++ breast cancers operable > 2cm or locally advanced or inflammatory (n = 417) THP (n = 107) docetaxel + trastuzumab + pertuzumab HP (n = 107) trastuzumab + pertuzumab FEC /3 w x 3 trastuzumab /3 w cycles 5 17 docetaxel /3 w x 4 FEC /3 w x 3 trastuzumab /3 w cycles 5 17 TP (n = 96) docetaxel + pertuzumab Schéma : /3 weeks x 4 FEC /3 w x 3 trastuzumab /3 sem cycles 5 21 CS, cancer du sein; FEC, 5-fluorouracile, épirubicine et cyclophosphamide *Localement avancé = T2 3, N2 3, M0 ou T4a c, tout N, M0; opérable = T2 3, N0 1, M0; inflammatoire = T4d, tout N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L, Lancet Oncol. 2012 Jan;13(1):25-32.

NeoSphere pcr (ITT) p = 0.0198 50 p = 0.0141 p = 0.003 40 30 45.8 20 29.0 24.0 10 0 16.8 TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L et al. SABCS 2010

Conclusion These data show that combining anti her2 +++ therapies and transduction pathways inhibitors could bypass resistance mecanisms and improve patients outcome without too much toxicity but a cost..

Biomarkers which predict who benefit to the addition of pertuzumab to Traztuzumab In the cleopatra study there are no blood predictive markers nor tissue markers J. Baselga et al., SABCS 2012, S5-1

Bevacizumab in neoadjuvant treatment for breast cancer Interest in triple negative cancers?

Biology of triple negative breast cancers identification of potential targets Triple negative breast cancers come from myoepithelial cells CK5-6, EGFR (1) Kinase Dysregulation Loss of PTEN (2) Activation of Akt pathway Amplification of FGF2, VEGFA, AR TN breast cancer high level of intracellular VEGF TN could have a higher sensitivity, to angiogenic inhibitors 1) Jones et al, 2004 2) Andre 2009 3) Turner et al, 2009 4) Linderholm et al, Ann Oncol, 20, 2009,

Bevacizumab added to neoadjuvant chemotherapy for breast cancer Harry D Bear;M.D; Ph D New england journal of médicine ; Janvier 2012

Design of the study Biopsy for biomarkers EC EC EC EC Operable breast cancers T2 T3 HER2 neg N: 1206 (2007-2010) R EC EC EC EC SURGERY EC EC EC EC E: Epirubicine 60 mg/m toutes les 3 semaines C: Cyclophosphamide: 600 mg/m toutes les 3 semaines X: Capecitabine 825 mg/m2 de J1 à J14 GEM:Gencitabine 1000 mg/m2 J1J8 BEV: Bevacizumab 15mg/m2 T: Docetaxel 100 mg/m2 dans le groupe 1 et 75mg/m2 groupe 2 et 3

Bevacizumab: pcr rate in the breast p = 0,75 p = 0,10 70 60 50 40 30 20 10 0 33,7 % T-AC p = 0,009 36,1 % 35,8% 31,6 % 27,6% 23,5 % TG-AC TX-AC T-AC TG-AC TX-AC Without Bevacizumab With bevacizumab

Bevacizumab: pcr rate in the breast and lymph nodes Bevacizumab addition do not significatively increase pcr rate in breast and lymph nodes (P=0,08)

Bevacizumab: pcr rate in breast and lymph nodes

pcr, % + IC 95 % Bevacizumab: pcr rate in the breast and lymph nodes in patients with RH+ tumors 70 60 50 40 30 20 10 11,1 % p = 0,03 16,8% Bevacizumab addition statistically increase pcr rate in breast and lymph nodes in RH+ tumors (p=0,03) 0 Without Bevacizumab With Bevacizumab

Design of the study, 1948 patients No response (clinical and/or ultrasound) >switch Taxol hebdo + Everolimus (group 2) pcr Her 2 (group 1) EC EC+ Bev Réponse R T T+ Bev 14,9 % 18,4 % P = 0,04 E: Epirubicine 90 mg/m2 C: Cyclophosphamide: 600 mg/m2 T:Docetaxel 100mg/m2 BEV: Bevacizumab 15mg/kg T: Docetaxel 100 mg/m2

Sub groups analysis Interaction test negative NS (p = 0.07) pcr in TN (663 pts) : 39,3% vs 27,9%, p = 0,0033 pcr in RH + 7,8% vs 7,8%, (p=1,00)

Comparison of the two studies pcr increase in the entire population low. pcr increase in TN tumors not found in NSABP study. BUT Smaller population (490 ptes) Inflammatory and T4 tumors in the Geparquinto not in the NSABP trial Anthracyclins given before in the Geparquinto Docetaxel dosage superior in the Geparquinto during 2 cycles Beva given for 2 cycles with antracyclins Only patients with objective response in the gepar received the Beva

Translational studies could targeted the patients who will answer «maybe» to Bevazusimab

Conclusion The neoadjuvant setting gives the unique opportunity to get insights in breast cancer biology It allows: to evaluate new therapies to find predictive factors for better individualization of the treatment.