ENFERMEDAD AVANZADA Qué hacemos con el triple negativo? Nuevas aproximaciones Javier Cortes, Hospital Universitario Ramon y Cajal, Madrid Vall d Hebron Institute of Oncology (VHIO), Barcelona
Triple Negative Breast Cancer Immunohistochemistry ER PR HER2 ER and PR <1% nuclear Histology HER2 negative : IHC 0 or 1+ staining or 2+ IHC staining with negative FISH High grade ductal
Poor Outcome of Metastatic TNBC (N=112) Initial therapy Time on Treatment First distant relapse 12 weeks 9 weeks 4 weeks Median D.F.I. First line chemo Second line chemo Third line chemo Kassam F, Enright K, Dent et al. Clin Breast Cancer 2009
What is Standard Therapy For TNBC? No specific systemic regimen guidelines exist Little data on which to base decisions Few historical controls making it challenging to design clinical trials for this subgroup
TNBC: Current Treatment Strategies Anthracyclines Capecitabine Biologic agents Taxanes Platinum agents TNBC paradox: chemosensitive but relapse more aggressive with worse OS Cannot treat with existing targeted therapies (hormonal therapy or trastuzumab) Manage same as other BCs with same grade & stage Limited data available from prospective trials in this population Best available data mostly subpopulation analyses
Martin et al, ASCO 2009 CMTN: Antraciclinas vs. Docetaxel CMTN HER2 Luminal B Docetaxel 100 mg/m 2 x 4 ciclos 29 33 14 Doxorrubicin 75 mg/m 2 x 4 ciclos 10 55 16 Single agent Neoadjuvant Chemotherapy study with Doxorubicin or Docetaxel for 4 cycles in Stage II-IIIa (> 3 cm) pcr rate by phenotype
Taxanes For Metastatic TNBC? Retrospective subgroup analyses Placebo arm data Trial Phase N Setting Taxane Outcome in TNBC CALGB 9342 1 III 44 First- or second-line metastatic ECOG 2100 2 III 110 First-line metastatic AVADO 3 III 52 First-line metastatic Paclitaxel weekly and q3w Paclitaxel weekly Docetaxel q3w ORR = 26% TTF = 2.8 months OS = 8.6 months ORR = 11.7% 4 PFS = 5.3 months ORR = 23.1% PFS = 6.1 months 1. Harris, et al. Br Cancer Res 2006 2. O Shaughnessy, et al. SABCS 2009 3. Glaspy, et al. EBCC 2010
Capecitabine For Metastatic TNBC? Retrospective subgroup analyses Placebo arm data Trial Phase N Setting Treatment Outcome in TNBC Pooled analysis 1 III 208 Third-line or greater metastatic Capecitabine ORR = 15% PFS = 1.7 months RIBBON-1 2 III 50 First-line metastatic Capecitabine + placebo ORR = 24% PFS = 4.2 months 1. Rugo, et al. SABCS 2008 2. Glaspy, et al. EBCC 2010
TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC Patients with ER-, PgR-/unknown, and HER2- or BRCA1/2+ metastatic or recurrent LA BC (N = 376) Carboplatin AUC6 q3w x 6 cycles (n = 188) Docetaxel 100 mg/m 2 q3w x 6 cycles ( n = 188) For both arms, crossover upon progression allowed Primary endpoint: ORR in ITT population Secondary endpoints: PFS, OS, ORR (crossover), toxicity Subgroup analyses: BRCA1/2 mutation, basal-like subgroups, HRD biomarkers Tutt A, et al. SABCS 2014
Response at Cycle 3 or 6 (%) Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC (TNT): ORR 90 80 70 Carboplatin Docetaxel Crossover P =.03 68.0% 60 50 40 30 20 31.4% P =.44 35.6% P =.73 22.8% 25.6% 33.3% P =.16 36.6% 28.1% 10 0 All Pts (n = 376) C D D C Crossover* (All pts; n = 182) BRCA1/2 Mutation (n = 43) No BRCA1/2 Mutation (n = 273) Tutt A, et al. SABCS 2014
Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC (TNT): Survival Survival, Mos Carboplatin Docetaxel Median PFS 3.1 4.5 BRCA 1/2 mutated 6.8 4.8 BRCA 1/2 not mutated 3.1 4.6 Median OS 12.4 12.3 Tutt A, et al. SABCS 2014
PFS estimate PFS estimate PFS estimate PFS estimate Bevacizumab-based Therapy: Significant Improvement in PFS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 5.8 E2100 (IRF assessment) 1 Bevacizumab + paclitaxel (n=368) Paclitaxel (n=354) 11.3 HR=0.48* (0.39 0.61) p<0.0001 0 6 12 18 24 30 36 Time (months) AVADO 2 Bevacizumab + docetaxel (n=247) Placebo + docetaxel (n=241) HR=0.67* (0.54 0.83) p<0.001 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 RIBBON-1: taxane/anthracycline cohort 3 8.0 9.2 Bevacizumab + taxane/ anthracycline (n=415) Placebo + taxane/anthracycline (n=207) HR=0.64* (0.52 0.80) p<0.0001 0 6 12 18 24 30 Time (months) RIBBON-1: capecitabine cohort 3 Bevacizumab + capecitabine (n=409) Placebo + capecitabine (n=206) HR=0.69* (0.56 0.84) p=0.0002 0.2 0 8.1 10.0 0 6 12 18 24 30 36 Time (months) 0.2 0 5.7 8.6 0 6 12 18 24 30 Time (months) *Censored for non-protocol therapy before disease progression 15mg/kg q3w; Exploratory p-value 1. Gray, et al. JCO 2009; 2. Miles, et al. JCO 2010 3. Robert, et al. ASCO 2009
Meta-analysis:Analysis of PFS by Subgroups O Shaughnessy et al. ASCO 2010
Meta-analysis of First-line Bevacizumab Plus Chemotherapy in taxanes-pretreated Triple-Negative Breast Cancer Miles DW, et al. ESMO, 2010
Deconstructing the molecular portraits of breast cancer Basal-like Claudin-low HER2-enriched Normal-like Luminal A and B Prat & Perou Mol Oncol 2011; Prat et al. BCR 2010
Identification of Human TNBC Subtypes Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features Lehmann BD, et al. J Clin Invest. 2011
How could TNBCs be stratified? LAR BL1, BL2 IM M, MSL
LAR Triple negative breast cancer is comprised of 6 molecularly distinct subtypes 10% are Luminal AR (LAR) LAR express higher levels of AR mrna vs other TNBC subtypes LAR breast cancers are heavily enriched in hormonally-regulated pathways Luminal AR is more closely related to hormone receptor positive breast cancer (Luminal A and B) than to other subtypes BL= Basal Like, IM = Immunomodulatory, ML= Mesenchymal-Like, MSL= Mesenchymal Stem-like, LAR = Luminal AR
LAR Triple negative breast cancer is comprised of 6 molecularly distinct subtypes 10% are Luminal AR (LAR) LAR express higher levels of AR mrna vs other TNBC subtypes LAR breast cancers are heavily enriched in hormonally-regulated pathways Luminal AR is more closely related to hormone receptor positive breast cancer (Luminal A and B) than to other subtypes BL= Basal Like, IM = Immunomodulatory, ML= Mesenchymal-Like, MSL= Mesenchymal Stem-like, LAR = Luminal AR
LAR All LAR cell lines had some response to bicalutamide Not all of AR+ cell lines were LAR (40%) The majority (70%) of AR+ cell lines responded to bicalutamide Lehman et al CCR 2011
LAR LAR Cell lines All LAR cell lines had some response to bicalutamide Not all of AR+ cell lines were LAR (40%) The majority (70%) of AR+ cell lines responded to bicalutamide Lehman et al CCR 2011
LAR L. Denne et al, SABC 2013
LAR
LAR Traina TA, et al, SABC 2014
PFS (%) PFS (%) Progression-Free Survival by PREDICT AR Status ITT Population 0 1 Prior Regimens 100 n = 118 100 n = 63 80 60 PREDICT AR+ mpfs 16.0 weeks (95% CI: 10.4, 26.1) 80 60 PREDICT AR+ mpfs 32.3 weeks (95% CI: 14.7, 60.3) 40 40 20 0 PREDICT AR mpfs 8.0 weeks (95% CI: 7.1, 12.6) 0 8 16 24 33 41 49 61 64 80 20 0 PREDICT AR mpfs 8.3 weeks (95% CI: 7.1, 15.7) 0 8 16 24 33 41 49 61 64 80 56 62 36 28 25 15 19 6 15 4 Weeks 13 4 10 2 2 1 1 1 0 0 Patients at risk PREDICT AR+ PREDICT AR 27 36 20 18 17 11 14 6 11 4 Weeks 10 4 7 2 2 1 1 1 0 0 ITT = Intent to Treat; mpfs = median progression-free survival; CI = confidence interval Cortes J, et al, ECCO 2015
Overall Survival (%) Overall Survival by PREDICT AR Status 100 ITT Population n = 118 80 60 PREDICT AR+ mos 75.6 weeks (95% CI: 51.6, 91.4) 40 20 PREDICT AR mos 32.3 weeks (95% CI: 20.7, 48.3) 0 Patients at risk PREDICT AR+ PREDICT AR 0 8 16 24 33 41 49 61 64 56 62 53 55 49 46 45 37 42 27 Weeks 40 24 PREDICT AR+ mos 18.0 months PREDICT AR mos 7.5 months 32 13 15 6 11 6 85 3 2 Data cutoff 1Jul2015 ITT = intent to treat; mos = median survival; CI = confidence interval;. Cortes J, et al, ECCO 2015
IM Tumor cell X X T cell Anti-PDL1 X X Lung T cell Anti-PDL1 X X Akbari O, et al. Mucosal Immunol. 2010; Matsumoto K, et al. Biochem Biophys Res Commun. 2008; Chen, et al. Immunity, 2013 Dendritic cell
Mutational load: somatic mutations act as tumor antigens Lawrence et al, Nature 2013
Breast cancer has fewer mutations p<0.0001
Objective responses to PD-1/PD-L1 blockade in advanced TNBC Merck anti-pd1 Ab Genentech anti-pd-l1 Ab ORR 18% centrally reviewed N=32 58% PDL1+ 1% Three ORRs >1 year duration ORR 19% centrally reviewed N=21 (4 ORR +3 pseudoprogression) 23% PDL1+ IHC 2+/3+ 5%/10% Nanda 2014; Emens 2015
ML, MSL Eribulin Mesylate (E7389): A Novel Tubulin Targeted Agent
ML, MSL Eribulin Mesylate (E7389): EMT to MET phenoype Yoshida T, et al. Br J Cancer 2014
ML, MSL Eribulin Mesylate (E7389): EMT to MET phenoype Migration Invation Yoshida T, et al. Br J Cancer 2014
EMBRACE Trial: Eribulin vs TPC Overall results (n=762) Age Race Receptor status No. of organs involved Sites of disease <40 (n=51) 40 - <65 (n=560) 65 (n=151) Caucasian (n=703) Non-Caucasian (n=59) ER/PR + (n=528) ER/PR - (n=187) Unknown (n=47) ER/PR/HER2-negative (n=144) 2 (n=537) >2 (n=217) Visceral (n=624) Non-Visceral (n=130) Hazard ratio (95% CI) 0.2 0.5 1.0 2 5 Favors ERIBULIN Favors TPC Based upon a stratified Cox analysis including geographic region, HER2 status, and prior capecitabine therapy as strata TPC: Treatment of Physician's Choice Cortes et al. Lancet 2011
Eribulin vs Capecitabine (Study 301) TN population Kaufman P, et al. JCO 2015
TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features
TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness)
TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF03084014, AACR 2012 M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features
TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF03084014, AACR 2012 Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features
TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF03084014, AACR 2012 Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features Agents targeting androgen receptor (enzalutamide, bicalutamide, etc)
TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF03084014, AACR 2012 Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 (eribulin?) Plus PI3Ki, RAS/MEK/Erk, MET, PTEN etc, etc Agents targeting androgen receptor (enzalutamide, bicalutamide, etc)