TNBC: Current Challenge and Perspectives. Henry L Gomez MD, PhD

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1 TNBC: Current Challenge and Perspectives Henry L Gomez MD, PhD

4 What Is a Triple-Negative Breast Cancer (TNBC)? Triple negative : ER negative, PgR negative, HER2 negative Depending on thresholds used to define ER and PgR positivity and methods for HER2 testing TNBC accounts for 10% to 17% of all breast carcinomas Significantly more aggressive than other molecular subtype tumors Majority grade 3 tumors Most frequently high grade invasive ductal carcinomas of no special type Reis-Filho JS, et al. Histopathology. 2008;52:

5 Triple-negative breast cancer: Range of histology. Hudis C A, and Gianni L The Oncologist 2011;16: by AlphaMed Press

7 Sobrevida Global a 10 años Peruvian Patients Carolina Breast Cancer Study 76.6% 66.3% 67.1% 59.8% Her2/neu Luminal A Luminal B BCL p < Source: Cruz et al. INEN Source: Carey et al. JAMA 2006; 295(21):

8 Distribución del Perfil Molecular de acuerdo a IHQ Breast cancer subtypes Peruvian patients* Southern Switzerland** The Caroline Breast Cancer Study *** Period of interest Luminal A 49.3% 73.2% 54.8% Luminal B 13.2% 13.8% 16.6% Basal cell like 21.3% 7.4% 21.5% Her2/neu 16.2% 5.6% 7.1% *, Gomez et al. ClinBreastCan Res in press **, Spitale et al. Annals of Oncology 20: , 2008 ***, Carey et al. JAMA 2006; 295(21):

9 No consistent association with nodal status or stage Relapse pattern Higher risk Early timing Sites differ from luminal: CNS 46% of time Clinical Characteristic of Metastatic TNBC HR Other (290 of 1421) Triple negative (61 of 180) Yrs After First Surgery n Bone, % Soft Tissue, % Viscera, % TNBC ER HER Liedtke C, et al. J Clin Oncol. 2008;26: Lin NU, et al. Cancer. 2008;113:

10 Characteristics and Features of TNBC Phenotype Weak relationship between tumor size and nodal status Rapid rise in risk of recurrence following diagnosis Peak risk of recurrence at 1-3 yrs Distant recurrence rarely preceded by local recurrence Local recurrence not predictive of distant recurrence Increased mortality rate first 5 yrs Majority of deaths occurs within first 5 yrs Rapid progression from distant recurrence to death Dent R, et al. Clin Cancer Res. 2007;13:

11 NCCN Guideline Recommended Chemotherapy Regimens for MBC Preferred single agents Anthracyclines (doxorubicin, pegylated liposomal doxorubicin) Antimetabolites (capecitabine, gemcitabine) Microtubule inhibitors (eribulin, vinorelbine) Taxanes (paclitaxel) Panel: little compelling evidence that combination chemotherapy is superior to sequential single agents for patients where immediate response is not necessary (ie, visceral crises) Chemotherapy combinations AC (doxorubicin/ cyclophosphamide) EC (epirubicin/cyclophosphamide GT (gemcitabine/paclitaxel) CMF (cyclophosphamide/ methotrexate/fluorouracil) FAC (fluorouracil/epirubicin/ cyclophosphamide) FEC (fluorouracil/doxorubicin/ cyclophosphamide) Paclitaxel/bevacizumab NCCN. Clinical practice guidelines in oncology: breast cancer. v

12 Antracyclinesfortriplenegativebreastcancer Trial Phase/no. TNBC pts Setting Regimen Outcome in triple-negative breast cancer Di Leo (2008) meta-analysis III n=157 Adjuvant Anthracycline vs CMF 23% reduction in risk of relapse(p=.11) Bidard(2008) II n=120 Neoadjuvant CEF x 4-6 PathologicalCOMPLETE RESPONSE = 17% Gluz(2008) III n=66 Neoadjuvant DD EC orcmf vs HD EC-Ecthiotepa 5 yrevent-free survivalwithhd 71% vs 26% withdd Abbreviations: C, cyclophosphamide; DD, dose dense; E, epirubicin; F, 5-fluorouracil; HD hogh dose; M, methotrexate HudisC A, and Gianni L The Oncologist 2011;16:1-11

TNBC Patients are Characterized by Receptor Negativity and Poor Prognosis PFS/TTP with chemotherapy regimens 1-7* Paclitaxel 175, 210 or 250 mg/m 2 q3w 1 n=44 2,8 Paclitaxel 90 mg/m 2 qw for 3 weeks

13 TNBC Patients are Characterized by Receptor Negativity and Poor Prognosis PFS/TTP with chemotherapy regimens 1-7* Paclitaxel 175, 210 or 250 mg/m 2 q3w 1 n=44 2,8 Paclitaxel 90 mg/m 2 qw for 3 weeks of a 4-week cycle 2 n=110 5,3 Paclitaxel 90 mg/m 2 qw 3 n=28 3,7 Cisplatin 75 mg/m 2 q3w 4 n=58 1,5 4 months Xeloda 2,000 mg/m 2 days 1-14 q3w 5 n=50 4,2 Xeloda 2,000 mg/m 2 days 1-21 q4w 6 n=33 2,5 Gemcitabine 1,000 mg/m 2 + carboplatin AUC2 days q3w 7 n=62 3, PFS/TTP (months) 1. Harris, et al. Breast Cancer Res 2006; 2. O Shaughnessy, et al. Cancer Res 2009; 3. Awada, et al. Ann Oncol 2010; 4. Baselga, et al. Cancer Res 2010; 5. Robert, et al. J Clin Oncol 2011; 6. Roché, et al. Ann Oncol 2010;7. O Shaughnessy, et al. N Engl J Med 2011

14 C9344 disease-free survival for paclitaxel by ER and HER-2 status. Hudis C A, and Gianni L The Oncologist 2011;16: by AlphaMed Press

15 Adjuvant anthracycline plus taxane for triple-negative breast cancer. Hudis C A, and Gianni L The Oncologist 2011;16:1-11

16 Sequential taxaneand anthracycline-containing neoadjuvant regimens: The sequential order impact Thiery-Vuillemin et al. The Breast 2011

17 Neoadjuvant doxorubicin vs docetaxel in TNBC Antitumor activity in intrinsic subtypes Martin et al. ASCO 2010

18 DifferentialResponseof TNBC to Docetaxeland Carboplatin-Based Neoadjuvant Treatment Chang et al. Cancer2010 pcr of the primary tumor in three types of breast cancer

19 Ixabepilone for triplenegative breast cancer Trial Phase/ Setting Regimen Outcome in triple-negative breast cancer Pivot(2009) Baselga(2009) III n=187 II n=161 Metastatic breast cancer resistant to anthracycline or taxane Ixabepilone+ cape vs cape alone Improvedoverallresponse rate(27% vs 9%) and progressio-free survival[4.1 vs 2.1 mo(s)] Neoadjuvant Ixabepilone Pathological complete response = 26% Abbreviations: Cape, capecitabine HudisC A, and Gianni L The Oncologist 2011;16:1-11

20 What About Platinums? Good preclinical rationale, particularly in BRCA-associated Clinical data: Trial Population Results Control arm BALI-1 (CDDP) Sporadic TNBC 10% RR Control arm phase III iniparib (gem/carbo) Sporadic TNBC 30% RR TBCRC 001 (cetuximab/carbo) Sporadic TNBC 17% RR 14-pt trials neoadj CDDP (Byrski + Silver) BRCA1+ 86% pcr 24-pt trial neoadjuvant CDDP (Silver) Sporadic TNBC 15% pcr Clinical role of platinums less clear: promising in BRCA+ CALGB and other trials designed to clarify Baselga J, et al. Ann Oncol. 2010;21(Suppl 8). Abstract 274O. O Shaughnessy J, et al. J Clin Oncol. 2011;29(Suppl). Abstract Carey L, et al. 2008;26(Suppl). Abstract Byrski T, et al. J Clin Oncol. 2010;28: Silver DP, et al. J Clin Oncol. 2010;28:

21 Bevacizumab for triplenegative breast cancer Trial/arm E2100 Paclitaxel (n=110) Paclitaxel + bevacizumab(n=122) AVADO Docetaxel + placebo (n=52) Docetaxel + bevacizumab 15 mg/kg (n=58) RIBBON-1 Taxane/anthracycline + placebo (n=46) Taxane/anthracycline + bevacizumab(n=96) Capecitabine + placebo (n=50) capecitabine + bevacizumab(n=87) ATHENA Taxane-based regimen + bevacizumab(n=577) Median PFS [mo(s)] in TNBC subset

22 Current Treatment for TNBC Many patients treated with adjuvant anthracycline, taxane, and cyclophosphamide PFS 4 mos with chemotherapy for metastatic disease [1] Ixabepilone with differential response in TNBC? [2] Eribulin with differential response in TNBC? [3] Bevacizumab/paclitaxel improves PFS vs paclitaxel alone [4] as well as bevacizumab/ixabepilone or bevacizumab/nab-paclitaxel; [5] may show differential benefit in TNBC? Addition of cetuximab to platinum adds little? (17% RR) [6] 1. Kassam F, et al. Clin Breast Cancer. 2009; 9: Perez EA, et al. Breast Cancer Res Treat. 2010;121: Kaufman PA, et al. SABCS Abstract S Miller K, et al. N Engl J Med. 2007; 357: Rugo HS, et al. ASCO Abstract CRA Carey LA, et al. J Clin Oncol. 2012;30:

23 Conventional Chemotherapy TNBC often responsive to conventional NAC with good outcome similar to other subtypes < pcr = poorer outcome Probability of Being Alive % 94% 88% 68% P =.24 P =.0001 pcr/non-tnbc 0.5 pcr/tnbc RD/non-TNBC 0.4 RD/TNBC Yrs After Surgery Liedtke C, et al. J Clin Oncol. 2008;26:

24 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center Dec. 4-8, 2012 Hypothesis Clinically silent micro-metastasis Residual disease Primary Tumor Bulk = CHEMO SURGERY Recurrence This presentation is the intellectual property of the authors/presenters. Contact them at carlos.arteaga@vanderbilt.edufor permission to reprint and/or distribute

25 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center Dec. 4-8, 2012 Approach Immunohistochemistry Ki67, ER, PR, HER2, AR 112/ clinically-defined TNBC patients with RD after NAC Next generation sequencing 182 oncogenes and tumor suppressors 81/114 Nanostring digital expression analysis 450 genes 89/114 Median Min Max Age N % Stage IIa 3 3% IIb 5 5% IIIa 13 12% IIIb 77 69% IIIc 10 9% NA 3 3% Taxane Yes 55 50% No 53 48% NA 3 3% Menopause Pre 55 50% Post 53 48% NA 3 3% Node status Pos 70 63% Neg 37 33% NA 4 4% This presentation is the intellectual property of the authors/presenters. Contact them at carlos.arteaga@vanderbilt.edufor permission to reprint and/or distribute

Basal-like: n=57 (64%); Her2: n=18 (20%); LumA: n=5 (5.6%); LumB: n= 5 (5.

26 Figure 1: Ki67 varies by molecular subtype A) The molecular subtype was determined from 89/104 TNBC samples using the PAM50 genes as assayed by Nanostring. Basal-like: n=57 (64%); Her2: n=18 (20%); LumA: n=5 (5.6%); LumB: n= 5 (5.6%); Normal ;n=4 (4.5%). B) Post-NAC Ki67 varied significantly by molecular subtype, ANOVA p= A B

27 Distribution of the intrinsic molecular and pathology-based subtypes within triple-negative and basal-like tumors.abbreviations: HR, hormone receptor; TNBC, triple-negative breast cancer by AlphaMed Press Prat A et al. The Oncologist 2013;18:

28 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center Dec. 4-8, 2012 Ki67was scored by IHCin the residual disease At least 500 tumor cells were counted in each case Ki67in post-nactnbcdoes not predict survival A cutoff of 15% was used based on previously published literature % Samples Basal-like Her2-enriched Luminal A Luminal B Normal-like Ki67 score after NAC (%) Basal-like Her2-enriched ANOVA P= Luminal A Luminal B Normal-like Percent relapse-free e 100 Ki67 > 15% 80 Ki67 < 15% Time (years) 100 Ki67 > 15% This presentation is the intellectual property of the authors/presenters. Contact them at carlos.arteaga@vanderbilt.edufor permission to reprint and/or distribute P=0.42 Percent surviving 80 Ki67 < 15% P= Time (years)

29 Number of samples with aberrations AKT3 PTEN PIK3CA TSC1 AKT2 AKT1 RAPTOR RICTOR PIK3R1 Clinically targetable pathways in TNBC BRCA2 BRCA1 ~90% of all patients had an aberration in at least one of these pathways ATM NF1 CRAF BRAF KRAS RB1 CDNK2A CCNE1 AURKA CCND3 CCND2 MET FGFR4 FGFR1 CCND1 IGF1R KIT CDK6 FGFR2 CDK4 EGFR PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs PI3K/mTOR inhibitors DNA-repair targeting agents RAF/MEK inhibitors Cell cycle/mitotic spindle inhibitors Targeted RTK inhibitors This presentation is the intellectual property of the authors/presenters. Contact them at carlos.arteaga@vanderbilt.edufor permission to reprint and/or distribute

30 Heterogeneities in the nomenclature and classification of triple-negative breast cancer Metzger-Filho O et al. JCO 2012;30: by American Society of Clinical Oncology

31 Conventional Cancer Treatment Diagnosis Stage, Grade, IHC Treatment Chemo, Radio, Surgery 31

32 Muito Obrigado

Triple negative breast cancer 2014 GASCO Annual meeting September 5 th 2014, Atlanta, GA

Triple negative breast cancer 2014 GASCO Annual meeting September 5 th 2014, Atlanta, GA Ruth M. O Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology,