Triple negative Breast Cancer Patient

Triple negative Breast Cancer Patient Alison L Jones November 2013

Mrs Trisha Negative Aged 52) Diagnosed November 2001 T2 N1 (2/11)M0 Left breast. No family history WLE/ANC then FEC/T + RT Relapsed 2013 bone and liver; PS 1 Normal FBC and LFT What next?

Options Weekly Taxol? Taxol + bevacizumab? Capecitabine? Eribulin? Platinum based?

Triple Negative Cancer; Definition TRN: immunophenotypic description ER (-) PR (-) Her-2/neu (-) 10-17% of all breast cancers, depending on the thresholds of tests

Early Relapse Others Triple negative Canada 456 pts Tischkowitz et al. BMC Cancer 2007;134:7

LN(+) or LN(-) Tischkowitz et al. BMC Cancer 2007;134:7

Higher Distant Metastasis Despite more patients in TN group received C/T: 48.6 v.s 25.5% Rebecca Dent et al. CCR 2007;13(15):4429

Triple Negative Breast Cancer: Definition ER- / PgR- / HER2- ~15% of all breast carcinomas Poorly differentiated; express cytokeratins 5/6, 17 Triple negative but not basal 10-30% can also include claudin-low, a subtype notable for high expression of stem cell markers Clinical assay (IHC) Triple negative and basal-like Gene arrays Basal but not triple negative 15-40% are ER+, PR+ or HER2+

TN and BP not Synonymous TN: heterogeneous group Small part Normal breast like Adenoid cystic carcinoma Medullary BP: also heterogeneous BRCA1 mutation Small part express ER Myoepithelial differentiation

There are 7 identified Triple negative subtypes These 7 subtypes predict for pcr in neoadjuvant studies but further follow-up is needed to see if they predict long-term outcome The 7 subtype classification mmay lead to innovative personalised medicine strategies for TRN breast cancer Masuda et al ASCO 2013

[TITLE] Presented By Hiroko Masuda, MD,PhD at 2013 ASCO Annual Meeting

Higher Distant Metastasis Despite more patients in TN group received C/T: 48.6 v.s 25.5% Rebecca Dent et al. CCR 2007;13(15):4429

Triple Negative Breast cancer Should we screen for metastatic relapse in high risk patients Should we screen for brain metastases in patients with established metastatic disease at other sites? Should we treat them with standard chemotherapy? Are there any other targets and treatment opportunities?

Treatment of TN Breast Ca. No standard therapies Lack of hormone, lack of Her-2/neu targeting agents BRCA1 dysfunction may be a target Cisplatin- DNA cross-link DNA repair- PARP1 inhibitor

Triple Negative Tumors are Chemosensitive Studies have shown that TNBC is more responsive to anthracycline or anthracycline/taxane chemotherapy than Luminal subtypes Patients who had a complete response to chemotherapy had good prognosis regardless of subtype Despite this, TNBC patients still have a worse distant disease free-survival and a poor prognosis Result of high likelihood of relapse in TNBC Most of the data are extrapolated from neoadjuvant studies of from unplanned subset analysis of metastatic trials (ixabepilone and eribulin)

Meta-analysis of patients previously treated with taxanes from three randomised trials of bevacizumab and first-line chemotherapy as treatment for MBC Trial Chemotherapy partner Population analysed Data cut-off for PFS Data cut-off for OS E2100 Weekly paclitaxel Taxane-pretreated patients Feb 2005 1 Oct 2006 4 AVADO 3-weekly docetaxel Taxane-pretreated patients in the placebo or bevacizumab 15 mg/kg arms Apr 2009 2 Apr 2009 2 RIBBON-1 (taxane/ anthracycline cohort) Docetaxel/nab-paclitaxel monotherapy or anthracycline-based combination therapy Taxane-pretreated patients in the docetaxel/nab-paclitaxel cohort Jul 2008 3 Feb 2009 5 RIBBON-1 (capecitabine cohort) Capecitabine None Miles DW et al Proc ESMO 2010: A279

Kaplan Meier estimate of OS (taxane-pretreated hormone receptor-negative population) Estimated probability 1.0 0.8 0.6 0.4 Treatment Bevacizumab + taxane (n=69) Taxane alone (n=52) Median (months) 25.6 15.0 Hazard ratio (stratified only by study) = 0.61 (95% CI 0.40 0.94) p=0.0247 a No. at risk 0.2 a Exploratory p-value Time (months) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 69 67 64 59 53 45 42 36 34 24 16 9 3 2 2 1 0 0 52 49 42 36 32 26 18 18 14 10 8 4 1 0 0 0 0 0

TURANDOT Study design HER2-negative measurable or non-measurable LR/mBC ECOG PS 0 2 Avastin PAC: Avastin 10 mg/kg d1 & 15 + PAC 90 mg/m 2 d1, 8, & 15 q4w No prior chemotherapy for LR/mBC Prior (neo)adjuvant chemotherapy and/or radiotherapy permitted only if completed 6 months before randomization a R Avastin Xeloda: Avastin 15 mg/kg d1 + Xeloda 1000 mg/m 2 bid d1 14 q3w Treat to PD, unacceptable toxicity, or withdrawal of consent Stratification factors: ER/PgR status Country Menopausal status Bid = twice daily; ECOG PS = Eastern Cooperative Oncology Group performance status; PD = progressive disease. a 12 months for taxane-based therapy. 18

TURANDOT: PFS in the TNBC Patient Subgroup Estimated probability 1. 0 0. 8 0. 6 0. 4 0. 2 0. 0 5.6 9.0 Avastin/Pac (n=63) Avastin/Xel (n=67) Events, n (%) 50 (79) 54 (81) Median, months (95% CI) Hazard ratio, stratified (95% CI) 9.0 (7.8-10.7) 1.37 (0.93-2.02) p-value a 0.1078 a Univariate Cox proportional hazards model b Two-sided log-rank test 5.6 (4.9-8.0) 0 6 12 18 24 Time (months) No. at risk: Avastin/Pac 63 45 14 5 2 Avastin/Xel 67 30 10 4 3 Inbar et al. ASCO 2013 (Abst 1040).

Trial Phase / No. of TNBC pts Sikov (2009) Torrisi (2008) Silver (2010) Leone (2009) Platinum Agents for TNBC Setting Regimen Outcome in TNBC II (n=12) Neoadjuvant Carbo-P vs carbo-p-h II (n=30) II (n=28) Retro (n=125) Neoadjuvant TNBC Neoadjuvant TNBC Neoadjuvant TNBC Kern (2010) II (n=10) Neoadjvuant TNBC E-Cis-F P Cis Platinum + D Carbo + D Uhm (2009) II (n=36) Metastatic Carbo-P or Cis- P Wang (2010) pcr=67% pcr=40%; ORR=86% pcr=22% pcr=34%, OS @ 5yr=55%, OS greater with cis vs carbo pcr=40% ORR 37.5% II (n=65) Metastatic Gem-carbo PFS=6.2 months, ORR=62.2% Carbo=carboplatin; Cis=cisplatin; D=docetaxel; E=epirubicin; F=5-FU; H=trastuzumab; P=paclitaxel; retro=retrospective.

TNT Trial n=450 KCL / ICR co-sponsors BRCA1 genotyping Naz Rahman ICR Central ER / PR / HER2 CK5/6 and EGFR Guy s KCL Bank

[TITLE] Presented By Melinda L. Telli, MD at 2013 ASCO Annual Meeting

[TITLE] Presented By Melinda L. Telli, MD at 2013 ASCO Annual Meeting

[TITLE] Presented By Melinda L. Telli, MD at 2013 ASCO Annual Meeting

PARP 1 Trials in Breast cancer PARP 1 is upregulated in Triple Negative Breast cancer Agent Sponsor Single / Combination Route Population Trial Number AZD2281 Astra Zeneca Kudos Single agent ICEBERG1 PO Advanced BRCA mutation ICEBERG1 NCT00494234 AZD2281 NCI Carbo / AZD2281 IV/PO Phase I BRCA mutation AG014699 CRUK / Univ Newcastle Single Agent IV Advanced BRCA mutation Breast BSI -201 AZD2281 BiPar/Sanofi Gem/Carbo +/_ PARPi Astra Zeneca Paclitaxel vs Paclitaxel Kudos AZD2281 IV IV/PO NCT00647062 N/A Advanced TN NCT00540358 Breast First Metastatic Relapse

Eribulin vs. capecitabine: Study 301Overall Survival Median OS (months) 1.0 Survival probability 0.8 Eribulin (n=554) 15.9 Capecitabine (n=548) 14.5 0.6 HR 0.879 (95% CI 0.770, 1.003) p value =0.056 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 Time (months) ITT population; HR Cox model including geographic region and HER2 status as strata p value from stratified log-rank test based on clinical database 36 40 44 48 52 56

Overall Survival By Receptor Status HR (95% CI) Subgroup Eribulin Capecitabine Median (months) 0.879 (0.770, 1.003) Overall 15.9 14.5 14.3 17.1 15.9 13.5 18.2 16.8 14.4 10.5 HER2 status 0.965 (0.688, 1.355) 0.838 (0.715, 0.983) Positive n=755 Negative ER status Positive 0.897 (0.737, 1.093) 0.779 (0.635, 0.955) n=449 Negative n=284 Triple negative Yes 0.2 No ITT population 0.5 Favors eribulin 1.0 0.702 (0.545, 14.4 0.906) 0.927 2(0.795, 17.5 1.081) Favors capecitabine 9.4 5 16.6

Potential Therapeutic Targets for Triple Negative Breast Cancer cetuximab dasatinib, sunitinib c-kit tyrosine kinase EGFR tyrosine kinase MAPK, Notch inhibitors MAP Kinase Pathway mtor/akt Pathway Angiogenesis bevacizumab Microtubule stabilization ixabepilone Transcriptional Control Cell Cycle Trabedectin, brostacillin DNA Repair pathwayplatinum agents, PARP inhibitors

Key messages TRN is not one disease For whom do platinums work? How do we integrate platinums with real PARP inhibitors? Is neoadjuvant now the best testing ground for TRN Should we devise trials for TRN subgroups (luminal vs the rest) Role of Androgen receptor and androgen receptor inhibitors in TRN AR+ breast cancer Are platinums ready for prime time? NB neoadjuvant may not predict results in MBC and vice versa (think BEATRICE and the endocrine resistance story)