Triple negative Breast Cancer Patient

Full text

(1)

Triple negative Breast Cancer

Patient

Alison L Jones

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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

(3)

Options

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

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Triple Negative Cancer; Definition

• TRN: immunophenotypic description

– ER (-) – PR (-)

– Her-2/neu (-)

• 10-17% of all breast cancers, depending on

(5)

Early Relapse

Others

Triple negative

Tischkowitz et al. BMC Cancer 2007;134:7

(6)

LN(+) or LN(-)

(7)

Higher Distant Metastasis

Rebecca Dent et al. CCR 2007;13(15):4429

Despite more patients in TN group received C/T: 48.6 v.s 25.5%

(8)

Triple Negative Breast Cancer:

Definition

ER- / PgR- /

HER2-• ~15% of all breast carcinomas

Poorly differentiated; express cytokeratins 5/6, 17

Triple negative

and basal-like

Basal

but not triple negative

•15-40% are ER+, PR+ or HER2+

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)

Gene arrays

(9)

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

(10)

There are 7 identified Triple negative subtypes

Masuda et al ASCO 2013

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

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Higher Distant Metastasis

Rebecca Dent et al. CCR 2007;13(15):4429

Despite more patients in TN group received C/T: 48.6 v.s 25.5%

(13)

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

(14)

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

(15)

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

(16)

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 20051 Oct 20064

AVADO 3-weekly docetaxel

Taxane-pretreated patients in the placebo

or bevacizumab 15 mg/kg arms Apr 20092 Apr 20092 RIBBON-1 (taxane/ anthracycline cohort) Docetaxel/nab-paclitaxel monotherapy or anthracycline-based combination therapy Taxane-pretreated patients in the docetaxel/nab-paclitaxel cohort Jul 20083 Feb 20095 RIBBON-1 (capecitabine cohort) Capecitabine None

(17)

Treatment Median (months) Bevacizumab + taxane (n=69) 25.6 Taxane alone (n=52) 15.0 Hazard ratio (stratified only by study) = 0.61 (95% CI 0.40–

0.94) p=0.0247a

Kaplan–Meier estimate of OS (taxane-pretreated hormone receptor-negative population)

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 E s ti m a te d p ro b a b il it y Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 1.0 0.8 0.6 0.4 0.2 0 No. at risk aExploratory p-value

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TURANDOT Study design

• HER2-negative measurable or non-measurable LR/mBC • ECOG PS 0‒2

• No prior chemotherapy for LR/mBC

• Prior (neo)adjuvant chemotherapy and/or

radiotherapy permitted only if completed ≥6 months before randomizationa Avastin‒PAC: Avastin 10 mg/kg d1 & 15 + PAC 90 mg/m2 d1, 8, & 15 q4w Avastin‒Xeloda: Avastin 15 mg/kg d1 + Xeloda 1000 mg/m2 bid d1‒14 q3w Treat to PD, unacceptable toxicity, or withdrawal of consent 18 R

Bid = twice daily; ECOG PS = Eastern Cooperative Oncology Group performance status; PD = progressive disease.a≥12 months for taxane-based therapy.

Stratification factors:

• ER/PgR status

• Country

(19)

TURANDOT: PFS in the TNBC Patient Subgroup Avastin/Pac (n=63) Avastin/Xel (n=67) Events, n (%) 50 (79) 54 (81) Median, months (95% CI) 9.0 (7.8-10.7) 5.6 (4.9-8.0) Hazard ratio, stratified (95% CI) 1.37 (0.93-2.02) p-valuea 0.1078 E s ti m a te d p ro b a b ili ty 0. 0 0 6 Time (months)12 18 24 0. 2 0. 4 0. 6 0. 8 1. 0

Inbar et al. ASCO 2013 (Abst 1040). No. at risk:

Avastin/Pac 63 45 14 5 2

Avastin/Xel 67 30 10 4 3

aUnivariate Cox proportional hazards model bTwo-sided log-rank test

(20)

Platinum Agents for TNBC

Trial Phase / No. of TNBC pts

Setting Regimen Outcome in TNBC

Sikov (2009) II (n=12) Neoadjuvant Carbo-P vs carbo-P-H pCR=67% Torrisi (2008) II (n=30) Neoadjuvant TNBC E-Cis-FP pCR=40%; ORR=86% Silver (2010) II (n=28) Neoadjuvant TNBC Cis pCR=22% Leone (2009) Retro (n=125) Neoadjuvant TNBC Platinum + D pCR=34%, OS @ 5yr=55%,

OS greater with cis vs carbo

Kern (2010) II (n=10) Neoadjvuant

TNBC

Carbo + D pCR=40%

Uhm (2009) II (n=36) Metastatic Carbo-P or

Cis-P

ORR 37.5% Wang

(2010)

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.

(21)

TNT Trial n=450

KCL / ICR co-sponsors

BRCA1 genotyping Naz Rahman ICR

Central ER / PR / HER2 CK5/6 and EGFR

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PARP 1 Trials in 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 NCT00647062 AG014699 CRUK / Univ Newcastle

Single Agent IV Advanced BRCA mutation

Breast

N/A

BSI -201 BiPar/Sanofi Gem/Carbo +/_ PARPi

IV Advanced TN

Breast

NCT00540358

AZD2281 Astra Zeneca Kudos Paclitaxel vs Paclitaxel AZD2281 IV/PO First Metastatic Relapse

(26)

Eribulin vs. capecitabine: Study 301Overall

Survival

S u rv iv a l p ro b a b il it y Time (months) 0 0.0 0.2 0.4 0.6 0.8 1.0 56 52 48 44 40 36 32 28 24 20 16 12 8 4 HR† 0.879 (95% CI 0.770, 1.003) p value=0.056 Median OS (months) Eribulin (n=554) 15.9 Capecitabine (n=548) 14.5

ITT population;†HR Cox model including geographic region and HER2 status as stratap value from stratified log-rank test based on clinical database

(27)

Overall 0.879 (0.770, 1.003) 15.9 14.5 HER2 status Positive 0.965 (0.688, 1.355) 14.3 17.1 Negative 0.838 (0.715, 0.983) 15.9 13.5 ER status Positive 0.897 (0.737, 1.093) 18.2 16.8 Negative 0.779 (0.635, 0.955) 14.4 10.5 Triple negative Yes 0.702 (0.545, 0.906) 14.4 9.4 No 0.927 (0.795, 1.081) 17.5 16.6

Subgroup HR (95% CI) Eribulin Capecitabine

Median (months)

ITT population

Overall Survival By Receptor Status

0.2 0.5 1.0 2 5

n=755

n=449

n=284

(28)

Potential Therapeutic Targets for Triple Negative Breast Cancer Cell Cycle Transcriptional Control

MAP Kinase Pathway mTOR/Akt Pathway EGFR tyrosine kinase c-KIT tyrosine kinase DNA Repair pathway-platinum agents, PARP inhibitors Angiogenesis Microtubule stabilization

MAPK, Notch inhibitors

dasatinib, sunitinib cetuximab

ixabepilone

Trabedectin, brostacillin

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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

Figure

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References

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