Systemic treatment of TN EEBR Masterclass 2019 earlyand ... › content › download › 204011 ›...

Christos Sotiriou, MD, PhD Breast Cancer Translational Research Laboratory J.-C. Heuson

Institut Jules BordetUniversité Libre de Bruxelles (ULB)

Brussels, Belgium

Systemic treatment of TN early and advanced BC

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1. Biology of Triple Negative Breast Cancer

2. How can biology help with treatment choice?

Outline

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1. TNBC – PAM50 classifier

Garrido-Castro AC, et al. Cancer Discov 2019

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TNBC molecular subtypes

BL1: Basal-like 1

BL2: Basal-like 2

IM: Immunomodulatory

M: Mesenchymal

MSL: Mesenchymal Stem-like

LAR: Luminal Androgen receptor

Lehmann BD, et al. JCI 2011

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TNBC molecular subtypes – multiomic analysis

Significant up-regulation displayed in black, down-regulation in white

Bareche Y, et al. Ann Oncol 2018

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The PIK3 signalling pathway is alteredin 75% of LAR subtype patients

Bareche Y, et al. Ann Oncol 2018

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TNBC subtypes – multiomic analysis

BLIS: basal-like and immune-suppressed

IM: Immunomodulatory

LAR: Luminal Androgen receptor

MES: Mesenchymal-like

Jiang YZ, et al. Cancer Cell 2019

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Belli C, et al. Breast 2019

• Germline BRCA1/2 mutations in 10-20% of TNBC pts

• Somatic BRCA1/2 mutations in 3-5% of TNBC pts

In Homologous Recombination Deficiency (HRD) the DNA repair mechanism engages non-homologous pathways, more prone to error and to genome instability

BRCA mutated tumours are sensitive to PARP inhibitorsand DNA damaging drugs, including platinum agents

2. BRCA and HRD

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Davies H, et al. Nature Med 2017

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures

HRDetect as a probabilistic classifier. (A) Pie charts depicting the BRCA1 and BRCA2 mutation status of samples in the data set of 560 breast cancers. (B) The HRDetect scores of 560 breast cancer samples ordered from lowest to highest score across the x axis. Colored bars represent both samples with monoalleleic mutations and those with loss of the second allele.

• HRDetect identified BRCA1/BRCA2-deficient tumors with 98.7% sensitivity

• Additional tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected were also identified

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3. Immune microenvironment

Savas P, et al. Nat Rev Clin Oncol 2016

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TNBC

HER2+

STAT1 metageneUntreated BC

Desmedt C et al. Clin Cancer Res, 2008

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TNBC

HER2+

Ignatiadis M et al. J Clin Oncol, 2012

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TNBC

Loi et al. J Clin Oncol, 2013

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Tumor Immune Micro-Environment – TIME subtypes

ID: Immune Desert

MR: Margin-Restricted

SR: Stroma-Restricted

FI: Fully Inflamed

Gruosso T, et al. J Clin Invest 2019

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TNBC subtypes have different immune landscape

Bareche Y, et al. Manuscript submitted

Distribution of the TIME subtypes within each TNBC molecular subtype

Associations between 16 immune cell subsets scores with TNBC molecular subtypesESO-E

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Low immune infiltration in metastatic BC

Robinson D et al., Nature 2017

MImmScore(metastastic immune infiltration)

TILs (129 patients)

Savas P et al., Nat Med 2018ESO-ESMO E

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“High” immune signal

1) More frequent in triple negative (TNBC) and HER2+ breast cancer (BC)

2) Improved outcome in TNBC and HER2+ BCs

3) Increased response to neoadjuvant chemotherapy

4) Low immune infiltration in metastatic BC

5) Immune ”signal” and response to checkpoint blockade?

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Garrido-Castro AC, et al. Cancer Discov 2019

Heterogeneity of TNBC

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1. Biology of Triple Negative Breast Cancer

2. How can biology help with treatment choice?

Outline

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1. Early disease

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Cortazar P, et al. Lancet 2014

pCR is an excellent surrogate for EFS and OS

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Association between pCR and long-term outcome in TNBC

Cortazar P, et al. Lancet 2014

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(B) Univariable analysis of TILs as a continuous marker for prediction of pCR(C) Multivariable analysis of TILs as a continuous marker for prediction of pCR

Denkert C, et al. Lancet Oncol 2018

TILs and pCR: Pooled analysis of 3771 BC patients treated with neoadjuvant therapy

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Loi S, et al. JCO 2019

TILs and prognosis: Pooled analysis of 2148 early-stage TNBC patients treated with adjuvant chemotherapy

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Poggio F, et al. Ann Oncol 2018

Role of platinum-based neoadjuvant chemotherapy in TNBC

(A) Odds ratios for pCR of platinum-based versus platinum-free (Controls) neoadjuvant chemotherapy in the randomized controlled trials using anthracycline- and taxane-based chemotherapy in both treatment arms

• Meta-analysis of 9 RCTs

• Overall, platinum-based neoadjuvant CHT significantly increased pCR rate from 37.0%to 52.1% (OR 1.96)

• Two RCTs (GeparSixto and CALGB 40603) reported the survival outcomes: no significant differences in EFS nor in OS were observed

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Δ in pCR cannot be used as surrogate for HR for DFS or OS

Spring LM, et al. SABCS 2018

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Predictive Model: the magnitude of pCR change is predictive of treatmenteffects on EFS with a certain amount of uncertainty


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Prediction: HR EFS vs ΔpCR (example)

• The CALGB 40603 trial resulted in pCR improvement of 13% (41% 54%) with the addition of carboplatin to standard chemotherapy, which would correspond to an EFS HR ≈ 0.87 (95% PI: 0.84-0.89), based on this prediction model.

Assuming 80% power and a 1:1 randomization ratio, 1,381 events must be observed to achieve statistical significance at 0.05 level (two-sided).

• In CALGB 40603 the HR for EFS for carboplatin was 0.84 (95% CI: 0.58-1.22), but this was not statistically significant (only 110 events were observed).

• Common theme for neoadjuvant studies, which are typically powered for primary endpoint of pCR and not secondary long-term survival outcomes.


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Poggio F, et al. Ann Oncol 2018

Role of platinum-based neoadjuvant chemotherapy in TNBC

Odds ratios for pCR of platinum-based vs platinum-free (Controls) neoadjuvant chemotherapy in: (A) BRCA-mutated breast cancer patients; (B) breast cancer patients without BRCA mutations

• Among the 96 BRCA-mutated patients included in 2 RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (from 54.3% to 56.2%, OR 1.17)

BRCA-mutated TNBC may also have increasedvulnerability to anthracycline-induced single-stranded and double-stranded DNA breaks

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Blum JL, et al. JCO 2017

• Three adjuvant trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49)• Patients randomized to TC for six cycles (2125 pts) or to a standard TaxAC regimen (2117 pts)• TaxAC regimens improved iDFS in patients with high-risk HER2-negative BC

Adjuvant chemotherapy – role of anthracycline

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Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, reduces the 10-year risk of recurrence

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Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)*, Lancet 2019

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What can we do for patients with residual disease?

Does more treatmentimprove outcome?

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Masuda N, et al. NEJM 2017

• Overall, DFS and OS were longer in the capecitabine group than in the control group (74.1% vs 67.6% and 89.2% vs83.6% at 5 years, respectively)

• TNBC subgroup: - 5-year DFS rate 69.8% vs 56.1%- 5-year OS rate 78.8% vs 70.3%

Residual disease after NACT in TNBC – CREATE-X trial

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Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing

Kim C, et al. Cell 2018

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• Genotypic evolution during chemotherapy was measured using single cell DNA copy number profiling (Navin et al. 2011, Nature) of N=900 cells

• Phenotypic evolution during chemotherapy was measured using nanowell single cell RNA sequencing (Gao et al. 2016, Nature Comm.) of N=6862 cells

4 clonal extinction 4 clonal persistence

• Single cell copy number profiling

• single cell RNA sequencing

• Single cell copy number profiling

• single cell RNA sequencing

Kim C, et al. Cell 2018

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• Three tumor clones were identified (A,B) that shared common CNAs in MYC, MET, APC and TP53, and divergent CNAs in ABL2, PTEN, FOXO3 and RELN

• 111 single tumor cells were profiled from 2 matched time points (pre/post treatment)

• All three clones were not detected in the post-treatment time point sample

Single Cell CNA Profiling in a Clonal Extinction Patients

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Adaptive Evolution in Clonal Persistence Patients

• Single cell copy number profiling of 98 cells from Patient 14 identified 3 major aneuploid subpopulations

• Clone A emerged in response to NAC, but was pre-existing at a low frequency (7.7%) in the pre-treatment sample and expanded to 71.8% in the post-treatment tissue

• Chemoresistant clone A had two focal hemizygous deletions on chrom 3p, including IL5RA and RARB ESO-E

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Take home messages - TNBC, early setting (neo)adjuvant therapy

1) Anthracyclines/taxanes-base chemotherapy remains the standard of care (dose dense schedule)

2) To favor neoadjuvant >>> adjuvant

3) Capecitabine should be considered in TNBC with residual disease

4) PARP inh still under investigation (i.e. Olympia)

5) TILs important prognostic factor ( clinical utility remains uncertain, immunotherapy?)ESO-E

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2. Metastatic disease

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Role of immunotherapy – IMpassion130

Schmid P, et al. NEJM 2018

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IMpassion130 – results – PFS


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IMpassion130 – results – OS (interim analysis)


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IMpassion130 – pts characteristics


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IMpassion130 – Analyses of PFS in key subgroups


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Tutt A, et al. Nature Med 2018

Response rates documented in the overall population, BRCA1/2 mutated and BRCAness subgroups

BRCA1/2 mutated TNBC – role of carboplatin – TNT Trial

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BRCA1/2-mutated TNBC – role of PARPi – OlympiAD trial

Robson M, et al. NEJM 2017

mPFS 7.0 vs 4.2 months

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BRCA1/2-mutated TNBC – role of PARPi – EMBRACA trial

Litton JK, et al. NEJM 2018

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Sacituzumab Govitecan-hziy in ≥ 3rd line

Bardia A, et al. NEJM 2019

• Sacituzumab govitecan-hziy is an antibody–drug conjugate in which SN-38 (an active metabolite of irinotecan), is coupled to the humanized antitrophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody hRS7 IgG1κ

• Trop-2, a transmembrane calcium signal transducer, is expressed in almost 90% of TNBC

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PD-L1+ (and de novo oligometastatic BC,

high TILs) ?

Atezolizumab+

nab-paclitaxel

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Heterogeneity of TNBC – opportunities for personalized treatment

Bareche Y, et al. Manuscript submitted

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Acknowledgments

Mattia Rediti

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Systemic treatment of TN EEBR Masterclass 2019 earlyand ... › content › download › 204011 ›...

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