Actualización

AACR 2014

Federico Rojo

Fundación Jiménez Díaz, Madrid

Next Generation Sequencing en cáncer

205 sesiones

744 comunicaciones

Metabolismo y cáncer

180 sesiones

495 comunicaciones

Inmunidad y cáncer

52 sesiones

562 comunicaciones

Inhibidores de CDK4/6 en cáncer

41 sesiones

62 comunicaciones

Principales topics en AACR 2014

Hanahan, D & Weinberg, RA. Cell 2011

Braking the cycle: Inhibition of the cyclin D-CDK4/6

pathway in breast cancer Robert T. Abraham, Todd VanArsdale, David V. Shields, Nathan V. Lee, Maria Koehler, Kim Arndt

Final results of a randomized Phase II study of PD

0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in

combination with letrozole vs letrozole alone for first-line

treatment of ER+/HER2- advanced breast cancer

(PALOMA-1; TRIO-18) Richard S. Finn, John P. Crown, Istvan Lang, Katalin Boer, Igor M. Bondarenko, Sergey O. Kulyk, Johannes Ettl,

Ravindranath Patel, Tamas Pinter, Marcus Schmidt, Yaroslav V. Shparyk, Anu R. Thummala, Nataliya L. Voytko, Xin Huang,

Sindy T. Kim, Sophia S. Randolph, Dennis J. Slamon.

Musgrove, MA et al. Nature Reviews Cancer 2011

• A variety of mitogenic signaling

pathways converge at cyclin D1

• Assembly and nuclear location of

cyclinD1-CDK4/6 act as master

integrator

• P21 and p16 are the negative

regulators of CDK4/6

• CDK4/6 phosphorylates and

inactivates RB, which release

transcription factor E2F

• E2F induces progression to G1/S

• Crosstalk between ER and

cyclinD1 causes endocrine-

resistance

• ER inhibition induces G0/G1

arrest by cyclin D1 downregulation

Braking the cycle: Inhibition of the cyclin D-

CDK4/6 pathway in breast cancer

Regulation of cell cycle checkpoint control

CDK-inhibitors in clinical development

ClinicalTrials.gov, November 2013

Rank Status

Condition: ER Positive, HER2 Negative Breast Cancer

Intervention: Drug: Letrozole, PD 0332991

Condition: Malignant Rhabdoid Tumors (MRT), Neuroblastoma

Intervention: Drug: LEE011

Conditions: Luminal A Breast Cancer;   Luminal B Breast Cancer;   CPS-EG Score;   Postneoadjuvant Treatment With CDK 4/6 Inhibitor;   Hormonreceptor Positive

Interventions: Drug: Palbociclib PD-0332991;   Behavioral: Patient reported outcomes;   Drug: Placebo

Condition: Ovarian Epithelial Carcinoma

Intervention: Drug: PD0332991

Conditions: Advanced Solid Tumor;   Lymphomas

Intervention: Drug: LEE011

Condition: Melanoma

Interventions: Drug: LGX818;   Drug: MEK162;   Drug: LEE011;   Drug: BGJ398;   Drug: BKM120;   Drug: INC280

Condition: Advanced Cancer

Interventions: Drug: LY2835219;   Drug: Fulvestrant

Condition: Mantle Cell Lymphoma

Intervention: Drug: LY2835219

Condition: Advanced, Metastatic Breast Cancer

Interventions: Drug: LEE011;   Drug: Letrozole;   Drug: Letrozole Placebo

Condition: Early Breast Cancer

Interventions: Drug: LEE011;   Drug: Letrozole

Condition: Colorectal Cancer

Intervention: Drug: PD-0332991, 5-FU, oxaliplatin

Condition: Breast Neoplasms

Interventions: Drug: PD-0332991;   Drug: Letrozole;   Drug: Placebo

Conditions: Sarcoma;   Liposarcoma

Intervention: Drug: PD0332991

Condition: Advanced Gastrointestinal Stromal Tumors

Intervention: Drug: PD-0332991 will be administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively.

Condition: Locally Advanced or Metastatic BRAF Mutant Melanoma

Interventions: Drug: LEE011;   Drug: LGX818

Condition: Breast Cancer

Interventions: Drug: LEE011;   Drug: Exemestane;   Drug: Everolimus

Conditions: Glioblastoma;   Gliosarcoma;   Anaplastic Astrocytoma

Intervention: Drug: PD 0332991

Condition: Breast Cancer

Interventions: Drug: LEE011;   Drug: Letrozole;   Drug: BYL719

Condition: Advanced and / or Metastatic Liposarcoma

Intervention: Drug: Pazopanib

Condition: Mantle Cell Lymphoma

Interventions: Drug: PD 0332991;   Drug: bortezomib

19 Recruiting Activity and Tolerability of Pazopanib in Advanced and/or Metastatic Liposarcoma. A Phase II Clinical Trial

20 Recruiting Trial of PD 0332991 Plus Bortezomib in Patients With Relapsed Mantle Cell Lymphoma

17 Recruiting A Study of PD 0332991 in Patients With Recurrent Rb Positive Glioblastoma

18 Not yet

recruiting

Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer

15 Recruiting Safety and Efficacy of LEE011 and LGX818 in Patients With BRAF Mutant Melanoma.

16 Recruiting Phase Ib/II Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of ER+ Her2- Advanced Breast Cancer

13 Recruiting PD0332991 in Patients With Advanced or Metastatic Liposarcoma

14 Not yet

recruiting

Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib

11 Recruiting PD-0332991, 5-FU, and Oxaliplatin for Advanced Colorectal Cancer

12 Recruiting A Study of PD-0332991 + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2)

9 Not yet

recruiting

Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer

10 Not yet

recruiting

A Pharmacodynamics Pre-surgical Study of LEE011 in Early Breast Cancer Patients

7 Recruiting A Phase 1 Study of LY2835219 In Participants With Advanced Cancer

8 Recruiting Study of LY2835219 for Mantle Cell Lymphoma

5 Recruiting A Trial of LEE011 in Patients With Advanced Solid Tumors or Lymphoma.

6 Recruiting LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma

3 Not yet

recruiting

A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery

4 Recruiting A Open Label Study of the Efficacy and Safety of PD0332991 a Selective Inhibitor of the Cyclin Dependent Kinases 4 and 6 in Patients With Recurrent Ovarian Cancer Demonstrating Rb-proficiency and Low p16 Expression

Study

1 Recruiting Letrozole and CDK 4/6 Inhibitor for ER Positive, HER2 Negative Breast Cancer in Postmenopausal Women

2 Recruiting Study of Safety and Efficacy in Patients With Malignant Rhabdoid Tumors (MRT) and Neuroblastoma

Palbociclib (PD-0332991) Receives

Breakthrough Designation for Treatment

of Breast Cancer

The FDA can assign the breakthrough designation for drugs that treat a life-threatening condition and

demonstrate a substantial improvement over existing therapies. The designation promotes an expedited

review by FDA during the development process, requiring fewer patients for clinical trials, and reducing the

amount of time required for these trials.

Palbociclib can seek fast-track designation, accelerated approval, and priority review for the drug.

Postmenopausal women with ER+/HER2-

advanced breast cancer were randomized

to receive letrozole plus palbociclib or

letrozole alone.

Pooled results found a median PFS of

20.2m with combination (95%CI, 13.8–27.5)

vs 10.2m with letrozole alone (95%CI, 5.7–

12.6), a 63% improvement in risk of

progression (HR=0.49; 95%CI, 0.31–0.75,

P< .001).

Response rates in patients with measurable

disease were 43% for the combination vs

33% for letrozole.

The clinical benefit rate (CR, PR and SD)

was 81% vs 58%, respectively.

Understanding metabolic heterogeneity in cancer Ralph J. DeBerardinis

The Complex Role of Autophagy in Cancer Andrew M. Thorburn

Targeting Autophagy in Cancer: Promise or Peril? Eileen P. White

Autophagy: Protein Degradation Systems

Cell death

NBR1 and p62 act as receptors for

selective autophagosomal degradation of

ubiquitinated targets.

Autophagy: Protein Degradation Systems

Autophagy: Therapeutical target

Autophagy: Antibody-drug conjugates

Autophagy: Antibody-drug conjugates: T-DM1

Characterization of T-cells infiltrating human breast cancer Soizic Garaud, Laurence Buisseret, Chunyan Gu, Edoardo Migliori, Jean-Nicolas Lodewyckx, Hugues Duvillier, Ligia

Craciun, Denis Larsimont, Karen Willard-Gallo

Mechanisms of recognition and elimination of tumor cells by

natural killer cells David H. Raulet

Immune checkpoint blockade in cancer therapy: New insights

and possibilities James P. Allison

Padmanee Sharma

The rapidly evolving role of PD-1 pathway inhibition in other

tumor types Mario Sznol

Tumor-associated lymphocytes as a continous parameter

50-60%

Lymphocyte predominant

breast cancer (LPBC)

Percentage of TILs

Definitions for histopathological evaluation

Denkert, C et al. J Clin Oncol 2010

Tumor-associated lymphocytes as

a predictor of response on

neoadjuvant anthracyclin/taxane CT

Denkert, C et al. J Clin Oncol 2010

pCR 42% vs 3%

iTu-Ly p=0.012 (OR 1.38, 95%CI 1.08 to 1.78)

GeparDuo, n=218

GeparTrio, n=840

Tumor-associated lymphocytes as

a predictor of response on

neoadjuvant anthracyclin/taxane CT

Wolff, DM et al. PLOS One 2014

Immune and proliferation gene co-

expression modules as hallmarks

of clinically relevant breast cancer

diversity

Leukocyte composition of

breast cancer

No lymphocytic infiltration: tumor avoids immune recognition

Lymphocytic infiltration: tumor promotes immune recognition

Worse clinical outcome

Lack of antigen recognition (why and

how?)

Tumor induced immunosupression

Better clinical outcome

Modified from Bianchini, G & Gianni, L. Lancet Oncol 2014

Prognostic value in breast cancer not receiving any systhemic treatment

Desmedt et al (2008) Immune response (STAT1) module

Increased expression of STAT1 module associated with decreased risk of relapse

Rody et al (2009) T-cell metagene Augmented expression of T-cell metage associated with lower risk of relapse

Staaf et al (2010) Her2-derived prognostic predictor

HER2-derived prognostic predictor enriched in genes linked with immune response defines a good prognosis group

Bianchini et al (2010) Immune kinase score Higher expression of immune related kinases associated with low risk of relapse

Predicitive value of pathological complete response from neoadjuvant chemotherapy

Bianchini et al (2010) Immune kinase score Immune-related kinase genes associated with pCR

Denkert et al (2010) Tumor-associated lymphocytes TILs are independent predictors of pCR Anthracycline and a taxane

Ignatiadis et al (2012) Immune modules Immune modules increase the predicitve accuracy por pCR Anthracycline alone or combined with a taxane

West et al (2011) Tumor-associated lymphocytes TILs are independent predictors of pCR Anthracycline

Denkert et al. (2011) Tumor-associated lymphocytes TILs are independent predictors of pCR, prospective validation Anthracycline and a taxane

Lee et al (2013) Tumor-associated lymphocytes TILs, CD3 and CD8 populations are independent predictors of pCR

Anthracycline alone or combined with a taxane

Issa-Numer et al (2014)

Tumor-associated lymphocytes

TILs are independent predictors of pCR, prospective validation in HER2- population

Anthracycline and a taxane

Predictive value of outcome from adjuvant chemotherapy

Loi et al. (2013) Tumor-associated lymphocytes TILs are independent predictors of outcome in TNBC Anthracycline and a taxane

Adams et al. (2013) Tumor-associated lymphocytes Stromal TILs are independent predictors of outcome in TNBC Anthracycline

Loi et al (2014) Tumor-associated lymphocytes TILs are predictors of diostant recurrence in TNBC Anthracycline and a taxane

Trastuzumab-induced NK cell-

mediated ADCC in breast

cancer

Bianchini, G & Gianni, L. Lancet Oncol 2014

Predictive value for benefit from trastuzumab-containing treatments

Bianchini et al (2010) Immunoglobulin metagene Augmented expression of Ig metagene is associated with more pathological complete response with trastuzumab and chemotherapy than with CT alone

Loi et al (2012) Tumor and stromal lymphocyte infiltration

High lymphocyte infiltration is associated with lower risk of relapse in patients treated with chemotherapy and trastuzumab compared with chemotherapy alone

Staag et al (2011) Interferon-g High expression of interferon-g is correlated with pCR after neoadjuvant trastuzumab and chemotherapy

Gianni et al (2012) Immune checkpoint-ralted genes and immune metagenes

After neoadjuvant treatment with HER2-targeted therapy, higher expression of PDL1 is associated with resistance and response

Loi et al (2014) Tumor and stromal lymphocyte infiltration

TILs are associated with decreased recurrence risk in adjuvant trastuzumab-chemotherapy in early HER2+ breast cancer

Loi et al (2013) Tumor and stromal lymphocyte infiltration

TILs are associated with pCR after neoadjuvant trastuzumab and chemotherapy (GeparQuattro) and mediated by NK ADCC response

Denkert et al (2013) Tumor and stromal lymphocyte infiltration

TILs are associated with pCR after neoadjuvant trastuzumab and carboplatin-containing chemotherapy (GeparSixto)

Preclinical and exploratory analysis of immune response and trastuzumab

Roberti et al (2012) NK response IL-2- or IL-15-activated NK cells enhance cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients

Gennari et al (2004) NK response NK and ADCC profile classified as responders and non-responders after a six-month trastuzumab regimen

Varchetta et al (2007) NK response Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable HER2+ breast cancer

Staaf et al (2010) Her2-derived prognostic predictor HER2-derived prognostic predictor enriched in genes linked with immune response defines a good prognosis group

Kohrt et al (2012) NK response Trastuzumab induces CD137 upregulation on NK cells following exposure to HER2+ tumor cells

Resistance to antibody-dependent cellular cytotoxicity

Musolino et al (2008) FccRIIa-H131 and FccRIIIa-V158 FccR isoforms are related with PFS and OS in metastatic HER2+ breast cancer

Tamura et al (2011) FccRIIa-H131 FccR isoforms are related with PFS in metastatic and pCR in HER2+ breast cancer

Checkpoint inhibitors with

trastuzumab are synergistic

in HER2+ mouse models

Anti-CTLA-4

Trastuzumab +

Anti-PD1

Trastuzumab +

Anti-CTLA-4

Trastuzumab Control

Anti-PD1

Ott, PA et al. Clin Cancer Res 2013

Immune checkpoints Improved survival with ipilimumab (anti- CTLA4)

in patients with metastatic melanoma. Hodi et al.

NEJM, 2010

Ipilimumab plus dacarbazine for previously

untreated metastatic melanoma. Roberts et al.

NEJM 2011

Safety and activity of anti-PD-L1 antibody

(BMS93559) in patients with advanced cancer.

Brahmer et al. NEJM 2012

Safety, activity, and immune correlates of anti-

PD-1 antibody (Nivolumab, BMS936658) in

cancer. Topalian et al. NEJM 2012

Safety and tumor responses with lambrolizumab

(MK3475, anti-PD-1) in melanoma. Hamid et al.

NEJM 2013

Development of immune

strategies in breast cancer

1. Considering results in other tumor types and preclinical studies, there is a

strong rationale to develop anti–programmed death 1 (PD1), anti–programmed

death 1 ligand (PDL1) or anti-CTLA4 antibodies in breast cancer.

2. Changing a TIL tumor into a TIL+ tumor. Ligands for TLR (TLR4 and TLR2)

have been shown to mediate chemokine release by cancer cells and

lymphocyte attraction. Several compounds are being investigated.

3. Anti-CD137 antibodies increases NK cell cytokine secretion and NK cell-

mediated cytotoxicity

4. Tumor vaccines could be developed as in other cancer types.

Development of immune

strategies in breast cancer

Mensajes finales

• Extraordinario avance en los conocimientos de la

genómica en cáncer: next generation sequencing

• Inhibidores de CDK4/6 en cáncer de mama

• Metabolismo-cáncer y conjugados anticuerpo-fármaco

• Respuesta inmune y cáncer: valor predictivo, pronóstico

y diana terapéutica