OE Webinar North Mod1 V4 - Amazon S3€¦ · • Clinical trials: Astellas, Janssen, Sanofi, BMS....

Module 1:

Prostate Cancer Heterogeneity: Clinical Implications

Optimizing Outcomes in Advanced Prostate Cancer

Scott North, MD, FRCPC, MHPE

University of Alberta

Medical Oncologist, Cross Cancer Institute, Edmonton

Conflict of Interest Disclosures

• Advisory board: Astellas

• Honoraria: Astellas, Janssen, Sanofi, Novartis

• Clinical trials: Astellas, Janssen, Sanofi, BMS

Learning Objectives

• Examine the incidence of prostate cancer in Canada and review the progression of prostate cancer, emphasizing the role of androgen signalling.

• Review the various types of heterogeneity that occur in patients with metastatic castration-resistant prostate cancer (mCRPC)

• Discuss the role that heterogeneity plays in the development of therapeutic resistance

• Explore the clinical implications of treatment resistance including patterns of treatment response and the need to appropriately monitor for progression

Overview of Prostate Cancer

Question

•What was the number of newly diagnosed cases of Prostate Cancer in Canada in 2014?

a) 2360

b) 5720

c) 12360

d) 23600

e) 57200

Incidence of Prostate Cancer in Canada

• Estimated incidence in 2014 - 23,600 new cases / 4,000 deaths1

• Most newly diagnosed patients present with clinically localized disease2

• A 28% 5-year survival rate was observed in patients with metastatic disease3

1985 1989 1994 1999 2004 2009 20140

20406080

100120140160

020406080100120140160

ASIR (per 100,000

Estim

ated

1. Canadian Cancer Statistics 2014. http://www.cancer.ca

2. Howlader N, et al. SEER stat fact sheet: prostate cancer. J Natl Cancer Inst 2012 November.(Epub April 2013)3. Howlader N, et al. SEER cancer statistics review: cancer of the prostate, table 23.1, J Natl Cancer Inst 2012 November. (Epub April 2013)

Metastatic

Disease Continuum in Prostate Cancer

Heidenreich A, et al. Eur Urol 2013;64:260-5

Reprinted from Eur Urol, 64, 2, Heidenreich A, et al., Castration-resistant prostate cancer: where we stand in 2013 and what urologists should know, 260-265. ©

2013, with permission from the European Association of Urology.

Disea

se Bur

den

Castration

1st-‐line therapies

Localtherapy

2nd-‐line hormonal therapy

Asymptomatic

CRPCHormone-‐sensitive

Symptomatic

Non-‐metastatic

Additional therapies

2nd-‐line therapies

Progression of mCRPC

mCRPC Progression

•mCRPC is a progressive disease with a poor prognosis that requires guideline-‐recommended monitoring of patients1,2

Treatment Resistance in mCRPC

•A proportion of patients with mCRPC have tumours with primary insensitivity or acquired resistance to first-‐line therapies6

•Monitoring for progression includes: PSA, bone and CT scans, and symptom assessments7

mCRPC Heterogeneity

• Tumours display pathological heterogeneity3 andmay be composed of both AR-‐positive and AR-‐negative cells4,5

Individualized Solutions for Patients With

mCRPC

•Monitoring based on patient and disease characteristics2

• Patient-‐centered treatment plans21. Heidenreich A, et al. Eur Urol2013;64:260-52. Burrell RA, et al. The NCCN Clinical Practice Guidelines in Oncology (NCCN

Guidelines®) for Prostate Cancer. V.2.2014. Nature 2013;501:338-453. Tang DG, et al. Mol Carcinog 2007;46:1-144. Isaacs JT, et al. Cancer Res 1981;41(12 Pt 1):5070-55. Scher HI, et al. J Clin Oncol 2008;26:1148- 596. Mukherji D, et al. Cancer Metastasis Rev 2014;33:555-66

Progression of mCRPC

Testosterone

5α-‐reductase

DHT

CorticosteroidsFlutamideOthers

P P

AR AR

P P

AR AR

Amplified AR

AR AR

Promiscuous AR

AR target genes

↑PSA ↑Growth ↑Survival

↑BCL2

Outlaw AR

AR AR

P P

AKT MAPK

Mitochondrion

RTK

Growth factors

P P

• Numerous adaptive mechanisms exist by which prostate cancer cells can bypass traditional androgen signaling pathways

Canonical AR signaling

Debes JD, et al. N Engl J Med 2004;351:1488-90 Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Cancer,

Feldman BJ, et al., 2001;1(1):34-45. © 2001.

Clinical Heterogeneity in Cancer

Heterogeneity in Cancer

• Heterogeneity develops as a consequence of genomic instability

• Multiple types of heterogeneity occur– Inter-patient– Intra-patient– Intra-tumour

Burrell RA, et al. Nature 2013;501:338-45 Reprinted by permission from Macmillan Publishers Ltd: Nature, Burrell RA, 2013;501(7467):338-345. © 2013.

Inter-Patient Pathological Heterogeneity

• CRPC is a heterogeneous group of diseases

– Different histologic patterns were identified from 30 rapid autopsy CRPC samples

– Immunohistochemistry revealed differential AR expression• 31% Tumour samples expressed > 50% AR• 41.5% Tumour samples expressed < 10% AR

0" 10" 20" 30" 40" 50" 60" 70" 80" 90"

Bone"Liver"

Lymph"node"Lung"

Soft"tissue"Dura"mater"

Adrenal"Brain"

Pancreas"Kidney"Testis"

Percentage"of"Cases"

Shah RB, et al. Cancer Res 2004; 64:9209–16. © 2004 American Association for Cancer Research.

Histologic AppearanceMetastatic Sites

Shah RB, et al. Cancer Res 2004;64:9209-16.

Small cell(n=2)

Undifferentiated(n=1)

Signet ring(n=1)

Gleason grade 5 (n=4)


Gleason grade 4 and 5

(n=18)

NE Differentiation (n=3)


Intra-Patient Pathological Heterogeneity

• AR expression was high in primary tumours and significantly downregulatedin nodal metastases in 119 hormone-naïve patients with prostate cancer

Fleischmann A, et al. Prostate 2011;71:453-60

Primary tumour

High AR staining

Lymph node metastasis

Low AR staining

Used with permission from Fleischmann A. Prostate. 2011;71(5):453-460. © 2010 Wiley-Liss, Inc.

Example of Intra-Patient Heterogeneity

H&E AR IHC PSA IHC

Liver metastasis

CT 23/07/2012 CT 09/10/2012

Pezaro CJ, et al. Eur Urol 2014;65:270-3

Docetaxel-‐based chemotherapy

Intra-tumour Pathological Heterogeneity

• Some prostate tumours have mixed features of neuroendocrine cells (AR-) and adenocarcinoma (AR+) cells

• Focal neuroendocrine differentiation is present in 10%–100% of localized prostate adenocarcinomas and increases with disease progression

Beltran H, et al. Cancer Discov 2011;1:487-95

Beltran H, et al. Cancer Discov 2011;1:487–95.© 2011 American Association for Cancer Research.

Heterogeneity May Have Prognostic Implications

Time from diagnosis, mo

Ove

rall su

rvival, %

0.0

0.4

0.2

0.6

0.8

1.0

p< 0.001

Lymph nodesBone

Visceral

Bone plus visceral

Reprinted from Eur Urol, Gandaglia G, et al.,Impact of the site of metastases on survival in patients with metastatic prostate cancer. DOI:

10.1016/j.eururo.2014.07.020. © 2014, with permission from the European Association of Urology.

The Site of Metastases CouldBe Prognostically Important

Bone

Time 0 6 12 18 24 30 36 42 48 54 60

Gandaglia G, et al. Eur Urol. 2014 (in press).

Median survival (95% CI)

Lymph nodes Bone Visceral Bone plus visceral

43 (35.1-‐50.9) 24 (22.9-‐25.1) 16 (12.9-‐19.1) 14 (12.0-‐15.9)

Heterogeneity and Treatment Resistance in Prostate Cancer

Two Models for the Development of CRPC

• Early-stage tumours are heterogeneous, containing both androgen-sensitive cells and small foci (clonal cells) that are inherently resistant to ADT

• Following destruction of the androgen-sensitive cells by ADT, the resistant clones emerge and drive growth of the ADT-resistant tumour

Selection Model

Zong Y, et al. Nat Rev Urol 2013;10:90-8

Co-‐existing heterogeneous prostate cancer cells

ADT

Killing of sensitivecancer cells

Proliferation anddifferentiationof resistant cells

Castration-‐resistant prostate cancer

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Urol, Zong Y, et al., 2013;10(2):90-98. © 2013.


• Tumours contain homogeneous cells that are sensitive to ADT

• Heterogeneity emerges during ADT

• Some cells may acquire additional features (eg, mutations, epigenetic changes) that render them resistant to ADT

• Expansion of these mutated cells manifests as clinical resistance to ADT

Zong Y, et al. Nat Rev Urol 2013;10:90-8

Adaptation Model

Androgen-‐dependent prostate cancer cells

ADT

Acquisition ofgenetic/epigeneticevents

Clonal expansionof resistant cells

Castration-‐resistant prostate cancer

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Urol, Zong Y, et al., 2013;10(2):90-98. © 2013.

Potential Heterogeneity-induced Mechanisms of Resistance to Treatment

1. Genetic alterations to drug targets1

2. Expression of multidrug resistance pumps2

3. Evasion of apoptosis– Altered miRNA expression3

– Altered chaperone expression4

1. Hornberg E, et al. PLoS One 2011;6:e19059.2. Sanchez C, et al. Prostate 2011;71:1810-7 3. Singh S, et al. PLoS One 2012;7:e40021.4. Higano CS. Onco Targets Ther 2013;6:785-97

AR Splice Variants are Associated with Poor Prognosis and Treatment Resistance

• The translation of splice variants results in proteins with altered activity and regulation1

AR Splice Variants• Exons 4-8 of AR are not required for transcriptional activity and splice

variants lacking this region may be constitutively active2

• Expression of AR variants lacking the ligand-binding domain in CRPC bone metastases was associated with poor prognosis2

• Detection of AR-V7 in tumour cells is associated with treatment resistance3,4

1. Edwalds-Gilbert, G. Nature Education 2010;3:432. Hörnberg E, et al. PLoS One 2011;6:e190593. Antonarakis ES, et al. AACR 2014; abstract 29104. Thadani-Mulero M, et al. Cancer Res 2014;74:2270-82

Full-‐length AR

919

2 3 4 5 6 7 8

Ligand-‐binding domain

1

1Amino acid

AR-‐V7

2 31

1644

Thadani-Mulero M, et al. Cancer Res. 2014;74(8):2270-2282. © 2014 American Association for Cancer Research.




3. Evasion of apoptosis• Altered miRNA expression3

• Altered chaperone expression4



• High expression of efflux pumps in response to chemotherapy treatment has been associated with chemoresistance in prostate cancer1

ChemosensitivePC-‐3 Cells

ChemoresistantPC 0.03 Cells

0.8

0.6

0.4

0.2

0

Increased Expression of MRP1 in Chemoresistant Cell Lines2

Reprinted by permission from Macmillan Publishers Ltd: Prostate Cancer Prostatic Dis, Zalcberg J, 2000;3(2):66-75. © 2000.

Relative Ex

pres

sion

1. Sánchez C, et al. Prostate 2009;69:1448-592. Zalcberg J, et al. Prostate Cancer Prostatic Dis 2000;3:66-75

Altered microRNA Expression and Chemoresistance

• miRNAs are small RNA molecules that target specific mRNAs and prevent expression of targeted genes1

• Dysregulation of miRNAs in prostate cancer cells leads to chemoresistance2

• miR34a and miR200c are downregulated in chemoresistant prostate cancer cell lines compared to chemosensitive prostate cancer cell lines2

1. Kent OA, Mendell JT. Oncogene 2006;25:6188-962. Singh S, et al. PLoS One 2012;7:e40021

Altered miRNAexpression

Drug-‐sensitive cancer cells Chemoresistant cells

Used with permission from Singh S, et al. PLoS One. 2012;7:e40021. © 2012 Singh S, et al.

Clusterin Protects Cancer Cells from Chemotherapy-induced Cell Death

• Clusterin is a molecular chaperone that has multiple roles in cell survival and stress response pathways1

• Overexpression of clusterin is a potential mechanism for evasion of apoptosis1

• Clusterin activity has been implicated in chemotherapy resistance in prostate cancer2

1. Sánchez C, et al. Prostate 2009;69:1448-592. Zalcberg J, et al. Prostate Cancer Prostatic Dis 2000;3:66-75

IGF-‐1RTGF-‐βR

Smads

Plasmamembrane

STAT1Jak

ER stress, UPR;Protein

aggregation

Treatment stress:Chemotherapy, XRT;Pro-‐survival signaling

Src

MEK

ERKFeed-‐forward loop

sCLU

IRS

Protease AKT

19S20S19SDegradation

Ub

MitochondriaGSK3β

Bax

UbCyt C

I-‐κDP P

Slug Egr-‐1 HSF-‐1

EMTmetastasis

NF-‐κB

Survival/decreased apoptosisTreatment resistance

Induce directlyInhibit

Nucleus

Twist1

COMM01

Republished with permission of Dove Medical Press, from Potential use of custirsen to treat prostate cancer, Higano CS, 6:785-797, © 2013; permission conveyed through Copyright Clearance Center, Inc.

Clinical Implications of Treatment Resistance

Question

• In a 76 year old man with mCRPC on first line therapy, how do you decide if he is progressing?

a) Clinical deterioration

b) Worsening disease on bone scan

c) PSA rising

d) None of these

e) All of these

Question

•Which of these indicators of disease progression do you think is the most important to use when deciding on changing to a second line therapy to maximize outcomes and minimize toxicity?

a) Clinical deterioration

b) Worsening disease on bone scan

c) PSA rising

d) None of these

e) All of these

Trajectory of Treatment Resistance in Prostate Cancer

• Not all patients respond to therapy, while others lose responsiveness over time

– Primary resistance (patients are initially refractory to therapy)

– Acquired resistance (patients develop resistance several months after treatment is initiated)

Sensitive to therapy

Acquired resistance to therapy

Primary resistance to therapy

Tumou

r Gro

wth

Time

CastrationResistance

Castration

1st-‐line therapy

Mukherji D, et al. Cancer Metastasis Rev 2014;33:555-66

Trajectory of Treatment Resistance in Prostate Cancer

Enzalutamide2

(AFFIRM)Abiraterone1

(COU-‐AA-‐301)

Primary resistance1 out of 3 patients

Progression = PSA + clinical + radiological

100

80

60

40

20

00 3 6 9 12 18

Months15

Placebo

Abirateroneacetate

0 6 93 12 15 18 21 24Months

EnzalutamidePlacebo

100

8090

7060

4030

10

50

20

0Prog

ression-‐free

Surviva

l (%) Primary resistance

1 out of 4 patients

1. de Bono JS, et al. N Eng J Med2011;364:1995-20052. Scher H, et al. N Eng J Med 2012 Sept; 367;13:1187-97

“Primary Resistance” as a Prognosticator in mCRPC

Time (days)

Proportion progressing

0 100 200 300 400 500 600

0.0

0.2

0.4

0.6

0.8

1.0

p < 0.0001

Primary Refractory Median No 421 days Yes 85 days

Time (months)

Survival

0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0

p = 0.0002

Refractory Median No not-reached Yes 16.7

Primary Resistant Median

Primary Resistant Median

Efstathiou E, et al ASCO 2014

Overall survival Time on Treatment

Appropriate Monitoring May Allow for Early Identification of Disease Progression

• NCCN recommends that patients be monitored closely with radiological imaging (ie, CT, bone scan), PSA, and clinical exams for evidence of progression1

• The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) provided comprehensive guidance on how to define disease progression using radiological, laboratory, and clinical findings2

PSWG2 Recommendations to Define Disease Progression2

Measure Frequency

PSA By cycle (every 3 or 4 weeks)

Bone scans Every 12 weeks

CT/MRI Every 12 weeks

Symptoms(pain, HRQOL, urinary or bowelCompromise)

Every cycle

1. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer. V.2.2014. http://www.nccn.org. Accessed June 25, 2014. 2. Scher HI, et al. J Clin Oncol 2008;26:1148- 59

Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Scher HI, et al: J Clin Oncol 2008;26(7):1148-1159.

Progression is a Composite End Point1

• Measurable disease2

– Measurable disease progression by Response Evaluation Criteria in Solid Tumours (RECIST) criteria

• The appearance of 1 or more new lesions

• At least a 20% relative increase in the sum of diameters of target lesions

• At least a 5 mm absolute increase in the sum

• Additional signs of disease progression (nonmeasurable disease)1

– Rising PSA levels1

– Pain1

– New lesions2

1. Scher HI, et al. J Clin Oncol 2011;29:3695- 7042. Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47

Initial PSA Response May Predict Treatment Outcome

• Poor PSA responses may be associated with primary resistance1

• Smaller PSA responses may be associated with worse treatment outcomes2,3

• Patients who fail to have an initial PSA response to a treatment may be more likely to have primary resistance1

1. Caffo O, et al. Future OncoL 2014;10:985-932. Berthold DR, et al. Ann Oncol 2008;19:1749-533. Hanninen M, et al. Can Urol Assoc J 2009;3:369-74

Summary

• Prostate cancer is a heterogeneous disease

• Heterogeneity is an important factor throughout the course of disease progression

– Primary tumour development

– Response to ADT

– Response to subsequent therapy

• Patients with mCRPC may have either primary or develop acquired resistance to therapeutic classes

• Individualizing treatment approaches based on guideline-recommended monitoring for progression may identify primary or acquired resistance and may lead to optimal patient outcomes

1. Caffo O, et al. Future OncoL 2014;10:985-932. Berthold DR, et al. Ann Oncol 2008;19:1749-533. Hanninen M, et al. Can Urol Assoc J 2009;3:369-74

OE Webinar North Mod1 V4 - Amazon S3€¦ · • Clinical trials: Astellas, Janssen, Sanofi, BMS....

Documents

Transcript of OE Webinar North Mod1 V4 - Amazon S3€¦ · • Clinical trials: Astellas, Janssen, Sanofi, BMS....