Is there a link between scleroderma and cancer?

Voon Ong

Outline

• Risk of cancer– general population and rheumatic diseases

• Biology of cancer• Cancer risk in scleroderma• Cancer as trigger for scleroderma

Epidemiology• Cancer is one of the most common diseases in

the developed world• Lifetime risk 20% • 5% of general population having current cancer

or history of cancer

• 1 in 10 women will develop breast cancer• 1 in 8 men will develop prostate cancer

Frequency of cancers in UK (2010)

• 325 000 new cases in UK• 164 000 of new males cases• 50 000 new cases of breast cancer• 40,000 new cases of prostate cancer

Females Males

Prepared by Cancer Research UK - original data sources are available from http://www.cancerresearchuk.org/cancer-info/cancerstats/

Cancer in rheumatic diseases

Rheumatoid arthritisSjogren SyndromeInflammatory muscle disease

LupusVasculitis

Giant cell arteritisAnkylosing spondylitisPsoriatic arthritis

LymphomaLung cancerOvarian and gastric cancer

Bowel cancer

Haematological cancer

Can

cer

risk

Cancer in rheumatic diseases – the risk factors

• Duration of disease• Disease activity• Disease pathogenic pathways

– B cell activation• Effect of treatment

– Reduction of inflammation– Immunosuppressive effect

• Smoking history, behavioural factors

Cancer in Scleroderma – how common?

No of patients

No of cancers

Follow-up (years)

SIR*

Rosenthal (2005)

917 69 8 1.5

Thomas (2000)

652 36 NA 1.15

Hill (2003) 441 47 6 1.99

Chatterjee (2005)

538 45 NA 0.91

Olesen (2010)

2040 222 6.4 1.4

Kuo (2012) 2053 83 5.8 1.63

*Standardised Incidence Ratio – Observed to expected cancer cases ratiosNA: Not available

Risk factors for cancer in scleroderma

• ?persistent and chronic inflammation• Severity of disease

– Lung fibrosis– Oesophageal cancer and Barretts disease

• Immunosuppressive effect of treatment– Cyclophosphamide

• Smoking– Disease severity

Cancer – how does it happens?

Virus Radiation Carcinogen Genetic factors

Normal cell

Abnormal cells

Immune system ineffective

Immune system effective

Cancer Destruction of abnormal cells

Immunoediting

Limited scleroderma

Diffuse scleroderma

0

10

20

30

40

50

Breast Lung GI GU Gynae Haem Skin Others

Cancer site

% SSc patients

(Moinzadeh et al Arthritis Res Ther, 2014)

Disease subset association with cancer in scleroderma

Retrospective RFH cohort study– 2177 patients with scleroderma– 154 (7.1%) had a history of cancer– 85.1% female– Median age 53– 34.4% diffuse SSc

0

10

20

30

40

50

Breast Lung GI GU Gynae Haem Skin Others

ACAScl70RNA pol

ACA (n=40)

Scl70 (n=28)

RNApol (n=41)

42.5

35.7

46.3

5

17.9

9.8

20

3.6

7.3

2.5

3.6

4.9

15

14.3

7.3

10

17.9

12.2

2.5

3.6

7.3

2.5

3.6

4.9

Anti-RNA polymerase III antibody associated with SSc-cancer

% SSc patients

• Overall frequency– Anti-RNA polymerase III (14.2%)– Anti-centromere (6.8%)– Anti-Scl70 (6.3%)

(Moinzadeh et al Arthritis Res Ther, 2014)

Frequency of all-cancers (n=129) across all three major antibody reactivities

Frequency of all-cancers for anti-RNAP antibody (n=38)

Frequency of breast cancers (n=60) across all three major antibody reactivities

Frequency of breast cancers (n=19) for anti-RNAP antibody

Num

ber

of c

ance

rs

Num

ber

of c

ance

rs

Num

ber

of b

reas

t ca

ncer

s

Num

ber

of b

reas

t ca

ncer

s

0

5

10

15

20

25

-300-240-180-120-60 0 42036030024018012060 480540

Time (months)

0

2.5

5

7.5

10

12.5

-300-240-180-120 -60 0 36030024018012060

Time (months)

-300 -240 -180 -120 -60 0 18012060

0

2

4

6

8

Time (months)-300-240-180-120 -60 0 36030024018012060

5

10

15

20

0

Time (months)

Cancer occurrence associates with onset of scleroderma

Breast Ca, Scl70 +Breast Ca, ACA +

Lack of association of breast cancer occurrence and onset of scleroderma for ACA and Scl70 antibodies subsets

Num

ber

of b

reas

t ca

ncer

s

Time (months)-200 0 200 400

0

1

2

3

Num

ber

of b

reas

t ca

ncer

s

Time (months)

-200 0 200 300-100 100

0

0.5

1.0

1.5

2.0

Frequency of breast cancers (n=15) for anti-centromere antibodies

Frequency of breast cancers (n=9) anti-Scl70 antibodies

Cancer occurrence and onset of SSc strongest for anti-RNA polymerase III – paraneoplastic

pattern

Prop

ortio

n fr

ee o

f ca

ncer

1.0

0.8

0.6

0.4

0.2

0

-200

Time to cancer onset (months)

0 200 400 600

Diagnosis of SSc

Scl70

ACA

ARA

Malignancy diagnosis within 3 years of scleroderma onset– 55.3% anti-RNA poly III

(ARA)– 23.5% have ACA– 13.6% have Anti-Scl 70

Moinzadeh et al Arthritis Res Ther. 2014

Clinical associations with ARA

Anti-RNA polymerase III

Renal crisisGAVE

PAH

Anti-RNA polymeraseIII antibody associates with high expression levels of RNApolymerase protein in cancer

tissue

Breast cancer SSc-ARA+

Control breast tissue

Khan, Ong, Denton (unpublished) 2014

Non-SScBreast cancer

Relevance to Scleroderma ??

Model for paraneoplastic scleroderma- cross-reactive immune response

Immune response against cancer

Scleroderma Immune response against cancer

Repair and regeneration pathways

Cancerous cells

Cancer proteins

Triggering event

Skin/other tissues

Cancerous and scleroderma tissues may share similar protein expression that are targeted by immune response

Hypothetical mechanism for cancer in scleroderma

Cancer

Cancer and autoantibodies

Cancer and scleroderma

Normal Autoantibodies alone Scleroderma

Autoimmunity

Can

cer

Conclusion

• Possible increased risk of cancer in rheumatic diseases

• Paraneoplastic scleroderma occurs in selected patients with anti-RNA polymerase III antibodies

• Potential role of ARA in pathogenic process in scleroderma– Linking anticancer immune response and

autoimmunity in scleroderma