The CIRAS Study: A case control study to define Clinical, Immunologic, and Radiographic features of the aromatase inhibitor Arthalgia Syndrome

October Research Noon ConferenceJames McCloskey

Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United States, 2009

Copyright ©2009 American Cancer Society

From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249.

Mortality rate among women with breast cancer has continually decreased since the 1990’s with earlier detection, thorough screening, increased awareness, and advances in treatment.

From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249.

Hormonal (Endocrine) Therapies:Mechanisms of Action

Smith, I, and Dowsett, MNEJM. 2003 348:2431-2442Copyright ©2003 NEJM

Tamoxifen: Selective Estrogen Receptor Modulator

Anastrole, Letrozole, Vorozole: Inhibit the production of Estrogen in peripheral tissues

• Now considered standard of care for post menopausal women.

70 % of breast malignancies are ER positive.

Efficacy of AI AloneIn a study of over

8000 women.• Letrozole

significantly decreased the risk of reoccurrence compared to tamoxifen.

• Especially at Distant sites.

The BIG 1-98 Group.NEJM 2005:353:2747Copyright 2005 NEJM

Combination AI and Tamoxifen Therapy

Results are shown for letrozole monotherapy as compared with tamoxifen followed by letrozole (Panels A) and for letrozole monotherapy as compared with letrozole followed by tamoxifen (Panels B).

Letrozole monotherapy is as efficient as combination letrazole and tamoxifen therapy.

The BIG 1-98 Collaborative Group. 2009. NEJM; 361:766-776 Copyright 2009 NEJM

Adverse Effects

Tamoxifen: Increased Hot Flashes, Vaginal bleeding/discharge, vascular events, Endometrial Ca, and DVT

AI: Increased Musculoskeletal Complaints, Decreased BMD and Higher Fracture Rate.

ATAC Trialist Group. Lancet. 2002;359:2131-2139. Copyright ©2003 NEJM

AI Associated Arthalgia Syndrome

Symptoms begin within a few months of starting therapy.

Include bilateral pain and stiffness most prominently in the hands, but also in the knees, feet, hips, lower back and shoulders.

Some have described sleeplessness as part of the syndrome as well.

Usually Resolve after the AI is stopped.

Prevalence Data suggest that 5-30%

of patients on AIs suffer from arthalgia symptoms.

The actual prevalence is likely higher as most of the data is based on patient self-reporting.

Most symptoms are mild to moderate

Some Chart reviews have shown up to 50% of women will discontinue AI due to side effects.

Studies estimate that 5-20% of patients will discontinue AI therapy due to arthalgias.

Burstein HJ.Breast. 2007 Jun;16(3):223-34Copyright 2009 Breast.

Etiology Etiology remains unclear, but is likely

related to estrogen deprivation and/or inflammation.

Natural hypoestrogenemia of menopause is also associated with arthalgias.

Opiod-containing neurons in the brain and spinal cord express estrogen receptors. These receptors may have a role in modulating pain and sleep.

Etiology Estrogen deficiency has been shown to

increase levels of inflammatory cytokines. Low estrogen states have been associated

with exacerbations of other inflammatory arthridities. RA often improves during pregnancy and is

exacerbated post partum. Some have postulated that inhibition of Vit

D hydroxylation leads to functional vit D deficiency (osteomalcia). Studies have shown normal Vit D levels in pts on

AIs with arthalgias (Singh 2006).

Tenosynovitis Small studies using MRI and US have

demonstrated increased rates of tenosynovitis and carpal tunnel syndrome in women on AIs.

There was no control group in this study.

Morales et al.Breast Cancer Res Treat. 2007Copyright 2007 Breast Res Treat.

The Problem

A significant number of women on AIs will experience arthalgia syndrome.

There is little data to identify risk factors. The syndrome and etiology remains poorly

understood. This makes studying interventions difficult. Symptoms result in significantly reduced

compliance and discontinuation of an otherwise beneficial therapy.

Purpose To evaluate the clinical,

immunologic, and radiographic features of AI associated Arthalgia Syndrome. Primary objective: Compare

DAS-28 between groups to demonstrate AS is an inflammatory arthritis.

Secondary Objective- compare ESR, TNF-alpha, and IL-6 Levels.

Compare US to evaluate for tenosynovitis.

Vitamin D levels to evaluate osteomalacia.

Autoantibodies, and hand X-rays to rule out underlying rheumatologic disease.

Design

Inclusion Criteria Post menopausal women over age 18 Stage I-III breast cancer Presence of hand pain No active malignant disease.

Exclusion Criteria Known autoimmune disease

RA, SLE, PMR, seronegative arthritis. Active Malignant disease History of Metastatic Disease. Age < 18 Unable to complete informed consent.

Stage I-III post-menopausal breast cancer patients followed at Lombardi Cancer Center with hand pain

Receiving Aromatase InhibitorCASES(n=24)

Not Receiving Aromatase InhibitorCONTROLS

(n=24)

RHEUMATOLOGIC EVALUATION (1 hour)History and Physical Examination by rheumatologist

DAS-28 joint examination (completed by rheumatologist)QUESTIONNAIRES (30 minutes):

Health Assessment Questionnaire (completed with GCRC staff)BLOOD TESTS(30 minutes):

Autoantibody screen: RF, CCP, ANAInflammatory Markers: ESR, CRPBone markers: 25-OH Vitamin D

Study biomarkers: TNF-α, IL-6IMAGING (1hour 30 minutes):

Hand X-Ray (30 minutes)Hand Ultrasound (1 hour)

Eligibility assessed, study discussed with patient, and obtain consent.

Schedule Study visit:(note all investigators blinded except recruiting team)

PATIENTS MUST ABSTAIN FROM NSAIDS FOR 48 HOURS PRIOR TO ULTRASOUND

Follow-up telephone call with Dr. Shanmugam to discuss results and if necessary arrange follow-up

Study Schema

September Research Elective

o Recruiting participants from Lombardio Literature Search

Currently 12 patients have completed the Study

7 cases, 4 controls Median age: 61 Median time since diagnosis: 6.29 years. Median duration of pain: 1.7 years

6 other consented, but not completed to date.

Thank You! Dr. Eng-Wong, Oncology Dr. Dr. Shanmugam, Rhuematology Dr. Allison, Radiology Department of Medicine Support

Grant Development Funds Award. Swing For The Cure Lombardi Breast Oncologists and

Surgeons• Dr. Isaacs• Dr. Cohen• Dr. Lui• Dr. Warren

• Dr. Feldman• Dr. Willi• Dr. Cocilovo • Dr. Evangelista

Advertisement

Dr. Shanmugam has lots of exciting projects for anyone interested in doing research!

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References

American Cancer Society Cancer Facts and Figures 2009. http://www.cancer.org/downloads/STT/500809web.pdf

ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60-62.

BIG 1-98 Collaborative Group. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009 Aug 20;361(8):766-76.

Burnstein, H. Aromatase inhibitor-associated arthalgia syndrome. The Breast 2007; 16:223-234.

Crew, KD, Greenlee H, Capodice J, et al. Prevalence of Joint Symptoms in Postmenopausal Women Taking aromatase inhibitors for early stage breast cancer. J Clin Oncology 2007; 25:3877-83.

Felton DT, Cumming ST. Aromatoase Inhibitors and the syndrome of arthalgias with estrogen depravation. Arthritis &Rheumatism 2005; 52: 2594-8.

Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262-1271.

Jemal, A. et al. ACS facts and figures 2009. CA Cancer J Clin 2009;59:225-249 Morales et al. Debilitating musculoskeletal pain and stiffness with letrozole and exemestane:

associated tenosynovial changes on. Breast Cancer Res Treat. 2007 Jul;104(1):87-91. Partridge, AH et al. Adherance to intial adjuvan anastrozole therapy among women with early

stage breast cancer. J Clin Oncology 2008; 26:556-62. Singh S, Vitamin D levels among patients with arthalgias: results from IBIS- II breast cancer

prevention study. San Antonio Breast Cancer Symposium, San Antonio, TX 2006. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:2431-2442

.

Background

Breast cancer remains the most common cancer among women.

The incidence of breast cancer in women in the united states is approximately 13% (nearly 1 in 8).

Mortality rate among women has continually decreased since the 1990’s with earlier detection, thorough screening increased awareness, and advances in treatment.

For women in the U.S. breast cancer is still the second most common cause of death related to cancer.

Recent studies using MRI have showed increased synovial fluid and enjancement/thickening of the synovial shealth.

Background

Tamoxifen and AIs have different side effect profiles.

Woman on tamoxifen experience significantly higher rates of hot flashes, vaginal bleeding/discharge, endometrial ca and DVTs than women on AIs.

AIs are associated with higher rates of, sexual dysfunction and musculoskeletal disorders (arthalgias, new-onset osteoporosis, fractures and possibly tenosynovitis and carpal tunnel).

Background

Adjuvant tamoxifen has been the mainstay of adjuvant endocrine therapy for decades for woman with early stage hormone receptor positive breast cancer.

The addition of aromatase inhibitors in post-menopausal women with hormone responsive breast cancer, as either initial therapy or after a 2-3 year period of tamoxifen therapy has been shown to decrease reoccurrence rates by 13-40%.

The incorporation of AIs is now considered standard of care therapy.

Efficacy As first line therapy

for post-menopausal women AIs Decrease

Reoccurrence rates. Increase time to

progression of disease.

Result in higher rates of tumor regression.

Smith, I, and Dowsett, MNEJM. 2003 348:2431-2442Copyright ©2003 NEJM