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.
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 Alone
In 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 2005:353:2747 Copyright 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
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.
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).
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. 2007 Copyright 2007 Breast Res Treat.
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.
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.
Post menopausal women over age 18
Stage I-III breast cancer
Presence of hand pain
No active malignant disease.
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 Inhibitor CASES (n=24) Not Receiving Aromatase Inhibitor CONTROLS (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, ANA Inflammatory Markers: ESR, CRP Bone markers: 25-OH Vitamin D Study biomarkers: TNF-α, IL-6 IMAGING (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
Recruiting participants from Lombardi
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.
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. Shanmugam has lots of exciting projects for anyone interested in doing research!
You can make a difference in one month!
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 .
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.
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).
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.
As first line therapy for post-menopausal women AIs