Do DMARDs Increase Risk of Breast Cancer Recurrence?

Researchers performed a retrospective analysis of 3 cohorts of women with prior history breast cancer and rheumatoid arthritis or inflammatory bowel disease to determine the risk of breast cancer recurrence with methotrexate, anti-TNF inhibitors, and thiopurines.

Risk of breast cancer recurrence in women with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) was not significantly increased by methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, according to research published in Arthritis & Rheumatology.                           

Ronac Mamtani, MD, MSCE, of the Perelman Center for Advanced Medicine at the University of Pennsylvania, and colleagues analyzed 3 retrospective cohort studies of women with either RA or IBD who underwent surgery for primary breast cancer. Data were collected from Medicare between 2000 and 2012 and obtained from databases from the Centers for Medicare and Medicaid Services.

Included patients had an International Classification of Diseases, Ninth Revision (ICD-9) code for a breast cancer diagnosis with related lumpectomy or mastectomy, a diagnosis of RA or IBD with a prescription for a disease-modifying antirheumatic drug (DMARD) either before or after the primary breast cancer surgery but before the start of follow-up, and were continuously enrolled in Medicare parts A, B, or D for 6 months prior to the initial breast cancer diagnosis.

High Yield Data Summary

  • The risk of breast cancer recurrence in patients with RA or IBD and prior operative intervention for breast cancer who received methotrexate, thiopurine, or anti-TNF therapy was not significantly increased in this cohort 

Primary outcome measure was the diagnosis of a recurrent breast cancer event more than 1 year after a patients’ primary breast cancer surgery.

Dr Mamtani and colleagues created 3 matched cohorts of 2684 women (85% aged 65 years or older) with prior history of breast cancer and either RA or IBD. Cohorts included 892 users and 892 nonusers of MTX, 52 users and 208 nonusers of a thiopurine, and 291 users and 1164 nonusers of anti-TNF therapy. The cohorts were not mutually exclusive. Median follow-up ranged from 2.4 to 3.4 years.

Among all patients, 107 women were diagnosed with recurrent breast cancer during the 5196 person-years of follow-up, with crude incidence rates of 20.3 and 19.6 per 1000 person-years in MTX users and nonusers, 32.3 and 17.6 per 1000 person-years in thiopurine users and nonusers, and 22.3 and 19.5 per 1000 person-years in anti-TNF users and nonusers.

No statistically significant association was found between MTX use and breast cancer recurrence (hazard ratio [HR]: 1.07; 95% confidence interval [CI], 0.67-1.69). Similarly, no significant association was found in an anti-TNF analysis (HR: 1.13; 95% CI, 0.65-1.97), and a repeat analysis among only patients with RA (>90% of the cohort) produced nearly identical results (HR: 1.11; 95% CI, 0.64-1.95). Thiopurine use was associated with an increased but not statistically significant risk of recurrent breast cancer (HR: 2.10; 95% CI, 0.62-7.14).

Subgroup analyses were performed on patients with immune-mediated disease who received immunosuppressant therapy before breast cancer surgery. Among prior MTX users, no increased recurrent breast cancer risk was identified (HR: 1.15; 95% CI, 0.63-2.08).

Similar data were identified among those who continued to receive anti-TNF therapy vs those who discontinued treatment (HR: 1.37; 95% CI, 0.57-3.30). Too few patients received prior thiopurine therapy to produce HR estimates. 

Summary and Clinical Applicability

“The risk of cancer recurrence must be considered when selecting a treatment regimen for patients with active symptoms of RA or IBD and a history of cancer,” wrote Dr Mamtani and colleagues. “For patients with a solid cancer within the preceding 5 years, the safety of starting or resuming biologic therapy is uncertain.”

When deciding to start or resume immunosuppressive therapy in this patient cohort, physicians should consider both the severity of the underlying immune disease and the biologic factors of the primary breast cancer, as well as potential alternative therapies.

Dr Mamtani and colleagues noted that the data collected from this study does not support current clinical practice, which typically avoids the use of anti-TNF therapy in patients with RA or IBD who were recently treated for breast cancer; data showed that patients treated with anti-TNF agents were not at a higher risk of breast cancer recurrence. Additionally, study data suggest that MTX does not increase a patients’ risk of experiencing a second breast cancer event.

Due to a HR >2.0, “additional studies addressing the risk associated with thiopurines are needed,” the researchers wrote.“The data from our study may help rheumatologists and gastroenterologists to better assess the risk-benefit relationship when choosing between commonly used immunosuppressant therapies for patients with a history of cancer,” Dr Mamtani and colleagues concluded. 

Limitations and Disclosures

  • Risk of unmeasured cofounding due to observational study design
  • Potential for surveillance bias if users of immunosuppressive therapy were more frequently surveyed than nonusers
  • Limited statistical power was identified for analyses related to thiopurine use and subgroup analyses related to duration of immunosuppressive therapy
  • Study results cannot be generalized to women with active breast cancer who are currently undergoing treatment

Dr Mamtani reports receiving consulting fees and Dr Scott reports receiving a research grant from Takeda. Dr Yun has received consulting fees from Janssen and Abbott, and both consulting fees and a research grant and from UCB. Dr Curtis reports receiving both consulting fees and research grants from Roche/Genentech, UCB, Janssen, the Consortium of Rheumatology Researchers of North America (CORRONA), Amgen, Pfizer, Bristol-Myers Squibb, Crescendo, and AbbVie. Dr Lewis has received consulting fees from Takeda, Amgen, Millennium Pharmaceuticals, Prometheus, Lilly, Shire, AstraZeneca, Janssen, Merck, and AbbVie, and research grants from Bayer, Shire, Centocor, Nestle, and Takeda. Dr Lewis has also served on a Data and Safety Monitoring Board for clinical trials sponsored by Pfizer. 


Mamtani R, Clark AS, Scott FI, et al. Association between breast cancer recurrence and immunosuppression in rheumatoid arthritis and inflammatory bowel disease. Arthrit Rheumatol. 2016;68(10):2403-2411. doi: 10.1002/art.39738

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