The first anti-metastatic drug for young women?
(See ryongraf.com for more articles)
15 August 2013
Mini-Review Research Commentary
The first drug that specifically targets the spread of breast cancer metastasis might be on the horizon. I’m particularly excited about this, because:
1) It’s a therapy for young mothers affected by pregnancy-associated breast cancer. 2) The drug(s) are already FDA approved, inexpensive, and have well-tolerated side effects.
Breast cancer affects an average of 1 in 100 women age 60+ in the U.S. every year, and through a confluence of awareness campaigns and morbid prominence it has found its way deep into the public psyche. With an aging population, we expect to see an increase in incidence in the coming years. Though advanced genomic techniques we know that breast cancer has at least several distinct genetic subtypes (1) that have been exploited by a new generation of targeted therapies. There have been great advances in controlling or even curing the disease in some patients, and the American Cancer Society has been reporting a decline in deaths from breast cancer for years now (2).
Although breast cancer affects mostly older women (3) there is a sinister twist for those that develop the disease younger. Or rather, those diagnosed within five years of their last pregnancy. Those that have young children in tow.
Pregnancy-associated breast cancer (PABC) has an unusually high incidence metastases to the liver, lungs, bones, and brain, making therapy very difficult. At two sites in Colorado between 1984 and 2001, Callihan and colleagues combined data from 619 women diagnosed with breast cancer under the age of 45 in a retrospective cohort study, and found that those diagnosed within 5 years of their last pregnancy had a three-fold higher risk of developing metastases (31.1%), and roughly a 60% chance of survival after 5 years, opposed to a nearly 100% 5-year survival for nulliparous women (4). Image adopted from Callihan et al. 2013
The epidemiological data indicates that an event associated with pregnancy, but independent of growth-promoting gestational hormones, promotes the elevated PABC metastasis: PABC does not correlate with tumor size, stage, nodal status, estrogen receptor status, or HER2 expression (5). In an elegant review article in Nature Medicine, Schedin proposed a mechanism by which spatial reorganization of breast tissue during involution (natural tissue re-organization program of the breast after a period of lactation) allows access of premalignant cells to mesenchymal cellular compartments in the breast that might not otherwise have access to, also hypothesizing that this might tip the delicate scale of anti- and pro- inflammatory signals toward the latter, promoting the release of proto-tumorigenic cells from their endothelial compartments (3).
In a series of elegant experiments, Schedin’s group spent years investigating this phenomenon and found that ductal carcinoma in situ (DCIS, usually considered a low-grade tumor) actually can be driven to seed the lungs postpartum by mammary involution (6). Lyons and colleagues found that remodeling of extracellular matrix proteins post-lactation was mediated by the COX-2 signaling pathway, and that the enhanced cancer spread to the lungs could be mitigated by NSAID’s, including celecoxib (Celebrex) and ibuprofen (Advil).
So, could ibuprofen or celecoxib be an effective anti-metastatic drug for women with DCIS postpartum? A clinical trial (NCT01881048) is currently underway to test this at the University of Colorado Denver, and the results should be available soon!
This could be a boon to young mothers fighting breast cancer. Visceral emotional tug aside, this is an interesting innovation, because this approach to therapy targets a process specific to breast cancer metastasis. All other advanced breast cancer therapies that have arrived in the clinic in the last decade target all breast cancer cells, not the most deadly subset: the seeds that will form the weeds of metastases. If the results from this clinical trial come through and the NSAID’s are validated, it opens the door for these to be used synergistically in conjunction with existing drugs, because they target different mechanisms and because we already have extensive knowledge of NSAID cross-reactions with other drugs.
References: 1. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012 Jun 21;486(7403):346-52. PubMed PMID: 22522925. Pubmed Central PMCID: PMC3440846. Epub 2012/04/24. eng. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: a cancer journal for clinicians. 2013 Jan;63(1):11-30. PubMed PMID: 23335087. Epub 2013/01/22. eng. 3. Schedin P. Pregnancy-associated breast cancer and metastasis. Nature reviews Cancer. 2006 Apr;6(4):281-91. PubMed PMID: 16557280. Epub 2006/03/25. eng. 4. Callihan EB, Gao D, Jindal S, Lyons TR, Manthey E, Edgerton S, et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast cancer research and treatment. 2013 Apr;138(2):549-59. PubMed PMID: 23430224. Pubmed Central PMCID: PMC3608871. Epub 2013/02/23. eng. 5. Daling JR, Malone KE, Doody DR, Anderson BO, Porter PL. The relation of reproductive factors to mortality from breast cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002 Mar;11(3):235-41. PubMed PMID: 11895871. Epub 2002/03/16. eng. 6. Lyons TR, O’Brien J, Borges VF, Conklin MW, Keely PJ, Eliceiri KW, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nature medicine. 2011 Sep;17(9):1109-15. PubMed PMID: 21822285. Epub 2011/08/09. eng.