Is there a biological reason for anti-CD20 therapy to increase your risk of developing breast cancer? #ResearchSpeak
There is nothing like a 'dirty little fact' to unseat a entrenched dogma. I was at a meeting yesterday and we were discussing cancer risks and DMTs. At some point I stated that the breast cancer signal in the ocrelizumab trials may turn out to be a false positive signal. I said this as I knew of no biological reason of how ocrelizumab could cause breast cancer within a 24-36 month period. I also thought that carcinogenesis (the biological process that leads to cancer) in relation to the breast took much longer than 3 years to occur. Similarly, I made the statement based on 'immunological dogma' that I didn't think it could be due to peripheral immune surveillance because that job is done by T-cells and NK-cells and I was not aware of B-cells playing a role.
A very good colleague of mine from Switzerland then shot me down and quoted the paper below. In this study from the Mayo Clinic, women having biopsies for benign breast disease were followed up to see who developed breast cancer. Women with reduced B-cells in their breast tissue had an almost 6-times higher risk of developing breast cancer in the future. This data suggests that B-cells may be critical in preventing disease progression from benign to malignant breast disease. If this study can be replicated it could explain the breast cancer risk with anti-CD20 therapies and suggests a new role for B cells in peripheral tumour immuno-surveillance. The other explanation is reverse causation and that benign breast lesions that don't recruit B-cells are different biologically to those that do and the B-cells are innocent bystanders.
I am now prepared to change my position on this topic and admit the breast cancer signal with ocrelizumab may prove to be real. However, if this is the case why should it be limited to ocrelizumab? If B-cells are necessary to keep breast cancer at bay then all B-cell depleting agents should increase the risk.
All I can say is that we can speculate until the cows' come home; so let's wait and see what happens in the post-marketing surveillance studies.
Degnim et al. Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development. Clin Cancer Res. 2017 Jan 26. doi: 10.1158/1078-0432.CCR-16-2026.
Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD).
Experimental Design: A breast tissue matched case-control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells).
Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4-23.1) for subsequent breast cancer risk.
Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk.
Labels: #ResearchSpeak, anti-CD20, breast cancer, ocrelizumab, Rituximab