How important is inflammation in breast cancer progression?

Not very, according to the REACT Study conducted by the Imperial College London. The study was predicated on the importance of COX-2 in driving inflammation that contributes to tumorigenesis. The thinking was that administering celecoxib (Celebrex), a COX-2 inhibitor, could reduce breast cancer progression, as suggested in smaller observational trials.

It was a rationale hypothesis, given that:

The biological role of COX-2, the inducible form of cyclooxygenase, is to convert arachidonic acid into prostaglandins (PGs) and thromboxanes (TXs). Overexpressed in many tumors, COX-2 plays a crucial role in cancer through synthesis of PGs which stimulate PGs receptors with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune responses.

Further, COX-2 has been shown to enhance the aromatase pathway (estrogen synthesis from androgens), especially in estrogen receptor-positive breast cancer.

In the study, 2,639 women with primary breast cancer (excluding T1, triple negative, and Her-2+ disease) received celecoxib or placebo for two years (in a 2:1 randomization). The primary endpoint of the study was disease-free survival (time from randomization to first recurrence, a new primary breast cancer, or death). Approximately 70% of women in both arms completed 2 years of dosing. After 5 years of follow-up, 83% of women in both groups were disease-free. Unrelated to breast cancer, but important given the question of cardiovascular side-effects of COX-2 inhibitors, was the finding of no difference in CV toxicities, except that the placebo group had a high incidence of stroke.

So, should we conclude from REACT that inflammation NOT important in cancer tumorigenesis? I think not.

  1. Perhaps, COX-2 is more important in initial tumorigenesis, that is, induction of proliferation to enable cancer cells to accumulate the requisite number of mutations for malignant transformation. For example, use of aspirin decreases the incidence of colon cancer in patients with polyps.
  2. Or, perhaps, two years of anti-COX-2 therapy in REACT is not sufficient to demonstrate an effect. For example, in the CANTOS trial of canakinumab (Ilaris; anti-interleukin-b1 MAb), patients were treated for five years. Further, in CANTOS, patients were at risk for developing lung cancer by virtue of having atherosclerosis (mostly secondary to smoking history), but, they were not diagnosed with lung cancer prior to the start of the study.

I believe that inflammation is critically important for the development of most if not all cancers. Once cancers have manifested themselves, I believe inflammation is less important because it is highly likely that some clones of the primary tumor will have accumulated mutations that render them less dependent on the contribution of inflammation for further progression. By this reasoning, efforts to reduce inflammation should be employed much earlier in the process. Perhaps, biomarkers will be able to identify groups of patients with precancerous lesions, or pre-cancerous mutations, who will benefit from anti-inflammatory therapy.

I also believe that anti-inflammatory therapy is important for slowing progression of cancer. The REACT study did not demonstrate this effect in these patients under these conditions.

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