At ASCO 2016, Oncologists reported the results of MA.17R, a randomised trial in which doubling the duration (from 5 to 10 years) of a daily oral dose of the aromatase inhibitor, letrozole, in postmenopausal women with early stage breast cancer, resulted in a significant decrease in the risk of disease recurrence. However, the side effects of letrozole, including hot flashes, decreased libido, insomnia, joint pains and an increased risk of bone fractures can be hard on many women. This can make the decision to take letrozole for an additional 5 years very difficult for those at risk of recurrence who struggle with side effects. But did you know that women who have side effects with anastrazole, an aromatase inhibitor virtually identical to letrozole, actually have a lower risk of recurrence than women who don't have symptoms? Read more in this CTV.ca/health blog I posted in 2008.
Why Antiestrogen Side Effects May Predict Decreased Risk of Breast Cancer Recurrence
by Dr. Lorne Brandes November 5, 2008
A just-published article in The Lancet Oncology suggests that women with breast cancer who develop some common side effects (hot flashes, night sweats or joint pain) within three months of starting tamoxifen or the newer aromatase inhibitor drug, anastrazole (Arimidex), are less likely to have a recurrence of their disease when compared to women who do not.
These latest findings stem from an ongoing analysis of the clinical outcome in thousands of post-menopausal women with early breast cancer who, several years ago, participated in a large international phase three clinical study called ATAC.
Following initial surgery, radiation and/or chemotherapy, patients were randomized to receive five years of therapy with anastrazole alone, tamoxifen alone or both drugs in combination. The object of the trial was to determine which, if any, of the three hormonal regimens was superior to decrease recurrence.
After several years of follow up, it was observed that women who developed joint pains within three months of starting anastrazole had a 14 per cent recurrence rate, whereas women in whom the drug did not cause this symptom had a 23 per cent recurrence rate. Excluding joint pain (a side effect limited to anastrazole), women who developed hot flashes or night sweats within three months of starting either tamoxifen or anastrozole had a recurrence rate of 18 per cent compared to a 23 per cent recurrence rate in those who did not report these symptoms.
The authors concluded that the increased beneficial response associated with these somewhat unpleasant symptoms of antiestrogen therapy should be discussed with patients when deciding on whether to continue the treatment for the full five years.
Given the size of the ATAC study, the difference in recurrence rates, depending on the presence or absence of early side effects associated with tamoxifen or anastrazole, is a significant finding that should be taken seriously. Yet, how can we explain it?
The short answer is that the hot flashes, sweating and bone pain probably indicate an optimal concentration of the drug in the body.
There are at least three variables that determine concentration: how much of the drug is absorbed from the bowel; once absorbed, how efficiently the drug is metabolized in the liver (either broken down or converted to an active form); and whether other substances are present, such as fruit juices or certain medications, that may interfere with bowel absorption and/or liver metabolism of the drug.
The walls of cells lining the bowel are richly endowed with tiny pumps that transport drugs and other substances from the gut into the bloodstream. Recently it has been found that bowel absorption of many medications is significantly decreased when pills are washed down with various fruit juices that block the action of the pumps. Do women who drink juice to help them swallow tamoxifen or anastrazole have significantly lower bowel absorption than women who down their pills with water? A fundamental but most important question that requires an answer!
Perhaps the best studied variable is how drugs such as tamoxifen are broken down in the liver, where a large family of metabolizing enzymes, called P450, reside. To be clinically effective, tamoxifen first must be converted by certain P450 enzymes to two active forms: endoxifen and 4-hydroxy-tamoxifen.
However, significant genetically-determined variations in the P450 enzymes that metabolize tamoxifen have been observed. A 2005 study, published in the Journal of Clinical Oncology, linked the presence of a “normal” enzyme profile to both the occurrence of hot flashes and improved disease-free survival. Women who had one or more variant enzymes, associated with impaired conversion of tamoxifen to the active forms, tended not to have hot flashes and also had significantly worse clinical outcomes.
Finally, many drugs, including antidepressants such as fluoxetine (Prozac) and paroxetine (Paxil), can interfere with the metabolism of tamoxifen, resulting in lower concentrations of the antiestrogen. This likely occurs because they compete with tamoxifen for the same P450 liver enzymes, thereby decreasing the conversion of tamoxifen to its two active metabolites.
Some advice: if you have recently started therapy with tamoxifen or an aromatase inhibitor (including Arimidex, Femara and Aromasin) and are experiencing hot flashes and/or joint pain, try to stick with the medication. Those side effects may be telling you that you have an increased chance of benefit down the road.
However, if you are NOT experiencing side effects, first determine whether you are using a fruit juice to swallow your pill or check to see whether you may be taking one or more interfering medications. If neither is the case, speak to your oncologist about whether your metabolism of tamoxifen can be assessed (a tissue sample can be obtained using a buccal swab to obtain cells from the lining of the cheek). In the case of aromatase inhibitors, a check of residual estrogen levels in the blood can be carried out by most hospital labs. The answer may be of great importance to the outcome of your treatment.
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