Tamoxifen Resistance?

FastWalker

How much of a problem is Tamoxifen resistance? I am considering skipping chemotherapy because it provides little-to-no-(additional)benefit over Tamoxifen in my particular case. However, I am scared to put all of my eggs into one basket. What if I can't metabolize Tamoxifen? What if my particular tumor is Tamoxifen resistant? Will chemo then provide a benefit, even to grade 1 highly ER+PR+? . . . BTW, my medical oncologist said that tests to determine Tamoxifen metabolism are not accurate. . .I didn't even think to ask him about the separate issue of Tamoxifen resistance. . . So many things to consider!

peggy_j

Interesting. I've never heard anyone talk about this, but since some women do have a recurrence on tamox, it seems possible. I googled and found some info on PubMed and other sources. Some researchers seem to think there may be a genetic component (so, in theory, you might be able to be tested for that gene) and other scientists think resistance does develop and they have a second set of drugs that might combat that. If it was me, I'd ask my doctor. Individual studies here and there may not be replicated and/or there may not be a consensus. If you learn anything definitive, could you pass it on to us here?

FastWalker

peggy_j: A member on another board was kind enough to post this:

Should I have the CYP2D6 tamoxifen resistance test?
Updated January 2011A growing number of companies have begun offering "direct to consumer" genetic testing or genetic "home testing."

One of the tests now available is the "tamoxifen resistance" or "CYP2D6" test. This test examines a gene called 2D6, which produces the enzyme CYP2D6. This enzyme is necessary for the body to metabolize a number of drugs, including tamoxifen.

Different people have different variations of this gene. Initial studies had suggested that some variations metabolize 2D6 drugs very quickly, while others don't metabolize them as well, or at all.

A study presented at the 2007 San Antonio Breast Cancer Symposium suggested that women who inherited a certain variation of the 2D6 gene were almost twice as likely to have their breast cancer recur, even though they were more likely to complete their tamoxifen treatment. About ten percent of the population has this variation.

The study also found that women who scored zero on the gene test rarely had any side effects from tamoxifen, whereas women with the highest scores did. This finding appeared to confirm previous research that had suggested that the side effects of tamoxifen were an indicator that the drug was working, and that women who were not experiencing side effects were not getting the full benefit of the drug because their body was not metabolizing it properly. It also supported a Food and Drug Administration Clinical Pharmacology Subcommittee recommendation, made in 2006, that the tamoxifen label carry a warning that the drug may not be as effective in women who carry a version of the 2D6 gene that does not metabolize the drug.

As a result of this research, between 2008 and 2010 some breast specialists began to recommend that a patient considering tamoxifen first have CYP2D6 testing. Others suggested that women who went on the drug monitor their side effects. If you were having side effects, it meant the drug was working. If you weren't, then it wasn't, and you would need to pursue other options.

As more women began to be tested, researchers continued to study tamoxifen resistance. And at the San Antonio Breast Cancer Symposium in December 2010, researchers presented data from two of these studies that brought into question what many doctors had come to believe about the CYP2D6 enzyme, tamoxifen and tamoxifen-resistance testing.

These studies used data from two large clinical trials that had been done to compare the effectiveness and safety of tamoxifen and an aromatase inhibitor. (Aromatase inhibitors are metabolized differently than tamoxifen, and are not affected by CYP2D6). These findings showed that women who had mutations in the genes that control the enzymes that metabolize tamoxifen were NOT more likely to have a recurrence, and that the scoring system that differentiates women into poor, intermediate, and extensive metabolizers did NOT predict recurrence. The studies also showed that women on tamoxifen who used antidepressants that were thought to inhibit CYP2D6were NOT more likely to have a recurrence.

In sum, the researchers concluded that for postmenopausal patients with hormone-sensitive early breast cancer, CYP2D6 testing is not justified to determine whether to give tamoxifen. In addition, the presence or absence of hot flashes should not be used as an indicator of whether tamoxifen is effective.

So, where does this leave us? Clearly, more studies need to be done. An overview of the data presented at the Symposium noted that, since 2003, 178 articles have been published on tamoxifen resistance. Fourteen of these studies showed that CYPD2D6 was associated with breast cancer recurrence in women on tamoxifen, and 15 found that it was not. This suggests that, right now, there appears to be little reason to have CYP2D6 testing, since it is now not clear what the findings of this test really mean. It also means that if you are not experiencing side effects, you should not conclude that the tamoxifen is not working.

 

FastWalker

peggy_j: I found this:

"Tamoxifen can work as a wonder drug, inhibiting cancer growth and shrinking tumors without the severe side effects often associated with chemotherapy Unfortunately, 30–40% of patients who take tamoxifen become resistant to endocrine therapy within 3–5 years."

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855007/

AND

"Unfortunately, a subset of patients who received adjuvant tamoxifen would eventually experience relapse and die as a result of the disease, 30% of ER+ tumors were not prevented by tamoxifen in National Surgical Adjuvant Breast and Bowel Project(NSABP) prevention trial(P1)"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951414/