Approach to Endocrine Therapy in Breast Cancer—Part I

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Interview by L Scott Zoeller. 2012 Sept 18, Daniel Hayes, MD

In Part I of this interview, Dr. Hayes discusses personalization and the optimal sequence of endocrine therapy in breast cancer. In Part II, Dr. Hayes discusses early vs late recurrence, extended therapy, and the potential for combination therapy.

Personalized Therapy

OncologySTAT: Would you discuss how modern adjuvant endocrine therapy is becoming increasingly personalized in breast cancer?

Dr. Hayes: That depends on what one means by "personalized." My answer is I don’t think it is. I think we got there 20 or 30 years ago and not much has changed. In my opinion, the concept of personalized oncology started in breast cancer with the observation by Bill McGuire many years ago, when he showed it was very unlikely that patients whose cancers were estrogen-receptor (ER) negative would benefit from so-called anti-estrogen therapy, which I’ll call “endocrine therapy” for this discussion. That observation led to a number of studies in the 1970s and early 1980s, which, ultimately, culminated in the worldwide Oxford Overview of breast cancer, which demonstrated that tamoxifen just simply doesn’t work compared with the placebo in patients with ER-negative breast cancer.¹

The flip side of that is consistent with every other study on this topic since that time: we’ve gone much further. The issue is that endocrine therapy doesn’t always work in ER-positive patients. In fact, it only works about half of the time. The questions are, can we identify ER-positive patients who are not going to benefit from any endocrine therapy, or can we identify patients who are likely to benefit more from one kind of endocrine therapy than another, or can we identify patients who are so likely to have toxicities from one sort of endocrine therapy that they would be better served without it?

I think the field has come up with a bunch of zeros, including my own research, in answer to all three of those questions. Not that people aren’t trying, and it’s not that there haven’t been very interesting preliminary observations; but, so far, I have yet to see any marker that tells us that a patient with ER-positive breast cancer is either so likely not to benefit or so likely to benefit from one type of endocrine therapy vs another, or so likely to have toxicities from specific endocrine therapies, that I would change her treatment based on a biomarker assay.

CYP2D6 Polymorphisms and Tamoxifen

However, right now, a really big controversy pertains to the question about the use of so-called pharmacogenetics, or pharmacogenomics, to direct endocrine therapy. The most widely publicized observation was that differences in inherited single nucleotide polymorphisms (SNPs) in the CYP2D6 gene might affect the activity of tamoxifen.

Tamoxifen by itself has some anti-estrogenic effect, but not very much. However tamoxifen is converted into a number of metabolites, some of which are completely inactive, but two are very active, maybe ten-fold more active than the parent drug. One of them is called 4-hydroxytamoxifen and the other is called 4-hydroxy-N-desmethyl-tamoxifen, which our group (the Consortium on Breast Cancer Pharmacogenomics—COBRA) named endoxifen, since it is easier to say. It turns out that women who are homozygous for an inactive allele of CYP2D6, who, in other words, have an inactive enzyme, make very little, if any, endoxifen. These patients still make 4-hydroxytamoxifen, but not endoxifen. In women with normal wild-type CYP2D6, there is approximately 10 times as much endoxifen as 4-hydroxytamoxifen.

Furthermore, women who have wild-type CYP2D6 and take tamoxifen, but who also take drugs that inhibit CYP2D6 activity, which would be the equivalent of inheriting two bad copies, also do not make much endoxifen; but, again, they do continue to make 4-hydroxytamoxifen.

COBRA published these pharmacogenetic observations about 10 years ago. We had hypothesized that maybe women who were CYP2D6 homozygous for the inactive allele, so-called poor metabolizers, might not benefit from tamoxifen and would be better served with an aromatase inhibitor. That observation led a number of other investigators to pull out samples from their banks, which were collected for a variety of reasons, and see if whether or not they could observe that or refute it.

To make a long story longer, there are now 14 or 15, or more, such papers out there, and probably half or more suggest that what I just said is true and probably half or more suggest it’s not true. A couple of them suggest that, if anything, women who are homozygous for the variant do better when they take tamoxifen.

There have been two recent papers published in the Journal of the National Cancer Institute. that report the results of two “prospective retrospective” studies addressing this issue using specimens collected from patients who participated in previously performed prospective clinical trials. I’m an author on one of them, Rae et al, which is a study of patients who participated in the ATAC trial.² The second paper is by Regan et al and concerns women who participated in BIG 1-98 trial.³ In both papers, the specific question was addressed in the groups of ER-positive patients that received tamoxifen only; there was no difference in outcomes between women whose genes are wild type for CYP2D6 vs women whose genes are either heterozygous or homozygous variant for CYP2D6.

So, while that was a very exciting concept in the mid part of the last decade, I think that the data reported in the last couple of years have suggested that it’s probably not true. However, ideally, we would prefer to have a prospectively conducted trial to address the issue, and one such trial is currently being conducted by the Eastern Oncology Group and the North American Breast Cancer Group, led by Vered Stearns, in women who are taking tamoxifen in the metastatic setting, and I would strongly urge investigators or physicians to participate in that trial, which, hopefully, will give us a better answer. Absent data from this latter study, I certainly would not recommend routine genotyping for women who are considering tamoxifen, although others disagree with me and continue to suggest it.

Optimal Sequence and Duration of Therapy

OncologySTAT: What is known at this point about the optimal sequence and duration of endocrine therapy in women with ER-positive breast cancer, and what is your personal approach?

Dr. Hayes: This depends on, first of all, their menstrual status and ovarian function. One thing that is very clear is that the aromatase inhibitors should not be given to women who have functioning ovaries or potentially functioning ovaries. So, in those patients, tamoxifen is clearly the drug of choice, unless one either takes the ovaries out or gives a GnRH agonist or antagonist to shut them off. And, even then, I believe, patients need to be monitored carefully because it is possible with an aromatase inhibitor that a patient can override a GnRH antagonist if they had previously had functioning ovaries. So, in a woman with currently functioning or potentially functioning ovaries, I think tamoxifen is the drug of choice, unless it is contraindicated (by, for example, a prior history of thrombosis).

In women who are clearly postmenopausal, I believe aromatase inhibitors are still controversial. Study after study has shown aromatase inhibitors to be slightly more effective than tamoxifen.⁴ There is a difference in side effects compared with tamoxifen, some which are overlapping, but some are quite different.

The long-term toxicities are also different, and, I think, most of us are most concerned about the risk of long-term bone effects—osteopenia, osteoporosis, and potential fractures. More recently, there has been a very slight signal that after long follow-up there may be a small increase in coronary artery disease associated with the aromatase inhibitors.

So, having said all of that, I believe if a postmenopausal woman has a relatively poorer prognosis (ie, node-positive disease or a larger tumor), a very small advantage of an aromatase inhibitor over tamoxifen is amplified because of the increased risk of an event, of a cancer event to begin with, and I would start that patient on an aromatase inhibitor.

In a patient with a relatively favorable prognosis, I don’t think it matters if an aromatase inhibitor or tamoxifen is used, and, in that case, I would try to sort out the patient’s most likely concern over toxicity. So, if I had a patient with a very high risk of venous or cerebral vascular thrombosis, I would go with an aromatase inhibitor because it doesn’t increase the risk of thrombosis, and tamoxifen does. If I had a patient with pre-existing osteoporosis, and especially a patient who is on a bisphosphonate and still has osteoporosis, then I might be inclined to go with tamoxifen over an aromatase inhibitor.

Finally, in terms of prolonged treatment, so-called prolonged adjuvant endocrine therapy, right now I think, for most patients, it’s tamoxifen for some period of time followed by an aromatase inhibitor. The BIG 1-98 study suggested that perhaps it might be preferable to go with an aromatase inhibitor first, and then switch over to tamoxifen.⁵ I tend to do the former, but I do have a few patients who I’ve treated with an aromatase inhibitor for a while and then switched over to tamoxifen. Part of that, sometimes, is because of the aromatase inhibitor–associated musculoskeletal syndrome, so-called AIMS, which is probably the single most important reason for patients’ discontinuation of an aromatase inhibitor. And, so not infrequently, they just struggle along for a couple of years with an aromatase inhibitor and finally say, “I can’t take this anymore.” In that case, I’ll switch over to tamoxifen, and I feel pretty comfortable doing that.

I think one of the issues, which was looked at in a randomized trial, which is completed but for which we’re still awaiting results, of prolonged aromatase inhibitor therapy vs 5 years and discontinuation, is whether we see either a substantial improvement in recurrence and death rates, or, conversely, a substantial increase in long-term toxicities. The results of that study might lead us to give an aromatase inhibitor for 5 years, and then switch to tamoxifen.

References

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of Chemotherapy and Hormonal Therapy for Early Breast Cancer on Recurrence and 15-Year Survival: An Overview of the Randomised Trials. Lancet. 2005;365(9472):1687-1717.
2. Rae JM, Drury S, Hayes DF, et al. CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients. J Natl Cancer Inst. 2012;104(6):452-460.
3. Regan MM, Leyland-Jones B, Bouzyk M, et al. CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women With Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial. J Natl Cancer Inst. 2012;104(6):441-451.
4. Dowsett M, Cuzick J, Ingle J, et al: Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen. J Clin Oncol. 2010;28(3):509-518.
5. BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer. N Engl J Med. 2009;361(8):766-776.
6. Fisher B, Dignam J, Bryant J, et al. Five Versus More Than Five Years of Tamoxifen for lymph Node-Negative Breast Cancer: Updated Findings From the National Surgical Adjuvant Breast and Bowel Project B-14 Randomized Trial. J Natl Cancer Inst. 2001;93(9):684-690.
7. Stewart HJ, Forrest AP, Everington D, et al. Randomised Comparison of 5 Years of Adjuvant Tamoxifen With Continuous Therapy for Operable Breast Cancer. The Scottish Cancer Trials Breast Group. Br J Cancer. 1996;4(2):297–299.
8. Goss PE, Ingle JN, Pater JL, et al: Late Extended Adjuvant Treatment With Letrozole Improves Outcome in Women With Early-Stage Breast Cancer Who Complete 5 Years of Tamoxifen. J Clin Oncol. 2008;26(12):1948-1955. Erratum in: J Clin Oncol. 2008;26(21):3659.
9. Mamounas EP, Jeong JH, Wickerham DL, et al: Benefit From Exemestane as Extended Adjuvant Therapy After 5 years of Adjuvant Tamoxifen: Intention-to-Treat Analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 Trial. J Clin Oncol. 2008;26(12):1965-1971.
10. Albain KS, Barlow WE, Shak S, et al: Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in Postmenopausal Women With Node-Positive, Oestrogen-Receptor-Positive Breast Cancer on Chemotherapy: A Retrospective Analysis of a Randomised Trial. Lancet Oncol. 2010;11(1):55-65.
11. Dowsett M, Cuzick J, Wale C, et al: Prediction of Risk of Distant Recurrence Using the 21-Gene Recurrence Score in Node-Negative and Node-Positive Postmenopausal Patients With Breast Cancer Treated With Anastrozole or Tamoxifen: A TransATAC Study. J Clin Oncol. 2010;28(11):1829-1834.
12. Paik S, Tang G, Shak S, et al: Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer. J Clin Oncol. 2006;24(23):3726-3734.
13. Mehta RS, Barlow WE, Albain KS, et al: Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer. N Engl J Med. 2012;367:435-444.

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