Approach to Endocrine Therapy in Breast Cancer—Part II

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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.

Early vs Late Recurrence

OncologySTAT: Would you talk about the data concerning risk of late recurrence in patients with ER-positive breast cancer after completion of long-term endocrine therapy?

Dr. Hayes: We’ve known for half a century that, in selective other cancers like colon or lung cancer, patients are either going to have a recurrence relatively quickly (in the first 5 to 6 years) or they’re cured.

This is not the case with breast cancer. Rather, we’ve seen a curious tail on the annual hazard for risk of recurrence stretching out many, many years—decades. My record is a patient who recurred about 35 years after her original diagnosis, and we could not find any primary cancer; and we’re certain that the recurrence was a metastasis from the original primary.

Over the last 2 decades, it’s become increasingly clear that this curious observation appears to be confined to patients with ER-positive breast cancer. ER-negative breast cancer appears to behave more like lung cancer, which is that it either recurs early or doesn’t recur at all. That’s not absolute, but is generally true.

Whereas the ER-positive patients have an early peak, which is dampened, if you will, by adjuvant endocrine therapy, and then a long-standing tail of 1% or 2% per year for many, many years of recurrence risk. Then, maybe, even a little secondary peak, or bubble, around 8 to 12 years out.

That observation has led to the concept that extended therapy could be worthwhile. Early trials of tamoxifen were 1 year vs nil and then 2 years vs nil and 5 years vs nil and 5 years vs 2 years, and, to make a long story short, in each of those cases, longer therapy appeared to be better than shorter therapy.

Though, neither of two randomized trials, one from National Surgical Adjuvant Breast and Bowel Project (NSABP)⁶ and one from Scotland,⁷ of more than 5 years of tamoxifen vs stopping at 5 years was positive for continuing tamoxifen. In fact, if anything, there appeared to be an increased risk of recurrence in women who continued tamoxifen, but not statistically so.

There are two much larger trials, which are also much less specifically designed, in which women were assigned to longer vs shorter therapy, but, for example, the definitions of “longer” and “shorter” are not nearly as precise as they were in the Scottish and NSABP trials. Neither of these have been conclusive. The authors have suggested that there is a benefit to be gained from a longer stretch of tamoxifen vs shorter, but many of us are not sure about that, and I still think that the optimal time for tamoxifen is 5 years.

That still leaves patients at risk for long-term recurrence downstream, and that goes back to extending therapy by, perhaps, giving 5 years of tamoxifen and switching over to an aromatase inhibitor for another 5 years, or giving 5 years of an aromatase inhibitor and then just continuing the aromatase inhibitor for more than 5 years, or giving 5 years of an aromatase inhibitor and then switching to tamoxifen for more than 5 years. Each of those is a reasonable approach. A couple of those have been addressed in clinical trials with tamoxifen followed by an aromatase inhibitor by both the North American Breast Cancer Group led by the Canadians and the NSABP.^8,9

The 5 years of an aromatase inhibitor followed by more aromatase inhibitor has been addressed in the clinical trial for which the results aren’t available, as I mentioned earlier. And, finally, 5 years of an aromatase inhibitor followed by tamoxifen has not been addressed, to my knowledge.

So, I think the second point is “who actually is at risk for late recurrence?” It’s certainly not everybody who gets to 5 years. A number of those patients are cured. And we really don’t have a way of identifying who is at risk and who should take extended adjuvant endocrine therapy.

It is very clear that prognosis at the original diagnosis does pertain to later risk of recurrence, but not nearly as much as it pertains to early risk of recurrence. It would be very nice if we had a way of evaluating patients who have gotten to 5 years or so and then determining their risk of subsequent relapse. Right now, that strategy just doesn’t exist. This is an area of enormous interest, and we’re going to see a number of research studies address it; but, right now, we don’t know much about it.

OncologySTAT: What are predictors of late vs early recurrence in ER-positive disease?

Dr. Hayes: Well, if by late vs early you mean early in the first 3 years vs after 5 years, there are methods to predict recurrence. One is the old-fashioned way, which is clinical and pathological staging (positive lymph nodes and the size of the tumor are clearly prognostic in terms of recurrence).

The second, more recently, has been the use of multigene assays that might provide prognostic information. Of those, I believe, the most widely accepted is the so-called 21-gene recurrence score; the brand name is Oncotype Dx. That assay, most of us feel, has been highly validated both analytically and clinically for use in node-negative ER-positive patients who will receive at least 5 years of endocrine therapy.

If those patients have a low recurrence score, they have such a favorable prognosis that, for example, the addition of chemotherapy cannot benefit more than a handful of patients, 2 or 3 at most, maybe 1 or 2, out of 100; therefore, most of us just don’t think chemotherapy is worth it in that group of patients.

If those patients have a high recurrence score that is greater than 31 (which was the value chosen), they are very likely to benefit from chemotherapy to the extent that it would outweigh the risk of side effects. Most of us would recommend chemotherapy for such a group. Then, in the intermediate-risk group, we don’t know what to do and we’re awaiting the results of the TAILORx trial, which has fully accrued, in which women who have node-negative ER-positive breast cancer all received endocrine therapy and were randomly assigned to chemotherapy vs not, and it will take a few years to get an answer for that.

What to do about node-positive disease is a different story. We and others have reported that the 21-gene recurrence score is indeed prognostic in women who have node-positive, ER-positive disease and only get tamoxifen (or others have reported an aromatase inhibitor), but the prognosis is not so favorable that one might withhold chemotherapy from this group.^10,11

However, there are now several studies, again, published by us¹⁰ and the NSABP¹² suggesting that, in addition to being prognostic, the 21-gene recurrence score may also be predictive of the relative effects of chemotherapy. It may just not work as well, or at all, in patients with low recurrence scores, and it may work quite well in women with high recurrence scores; so, if a patient is node-positive, her prognosis is still relatively poor compared with someone who is node-negative. But chemotherapy may not improve that prognosis if the patient has a low recurrence score. And that’s the subject of an ongoing prospective trial, the so-called RxPONDER trial. It’s being led by SWOG and being conducted in the North American Breast Cancer Group right now.

So, as for recurrence in the early setting, again, once a patient gets beyond 5 years, we really don’t have very good prognostic factors for later, and that is, as I said, an area of great research.

Combination Therapy

OncologySTAT:What about combining endocrine therapies?

Dr. Hayes: The issue of combining endocrine therapies has been around since the thought occurred of combining any therapy for any cancer. And, I think, historically it’s just interesting. Back in the 1950s, when Dr. Farber and Dr. Karnofsky were starting to do chemotherapy, they were giving it as a single agent, treating patients until they progressed, and, then, when they progressed, they would try some other agent. The good news is that those therapies worked in terms of reducing responses. The bad news is they rarely ever cured a patient.

And Drs. Frei, Freireich, and Zubrod wondered if maybe putting several drugs together at one time might affect the cancer cell in different ways, and it would never have a chance to recover and die. So, they came up with the concept of combination chemotherapy, and, sure enough, that led to not only remarkable responses, but cures rates which had not been seen before in childhood leukemia. Then Drs. DeVita and Young and others gave combination chemotherapy to patients with non-Hodgkin’s lymphoma and Hodgkin’s lymphoma; again, resulting in substantial cure rates. Dr. Einhorn and others then did the same in testicular cancer.

This established the concept that combination chemotherapy might cure diseases that were otherwise simply palliated with sequential single agents. Unfortunately, that concept for chemotherapy has really not transferred to the solid tumors—lung, colon, breast, ovarian, prostate. And, in spite of multiple trials testing sequential single-agent vs combination chemotherapy, so far, there has been little if any advance in overall survival in the metastatic setting.

In the adjuvant setting, we do use multiple chemotherapy agents because we’ve shown that, whether used sequentially or in combination, more than one drug is better than one drug alone.

That whole concept, then, was embraced by people who were studying endocrine therapy for breast cancer. Again, going back to the late 1970s, early 1980s, a number of investigators, both in England and in the United States, said, “How about if we used two endocrine therapies instead of one?” Combinations like tamoxifen plus megestrol acetate or tamoxifen plus ovarian suppression in premenopausal women; then, more recently, combinations like aromatase inhibition plus tamoxifen, and so on and so forth.

In the metastatic setting, in most of those trials, response rates are higher than sequential single-agent therapy. However, in very few of those trials is there any evidence of the survival benefit by giving two drugs at once as opposed to just giving them sequentially. And that, really, I think, led most of us to adopt giving sequential single-agent endocrine therapy in the metastatic setting, and certainly that’s what we’ve been doing as I’ve just discussed in the adjuvant setting.

Most recently, in SWOG, we conducted a trial led by Rita Mehta, in which postmenopausal ER-positive women with metastatic breast cancer were randomly assigned to an aromatase inhibitor, anastrozole, vs the selective estrogen down-regulator fulvestrant.¹³

That study was conducted from 2001 until about 2008, and then, with follow-up, was reported at last year’s San Antonio Breast Cancer Symposium and recently published in the New England Journal of Medicine. It showed not only an increase in response rate for the combination vs single agent, about which we’re excited, but actually showed a survival benefit.

But the survival benefit, interestingly enough, is almost entirely confined to women who have not had prior endocrine therapy in the adjuvant setting. And, curiously, about 40% of the patients in this study were patients who presented with what we refer to as de novo metastasis, meaning that they had not had a prior history of a primary cancer, which was treated, and then relapsed later; but, they actually walked in the door with their first presentation, both primary breast cancer and a metastasis.

Those data, however, are applicable to that select group of patients, which is not very common. The real issue is whether this observation would translate into the adjuvant setting or, perhaps, whether getting these two drugs together would be better than either one alone or in sequence.

Fulvestrant has not been studied in the adjuvant setting to a great extent, and there are no data to really suggest it should be used in the adjuvant setting right now. However, obviously, the results of the SWOG trial have led many investigators to wonder whether we should investigate it in the adjuvant setting, and, I suspect, there will be trials started in the near future to do so.

So, right now in the metastatic setting, I usually don’t combine endocrine therapies. We get higher toxicities with two drugs or two strategies vs one. And, for the average patient, I don’t believe there is a survival benefit, nor is there an obvious proven prolongation in terms of the time to when they start more toxic chemotherapy for palliation. So, I tend to use sequential single-agent endocrine therapy, but I certainly wouldn’t argue with a colleague who gives combined endocrine treatments. I don’t think there’s anything wrong with it; I’m just not sure that it’s any better.

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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