Endocrine Therapy: An Important Treatment Limited by Major Challenges


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“Endocrine therapy remains the most effective and least toxic treatment for breast cancer, but we have many problems to solve. And there will have to be many different solutions,” according to George W. Sledge, MD, FASCO, Professor of Medicine and Chief of the Division of Oncology at Stanford University, who shared his thoughts on challenges related to endocrine therapy at the 2018 Miami Breast Cancer Conference.1

“Endocrine therapy is the systemic treatment that has saved the most lives of women with breast cancer, with the least toxicity and at the lowest expense of any cancer drug on the planet; however, it’s not universally effective. This leads to the question of how we can develop new approaches that will be even more effective and further reduce breast cancer mortality,” Dr. Sledge said. 


Endocrine therapy is the systemic treatment that has saved the most lives of women with breast cancer, with the least toxicity and at the lowest expense of any cancer drug on the planet; however, it’s not universally effective.
— George W. Sledge, MD, FASCO

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The biologic underpinnings of endocrine therapy involve a network that is much more complex than was recently believed. There is growing appreciation of the cross-talk between the estrogen receptor and other growth factor receptors and of the chain of molecular events leading from the membrane to the nucleus. The downstream effects include those related to the inhibition of cyclin-dependent kinase (CDK) 4/6. 

Our understanding of how endocrine therapy works “has gone in a fairly short time from being a very simple mechanism to being a very complex mechanism, with lots of bells and whistles, lots of on-and-off switches, all of which affect the response to treatment,” he said.

“The simple question now is, ‘What are the problems we are trying to solve as we develop new approaches to endocrine therapy?’” he said. “There are a number of issues that I think we need to solve, and in some cases we can solve them.”

According to Dr. Sledge, these issues are drug resistance, late recurrence, difficult drugs, and poor compliance to treatment—all separate, though interrelated, problems. 

Drug Resistance

The challenge of effectively fighting drug resistance is the problem is multifactorial, ie, “dozens” of mechanisms of resistance have been observed in the laboratory, for essentially all drugs, and to varying degrees in the clinic, he said. While the amount of preclinical data is “enormous,” it has been difficult to measure mechanisms of drug resistance in daily clinical experience, he said. 

Even those drugs that have been developed to overcome resistance to endocrine therapy—such as PI3 kinase and AKT inhibitors—are problematic themselves. They, too, are associated with significant toxicity because they inhibit critical functions within the body, and they also trigger new mechanisms of resistance.

“This is a real problem, and a fairly significant one, for which there is unlikely to be a single silver bullet,” Dr. Sledge -concluded. 

[Drug resistance] is a real problem, and a fairly significant one, for which there is unlikely to be a single silver bullet.
— George W. Sledge, MD, FASCO

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This challenge is being addressed through the development of novel therapeutics, including more selective PI3 kinase and AKT inhibitors, mammalian target of rapamycin antagonists, and combination therapy, at least preclinically. The ability to measure mechanisms of resistance in the clinic, for example, through circulating tumor DNA (ctDNA), holds promise as well. 

“We have pretty decent evidence,” he said, “to suggest that ctDNA is not bad at predicting resistance to endocrine therapy.” In the PALOMA-3 trial of palbociclib (Ibrance), PIK3CA levels above the median were associated with approximately a fivefold increased risk for the development of resistance to this CDK4/6 inhibitor within several months.2 Similarly, the detection of certain mutations via ctDNA assessment may predict for clinical progression in patients on aromatase inhibitors. One relatively consistent observation is the association between ESR1 mutation after treatment with the rapid onset of -resistance.

This points to the potential for a blood draw to reveal the emergence of resistance in real time, said Dr. Sledge, but whether this is beneficial in treating the patient is still an unanswered question. It is premature to apply this approach in the clinic, but this information may help in the development of novel, individualized approaches, he added. 

Late Recurrence 

“Late recurrence of estrogen receptor–positive breast cancer is, perhaps, the crucial issue in breast cancer today,” Dr. Sledge continued. “Since we can cure these patients, improvements in the adjuvant setting are most likely to have the biggest bang for our buck going forward. But if we look at what actually happens to patients with estrogen receptor–positive breast cancer, we see a continuing risk of late relapse that never goes away.” 

ENDOCRINE THERAPY CHALLENGES

  • Endocrine therapy is the most effective and least toxic treatment for breast cancer, but it poses challenges that need to be overcome.
  • The major challenges are drug resistance, late recurrence, painful injection (with fulvestrant), and lack of compliance.
  • Novel agents in development may help address some of these issues. 

A recent landmark study found that tamoxifen-treated patients continued to relapse 20 years later at the same rate they relapsed at 10 years.3 “This represents a crucial problem for us in terms of dealing with patients with estrogen receptor–positive breast cancer,” he commented. “This is an issue many of us are thinking about now, for which we don’t yet quite have a solution.”

Earlier detection of late recurrences may allow for prompt intervention; better molecular characterization could lead to better therapeutics; and clinical trials dedicated to this problem could provide some solutions. For example, patients with circulating tumor cells could be randomized to treatment with a CDK4/6 inhibitor or placebo. In fact, a study presented by Sparano et al at the 2017 San Antonio Breast Cancer Symposium, of 353 patients with estrogen receptor–positive disease at 5 years or more post diagnosis, showed that the presence of ctDNA was associated with a 21-fold increased risk of recurrence in less than 2 years.4 

Difficult Drugs

There are a number of oral selective estrogen receptor degraders (SERDs) now in development that could have advantages over fulvestrant (Faslodex). While fulvestrant “does not pose much of a biologic problem,” it has proven to be difficult to administer in the clinic, according to Dr. Sledge. 

“Fulvestrant is a great drug, but ‘Ouch!’” he commented. “It is simply not a drug that anyone likes very much, and despite the fact that it may well be the most active single agent we have for metastatic estrogen receptor–positive breast cancer, it’s a drug that has never made it into the adjuvant setting. Indeed, the idea of a healthy woman coming in every month for 5 or 10 years for an injection of 5 mL of viscous fluid in each buttock is probably unrealistic.” 

Several of the oral SERDs in development show early evidence of activity in patients with ESR1 mutations and in fulvestrant-resistant patients. Although the biology of these effects needs to be further explored, “there is great excitement around the development of such agents,” he said. 

The new oral SERDS are being studied, for example, in the following ongoing trials:

  • Oral SERD vs fulvestrant in either a first- or second-line setting
  • Oral SERD following treatment with fulvestrant
  • Oral SERD plus CDK4/6 inhibitor vs aromatase inhibitor plus CDK4/6 inhibitor. 

Compliance

“Lack of compliance is one of the great problems in estrogen receptor–positive breast cancer but one that is rarely discussed in meetings such as this,” he continued. 

Two phase III trials that examined extended adjuvant aromatase inhibitor therapy—DATA5 and IDEAL6—both showed a consistent drop-off in compliance over a 5-year period. “Perhaps 35% to 40% of patients will stop a therapy that’s potentially life-saving,” he said. “Why? Well, in some areas it’s related to the financial toxicity of these agents, particularly for patients of lower socioeconomic status. In some areas, it’s an access issue. Patients don’t actually have an oncologist telling them they need to take this drug. Apparently, we need to improve patient education, and I would also argue, perhaps physician education in this regard. Most importantly, we need to learn how to deal with the side effects.” ■

DISCLOSURE: Dr. Sledge is on the scientific advisory board of Radius Pharmaceuticals (which has an oral selective estrogen receptor degrader in development) and Syndax Pharmaceuticals (histone deacetylase inhibitor in development for estrogen receptor–positive breast cancer).

REFERENCES

1. Sledge GW: New endocrine approaches in breast cancer: How best to develop them. 2018 Miami Breast Cancer Conference. Presented March 10, 2018.

2. Rugo HS, Diéras V, Gelmon KA, et al: Impact of palbociclib plus letrozole on patient-reported health-related quality of life. Ann Oncol 29:888-894, 2018

3. Pan H, Gray R, Braybrooke J, et al: 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years.  N Engl J Med 377:1836-1846, 2017

4. Sparano JA, O’Neill A, Alpaugh K, et al: Circulating tumor cells 5 years after diagnosis are prognostic for late recurrence in operable stage II-III breast cancer. 2017 San Antonio Breast Cancer Symposium. Abstract GS6-03. Presented December 8, 2017.

5. Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, et al: Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA). Lancet Oncol 18:1502-1511, 2017.

6. Blok EJ, van de Velde CJH, Meershoek-Klein Kranenbarg EM, et al: Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy: Results of the randomized phase III IDEAL trial (BOOG 2006-05). 2016 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 7, 2016.


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