Three Experts Examine the ER-Positive Treatment Landscape

Joanne L. Blum, MD

The management of patients with hormone receptor (HR)-positive breast cancer continues to evolve, with phase III studies shedding light on the length of adjuvant antiestrogen therapy, a novel treatment gaining approval, and new trials exploring combination strategies.

With the evolution of treatment under way, OncLive interviewed three world-renowned experts in the field: Joanne L. Blum, MD, PhD, Adam M. Brufsky, MD, PhD, and Harold J. Burstein, MD, PhD.

“We’re now entering the area of truly targeted agents. We have things like palbociclib. We have everolimus. We really have an enormous amount of things,” said Brufsky, co-director of the Comprehensive Breast Cancer Center at the UPMC Cancer Centers and the University of Pittsburgh. “I think that our issue is that, with such a wealth of choices, it really becomes fairly complicated to figure out the right therapy for the right patient.”

Adjuvant Therapy Duration Enumerated

Traditionally, a 5-year regimen of adjuvant tamoxifen was utilized following surgery for women with early-stage breast cancer. However, results from the phase III ATLAS and aTTom studies demonstrated that extending the duration of adjuvant tamoxifen therapy from 5 to 10 years further reduced the risk of recurrence and breast cancer mortality.^1,2

“There were two trials that came forward in the past couple of years that looked at 10 years versus 5 years,” explained Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor at Harvard Medical School. “With a very long follow-up, they showed a small but real survival advantage and a reduction in the chance of breast cancer recurrence with the longer duration.”

In the ATLAS trial, patients who continued tamoxifen for 10 years had a 12.2% risk of dying due to breast cancer versus 15% for those who had 5 years of treatment, and the rate of recurrence was 25% less with the longer course of treatment. In the aTTom study, women continuing tamoxifen for 10 years had a 25% lower recurrence rate and a 23% lower breast cancer mortality rate compared with those who stopped at 5 years.

Based on these studies, ASCO updated its clinical practice guideline to recommend treatment with adjuvant tamoxifen for 10 years in women with stage I-III HR-positive breast cancer. However, there are still many factors to consider when assessing the duration of adjuvant therapy, including tumor burden, tumor biology, comorbidities, and age.

In older patients with small, node-negative disease, it is prudent to administer tamoxifen for 5 years, Brufsky noted. However, in younger patients with several positive nodes, there is an impetus for longer treatment.

“I think it’s important to note that you really have to balance the patient’s risk,” said Brufsky. “What’s really interesting is that there’s a number of genomic assays right now that are coming to the plate that may help us kind of select people based on their prognosis.”

One of the tests available, the Breast Cancer Index, provides a prediction for the risk of recurrence at various time points, noted Brufsky. This tool reports on the probably of early recurrence (0-5 years), late recurrence (5-10 years), and overall recurrence (0-10 years). Additionally, the test provides information on the likelihood of benefit from extended endocrine therapy.

“Tamoxifen isn’t totally benign,” Brufsky added. “There is going to be a certain rate of endometrial cancer, a certain small rate of blood clots. That’s the tradeoff—a lowered risk of recurrence but a slightly increased rates of those two complications.”

Adding to the question of duration, the TEXT and SOFT stud- ies demonstrated that adjuvant ovarian function suppression (OFS) plus exemestane or tamoxifen reduced the relative risk of developing subsequent invasive cancer.

In the SOFT trial, which was presented at the 2014 San Antonio Breast Cancer Symposium (SABCS), adding tamoxifen to OFS reduced the risk of disease recurrence by 22% versus tamoxifen alone (HR = 0.78; 95% CI, 0.60-1.02).³ Further benefit was observed with exemestane, which reduced the risk of recurrence by 35% when combined with OFS versus treatment with standard tamoxifen (HR = 0.65; 95% CI, 0.49-0.87).

Similarly, in a joint analysis of the SOFT and TEXT trials, exemestane plus OFS reduced the relative risk of recurrence by 34% compared with tamoxifen plus OFS, according to findings presented at the 2014 ASCO Annual Meeting.⁴ Cancer-free survival at 5 years was 91.1% in the exemestane arm compared with 87.3% in the tamoxifen arm. Similar 5-year overall survival rates occurred in both arms, with a 95.9% survival with exemestane compared with 96.9% with tamoxifen.

Frontline Therapy for Advanced Disease

The treatment of patients with HR-positive metastatic breast cancer is complicated, with several agents approved. Traditionally, the selection of frontline therapy for women with estrogen receptor (ER)-positive advanced breast cancer depends on many factors, such as disease burden and the duration of a patient’s disease-free interval from the original diagnosis.

“If the patient has extensive lung or liver metastatic disease, treatment decisions even in the ER-positive setting will be quite different versus a patient with bone only or bone lymph node, or bone soft tissue lymph node, long pleural disease,” said Blum, a medical oncologist at the Texas Oncology-Baylor Charles A. Sammons Cancer Center. “It’s a bit of a complicated decision and it’s clearly not a one-size-fits-all type of approach, especially in ER-positive disease.”

In most situations, hormone therapy is administered as an initial treatment for postmenopausal patients with ER-positive newly diagnosed metastatic breast cancer. This treatment is particularly beneficial if the patient has not received adjuvant antiestrogen therapy or has been off antiestrogen therapy for longer than 1 year.

“For ER-positive breast cancer, we almost always want to go with endocrine therapy as our initial treatment,” said Burstein. “It’s unusual that a patient would need chemotherapy as their first treatment for ER-positive metastatic disease.”

A variety of endocrine treatment options exist, including tamoxifen or an aromatase inhibitor (AI). In many situations, the therapy utilized upfront in the advanced or metastatic setting can be customized based on the treatment received in the adjuvant setting.

The question of which hormonal therapy makes the best frontline treatment has been the topic of multiple studies. Recently, results from the phase II FIRST trial, presented at the 2014 SABCS, demonstrated that frontline treatment with fulvestrant could be superior to anastrozole at prolonging overall survival.⁵

In this analysis, fulvestrant improved overall survival (OS) by 5.7 months compared with anastrozole as a frontline treatment for postmenopausal women with HR-positive metastatic breast cancer. The median OS was 54.1 months with fulvestrant compared with 48.4 months with anastrozole (HR = 0.70; 95% CI, 0.50-0.98; P = .041).

“Typically in patients who have already had an aromatase inhibitor, we reach for fulvestrant as our initial first line of therapy,” Burstein said. “In patients who’ve had tamoxifen, we would use an aromatase inhibitor as first-line treatment.”

Traditionally, hormonal therapy has been administered as a single agent. However, clinical trials have sought to combine treatment options, including antiestrogens with AIs and AIs with novel agents, such as cyclin-dependent kinase (CDK) 4/6 inhibitors. In a phase III trial conducted by SWOG, the combination of anastrozole and fulvestrant demonstrated an improvement in survival.⁶

Patients in the combination group experienced a median progression-free survival (PFS) of 15.0 months compared with 13.5 months in the anastrozole-alone group (HR = 0.80; 95% CI, 0.68-0.94, P = .007). The combination group also experienced a higher median OS of 47.7 months compared with 41.3 months in the anastrozole-alone group (HR = 0.81; 95% CI, 0.65-1.00, P = .05).

In the phase III SoFEA trial, fulvestrant plus anastrozole or placebo was compared with exemestane alone for postmenopausal patients with HR-positive breast cancer who progressed on nonsteroidal AIs.⁷ This study failed to show an advantage for the combination over single-agent fulvestrant or exemestane.

“In women who are a long way out from their original breast cancer diagnosis or who have had minimal treatment previously, it does look like the combination of an aromatase inhibitor with fulvestrant gives results that are a little bit better than just one of those drugs alone,” Burstein said. “In that small patient population who are many years removed from their original diagnosis or have de novo ER-positive metastatic disease, I do sometimes go with that combination.”

In the frontline setting, treatment with an endocrine therapy plus the CDK 4/6 inhibitor palbociclib recently gained FDA approval, based on data from the PALOMA-1 trial. This option is set to become a standard frontline treatment for many patients with ER-positive advanced breast cancer, Blum suggested.

In the open-label phase II PALOMA-1 study, treatment with palbociclib plus letrozole reduced the risk of disease progression by 51% compared with letrozole alone. The median PFS with palbociclib was 20.2 months versus 10.2 months for letrozole alone (HR = 0.488; P = .0004).⁸

Other Frontline Considerations

Treatment with upfront chemotherapy may be warranted in patients with highly proliferative, liver-predominant, extensive visceral disease, said Blum. However, in patients with less symptomatic breast cancer with a limited burden of disease, endocrine therapy can be administered for a longer duration.

“In a patient with a large burden of disease, visceral-predominant, ER-positive particularly, my first combination therapy is often paclitaxel and capecitabine,” Blum explained. “There are other combinations that one can use in that setting as well, but that’s my go-to regimen.”

In addition to endocrine or cytotoxic therapy, there is a need to consider bone health in patients with metastatic breast cancer. The primary therapies used to prevent skeletal-related events in these patients are zoledronic acid and denosumab. Each therapy comes with a unique set of pros and cons.

“The vast majority of women who present with ER-positive metastatic breast cancer will also have bone metastases,” said Brufsky. “They’ll need some sort of bone agent to protect the bone, prevent fracture, and other skeletal-related events.”

Second-Line and Beyond

Second-line treatment selection is often guided by the response to frontline therapy. Following progression on an AI, an antiestro- gen such as fulvestrant can be administered. For patients who develop endocrine therapy resistance, adding the mTOR inhibitor everolimus could offer additional benefits, suggested Blum.

In the BOLERO-2 trial, the combination of everolimus and exemestane was examined following progression on front- line therapy.⁹ Among participants in this trial, prior therapies included letrozole or anastrozole (100%), chemotherapy (68%), tamoxifen (48%), and fulvestrant (16%).

In the phase III trial, PFS was significantly extended for pa- tients with HER2-negative, ER-positive metastatic breast cancer who received treatment with everolimus plus exemestane versus exemestane alone. The median PFS by local investigator assessment was 6.9 months with everolimus plus exemestane compared with 2.8 months with exemestane alone (HR = 0.43; P <.001). The overall response rate by local assessment was 9.5% in the combination arm versus 0.4% with exemestane alone.

While this approach offers benefits for patients who develop resistance to endocrine therapy, Blum suggested a different approach for patients who progressed after AI treatment was halted.

“For a patient who relapsed after a period of time off an aromatase inhibitor, one could come back in with an aromatase inhibitor, particularly if the patient had tolerated therapy well,” Blum said.

In addition to hormonal therapy with or without everolimus, several chemotherapy regimens are available. Chemotherapy regimens containing cyclophosphamide, doxorubicin, and docetaxel are commonly administered; additionally, monotherapy with capecitabine, ixabepilone, paclitaxel, nab-paclitaxel, and eribulin has shown promise.

“In terms of chemotherapeutic agents, we’ve gone from just simply having anthracyclines to now the taxanes, which are all generic,” Brufsky said. “We have new formulations of taxanes such as nanoparticle paclitaxel and agents like eribulin that we’ve never had before. Capecitabine, ixabepilone, and new uses of gemcitabine.”

Capecitabine was the first oral chemotherapy to gain approval as a treatment for breast cancer in 1998. This agent quickly became the standard of care across many settings, for its ease of administration, efficacy, and side effect profile. Recently, eribulin has attempted to supplant capecitabine as the first-line chemotherapy of choice.

“Eribulin has activity in both ER-positive as well as ER- negative disease. It’s very well tolerated. It has very minor side effects, quite honestly—mild neutropenia, mild cytopenias, mild neuropathy, some alopecia but not much,” explained Blum. “For a patient who has progressed despite an anthracycline and a taxane, it’s the next obvious choice to use in that setting.”

In addition to these trials, a phase III study compared eribulin with capecitabine as a treatment for patients who had received fewer than three prior therapies.¹⁰ The median OS was 15.9 months for eribulin compared with 14.5 months for capecitabine (HR = 0.879; 95% CI, 0.770- 1.003; P = .056) and the median PFS was 4.1 months and 4.2 months, respectively (HR = 1.079; 95% CI, 0.932-1.250; P = .305).

Interestingly, subgroup analysis suggests that eribulin was superior to capecitabine in patients with HER2-negative, ER- negative, or triple-negative breast cancer.

“Eribulin is a valuable drug, it’s FDA-approved for the treat- ment of refractory breast cancer. We use it in a lot of different contexts,” explained Burstein. “We’re actually doing a study of using eribulin earlier in the management of the disease. In the trial, we’re using the standard dose of eribulin in first- or second-line treatment of ER-negative breast cancers. And so hopefully we’ll have some more experience with it in that setting.”

References

1. Davis C, Hongchao P, Godwin J, et al. ATLAS. 10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease: effects on outcome in the first and in the second decade after diagnosis. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S1-2.
2. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 in 6,953 women with early breast cancer. J Clin Oncol. 2013;31 (suppl; abstr 5).
3. Francis PA, Regan MM, Fleming GF, et al. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): analysis of the SOFT trial. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract S3-08.
4. Pagani O, Regan MM, Walley B, et al. SOFT and TEXT Investigators and International Breast Cancer Study Group. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT. Presented at: 2014 American Society of Clinical Oncology Annual Meeting. Abstract LBA1.
5. Robertson JFR, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: overall survival from the phase II ‘first’ study. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S6-04
6. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer [published online ahead of print August 2, 2012]. N Engl J Med. 2012; 367(5): 435-444.
7. Johnston SR, Kilburn LC, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial [published online July 29, 2013]. Lancet Oncol. 2013;14(10):989-998.
8. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor- positive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): a randomised phase 2 study [published online December 15, 2014]. Lancet Oncol. 2015; 16(1):25-35.
9. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer [published online ahead of print December 7, 2011]. N Engl J Med. 2012;366(6):520-529.
10. KaufmanPA,AwadaA,TwelvesC,etal.AphaseIII,open- label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S6-6.

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