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PRIORITY PRESS - 36th Annual San Antonio Breast Cancer Symposium (SABCS)

San Antonio, Texas / December 10-14, 2013

San Antonio - Endocrine therapy is an important weapon in a clinician’s armamentarium against metastatic breast cancer (mBC). Several endocrine therapies are considered standard for hormone receptor-positive (HR+) postmenopausal women. Results from a recent landmark study demonstrate a significant treatment benefit for post-menopausal women at high risk of developing breast cancer.  A higher dose of an estrogen receptor antagonist treatment provides better disease control and IV therapy may offer advantages over oral treatment. Physicians need to balance the risks and benefits in selecting appropriate treatments. Recent data provides new insight into treatment options.  

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

As presented here, results from the International Breast Cancer Intervention Study II (IBIS-II) show that the oral drug anastrozole can reduce breast cancer incidence by 53% (P<0.0001) in postmenopausal women who are at high risk for developing breast cancer. The study involved nearly 4,000 high-risk, postmenopausal women, half of whom received daily anastrozole for five years and half who received placebo (Abstract S3-01).

“These results provide strong support for the use of anastrozole in high-risk postmenopausal women,” said Dr. Jack Cuzick, Lead Researcher, Head of the Centre for Cancer Prevention, Queen Mary University, London, UK.

Reconsidering First-Line Therapy

Anastrozole is not the only drug finding a new role in the war on breast cancer. Evidence is building that fulvestrant may move to front-line therapy. Fulvestrant, an estrogen receptor antagonist that has no agonist effects, is a once-monthly injection treatment approved for post-menopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC) who have progressed following anti-estrogen therapy. This drug was originally approved at the 250 mg dose, but after evidence from clinical trials suggested that a larger dose could improve outcomes, investigators launched CONFIRM. Presented at last year’s meeting, this phase III trial compared a 250 mg dose and a 500 mg dose of fulvestrant in patients with advanced breast cancer and demonstrated that the higher dose offered better disease control.

The final overall survival results from this trial were recently published in the Journal of the National Cancer Institute (2013 Dec. 7. Epub ahead of print). In total, 736 women were randomized 1:1 to receive either 500 mg or 250 mg on days 0, 14, and 28 and every 28 days thereafter. At the final analysis, 75.3% of the patients had died. The median overall survival was increased by 4.1 months with the higher dose (26.4 months vs. 22.3 months; hazard ratio, 0.81; P=0.02).

“The 500 mg dose was tolerated just as well as the 250 mg dose,” said Dr. John Robertson, Professor, Surgery and Head of the Division of Breast Surgery, University of Nottingham, England. “There are no extra side effects with the higher dose and that is pretty unusual for doubling a dose of an anticancer treatment.”

Based on these results, clinicians wondered whether fulvestrant could outperform aromatase inhibitors (AI) if moved earlier in the treatment paradigm. Results from the Phase II, multicenter FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) indicate that it can. This study randomized 205 women with advanced breast cancer to either fulvestrant (500 mg/month plus 500 mg on day 14 of month 1) or oral anastrozole (1 mg daily). At last analysis, when 75% of patients had discontinued therapy, the median time to progression was 23.4 months in the fulvestrant arm compared with 13.1 months in the anastrozole arm (HR, 0.66;
P=0.01) (Breast Cancer Res Treat 2012;136:503-511).

Oral vs. IV Therapy

The results above sparked FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer). Discussed at this year’s meeting (Abstract OT3-2-09), this phase III trial is pitting fulvestrant 500 mg against anastrozole 1 mg in postmenopausal women with HR+ locally advanced breast cancer or mBC who have not previously been treated with any hormonal therapy. The primary endpoint is progression-free survival (PFS). Investigators will also explore how tumor biomarker variations in DNA, RNA, and proteins may influence cancer development and/or response to treatment. As of November 2013, the study had enrolled 255 patients and was aiming for 450. The study is expected to be completed by September 2017.

“In the phase II study, the 500 mg dose of fulvestrant almost doubled the amount of control compared with the AI, which is a standard of care, and that led to the phase III trial,” said Dr. Robertson. “To prove in a larger number of patients that the initial findings hold up would change clinical practice, and the 500 mg dose would become the standard of care for hormone therapy.”

He pointed out that the two treatments were tolerated similarly and that while some patients prefer an oral drug, others prefer an injection. “Some patients prefer the injections. It lets them forget that they are in treatment, in the sense that it is once a month and they don’t have to take tablets,” said Dr. Robertson.

Backbone Therapy

While the FALCON researchers test the waters to improving first-line endocrine therapy, other investigators are looking to improve later lines of therapy with new investigational drugs combined with a fulvestrant backbone. Several posters discussed this approach.

A phase III trial is comparing the oral agent palbociclib plus 500 mg fulvestrant to palbociclib plus placebo in women with HR+, HER2-, mBC who have progressed on prior endocrine therapy. Some women will also receive goserelin. The accrual goal is 417 patients, and the primary endpoint is PFS. This study is supported by data from a phase II trial testing first-line letrozole with or without palbociclib in postmenopausal women with ER+, HER2- advanced breast cancer. Women receiving combination therapy had a longer PFS (26.1 vs. 7.5 months; hazard ratio, 0.37; P<0.001), and the combination was well-tolerated, with the most common adverse event being low-grade neutropenia.

“Fulvestrant 500 is the most active hormonal therapy in women who have failed prior hormone therapy, and was selected for this study on that basis,” explained Dr. Nicholas Turner, Royal Marsden Hospital, London, United Kingdom (Abstract OT3-2-10). “There is substantial evidence that palbociclib is active in hormone resistant breast cancer and will therefore work with fulvestrant to prolong disease control.”

Other trials tested exemestane- and letrozole-backboned therapies. A 120-patient phase II trial showed that compared with letrozole alone, letrozole plus dasatinib improved PFS by 10.2 months (20.1 vs. 9.9) in HR+, HER2-, postmenopausal mBC patients receiving first-line AI therapy (Abstract S3-7). “These findings suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy,” said Dr. Devchand Paul, Breast Oncologist, US Oncology and Rocky Mountain Cancer Centers, Denver, Colorado.

Options for Managing Endocrine Resistance

In the past two years, clinicians have had the opportunity to use everolimus for mBC patients with endocrine resistance. In 2012, everolimus was approved in combination with exemestane for patients with advanced HR+, HER2- negative breast cancer after recurrence or progression following letrozole or anastrozole. In the BOLERO-2 trial, everolimus plus exemestane increased PFS to 7.8 months compared with 3.2 months for exemestane alone. As presented here, investigators reported secondary endpoints of the BOLERO-2 trial (Abstract P2-16-17). Patients who received therapy with everolimus had a higher clinical benefit rate (51.3% vs. 26.4%) and objective response rate (12.6% vs. 1.7%). The results support combining everolimus with exemestane to elicit objective response and improve clinical outcomes in HR+, HER2- advanced breast cancer recurring/progressing on or after non-steroidal AI.

While everolimus is certainly a good option for this patient population, some clinicians see it more as a drug of last resort due to the toxicity. “Patients in the BOLERO-2 had many hormone treatments; more than half had received three or more agents,” said Dr. Robertson.  In BOLERO-2, 24% of patients experienced treatment-emergent adverse events that resulted in permanent discontinuation of everolimus.

According to Dr. Hope Rugo, Director, Breast Oncology Clinical Trials Program, University of California-San Francisco, toxicity can be a concern with everolimus. It can cause upfront stomatitis and delayed interstitial pneumonitis and for those with glucose intolerance, hyperglycemia can be an issue. “It is likely that many of these [mBC] patients will receive all of the drugs at some point,” said Dr. Rugo. “It is really a strategy of balancing efficacy versus toxicity.”

Summary

There are currently many drug options for patients with hormone-responsive mBC, and it is likely that options will increase in the future. Results from IBIS-II demonstrates effective treatment and provides new hope for post-menopausal women at high risk of developing breast cancer. With a number of breast cancer treatment agents to choose from, clinicians need to consider appropriate treatments by balancing risks and benefits.

PP