Women with hormone-sensitive breast cancer face years of adjuvant therapy with antiestrogen drugs, with the latest data suggesting that these drugs should now be taken for 10 years instead of the previously recommended 5 years.
A decade of taking an antiestrogen therapy is a lot to ask.
So a new study suggesting that taking a temporary drug holiday is safe is welcome news.
The results come from the Study of Letrozole Extension (SOLE) and show that after 4–6 years of initial endocrine therapy the clinical benefits of intermittent or continuous dosing of letrozole were similar.
Women in the intermittent dosing group took a ‘drug holiday’ of 3 months off therapy for 4 years (in years 6–9 of the decade), after completing 5 years of continuous therapy (year 1–5) and finishing off with a year of continuous therapy (year 10).
SOLE was published online November 17 in Lancet Oncology.
The investigators, led by Marco Colleoni, MD, from the International Breast Cancer Study Group in Milan, Italy, conclude that the study results on “intermittent administration [of letrozole] provides clinically relevant information about extended adjuvant endocrine therapy with letrozole and support the safety of this option for temporary treatment breaks in select patients who may require them.”
SOLE can be regarded as a “planned nonadherence study,” say V Craig Jordan, OBE, PhD, DSc, and Balkees Abderrahman MD, from the department of breast cancer oncology at the University of Texas MD Anderson Cancer Center, Houston.
“The pauses in SOLE [drug holidays] are an advantage to patients because they create improvements in their quality of life,” the pair write in a commentary published online November 16 in JAMA Oncology.
“The women receiving intermittent letrozole therapy could be viewed as women noncompliant to treatment,” Dr Jordan commented to Medscape Medical News.
Nonadherence to endocrine therapy has been a challenge in the clinical management of these patients, Dr Jordan acknowledged.
The results from SOLE suggest that women noncompliant to extended antiestrogen therapy should be urged to resume therapy. “They still stand to gain from therapy even after the drug holiday,” he said.
SOLE Results
SOLE was a multicenter study conducted in 4884 postmenopausal women with node- and hormone-receptor positive, early breast cancer who had remained relapse free after 4–6 years of adjuvant antiestrogen therapy. During that time, they had been taking an aromatase inhibitor (42%), a selective estrogen receptor modulator (SERM) such as tamoxifen (18%), or a sequential combination of both (40%).
After the 4–6 year period of endocrine therapy, all women were given letrozole, but took the drug according to one of two schedules.
Women in the continuous group (n = 2441) received letrozole 2.5 mg/day for 5 years.
Women in the intermittent group (n = 2443) received letrozole 2.5 mg/day orally for the first 9 months followed by a 3-month break in therapy during years 1 through 4, and then continuous letrozole for another 12 months.
After a median 60 months’ follow-up, 5-year disease-free survival was similar between groups: 85.8% for the intermittent group and 87.5% for the continuous group.
Distance recurrence was also similar: 7% for each group.
So was the percentage of patients free from distant recurrence at 5 years: 93.2% for the intermittent group and 92.5% for the continuous group.
Five-year overall survival was 94.3% for the intermittent group and 93.7% for the continuous group.
Intermittent letrozole users did not show significant improvement in disease-free survival compared with continuous letrozole users, as had been expected from animal models, the researchers note.
“This may be partly related to the short period of interruption of letrozole use chosen,” the SOLE investigators write. In addition, the follow-up of 60 months, which is ongoing, may not have been long enough, they comment.
Less Worsening of Quality of Life With Intermittent Dosing
At the time of analysis, 70% of women had stopped treatment. Patterns of permanent discontinuation were similar across the intermittent and continuous groups for adverse events (14% vs 15%) and patients’ decision (7% vs 6%).
Adverse events were as expected for letrozole and similar between the two groups. The most common grade 3–5 adverse events were (intermittent vs continuous): hypertension (24% vs 21%), arthralgia (6% for each group), CNS cerebrovascular ischemia (1% for each group), CNS hemorrhage (< 1% for each group), and cardiac ischemia (1% for each group).
The researchers note that patient-reported symptoms and quality-of-life changes were small between groups, but less worsening was consistently reported in the intermittent group.
Women in the intermittent group reported significantly less worsening of vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being, and mood, and a significant improvement in hot flashes, they note.
Although intermittent letrozole use was associated with an improvement in patient-reported outcomes and quality-of-life measures, the SOLE investigators point out that only 20% of patients were selected to participate in this analysis; therefore, the results may not be generalizable.
However, given that adherence rates for letrozole were similar between groups, the findings of SOLE support “the feasibility of extended treatment with aromatase inhibitors through different schedules, including intermittent administration,” they add.
They also point out that given the current recommended 10 years of endocrine therapy, an intermittent dosing schedule may be cost effective.
“The intermittent use of letrozole might be an attractive approach considering the reduced economic cost and spared resources of 12 fewer months of treatment during interruptions, possibly improving existing socioeconomic disparities in patients with breast cancer,” they write in their discussion.
Study Limitations
Several limitations of SOLE are highlighted in an accompanying commentary in Lancet Oncology by Rowan T Chlebowski, MD, PhD, of the department of medical oncology and therapeutics research at the City of Hope National Medical Center, Duarte, California, and Kathy Pan, MD, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
“Findings from the SOLE trial present new evidence regarding use of extended duration of endocrine adjuvant therapy, but inclusion of previous tamoxifen users complicates interpretation of these findings,” they write.
They also voice caution over the study criteria used for postmenopausal status. In addition to women 55 years or younger with biochemical evidence of postmenopausal status, the study included women of any age who had bilateral oophorectomy and were amenorrheic for longer than 3 months.
This may be a problem, they suggest, as it “describes current ovarian function but not future ovarian status, especially in the setting of aromatase inhibitor use, which itself can stimulate ovarian function,” they write.
Dr Chlebowski and Dr Pan suggest that based on the biochemical criteria used to define postmenopausal status, some patients who were previous tamoxifen users “might have regained ovarian function with or without resuming menses.”
“Premenopausal estrogen concentration would then probably preclude any letrozole anticancer effect in either randomization group,” they explain.
“Such an outcome could explain a null effect but not a detrimental effect for intermittent letrozole use,” they suggest.
A New Idea: Pre-emptive Strike
Now that SOLE has established the idea of taking a short ‘drug holiday’ from extended adjuvant therapy, there is a bold proposal for how to take advantage of this.
“The pause in adjuvant therapy proven to be safe in SOLE can now be used as a therapeutic window to treat high-risk patients,” Dr Jordan and Dr Abderrahman write in their commentary.
The women in the intermittent letrozole group had 3 months off therapy in years 6–9 of the decade-long treatment.
For women at high risk of breast cancer recurrence, this break in antiestrogen adjuvant therapy offers a window during which to use other drugs
Breast cancer recurrences are due to micrometastases, Dr Jordan explained in an interview with Medscape Medical News.
“We can kill micrometastases with short intervals of sharp precision medicines,” Dr Jordan said. But as to which agents could be used as pre-emptive salvage therapy, he said “we have to work on that.”
“It is all about tumor burden,” he explained. “The low tumor burden of micrometastatic disease in the adjuvant disease setting suggests preemptive strikes with a cocktail of antiestrogens along with precision medicines such as palbociclib [Ibrance, Pfizer] or everolimus [Afinitor, Novartis],” he said. Both agents have been approved for the treatment of women with HR+, HER2-negative metastatic breast cancer — each in combination with antiestrogen therapy.
“The traditional model of long-term combination with adjuvant therapy will not need to be tested,” Dr Jordan and Dr Abderrahman write. “Adherence will be ensured because in the new strategy [that they are proposing], the duration of preemptive salvage therapy is only 3 months,” they add.
The way forward, they propose, is to include affordable, intermittent short bursts of salvage therapy within the extended period of adjuvant antiestrogen therapy.
In their commentary, Dr Jordan and Dr Abderrahman state that they hope in the future, “an integrated cytotoxic cocktail of precision medicines will allow the majority of patients with ER [estrogen receptor]-positive breast cancer to live the natural course of their lives.”
SOLE was funded by Novartis and the International Breast Cancer Study Group. Disclosures for the SOLE investigators are listed in the publication. Dr Chlebowski reports receiving speaker’s fees and honoraria from AstraZeneca, Novartis, and Genentech, and honoraria for advisory boards and consulting from AstraZeneca, Novartis, Pfizer, Genentech, and Amgen. Dr Jordan and Dr Abderrahman have reported no relevant financial relationships.
Lancet Oncol. Published online November 17, 2017. Abstract, Comment
JAMA Oncol. Published online November 16, 2017. Invited commentary
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