Extending hormonal therapy by 5 years provides no additional survival benefits over a 2-year extension in postmenopausal women with hormone-receptor positive (HR+) breast cancer, and the longer treatment interval was associated with a higher risk of bone fracture, a prospective, phase III study found.
At a median follow-up after randomization of 118.0 months (Interquartile range (IQR), 97.8-121.1 months), disease-free survival rates were virtually identical in the 2 groups at 73.6% in women who received an additional 2 years of aromatase-inhibitor therapy versus 73.9% for women who received an additional 5 years of the same treatment, at a hazard ratio (HR) for disease recurrence or death of 0.99 (95% CI, 0.85-1.15; P=0.90), Michael Gnant, MD, Medical University of Vienna, Vienna, Austria and colleagues reported in The New England Journal of Medicine.
On the other hand, the risk of clinical bone fracture at 5 years after randomization was 35% lower in the 2-year extension group at 4.7% compared to the 5-year extension group at 6.3% at a HR of 1.35 (95% CI, 1.00-1.84). The higher risk of fracture in the 5-year extension group occurred despite equal use of bone-targeted therapies in the 2 groups, the study authors noted.
“The specific goal of this trial was to assess the benefits and harms of extending aromatase-inhibitor therapy beyond a total treatment duration of 7 years in postmenopausal women,” Gnant and colleagues wrote. They concluded that there was no benefit of prolonged aromatase-inhibitor therapy in this patient population.
The Secondary Adjuvant Long-Term Study with Arimidex [anastrozole] (SALSA) initially enrolled 3,484 postmenopausal women with early stage (stage I, II, or III) HR+ breast cancer who had already received endocrine treatment for 5 years. None of the participants had evidence of disease recurrence on study entry and all women had received at least 5 years of adjuvant endocrine therapy with tamoxifen, aromatase inhibitors or both sequentially up until 12 months prior to randomization.
Women were assigned to receive oral anastrozole at a dose of 1 mg a day as extended treatment for either an additional 2 or an additional 5 years after randomization.
Median age at the time of study enrollment was 64 years; 77.3% of participants were positive for both estrogen and progesterone receptors, and almost 80% had been treated with breast-conserving surgery. Slightly over half at 51% had received tamoxifen alone for the initial 5 years; 7.3% had received an aromatase inhibitor alone, while 41.7% had received an aromatase inhibitor in combination with tamoxifen.
Two years after randomization, disease progression or death had occurred in 20.9% of patients in each treatment group, the investigators reported. “No between-group difference was noted for overall survival at 8 years,” they added—at 87.5% for the 2-year extension group compared with 87.3% for the 5-year extension group.
Subgroup analyses also did not show that any particular subgroup benefited more from anastrozole therapy in the shorter versus the longer treatment extension group. However, rates of serious adverse events (AES) related to anastrozole were lower at 2.3% in the 2-year extension group compared to 4% for the 5-year extension group, osteoarthritis being the most frequently reported AE at 1.7% in the 2-year group versus 4.3% in the 5-year group, investigators noted.
“A similar percentage of patients in the two trial groups discontinued extended anastrozole therapy over time,” investigators acknowledged—an observation that would very likely have been significantly more pronounced outside of a clinical trial. For example, approximately 20% of patients were no longer taking anastrozole within the first 2 years following randomization—a percentage that increased to roughly one-third by 5 years.
Landmark analyses of disease-free survival showed slightly better outcomes in patients who adhered to their treatment over the full study interval, but results were nevertheless similar between the 2 groups with respect to both disease-free and overall survival, the authors stressed.
“The effect of extended aromatase-inhibitor treatment on patients’ quality of life is not trivial, since musculoskeletal symptoms such as arthralgia and bone and joint pain frequently occur and these sequelae may persist for years,” Gnat and colleagues pointed out.
Others have reportedly complained of cognitive impairment, sexual dysfunction and weight gain while taking the same extended aromatase inhibitor treatment.
Thus, “it is evident that having these sequelae and being at risk or them for 3 additional years was a disadvantage for patients in the 5-year group,” the authors observed.
“[And e]ven though these side effects can be alleviated by pharmaceutical and lifestyle interventions, their occurrence often leads to a high rate of nonadherence to treatment,” they wrote.
Commenting on the findings, Pamela Goodwin, MD, University of Toronto, Toronto, Ontario, pointed out that findings from this prospective, phase III study are “consistent” with those of 2 earlier trials—Peer et al and Blok et al—that examined a longer versus a shorter duration of extended adjuvant aromatase-inhibitor therapy in women with HR+ breast cancer.
“[N]either trial showed a significant between-group difference in either disease-free or overall survival,” Goodwin pointed out.
“These results provide strong evidence against the routine use of more than 2 years of extended aromatase-inhibitor therapy in women who are at low or average risk, similar to those who were included in this trial,” she emphasized.
However, Goodwin also noted that women with HR+ breast cancer remain at an annual risk of breast cancer recurrence for at least 20 years after being diagnosed so new strategies are needed to improve late outcomes in patients with this specific type of breast cancer.
Among efforts that are currently being made to improve late outcomes is the use of assays of dynamic disease markers including circulating tumor cells and circulating tumor DNA, both being developed to detect and monitor minimal residual disease in this patient population, as the editorialist observed.
Similarly, the detection of circulating tumor cells by means of CellSearch technology in patients with HR+ disease 5 years after diagnosis has been associated with an increased risk of recurrence by a factor of 13 and a median time until clinical recurrence of 2.8 years.
“This interval may be sufficiently long that therapeutic intervention can prevent the development of incurable clinical metastases,” Goodwin suggested.
[But c]ontinued improvement in these assays and the development of new therapies that target the unique biological features of dormant cells will no doubt be required for a major reduction in late recurrence risk,” she acknowledged.
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Extending aromatase-inhibitor therapy for an additional 5 years did not improve disease-free or overall survival compared with an additional 2 years in HR+ breast cancer.
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Extending anastrozole therapy in HR+ breast cancer for an additional 3 years has the potential to significantly impair quality of life due to musculo-skeletal related side effects.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group.
Gnant reported consulting and/or lecture fees from Amgen, AstraZeneca, Daiichi Sankyo Company, Eli Lilly, LifeBrain, NanoString Technologies, Inc., Novartis, Sandoz, TLC, and TOLMAR, Inc.
Goodwin reported grants from the Breast Cancer Research Foundation and EPIC Sciences.
Cat ID: 22
Topic ID: 78,22,730,22,935,191,691,192,925
