Two Studies Indicate Potential Predictors of Survival Benefit from Endocrine Therapy 


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Two studies published in Journal of Clinical Oncology indicate that treatment-related symptoms and mammographic density reduction may predict whether a woman with hormone receptor–positive breast cancer will benefit from adjuvant endocrine therapy. In one study, women who had specific adverse events, particularly vasomotor symptoms, during their first year of endocrine therapy had improved disease-free and overall survival. In the other study, women who had a relative mammographic density reduction of more than 20% between baseline and the first-follow-up mammogram had a 50% reduced risk of death as a result of breast cancer.

An editorial accompanying the two articles points out that a “patient might be more willing to tolerate” the considerable side effects of endocrine therapies “if she knows that she is obtaining benefit from the medication.”

Specific Adverse Events

The International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis investigated the relationship between survival outcomes and specific adverse events among 9,325 patients participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial, a randomized, phase III trial conducted in nine countries including the United States. Participating patients were postmenopausal women with estrogen receptor– and/or progesterone receptor–positive breast cancer eligible for adjuvant endocrine treatment.

“Patients were randomly assigned to receive either exemestane 25 mg once daily for 5 years or tamoxifen 20 mg once daily for 2.5 to 3 years, followed by exemestane 25 mg once daily for 2.5 to 2 years (sequential regimen),” the researchers reported.

The analysis included all adverse events reported in the first year of adjuvant endocrine therapy. Vasomotor symptoms were defined as “a subjective and transient sensation of heat, including hot flashes and night sweats.” Musculoskeletal adverse events “were all accounts of arthralgia, arthritis, arthrosis, myalgia, and bone pain.” Osteoporosis was not considered a musculoskeletal adverse events “due to the fact that osteoporosis is a long-term process, likely to take more than 1 year to become evident,” the investigators explained. Vulvovaginal symptoms included “all accounts of vaginal dryness/itching, vaginal discharge, dyspareunia, and endometrial and libido disorders.”

Patients with specific adverse events vs those with nonspecific or no adverse events had better disease-free survival and overall survival. “The strongest effect on distant recurrence and survival outcomes was reported for [vasomotor symptoms]. A decreasing incidence of distant metastases, disease relapse, and death was noted in patients reporting increasing numbers of different specific [adverse events],” the researchers wrote.

Multivariate hazard ratios for disease-free survival were 0.731 for vasomotor symptoms, 0.826 for musculoskeletal adverse events, and 0.769 for vulvovaginal symptoms. Multivariate hazard ratios for overall survival were 0.583 for vasomotor symptoms, 0.811 for musculoskeletal adverse events, 0.570 for vulvovaginal symptoms. “Outcomes were unrelated to treatment allocation,” the researchers stated.

“Although our results must be considered hypothesis generating, our findings show an association between specific adverse effects caused by endocrine therapy and outcomes and may thus potentially be a valuable predictor and biomarker of treatment efficacy,” the investigators concluded. “Future prospective studies, however, are warranted to advance the personalization of treatment strategies for patients with breast cancer.”

Mammographic Density Reduction

Tamoxifen recipients who had a relative density reduction of more than 20% between baseline and first follow-up mammogram showed a 50% reduced risk of breast cancer–related death (hazard ratio = 0.50; 95% CI = 0.27–0.93) compared with women who had stable mammographic density, according to results of a population-based case-control study in Sweden.

The study involved 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up mammogram. “On the basis of treatment information abstracted from medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic density was measured by using an automated thresholding method and expressed as absolute dense area,” the authors explained. “Change in mammographic density was calculated as percentage change from baseline.”

During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. “In the tamoxifen-treated group, 35% of the women who died as a result of breast cancer had a reduction of [dense area] of 20% or more compared with 48% in women who did not die as a result of breast cancer (P = .017),” the investigators noted. “Among women treated with tamoxifen who experienced a decrease in [dense area] of 20% or more, the relative risk of death was 0.50 [95% CI = 0.27–0.93] compared with that of women treated with tamoxifen who had stable mammographic density.” The relationship between mammographic density change and survival did not reach statistical significance, but a trend for improved survival was seen with a decrease in dense area, the researchers noted.

The association of mammographic density reduction with better long-term breast cancer–specific survival being found only in the tamoxifen group suggests that a change in dense area “could be a convenient biomarker for tamoxifen therapy response,” the investigators concluded. “If validated, mammographic density change has the potential to be an early marker for therapy response and provide clinicians with a tool for monitoring the effect of postsurgical adjuvant therapy beyond the current wait-and-see approach. In fact, given ongoing developments in automatic algorithms for mammographic density measurement, implementing this as a routine clinical tool could be cost-effective.” ■

Henry NL, Stearns V: J Clin Oncol 31:2233-2235, 2013.
Li J, et al: J Clin Oncol 31:2249-2256, 2013.
Fontein DB, et al: J Clin Oncol 31:2257-2264, 2013.


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