Breast density modulation, AEs predicted response to therapy

Issue: June 25, 2013

Breast density modulation and specific treatment-associated adverse events may serve as early markers that help predict response to treatment with tamoxifen, which could lead to improved survival in women with breast cancer, results of two recent studies suggest.

Breast density and OS

In the first study, women with breast cancer who were treated with tamoxifen-based therapy and had a relative reduction in absolute mammographic dense area of more than 20% were at 50% reduced risk for death compared with women who experienced relatively little or no change in breast density (HR=0.50; 95% CI, 0.27-0.93).

"The beauty of our results is that, without large means, clinicians could immediately start using our ‘prognosticator,’" Per Hall, MD, PhD, of the department of medical epidemiology and biostatistics at the Karolinska Institutet in Stockholm, told HemOnc Today. "Breast cancer patients always have a baseline mammogram and repeated mammograms as part of their follow-up. The big challenge is to decide how to measure density and, thereby, density change."

Per Hall

Reductions in mammographic density are a significant indicator for response to tamoxifen therapy. For this reason, Hall and colleagues assessed the hypothesis that alterations in density after adjuvant therapy would influence breast cancer-specific survival.

The study included 974 postmenopausal women with breast cancer who had both a baseline and follow-up mammogram. Of these women, 474 received tamoxifen and 500 did not.

During the 15-year follow-up, 12.4% of patients died. Among women not treated with tamoxifen, no statistically significant association was observed between changes in mammographic density and OS.

"For the first time, we are able to identify the individual response to adjuvant therapy," Hall said. "Women who have a mammographic density decrease of more than 20% during the first 5 years of follow-up on tamoxifen treatment have a 50% reduction in the risk for dying from breast cancer during the coming 15 years."

TEAM trial

Results of the phase 3 Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial demonstrated that specific adverse events were associated with superior survival.

In the randomized, international, open-label TEAM study, researchers assessed DFS, OS and distant metastases in 9,325 patients.

Cornelis J.H. van de Velde

"We found that the presence of specific adverse events associated with endocrine therapy — including vasomotor symptoms such as hot flashes and night sweats, musculoskeletal symptoms and vulvovaginal symptoms — were related to better survival outcomes," Cornelis J.H. van de Velde, MD, PhD, FRCPS, FACS, professor of surgery at Leiden University Medical Center in the Netherlands, told HemOnc Today. "Patients who suffered the aforementioned adverse events were also found to develop fewer accounts of distant metastases than patients who did not report adverse events during treatment. It appears, therefore, that we may be able to predict outcomes of breast cancer based on whether patients experience these adverse events."

Multivariate HRs for DFS were 0.731 (95% CI, 0.618-0.866) for vasomotor symptoms, 0.826 (95% CI, 0.694-0.982) for musculoskeletal adverse events, and 0.769 (95% CI, 0.585-1.10) for vulvovaginal symptoms.

Multivariate HRs for OS were 0.583 (95% CI, 0.424-0.803) for vasomotor symptoms, 0.811 (95% CI, 0.654-1.005) for musculoskeletal adverse events, and 0.57 (95% CI, 0.391-0.831) for vulvovaginal symptoms.

Patients who had an increased number of specific adverse events also had better OS. Outcomes were not associated with treatment allocation, according to the researchers.

"We know that noncompliance rates are very high in patients who are treated with adjuvant endocrine therapy, based upon an earlier publication by our study group," van de Velde said. "We also know that most patients who discontinue treatment before the predesignated end date do so because of treatment toxicities, including hot flashes, night sweats and musculoskeletal symptoms."

It is important that clinicians and patients are aware that these symptoms may be associated with improved survival, van de Velde said.

"Several studies being performed worldwide are showing that longer treatment durations, such as more than 5 years of adjuvant endocrine therapy, provide an additional survival benefit in breast cancer patients," he said. "Patients need to be convinced and motivated to continue their treatment, as long as
the toxicities do not become too debilitating."

‘Valuable’ information

To date, no clinical or biochemical markers have been identified to determine whether an individual patient will benefit from adjuvant endocrine therapy, N. Lynn Henry, MD, of the University of Michigan Comprehensive Cancer Center, and Vered Stearns, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, wrote in an editorial that accompanied the two studies.

"These studies support the rationale for prospective collection of patient-reported outcomes — both at baseline and during therapy — in future clinical trials addressing adjuvant endocrine therapy, as well as for assessing adherence to therapy, concomitant medications and nonpharmacologic approaches to symptom management and breast cancer outcomes," Henry and Stearns wrote.

Studies that provide a comprehensive analysis of patient-reported outcomes, rather than physician-graded toxicity, will enhance the understanding of the true effect of symptom emergence or breast density modulation during adjuvant endocrine therapy on breast cancer outcomes, according to Henry and Stearns.

"This information would be valuable for counseling patients who are receiving adjuvant endocrine therapy, both to enhance adherence and to provide individualized treatment recommendations," they wrote. – by Jennifer R. Southall

References:

Fontein DB. J Clin Oncol. 2013;doi:10.1200/JCO.2012.45.3068.

Henry NL. J Clin Oncol. 2013;doi:10.1200/JCO.2013.48.9153.

Li J. J Clin Oncol. 2013;doi:10.1200/JCO.2012.44.5015.

For more information:

Per Hall, MD, can be reached at per.hall@ki.se.

Cornelis J.H. van de Velde, MD, PhD, FRCPS, FACS, can be reached at C.J.H.van_de_Velde@lumc.nl.