Meeting Highlights From the 2011 Breast Cancer Symposium
“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”
She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.
“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”
Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.
Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).
“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.
In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.
“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.
In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).
When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.
Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.
In the pipeline: entinostat may overcome AI resistance
Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.
Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.
“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.
“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.
In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.
These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.
Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.
The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.
