New Approaches for Triple-Negative Breast Cancer

September 18, 2012

Several presentations at the ASCO Breast Cancer Symposium addressed important questions in triple-negative breast cancer: are there promising new treatment approaches for these patients and how can we identify which patients are high risk?

Triple-negative breast cancer remains the hardest breast cancer subtype to treat, because the disease is a compilation of different breast cancer subtypes. Researchers are actively attempting to classify these subtypes and identify new treatments.

Several presentations last week at the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium in San Francisco addressed important questions in triple-negative breast cancer: Are there promising new treatment approaches for these breast cancer patients, and how can we identify which patients are high risk?

Size of Residual Triple-Negative Disease Matters for Prognosis

A retrospective study analyzed the prognosis of triple-negative breast cancer patients without a pathological complete response and found a positive correlation between residual disease tumor size and patient outcome. Survival at 24 months was seen in 88% of patients with small volume of residual disease, compared to 77% of those with larger volumes, a significant difference (P < .05).

Currently, risk stratification is based on either a pathological complete response or a non–pathological complete response, but some of these latter patients do have a favorable prognosis. Peter Kern, MD, the Breast Center Dsseldorf Louis Hospital in Germany, presented the results of the cohort study. Pathological complete response is generally defined as no evidence of invasive or in situ residual disease in the breast and lymph nodes. More than 500 patients in Germany with a non–pathological complete response after neoadjuvant or adjuvant chemotherapy were analyzed at 24 months after surgery.

Melinda L. Telli, MD

Melinda L. Telli, MD, assistant professor of medicine at Stanford University and the discussant for the session, highlighted the large cohort as a strength of the trial, but pointed out that the nodal status is extremely important for prognosis, but was not analyzed in this study.

The percent tumor cellularity also was not analyzed. “Sometimes the pathology report of a patient who has received chemotherapy shows a few scattered tumor cells across the tumor bed,” said Telli. “We know these patients, who have minimal residual disease actually have a favorable prognosis.”

Telli also pointed out that 24 months is a short follow-up for the study-a 5-year follow-up would be more reasonable.

Early Results of mTOR Inhibitor for Triple-Negative Breast Cancer

A small phase II trial with everolimus (Afinitor), an oral mTOR inhibitor, in combination with carboplatin has met its primary endpoint of clinical efficacy. The overall response rate was 29%. Of 25 patients treated, 21 were evaluable for response. One patient had achieved a complete response, five a partial response, and eight have stable disease. The median duration of response was 13 weeks.

Everolimus has recently been approved for advanced estrogen receptor–positive breast cancer. The rationale for combining an mTOR inhibitor plus a platinum-based chemotherapy is the observed synergistic effect of the two agents to elicit apoptosis and inhibit growth of breast cancer in breast cancer cell lines. Patients on the trial had unexpected dose-limiting thrombocytopenia that required a lowering of the carboplatin doses.

Amy Tiersten, MD

Amy Tiersten, MD, associate professor of medicine at the New York University Clinical Cancer Center and lead author of the abstract, told Cancer Network that a phase III trial has not yet been planned. “The toxicity is not a major deterrent at all after we changed the [initial] dosing,” said Tiersten.

In her discussion of the study results, Telli highlighted the biological rationale for testing an mTOR inhibitor for metastatic triple-negative breast cancer, but emphasized that much more data is needed to understand the role of everolimus in treating triple-negative breast cancer.

“This is a combination that appears feasible, using the lower carboplatin dose,” said Telli. “These data justify a randomized phase II study to try to understand whether adding everolimus to carboplatin will additionally benefit patients.” Telli believes there is good rationale for trying everolimus in triple-negative and other subtypes of breast cancer. “Preclinical studies suggest that there may be subsets within triple-negative breast cancer that may particularly benefit,” said Telli. What mTOR inhibitors add in terms of efficacy is being actively explored.

Preliminary Results of Vaccine Study Warrant Further Testing

A clinical benefit was seen in a study of the AE37 peptide vaccine for triple-negative breast cancer patients who were node-positive and had low HER2 expression, as well as for high-risk, node-negative patients who were disease free after standard-of-care treatment. The initial results of the phase II trial were first presented at the annual ASCO conference in June.

The disease-free rate among the triple-negative breast cancer patients in the vaccine group was 83.3% compared to 47.6% in the control group-a 68% risk reduction. Due to the small patient population, the results are not yet statistically significant.

Elizabeth Ann Mittendorf, MD

“All of the HER2-derived peptide vaccines that our group has been investigating continue to show greater effect in patients with HER2 low-expressing disease,” said lead author of the study, Elizabeth Ann Mittendorf, MD, the University of Texas MD Anderson Cancer Center. “Although the number of patients was small, 14 vaccinated patients and 26 control patients, we were pleased to see that after a median follow-up of 28 months, the disease-free survival rate was 83.3% vs 51.5% in the control group,” said Mittendorf. The results show that triple-negative breast cancer patients, who have a low expression of HER2-not quite enough to classify them as HER-positive, could benefit from the vaccination. “We would encourage physicians to consider identifying these patients and enrolling them onto our clinical trial,” added Mittendorf.

Mittendorf is hopeful that the vaccine will soon move into a phase III trial. Although the data presented did not reach statistical significance due to the small number of trial participants, Telli believes the “main weakness of the study was that it was underpowered,” but believes the results warrant “further exploration in a bigger study.”