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Platinum-based agents have been used as adjuvant therapy for patients with residual triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy, based on clinical trial data showing improved pathological complete response (pCR) rates. Newer data, however, should discourage this practice, scientists said.

The trial found that platinum-based chemotherapy did not extend invasive disease-free survival compared with capecitabine in patients with TNBC residual disease following neoadjuvant chemotherapy, regardless of the cancer subtype, and was associated with more severe toxicity.

In 308 patients with residual TNBC basal subtype followed for a median of 20 months, the 3-year invasive disease-free survival rate was 49% for capecitabine versus 42% for platinum therapy (HR 1.06, 95% CI 0.62-1.81). In addition, grade 3 and 4 toxicities were more common with the platinum agents, reported Ingrid Mayer, MD, of Vanderbilt University in Nashville, and colleagues.

As shown in their study online in the , the results were similar when the researchers examined 102 non-basal patients separately as well as the entire group of 410 patients.

"As such, these findings have an immediate impact in clinical practice, as they should discourage the adjuvant use of platinum agents in patients with residual TNBC after neoadjuvant chemotherapy outside of a clinical trial," the team wrote. "For now, the use of adjuvant platinum agents in unselected patients with TNBC remains investigational, and capecitabine remains the standard therapy."

In the following interview, Mayer, co-leader of the Breast Cancer Research Program and chair of the Data and Safety Monitoring Committee, discussed the details of the trial as well as ongoing research into more effective therapies for this high-risk population.

The majority of patients in your study had the basal subtype of TNBC. Why did you focus on this group in particular?

Mayer: The reason we focused on this group is that preclinical and retrospective clinical data showed that (a) of all subtypes of TNBC, the basal subtype had the highest risk of recurrence, due to its aggressive biological behavior; and (b) basal-subtype TNBC has a dependency on DNA-damaging agents. Therefore, we hypothesized that the group of patients who would benefit the most from receiving a DNA-damaging chemotherapy agent (i.e., platinum) would be the patients with the highest risk of recurrence and with a cancer in which a DNA-damaging agent would be a targeted treatment, potentially.

Did you find any notable differences when you compared basal subtype with non-basal patients?

Mayer: Albeit not statistically significant, non-basal tumors had a better response to capecitabine (but not platinum) than basal TNBC.

What are some of the potential explanations for the lack of benefit with platinum agents found in your study?

Mayer: There are potentially several explanations for this, but the most plausible one is that untreated and treated TNBC behave differently within the different treatment scenarios: in the neoadjuvant setting, where TNBC is treatment-naïve, a good proportion of basal subtype TNBCs are likely sensitive to DNA-damaging agents, and therefore likely to achieve a pCR.

This would explain why in the neoadjuvant setting the use of a platinum agent increases the rate of pCR, but since achievement of a pCR was an exclusion criteria in the EA1131 trial, the TNBC post-neoadjuvant chemo and surgery that did not achieve a pCR was likely resistant to DNA-damaging agents to begin with, and therefore not differentially responsive to platinum agents in the adjuvant setting.

Is there any role at present for platinum-based agents in the patient population you studied?

Mayer: Not in the adjuvant setting for patients with residual TNBC post-neoadjuvant chemo completion. But it is unclear if its use in the neoadjuvant setting is helpful, where despite an increase in pCR rates, we don't have long-term outcomes in phase III trials. We also don't know if used in the adjuvant setting in unselected patients where surgery was the first treatment step platinum would be helpful; the is still ongoing.

Can you tell us about some of the other ongoing research into improved therapies for patients with residual TNBC?

Mayer: One of the clear directions we need to be moving into is to find better treatment strategies for this high-risk group (i.e., TNBC with residual disease post-neoadjuvant chemo completion), where novel chemotherapy agents, such as antibody conjugates, or immunotherapy (as it is being explored in the ) need to be studied.

Alternatively, finding ways to increase rates of pCR in the neoadjuvant setting to a degree that corresponds to long-term benefit is also important.

Read the study here and expert commentary about the clinical implications here.