Bevacizumab Works in Triple-Negative Breast Cancer Subtype

Kate Johnson

December 11, 2014

SAN ANTONIO — New results could potentially reignite interest in the use of bevacizumab (Avastin, Genentech, Inc) in breast cancer, specifically in subtypes of triple-negative breast cancer (TNBC), which is notoriously difficult to treat. The new correlative findings come from the previously reported CALGB 40603 trial, which investigated adding either bevacizumab or carboplatin (Paraplatin, Corden Pharma International GmbH) to standard paclitaxel neoadjuvant chemotherapy.

Although it was previously reported that "the jury is still out" regarding the role of carboplatin in this setting, the new findings potentially "could resurrect interest" in the role of bevacizumab in stage I-III triple-negative disease, lead author William Sikov, MD, told Medscape Medical News.

Dr Sikov, who is associate director of clinical research for the Program in Women's Oncology at Women and Infants Hospital and associate professor of medicine at the Alpert Medical School of Brown University, in Providence, Rhode Island, reported the new findings here at San Antonio Breast Cancer Symposium (SABCS) 2014.

Molecular classification of TNBC samples into basal-like (87%) and non-basal-like subtypes revealed that when bevacizumab was added to standard neoadjuvant chemo, pathologic complete response (pCR) rates were significantly improved compared with results using paclitaxel alone in patients with basal-like disease (from 45% to 64%, P = .0009; odds ratio [OR], 2.15), but were reduced in those whose TNBC was not basal-like (from 60% to 43%, P = .25; OR, 0.50).

Bevacizumab also resulted in improved pCR rates among patients whose cancers expressed high proliferation, low estrogen expression, or TP53 mutation mRNA signatures, "all markers of more aggressive biology," he explained.

In contrast, disease subtype did not affect the positive pCR response seen when carboplatin was added to paclitaxel.

"This is the fun part of science, when you see unexpected events," commented Lajos Pusztai, MD, DPhil, chief of breast medical oncology at Yale School of Medicine, in New Haven, Connecticut, who was approached for comments. The finding "raises the possibility" that re-examining these older trials in which bevacizumab had little or no benefit "may reveal that the basal-like TNBC significantly benefited from the drug, but since the other TNBC subtypes were harmed, the net effect was a wash," Dr Pusztai told Medscape Medical News.

The findings "highlight once again the clinical implications of TNBC breast cancer heterogeneity," said Aleix Prat, MD, PhD, from the Translational Genomics Group, Vall d'Hebron Institute of Oncology, in Barcelona, Spain, who was also approached for comment. "In my opinion, future clinical trials that focus on triple-negative breast cancer should stratify patients as having basal-like vs not having basal-like disease."

At present, TNBC patients do not routinely receive bevacizumab with their neoadjuvant chemotherapy, even though a number of studies have shown that it increases pCR rates, said Dr Sikov.

"It is expensive, not approved for this indication, associated with serious and occasionally life-threatening toxicities, and has not been shown to improve recurrence-free or overall survival," he explained.

Although last year he strongly recommended against routinely adding bevacizumab to neoadjuvant chemotherapy in patients with TNBC, the new findings suggest there is a subset of these patients for whom this combination may be beneficial, he said.

With regard to carboplatin, the same tissue analysis showed that its addition to paclitaxel was associated with pCR benefits regardless of subtype. Patients with basal-like or non-basal-like disease had similar PCR improvements (47% to 61% and 45% to 58%, respectively), all of which were statistically significant (P = .014, OR 1.76; and P = .55, OR 1.67).

"What we haven't done is identify a subgroup in whom the benefit is much greater, but then again, we haven't identified a subgroup who doesn't benefit from the addition of carboplatin," Dr Sikov concluded.

And although last year he recommended the routine addition of carboplatin in this setting, the new findings may leave clinical decision-making less cut and dried, he said.

"I think it depends on your interpretation," he said, explaining that with a 14% overall absolute increase in pCR and the toxicities associated with carboplatin, the choice is debatable. "I don't think the results presented today would really change anyone's mind."

There is now evidence from three randomized trials showing that pCR rates can be increased by adding carboplatin to current standard adjuvant or neoadjuvant chemotherapies in TNBC, said Dr Pusztai.

"However, this significant but small improvement comes at the price of increased toxicity," he said. "Since the average rate of pCR increased only modestly between the two trial arms, this implies that only a minority of patients benefited from the addition of carboplatin. Who are they? Can a biomarker identify them?"

Funding for the study was provided by the National Cancer Institute, Roche-Genentech, and the Breast Cancer Research Foundation. Dr Sikov has disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S4-05. Presented December 11, 2014.

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