Carboplatin Yes, Bevacizumab No for Triple-Negative Breast Cancer

Neil Osterweil

December 13, 2013

SAN ANTONIO — Adding carboplatin to paclitaxel in the neoadjuvant setting for triple-negative breast cancer significantly improves pathologic complete response (pCR) rates. So, for that matter, does adding bevacizumab (Avastin) — somewhat.

The catch is that bevacizumab adds only an incremental benefit, does not have synergistic activity with carboplatin, and is associated with significantly increased toxicities that could outweigh the benefit, said William M. Sikov, MD, from the Warren Alpert Medical School of Brown University in Providence, Rhode Island.

"Should carboplatin be routinely added to stage II or III triple-negative breast cancer? With the caveat...that we do not have long-term results — I think if you're looking in the neoadjuvant setting, my answer to that question would be yes," Dr. Sikov said in a media briefing prior to his presentation.

He explained that carboplatin improved the pCR rate, but it is not known if that will result in significant improvement in recurrence-free or overall survival.

Although bevacizumab also increased the pCR rate, it came "at the cost of significant toxicities, and I don't think it should be routinely added to neoadjuvant chemotherapy," he said.

Jeffrey B. Smerage, MD, PhD, a breast cancer specialist from the University of Michigan Comprehensive Cancer Center in Ann Arbor, who was not involved in the study, told Medscape Medical News that "Dr. Sikov's comments make a lot of sense to me."

He noted that the addition of carboplatin to a standard neoadjuvant regimen "clearly" showed evidence of an increase in pCR.

Even without long-term data, the results are helpful to clinicians, he suggested.

Dr. Smerage explained that in the neoadjuvant setting, patients tend to have larger tumors, often have clinically positive lymph nodes, and generally have higher risks at baseline.

"It's also a setting in which your goal is response. Maybe the goal is to allow a more effective surgery, even if the surgery is going to be a mastectomy.... Maybe your goal is to be able to attempt a lumpectomy, where the goal of that therapy is response but not necessarily prolonged progression-free survival," he said.

Tough Nut to Crack

Triple-negative breast cancers — so called because they lack the drug targets of estrogen, progesterone, and HER2 receptors — comprise approximately 20% of breast cancers, and are more common in blacks, Hispanics, younger women, and those with BRCA1 mutations.

Although there have been advances in chemotherapy in the adjuvant setting, patients with triple-negative disease still have worse prognoses than patients with either estrogen-receptor-positive or HER2-positive tumors. Median overall survival for patients with advanced triple-negative cancers is less than 1 year, Dr. Sikov said.

In the neoadjuvant setting, evidence of a benefit in women with triple-negative disease comes from a meta-analysis presented at last year's SABCS (abstract S1-11). That study showed that 34% of patients had a pCR with neoadjuvant chemotherapy and a better clinical course than women with similar tumors who had residual disease going to surgery.

Dr. Sikov's team chose to study carboplatin for 2 reasons: its activity in patients with BRCA mutation-related cancers, which are similar to sporadic triple-negative cancers in several respects; and the high pCR rates in pilot studies in which carboplatin was added to standard chemotherapy in patients with triple-negative tumors.

2 × 2 Design

The CALGB 40603 study was a randomized phase 2 trial with a 2 × 2 randomization scheme in which all patients received paclitaxel 80 mg/m² weekly for 12 weeks, plus 1 of 3 treatments: bevacizumab 10 mg/kg every 2 weeks for 9 cycles; carboplatin to the area under the curve (AUC) 6 every 3 weeks for 4 cycles; or both carboplatin and bevacizumab.

All patients went on to dose-dense chemotherapy with doxorubicin and cyclophosphamide for 4 cycles.

The trial was designed to look at pCR rates in the breast and axilla, but was not powered to compare individual treatment groups or to detect differences in recurrence-free or overall survival, Dr. Sikov noted.

A total of 443 patients were enrolled, and 427 went on to surgery and were included in the pCR analysis. (Dr. Sikov explained that progression-free and overall survival will be reported at a later date.)

Rates of pCR in the breast were lower in patients who did not receive carboplatin than in those who did (46% vs 60%). The odds ratio (OR) for carboplatin was 1.76 (P = .001).

Rates of pCR in the breast were also lower in patients who did not receive bevacizumab than in those who did (48% vs 59%). The OR for the angiogenesis inhibitor was 1.58 (P = .0089).

However, there was no evidence of a synergistic interaction between the carboplatin and bevacizumab, the investigators found.

Looking at pCR in the breast and axillary lymph nodes, they again saw an effect on pCR in women treated with carboplatin, compared with those who were not (41% vs 54%). The OR for carboplatin in the breast/axilla was 1.71 (= .0029). The same pattern was seen with bevacizumab (44% vs 52%). The OR was 1.36, but it just missed being statistically significant (= .057)

Again, the investigators saw no evidence of synergy in the effect of the drugs on pCR in the breast and axilla combined.

Bevacizumab in this study was also associated with increases in grade 3 toxicities, including hypertension, febrile neutropenia (especially with carboplatin), serious infections despite a normal absolute neutrophil count, bleeding, and thromboembolic and surgical complications.

"We await results of correlative studies, including subtype analysis, to see if we can identify markers of response or resistance to standard neoadjuvant chemotherapy, as well as to the addition of carboplatin or bevacizumab," Dr. Sikov said.

The study was funded by the National Cancer Institute, Genentech, and the Breast Cancer Research Foundation. Dr. Sikov and Dr. Smerage have disclosed no relevant financial relationships.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-01. Presented December 13, 2013.

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