BY ED SUSMAN
The addition of carboplatin to standard chemotherapy for women diagnosed with triple-negative breast cancer appears to significantly increase the percentage of women who achieve a pre-surgery pathologic complete response, researchers reported at the San Antonio Breast Cancer Symposium.
In the Cancer and Leukemia Group B (CALGB) 40603 trial, 46 percent of the 212 women who did not receive carboplatin achieved a pCR – the primary endpoint of the trial -- compared with 60 percent of the 221 women who did receive carboplatin, reported William M. Sikov, MD, Associate Professor of Medicine at Warren Alpert Medical School of Brown University.
For the secondary endpoint, 41 percent of women who did not receive carboplatin achieved a pCR in the breast and axillary lymph nodes compared with 54 percent of patients who received the platinum-containing drug.
“In Stage II-III triple-negative breast cancer, the addition of carboplatin to standard neoadjuvant chemotherapy significantly increased the pathologic complete response rates in the breast and in the breast and axilla,” he said at a news conference. “These preoperative data are encouraging.
“Should carboplatin be routinely added to neoadjuvant chemotherapy for stage II-III triple-negative breast cancer? With the caveat that we do not have long-term results -- we don’t know if increasing the pathologic complete response rate will result in significant improvements in recurrence free or overall survival -- I think that if you are looking in the neoadjuvant setting, the answer would be yes.”
The trial simultaneously found benefit in treatment of triple-negative breast cancer with the anti-angiogenesis drug bevacizumab, he added. Among the 218 women who were not treated with bevacizumab, 48 percent achieved a pCR in the breast compared with 59 percent of the 215 women who did receive bevacizumab.
Among the women who were not treated with bevacizumab, 44 percent had a pCR in the breast and axilla compared with 52 percent of the women who received bevacizumab.
“The addition of bevacizumab significantly increased the pathologic complete response rate in the breast but not in the breast and axilla,” Sikov said. “Because bevacizumab increases toxicities, I don’t think it should be routinely added to neoadjuvant chemotherapy.
“Triple-negative breast cancer accounts for about 20 percent of invasive breast cancers in the United States. We know this is an aggressive type of cancer and that it is more common in blacks, Hispanics, younger women, and BRCA1 gene mutation carriers.
“Although there have been significant advances in treating women with this disease in the past 20 years, we know that women with early-stage triple-negative disease remain at higher risk of early recurrence and that prognosis for patients with advanced-stage disease is very poor,” he added.
In advanced triple negative -- estrogen receptor-negative, progesterone receptor-negative, and HER2-negative – disease, the median overall survival is less than one year.
Sikov noted that at the 2012 San Antonio Breast Cancer Symposium, a meta-analysis was reported showing that with standard neoadjuvant chemotherapy about 34 percent of patients diagnosed with triple-negative breast cancer achieve a pathological complete response – i.e., with no viable residual disease in either the breast or the lymph nodes at surgery: “These patients do significantly better than women who have residual disease at surgery. One of the clinical goals of our study was to try to increase the percentage of patients to achieve a pathologic complete response.”
In the CALGB 40603 study, a control group of women with triple-negative disease were treated with paclitaxel at 80 mg/m2 weekly for 12 weeks followed by dose-dense doxorubicin and cyclophosphamide for four cycles -- a regimen that has been shown to benefit women diagnosed with triple-negative breast cancer. A second group of women were given the same chemotherapy regimen along with bevacizumab at a dose of 10 mg/kg every two weeks for a total of nine doses.
“We decided to investigate bevacizumab based on improvements in time to progression in patients with metastatic triple-negative disease,” he said.
A third group of women received the same chemotherapy regimen, but with carboplatin dose to an area under the curve (AUC) of six every three weeks for four cycles.
A fourth group of women received chemotherapy, plus carboplatin plus bevacizumab. There was one on-treatment death in this protocol.
Sikov explained that the study was designed as a Phase II trial with a 2-by-2 randomization. The trial was designed to study the two arms of patients who received carboplatin with the two arms who did not receive the platinum-containing drug; and the two arms that contained bevacizumab with those women who did not receive the biologic agent.
“The study was not powered to compare the individual treatment arms,” he said. The trial was not powered to determine statistically significant differences in progression-free survival or in overall survival.
After the chemotherapy was administered, women then were treated with surgery and/or radiotherapy at the discretion of the treating physician. The trial did not include any planned adjuvant systemic therapy -- also leaving that decision to the treating physician.
Women were eligible if they were diagnosed in clinical Stage II-III disease; had 10 percent or less estrogen plus progesterone receptor positivity and were HER2-negative. Patients also could not have a contraindication to bevacizumab. They underwent baseline evaluation including breast magnetic resonance imaging or breast ultrasound imaging for tumor measurement.
‘Good Representation of Black Patients’
A total of 443 women were enrolled in the study over a period of 36 months. About 60 percent of the women were between the ages of 40 and 59; about 72 percent of the participants were white, and 22 percent were black: “We reached out to the black community to enroll in the study, and had a good representation of black women in the trial,” Sikov said.
About 68% of the women were diagnosed in clinical Stage II, and 32 percent were in clinical Stage 3. About 66 percent were diagnosed with T2 tumors, and 20 percent had T3 tumors. About 45 percent of the women were clinical node-negative, and 55 percent were node positive.
The toxicities reflected the known profiles of the treatments, he said: Neutropenia was common, with 22 percent of the control arm patients experiencing neutropenia, increasing to 27 percent with bevacizumab added. This increased even further to 56 percent if carboplatin was added to chemotherapy, and to 67 percent if the patient was given bevacizumab plus carboplatin plus the standard chemotherapy.
Thrombocytopenia occurred in the range of three to four percent, unless carboplatin was added to treatment and then 20 percent of the women experienced thrombocytopenia; the combination of chemotherapy, carboplatin, and bevacizumab was associated with a 26 percent rate of thrombocytopenia. “However, only the groups that received both carboplatin and bevacizumab experienced higher rates of febrile neutropenia,” Sikov said.
Hypertension occurred in about 12 percent of the women in the bevacizumab arms, but was uncommon in women not taking the anti-angiogenesis drug. Bleeding and thrombosis were also seen more other with bevacizumab- treated patients.
“When we turn to serious adverse events, there were increases with carboplatin but the most concerning adverse events were seen among those women taking bevacizumab,” he said. Those adverse events were mainly infections and thrombosis and a higher rate of postsurgical complications, even though bevacizumab therapy had ended at least six weeks prior to surgery.
The patients who received both drugs had the highest pathologic complete response rate, 67 percent, in the breast; and the highest pathologic complete response rate, 60 percent, in the breast and axilla. However, Sikov said, treatment with both drugs did not show a synergistic effect.
Critical Questions Still Unanswered
Sikov said the results of CALGB 40603 trial and the earlier GeparSixto trial provide evidence that carboplatin improves outcomes in triple-negative breast cancer, but still leaves critical questions unanswered, including the optimal dose and schedule to enhance efficacy and reduce adverse events.
If a clinician believes a women with triple-negative breast cancer is a candidate for neoadjuvant chemotherapy based on tumor size or a desire to improve the chances for breast-conservation surgery, “then I think it makes sense to add carboplatin, and that you can comfortably do so with acceptable additional toxicity,” Sikov said.
The lead investigator of the GeparSixto trial, Gunter von Minckwitz, MD, PhD, Chairman of the German Breast Group, cautioned, though, about comparing his trial and the CALGB trial: “The regimen for GeparSixto was completely different. We had different combinations; we used an 18-week schedule instead of 24 weeks.
“We had to reduce the dose of carboplatin from AUC 2 to AUC 1.5. We have now done further safety analyses of the study and we have seen that the AUC 1.5 dose is much better tolerated.”
Sikov was less enthusiastic about use of bevacizumab. “There now have been three studies that indicate that the use of bevacizumab increases the pathologic complete response rate, but none of these trials are powered to look at progression-free survival or overall survival, and there are increases in toxicities such as febrile neutropenia, bleeding, clotting, and post-surgical complications,” he noted.
“Correlative studies are pending to see if we can identify markers predictive of response -- or resistance -- to the standard and investigational regimens.”
The trial received funding from the National Cancer Institute, Genentech, the Breast Cancer Research Foundation, and the American Recovery and Reinvestment Act of 2009.