SAN ANTONIO—Women diagnosed with Stage 2 or 3 triple-negative breast cancer—considered one of the most difficult breast cancers to treat—and who achieve a pathologic complete response after neoadjuvant chemotherapy appear to have a significant chance of remaining disease-free over a mean follow-up of 39 months, researchers reported at the San Antonio Breast Cancer Symposium (Abstract S2-05).
William Sikov, MD, Professor of Medicine at Brown University School of Medicine, reported that about 86 percent of women who achieved a pathologic complete response in the breast and axilla were free of events compared with 62 percent of women who did not achieve a complete response—a 70 percent relative risk reduction that he called highly statistically significant (P<0.0001).
Overall survival in these triple-negative breast cancer patients who achieved a pathologic complete response was also significant: About 93 percent of these women were still alive compared with 73 percent of the women who did not achieve a pathologic complete response, an 80 percent reduction in the risk of dying, he said at a news conference.
“Our new data show that patients on any arm of this study who had a pathologic complete response had far superior outcomes compared with those who did not have a complete response. After three years of follow-up, only nine percent of patients who had a pathologic complete response had developed a distant recurrence and only six percent had died, compared with 27 and 25 percent, respectively, of patients who did not have a pathologic complete response.”
However, as also part of the CALBG 40603/Alliance study, the results did not show that use of carboplatin or bevacizumab was associated with statistically significant improvements in outcome.
‘Not Sufficiently Large...’
“Our study was not sufficiently large to have the statistical power to determine whether adding carboplatin or bevacizumab to standard neoadjuvant chemotherapy improved event-free and overall survival,” Sikov continued. “On the basis of these results, at the present time, neither carboplatin nor bevacizumab should be considered part of the standard neoadjuvant chemotherapy regimen for stage 2 or 3 triple negative breast cancer.”
He did note that previous studies have found that the addition of bevacizumab failed to demonstrate improvements in long-term outcomes. Results from other completed studies, he said, in the neoadjuvant and adjuvant settings should help clarify whether the addition of carboplatin benefits patients with early stage triple-negative breast cancer.
In the new study, event-free survival at three years was 76 percent among patients on carboplatin compared with 71 percent among patients who did not receive carboplatin, but that 16 percent relative risk reduction was not statistically significant (P=0.36), he said.
Similarly, about 75 percent of patients taking bevacizumab were able to remain disease-free for three years compared with 72 percent of patients who were not on bevacizumab—a 20 percent relative risk reduction that also fell short of statistical significance (P=0.25).
“A person who achieves a pathological complete response with a standard regimen is going to have a very good outcome,” he told OT. “The difficult case is the patient who gets the neoadjuvant chemotherapy and does not achieve the complete response and has significant residual disease at surgery.
“We still don't know if they would benefit from carboplatin or bevacizumab. We are doing clinical trials now to determine that.”
He said that if he had access to clinical trials he would offer that to his patients first; and if no trial was available, he would not offer the platinum-based treatment because it is not a proven regimen.
The question with bevacizumab is more difficult, he said, because of the expense of the drug. Carboplatin is now a generic medication and is relatively inexpensive. So he might not offer bevacizumab because it is expensive—and unproven, Sikov said.
“If I had a patient with triple-negative breast cancer, I think it would be appropriate to offer her chemotherapy and a study to determine if carboplatin is helpful. If I had a patient—off study—with more concerning disease characteristics I would be willing to offer carboplatin along with standard chemotherapy in the neoadjuvant setting based on the local/regional effects we observed in our study.”
He suggested that treating these patients with carboplatin falls into the arena of the art of medicine “because we did not show if carboplatin was better or worse for our patients.”
‘All Going in Same Direction’
The moderator of the news conference, Virginia Kaklamani, MD, Professor of Medicine at the University of Texas Health Science Center at San Antonio, said in an interview: “One study may not be enough for us to accept the results. Sometimes we need two or three or four studies, and sometimes those studies will not give you new data, per se, but they confirm the old data. This is another confirmatory study. It is important because it shows we are all going in the same direction.
“The concerning factor in this study is the effect of carboplatin,” she continued. “Carboplatin is a drug we all like using in triple-negative breast cancer patients because we don't feel that the chemotherapy we use now is good enough. Now there are a group of patients who do really well regardless of whether we use carboplatin, and that is great. This was a neoadjuvant trial so we didn't know which group was going to do well.
“When you look at the survival curves with carboplatin, there is nothing that excites you. You could have added another 1,000 women and even if you got a statistically significant difference it would be two percent. Is a two percent difference clinically meaningful to my patients? Probably not. The worst-case scenario is that carboplatin is not better, and you get more toxicities from it.”
Kaklamani said that she would talk to women who were BRCA mutation positive as well as BRCA-negative patients who are triple-negative about adding carboplatin to their regimens. But since there is an adjuvant study underway, “I would put all my patients on that study, because we need to know the answer.”
In Sikov's trial, the researchers recruited 443 patients with operable stage 2 or 3 triple-negative breast cancer. Patients were randomly assigned to standard neoadjuvant chemotherapy, standard neoadjuvant chemotherapy plus carboplatin, standard neoadjuvant chemotherapy plus bevacizumab, or standard neoadjuvant chemotherapy plus carboplatin and bevacizumab. Surgery was performed four to eight weeks after the completion of neoadjuvant treatment.
“In regards to the question as to whether there is a benefit to adding either carboplatin or bevacizumab to standard chemotherapy for stage 2 or 3 TNBC, it is important to highlight that this is not a negative study,” he said. “Our results need to be considered alongside data from prior and ongoing studies with these agents in triple-negative breast cancer. “
The study was supported by the National Cancer Institute's Cancer Therapy Evaluation Program, Genentech, and the Breast Cancer Research Foundation.