We know that triple negative breast cancer is the most aggressive subtype of this disease. The main treatment in patients with non-metastatic stage is essentially chemotherapy and more recently we have some immune checkpoint inhibitors in the neoadjuvant setting. One of the agents that has long been explored but not definitively proven is platinum. Although there are several lines of reasoning and there is a biological rationale for the use of platinum agents in triple negative breast cancer, there have been very few studies, definitive studies, to explore the role of these agents in patients with non-metastatic triple negative breast cancer and almost all of these studies have been phase II and not powered for survival outcomes.
So we started a randomised controlled trial of adding carboplatin to anthracyclines, taxanes and cyclophosphamide in patients with operable and locally advanced triple negative breast cancer in 2010. Our study, unlike some of the other studies, was powered for event free survival and we accrued patients for about ten years. More recently, I reported the results of this study at the San Antonio Breast Cancer Symposium in 2022.
What were the key findings?
The primary endpoint was event free survival and for this endpoint in our study there was about a 6% benefit in five-year event free survival rate with the addition of carboplatin to taxanes and anthracyclines in the neoadjuvant setting. But this was only borderline statistically significant with a p-value of 0.08.
One of the key secondary endpoints of our study was overall survival and in the full study population of 717 patients we had a statistically significant and clinically meaningful increase in overall survival by 7.6% with the addition of carboplatin. So the headline result is that event free survival was borderline significantly improved but overall survival was significantly increased with the addition of carboplatin in the neoadjuvant setting.
The other key finding of our study was that we analysed the effect of carboplatin by age subgroups in women younger than 50 years of age and in those older than 50 years of age. The entire benefit of carboplatin, about a 12.5% improvement in event free survival and about an 11.6% improvement in overall survival, was confined to younger women who were younger than or equal to 50 years of age.
So the main finding of our study is that the addition of carboplatin is highly beneficial in terms of long-term survival outcomes in younger women or those who are premenopausal and who have operable or locally advanced triple negative breast cancer.
How could these findings impact the future treatment of breast cancer?
Until now there has been equipoise with respect to the use of platinum agents in triple negative breast cancer although they have either been used or not used, depending on which country and which professional society you see. After the results of our study there will no longer be any questions about the overall utility of platinum in triple negative breast cancer.
I must add that some recent immune checkpoint inhibitor-based studies like the one with pembrolizumab, KEYNOTE-522, have already incorporated carboplatin in the neoadjuvant chemotherapy regimen as part of the chemotherapy backbone. What our results will do is to solidify the use of platinum as neoadjuvant chemotherapy in these patients and these will now be routinely offered, with or without the use of immune checkpoint inhibitors, to all patients of triple negative breast cancer.
Is there anything else that you would like to add?
The only other thing that I wish to add is two: first, that the toxicity of adding weekly carboplatin was not very high, although there was a slightly higher rate of haematological toxicity in the carboplatin arm but it was well-tolerated. The overwhelming majority of patients, more than 80% actually, completed their neoadjuvant regimen.
The second thing that I would like to add is that the biological basis of younger patients benefitting from platinum and older patients not seeming to benefit from platinum is not very well understood but some translational studies are underway to explore these results.
The third thing is that we hope to be able to look at some other endpoints such as the occurrence of gene expression profiling signatures or abnormalities of BRCA and other homologous recombination deficiency related genes in this dataset to be able to explain the results in the future.