Despite progress, TNBC still has significantly lower responses to therapy compared to other molecular subtypes of breast cancer. Several factors hinder treatment of TNBC, such as: a high tendency to metastasize to other organ sites, lack of FDA-approved targeted therapies, high rates of recurrence after diagnosis, and extreme heterogeneity of TNBCs [2].
The response to neo-adjuvant chemotherapy varies with breast cancer molecular subtype. Studies have shown that both TNBC and Her2-positive breast cancer have excellent prognosis once pCR is achieved after neo-adjuvant chemotherapy compared to other molecular subtypes [9]. There are six subtypes of TNBC based on molecular sub-typing and gene expression studies. These include: basal-like-1, basal-like-2, immune-modulatory, mesenchymal, mesenchymal-like and a luminal androgen receptor subtype [3]. Among the subtypes, 75% are basal-like and these are most commonly associated with BRCA1 mutations. Platinum compounds are found to be especially useful in cancer cells with deficiencies in DNA repair such as those with BRCA gene mutations, due to the formation of platinum-DNA adducts. The TNT phase III trial randomized 376 patients with metastatic TNBC to docetaxel or carboplatin. In the BRCA mutation carriers (n = 29) response rates to carboplatin were 68% compared to 30% for docetaxel [23]. It is therefore warranted to investigate this relationship between BRCA mutation and chemo-sensitivity.
The benefit of neoadjuvant chemotherapy among TNBC shown in our results is consistent with current recommendations. Among the 2415 TNBC patients who underwent platinum-based neoadjuvant chemotherapy, this study showed statistically significant improvement in pCR rates compared to non-platinum-based treatment. However, this data is affected by moderate heterogeneity among the studies, which has been associated with the varied agents combined with the platinum therapy. It remains unclear how platinum should be incorporated and whether concomitant use of platinum could be used to substitute for anthracycline, taxane or an alkylator. Subgroup analyses of the neoadjuvant platinum-based regimen showed that platinum combined with taxane has statistically significant improved pCR. This is consistent with the BrightTNess trial [22] in 2018 which showed that combination of carboplatin and paclitaxel increased pCR rates.
Platinum-containing agents are not regarded as a standard for neoadjuvant therapy of TNBC, for several reasons. One reason is that given that the addition of platinum results in greater toxicity as seen in the previous studies, the clinical benefits of its use should be clear. It is also possible that the improvements in pCR rates may be a result of down staging of low-volume residual disease, which is not known to translate to lower recurrence rates. In addition, pCR may not be associated with improved outcomes in BRCA1/2 mutation carriers, suggesting the inconsistency of its prognostic effect.
In the metastatic setting, this metanalysis did not show any advantage in terms of PFS among TNBC patients. Platinum-based chemotherapy has been suggested to potentially be more effective than non-platinum-based chemotherapy in metastatic TNBC. In the CBCSG006 trial by Hu et al. [17], where Gemcitabine was used as the backbone, Cisplatin was compared to Paclitaxel as a first line metastatic treatment. Over-all response rate was higher in Cisplatin-Gemcitabine combination than in Paclitaxel-Gemcitabine (64% vs 49%, p < 0.018) with a PFS advantage of 1.26 months (HR 0.692, 95% CI 6.19–9.30, p < 0.0001). No overall survival difference was noted. However, several limitations were noted in this particular study including potential bias in the definition of TNBC and financial limitations which preclude central assessment, and further classification into TNBC subtypes.
The TBCRC 001 trial divided the study cohorts into three arms and investigated Cetuximab with or without Carboplatin. Expression of Epidermal Growth Factor Receptor (EGFR), a key gene in the basal-like TNBC, was assessed. However, the limited activity of Cetuximab shown in this study by Carey et al. [16]. suggests that TNBC may have constitutive pathway activation via downstream components such as KRAS amplification or CRYAB expression. The study by Fan et al. [25], with a Taxane-based treatment compared Cisplatin (TP) and Capecitabine (TX). Regardless of the metastasis, the response rates were noted to be higher in the TP arm than in the TX arm (63% vs 15.4%, P = 0.001). Median PFS and Median OS were also statistically longer in the TP arm.
The current conflicting data using platinum among TNBC patients in the metastatic setting may not be sufficient to warrant further study, however, the potential of platinum therapy in certain subtypes of TNBC may be explored further.
