Discussion
tumor, cancer typesThe, breast cancer, cancer, disease stage, primary breast cancer
TUMOR, BREAST CANCER, ADVERSE EVENTS, CANCER, DISEASE, SECONDARY
The primary aim of this randomized, controlled, phase II trial was to investigate the clinical effect of delta-tocotrienol in combination with standard neoadjuvant treatment in primary breast cancer. The results showed no difference in response rate to neoadjuvant breast cancer treatment between patients who received delta-tocotrienol and the control group. Also, there was no difference in the frequency of serious adverse events, OS, and IDFS between the two arms. Thus, in this study we found that delta-tocotrienol did not enhance the efficacy of neoadjuvant treatment and did not reduce the frequency of side effects.Although the study was conducted as a randomized, controlled trial, it has several limitations. Despite the randomization, balanced diagnostics showed imbalance with regard to ER-status, tumor size, tumor grade and pathological lymph nodes, indicating slightly more advanced disease stage in the control group. However, since no difference in outcome was observed between the arms, and the imbalance points towards more advanced disease in the control group, we expect the implications of the imbalance to have very limited significance in relation to the overall outcome of this study. The lack of blinding might have induced bias, as it cannot be ruled out that patients randomized to the control arm self-administered a vitamin E product without reporting it. Also, the unblinded design might have caused information bias in the reporting of side effects. The risk of a type two error was 20% and as the Simon’s two stage design is exploratory as opposed to confirmatory, the results call for further investigation. Therefore, based on this study and previous clinical trials across cancer typesThe secondary aim of this study was to develop an assay for detection of ctDNA in breast cancer. In general, ctDNA detection in patients with a low tumor burden is challenging due to low concentrations of ctDNABased on the multiplex ctDNA assay we investigated the association between treatment response and the presence of ctDNA during and after neoadjuvant breast cancer treatment (independent of randomization group). There was no association between ctDNA status and pCR (RCB 0), neither midterm (A recent meta-analysis including six studies did not demonstrate any association between the presence of ctDNA at baseline and the achievement of pCR, but in three of the studies the presence of ctDNA 2–3 weeks after initiation of neoadjuvant breast cancer treatment was associated with lower pCR ratesIt has previously been reported that presence of ctDNA during and after completion of neoadjuvant breast cancer treatment associates with poor survivalIn conclusion, delta-tocotrienol did not enhance the efficacy of neoadjuvant breast cancer treatment and did not reduce the frequency of side effects. The results showed no association between the presence of ctDNA and response to neoadjuvant treatment. The sensitivity of the ctDNA assay can be increased by targeting a combination of tissue specific and cancer specific markers and by applying sense and antisense analyses, which allowed for detection of ctDNA in half of the patients. According to existing literature, ctDNA holds the potential of serving as early markers of response to neoadjuvant breast cancer treatment, but there is an obvious need for well planned prospective, preferably randomized trials with high analytical sensitivity.