Despite advances in clinical management, a proportion of patients with early-stage triplenegative breast cancer (TNBC) recur after local treatment. The concept of neoadjuvant systemic therapy has been widely adopted to improve clinical outcomes of patients with TNBC and other breast tumour types. Recently, promising data were reported from the first prospective phase III, randomised trial assessing neoadjuvant chemotherapy combined with the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab versus placebo in patients with early-stage TNBC. The addition of pembrolizumab resulted in a significant increase in pathologic complete response (pCR) rates. Similarly, in the IMpassion031 trial, the use of atezolizumab in combination with neoadjuvant chemotherapy in patients with early-stage TNBC led to improved pCR rates compared to placebo, regardless of programmed death ligand 1 (PD-L1) expression. Ongoing trials are testing other PD-1/PD-L1 inhibitors in combination with neoadjuvant chemotherapy in TNBC and other tumour subtypes. However, not all patients benefit from the addition of immunotherapy, while a proportion of patients experiences serious adverse events. It is critical to identify predictive biomarkers of response, to accurately select patients who will benefit from immunotherapy, thus sparing the rest from ineffective treatments with unnecessary toxicity and treatment costs. In this review, we summarise the literature on reported and ongoing neoadjuvant clinical trials evaluating immunotherapy in breast cancer.
Backround
Accurate surrogate parameters for radio resistance are warranted for individualized radiotherapy (RT) concepts in prostate cancer (PCa). The purpose of this study was to assess intertumoral heterogeneity in terms of radio resistance using an ex-vivo γH2AX assay after irradiation of prostate biopsy cores and to investigate its correlation with clinical features of respective patients as well as imaging and genomic features of tumor areas.
Methods
Twenty one patients with histologically-proven PCa and pre-therapeutic multiparametric resonance imaging and prostate-specific membrane antigen positron emission tomography were included in the study. Biopsy cores were collected from 26 PCa foci. Residual γH2AX foci were counted 24 h after ex-vivo irradiation (with 0 and 4 Gy) of biopsy specimen and served as a surrogate for radio resistance. Clinical, genomic (next generation sequencing) and imaging features were collected and their association with the radio resistance was studied.
Results
In total 18 PCa lesions from 16 patients were included in the final analysis. The median γH2AX foci value per PCa lesion was 3.12. According to this, the patients were divided into two groups (radio sensitive vs. radio resistant) with significant differences in foci number (p < 0.0001). The patients in the radio sensitive group had significantly higher prostate specific antigen serum concentration (p = 0.015), tumor areas in the radio sensitive group had higher SUV (standardized uptake values in PSMA PET)-max and -mean values (p = 0.0037, p = 0.028) and lower ADC (apparent diffusion coefficient-mean values, p = 0.049). All later parameters had significant (p < 0.05) correlations in Pearson’s test. One patient in the radio sensitive group displayed a previously not reported loss of function frameshift mutation in the NBN gene (c.654_658delAAAAC) that introduces a premature termination codon and results in a truncated protein.
Conclusion
In this pilot study, significant differences in intertumoral radio resistance were observed and clinical as well as imaging parameters may be applied for their prediction. After further prospective validation in larger patient cohorts these finding may lead to individual RT dose prescription for PCa patients in the future.
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