This represents, to our knowledge, the first reported case of an unusually dramatic and durable tumor response to palliative intent RT after SD obtained initially with 6 cycles of Docetaxel and ADT in PC patients.
MMR defects are represented in all tumor histology subtype (mostly endometrial, colorectal and gastric), and it is estimated that dMMR cancers are approximately 2–4% of all those diagnosed [8, 9]. Loss of MMR activity, due to the lack of function of any of its functional elements, is associated with tumor development and MSI. At the genomic level, dMMR tumors accumulate large numbers of frameshifts (FS) and single-nucleotide variants (SNV), and are therefore characterized by high mutational burden .
The peculiar genomic landscape of MSI tumors uniquely contributes to the quality of the tumor neoantigen profiles. Neoantigens result from FS and SNV, therefore an increasing number of FS and SNVs increases the probability that the tumor forms immunogenic antigens which can induce an immune response. Tumors with a fewer number of mutations are less likely to produce immunogenic antigens and probably will be less responsive to immunotherapy and vice versa . Likely as a consequence, when compared with their microsatellite stable (MSS) counterpart, MSI tumors typically have a higher density of Th1 and effector-memory T cells, more in situ proliferating T cells, upregulated expression of immune checkpoints inhibitors (ICIs), including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), and higher infiltration by mutation-specific cytotoxic T cells .
Based on the assumption that MSI plays a key role in the genetic tumor development and ongoing genetic modifications in established tumors, a potential correlation between response to ICIs and dMMR has been investigated. Le et al. evaluated immunotherapy with pembrolizumab in patients affected by MSI cancer (both CRC and nonCRC) and MSS CRC. Objective response rates (ORRs) for MSI CRC and MSI nonCRC were 40% and 71%, respectively, compared with 0% for microsatellite stable CRC . These data suggest that MSI tumors might be particularly responsive to ICIs. Subsequent retrospective analyses have been conducted to confirm previous results . Pembrolizumab was finally approved in May 2017 by the US Food and Drug Administration for unresectable or metastatic MSI-H solid tumor treatment, if progressed after standard treatment and in the absence of other valid alternatives.
The role of MSI in response to anti-PD-1 ICIs in PC was largely unknown because only one patient with PC was included in the series by Le et al . More recent [15, 16] demonstrated that pembrolizumab leads to responses or stable disease in subsets of patients with MSI-H CRPC, including those whose tumor expressing PD-L1. Although molecular features that contribute to response are currently not completely known, it seems now clear that MSI leads to an enhanced and effective immune system response, if stimulated by ICIs.
The role of RT in stimulating immune response has been investigated for a long time. To date we know that radiation causes DNA DSBs and Deng et al. suggested that RT damage plays a key role in stimulating interferon (IFN) expression, perhaps most efficiently by moderately hypofractionated RT regimens . Furthermore Dewan et al. demonstrated that RT with hypofractionated regimens can stimulate “abscopal responses” when combined with ICIs. Other studies hypothesized also that, in some cases, RT may successfully immunize the patient against the cancer, converting the irradiated tissue into an in situ vaccine and endowing the host with a set of new and powerful tools to control systemic disease .
Clinical experiences regarding the response of MSI tumors to RT are mainly retrospective.
Main evidence obviously relates to CRC and several studies showed no significant correlation between MSI and a better response to RT , contrary to what could be expected from the in-vitro analyses mentioned above [6, 7]. Further investigations have been conducted in the context of MSI endometrial cancer. These retrospective analyses again did not highlight a correlation between MSI and radiosensitivity , but rather showed a significant association between MSI and poorer 10-year local disease-free survival, disease-free survival, and cancer-specific survival , while on the other hand an excellent response and even abscopal effects were reported for the combination of RT and ICIs . Therefore, the correlation between RT response and MSI has yet to be clearly understood, as controversial results between preclinical and clinical data have been reported and as there are inconclusive data regarding the effect of RT only vs. a combination of RT and IT.
Our experience, however, suggests that investigation of MSI-status in these patients may be worthwhile in patient-specific treatment choice with minimal toxicity, either as monomodality treatment (for example in the case of RT with moderate doses to large volumes encompassing all macroscopic disease) or - even more likely to result in local and systemic response - as a combination of RT and IT , which may result in a dramatic benefit for these patients. The concept of applying moderate RT doses to macroscopic disease in combination with newer sensitizing systemic agents is currently investigated in various settings, with first promising results, for example for the combination of palliative dose RT and Trabectidin in patients with metastatic soft tissue sarcoma, having been reported recently .