Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we (1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, (2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and (3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches.

The transfer of a small number of cells between parent and offspring during pregnancy, commonly referred to as microchimerism, is thought to occur in all human pregnancies. The impact of microchimeric cells on health outcomes in mothers and offspring with respect to cancer, remains unknown. Molecular and epidemiological studies yield conflicting results on the link between microchimerism and cancer, underscoring the complexity of this phenomenon. Further, most studies on microchimerism and cancer focus on the relationship between circulating fetal cells in parous women. Given that the cellular exchange between the mother and offspring is thought to have arisen due to the evolution of internal gestation, we provide an evolutionary perspective on how internal gestation may impact the risk of cancer in humans. We highlight the potential mechanisms that may play a role in cancer vulnerability in mammals, such as genomic conflict and placental invasion. We then review the literature to investigate the effects of microchimerism on cancer outcomes in parous women, highlighting each study's interpretation of the role microchimeric cells play in cancer development, whether it is a protective or contributing role. We conclude that our current understanding of the relationship between microchimerism and cancer is poorly understood and propose mechanisms for when we would expect to see microchimerism contribute to a role in protecting the host from cancer and when microchimerism may contribute to tumor development. Future studies, including more advanced methods to detect and identify microchimerism, will be important for elucidating the link between microchimerism and cancer initiation and progression.