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Magnetic resonance imaging (MRI) is increasingly used to triage patients for prostate biopsy. However, 9% to 24% of clinically significant (cs) prostate cancers (PCas) are not visible in MRI. We aimed to identify histomic and transcriptomic determinants of MRI visibility and their association to metastasis, and PCa‐specific death (PCSD). We studied 45 radical prostatectomy‐treated patients with csPCa (grade group [GG]2‐3), including 30 with MRI‐visible and 15 with MRI‐invisible lesions, and 18 men without PCa. First, histological composition was quantified. Next, transcriptomic profiling was performed using NanoString technology. MRI visibility‐associated differentially expressed genes (DEGs) and Reactome pathways were identified. MRI visibility was classified using publicly available genes in MSK‐IMPACT and Decipher, Oncotype DX, and Prolaris. Finally, DEGs and clinical parameters were used to classify metastasis and PCSD in an external cohort, which included 76 patients with metastatic GG2‐4 PCa, and 84 baseline‐matched controls without progression. Luminal area was lower in MRI‐visible than invisible lesions and low luminal area was associated with short metastasis‐free and PCa‐specific survival. We identified 67 DEGs, eight of which were associated with survival. Cell division, inflammation and transcriptional regulation pathways were upregulated in MRI‐visible csPCas. Genes in Decipher, Oncotype DX and MSK‐IMPACT performed well in classifying MRI visibility (AUC = 0.86‐0.94). DEGs improved classification of metastasis (AUC = 0.69) and PCSD (AUC = 0.68) over clinical parameters. Our data reveals that MRI‐visible csPCas harbor more aggressive histomic and transcriptomic features than MRI‐invisible csPCas. Thus, targeted biopsy of visible lesions may be sufficient for risk stratification in patients with a positive MRI. [ABSTRACT FROM AUTHOR]

Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient‐derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug‐sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer‐specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR‐inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug–response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients. What's new? The comparison of drug responses among multiple variants of patient‐derived cells (PDCs) exhibited the impact of intra‐tumor genomic heterogeneity, as the individual PDCs from different tumor regions showed distinct drug sensitivity profiles. These data illustrate an approach that could facilitate the design of effective personalized drug combinations needed to target multiple subclones in cancer and for elucidating pharmacogenomic biomarkers. [ABSTRACT FROM AUTHOR]

Antihypertensive (anti‐HT) drugs targeting renin‐angiotensin‐aldosterone (RAA)‐ system have been associated with improved prostate cancer (PCa)‐specific survival. Challenge is that often multiple drugs are used simultaneously. We evaluated the association between use of anti‐HT drugs and PCa survival among 14,422 surgically treated Finnish PCa patients. Information on drug purchases was obtained from a national prescription database. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of PCa death and initiation of androgen deprivation therapy (ADT) with adjustment for age, tumor extent, use of statins and for Charlson Comorbidity Index. Angiotensin‐converting enzyme (ACE)‐ inhibitors, angiotensin‐ receptor (ATR)‐blockers, diuretics, calcium‐channel blockers, beta‐blockers and other anti‐HT drugs were analyzed as separate time‐dependent variables to model simultaneous use. Overall anti‐HT drugs were associated with an increased risk of PCa death. Conversely use of ATR‐blockers was associated with decreased risk of PCa death (HR: 0.43, 95% CI: 0.26–0.72 and HR: 0.60, 95% CI 0.37–0.97 for pre‐ and post‐diagnostic use). Similar risk decrease was not observed in other drug groups. Anti‐HT drugs were also associated with an increased risk of starting ADT, with the exception of ATR‐blockers (HR: 0.81 CI:0.71–0.92). ATR‐ blockers differ from other anti‐HT drugs as the survival is better in users of this drug group. The result partly supports the role of RAA system in PCa progression. Nevertheless, the risk decrease was not observed in ACE‐inhibitor users. Further research is needed to elucidate the molecular mechanism for the potential anticancer effect of ATR‐ blockers. What's new? While hypertension is a suspected risk factor for prostate cancer, it remains unclear whether antihypertensive drugs reduce prostate cancer risk or improve prognosis. Moreover, previous studies have identified potentially harmful associations. Along those lines, the authors of the present study found an association between overall antihypertensive drug use and increased risk of prostate cancer death. Investigation of specific drugs, however, suggested that angiotensin‐receptor blockers are associated with reduced risks of initiation of androgen‐deprivation therapy and prostate cancer death. Survival was also higher among patients who used angiotensin‐receptor blockers, compared to other antihypertensive drugs. [ABSTRACT FROM AUTHOR]

Lai I et al i . wonder whether androgens would be a potent confounding subject for prostate cancer (PCa) diagnosis. However, considering the question asked, there is evidence that androgen levels are, in fact, not associated with PCa risk,[2] nor is testosterone therapy given as hormone replacement therapy.[3] Thus, it is not likely that androgens serve as confounding factors for PCa risk. So, if not considered in earlier studies, it may even be possible that reduced risk of PCa diagnosis among calcium channel blocker users is caused by, for example, angiotensin-receptor blockers (ATR-blockers) used together with calcium channel blocker therapy. [Extracted from the article]