Is PFOA a renal carcinogen?

Research Highlights P R O S TAT E C A N C E R K ID N E Y C A N C E R Final SPARTAN data show OS benefit Mature data from the SPARTAN study, which evaluated the outcomes of apalutamide treatment versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and a PSA doubling time of ≤10 months, have shown a significant overall survival (OS) benefit in this patient group. Primary analysis results from SPARTAN have previously been published and showed that apalutamide improved median metastasis-free survival (MFS) by 2 years over placebo plus androgen deprivation therapy (ADT). These interim data led to the approval of apalutamide for the treatment of nmCRPC and metastatic castration-sensitive prostate cancer; however, the OS data were immature, although interim analysis of progression-free survival data did suggest an improvement with apalutamide therapy. The prespecified, event-driven final analysis data for SPARTAN have now been reported in European Urology. In SPARTAN, patients with nmCRPC were randomized 2:1 to receive 240 mg apalutamide daily (n = 806) or placebo plus ongoing ADT (n = 401). Patients who developed distant metastases remained blinded to their treatment but were permitted subsequent therapy of abiraterone plus prednisone. The primary end point was MFS, with OS and time to cytotoxic chemotherapy (TTChemo) as secondary end points. After unblinding, 76 (19%) patients in the placebo group without disease progression crossed over to receive openlabel apalutamide; of the 401 patients initially randomized to the placebo group, 338 (84%) received either life-prolonging active therapy upon disease progression or apalutamide as a crossover treatment option without progression after unblinding. Median treatment duration was 21.4 months longer on apalutamide than placebo (32.9 and 11.5 months, respectively). Apalutamide decreased the hazard of death by 22% compared with placebo in the intent-to-treat population (HR 0.78 (95% CI 0.64–0.96); P = 0.016). A statistically significant improvement was observed in OS; median OS was 73.9 (61.2–not reached) months for apalutamide and 59.9 (52.8–not reached) months for placebo. At final analysis, 258 patients had begun chemotherapy (155 on apalutamide; 103 on placebo). Apalutamide decreased the hazard of initiating cytotoxic chemotherapy by 37% versus placebo (HR 0.63 (95% CI 0.49–0.81); P = 0.0002), and median TTChemo was not reached in either group. These results from SPARTAN, alongside data from the PROSPER and ARAMIS trials (evaluating treatment with enzalutamide and darolutamide, respectively), illustrate the clinical benefit of the addition of an androgen signalling inhibitor to ADT for patients with nmCRPC. Annette Fenner Original article Smith, M. R. et al. Apalutamide and overall survival in prostate cancer. Eur. Urol. https://doi.org/10.1016/j.eururo.2020.08.011 (2020) Related article Schmid, S. & Omlin, A. Progress in therapy across the spectrum of advanced prostate cancer. Nat. Rev. Urol. 17, 71–72 (2020) 602 | NOVEMBER 2020 | volume 17 Is PFOA a renal carcinogen? Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are highly per sistent hydrophobic, lipophobic and heat-resistant chemicals. Their widespread commercial and industrial use over the past 70 years means that they have been released into the environment and their C–F bonds ensure that they resist degradation, contaminating ground and surface water and soil and accumulating in drinking water. PFAS have been detected in >98% of the US population in the US National Health and Nutrition Examination Survey (NHANES), but whether they act as renal carcinogens in the concentrations they are found in the general population remains uncertain. Perfluorooctanoic acid (PFOA) has been classified as a possible human carcinogen in renal cell carcinoma (RCC) by the International Agency for Research in Cancer, but other PFAS remain unstudied in terms of kidney cancer risk. “To our knowledge, no studies have examined whether PFOA is associated with increased risk of RCC at levels of exposure comparable to those seen in the US general population,” corresponding author Jonathan Hofmann tells Nature Reviews Urology. “Additionally, associations with RCC for other PFAS have not been evaluated.” Hofmann’s team investigated the role of PFAS in renal cancer in patients from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) and matched control samples. Prediagnostic serum concentrations of ten PFAS analytes including PFOA and perfluorooctane sulfonic acid (PFOS) and isomers thereof were measured. Concentrations were reported for PFOA and PFOS as the sums of their respective isomers. Serum cystatin C and creatinine were also measured in all samples in order to account for the fact that reduced kidney function might affect serum PFAS concentrations. Data were available from 324 patients who went on to develop RCC and 324 controls. “This is the first prospective study to investigate the associations between blood serum concentrations of individual PFAS and RCC risk in a group of people with PFAS concentrations comparable to those found in the general population,” comments Hofmann. Statistical analysis revealed significant positive trends between increased RCC risk with increasing prediagnostic concentrations of several PFAS including PFOA (highest quartile versus lowest, OR 2.63, 95% CI 1.33–5.20; Ptrend = 0.007), PFOS (OR 2.51, 95% CI 1.28–4.92; Ptrend = 0.009) and perfluorohexane sulfonic acid (OR 2.07, 95% CI 1.06–4.04; Ptrend = 0.04). When PFAS concentrations were modelled continuously, a doubling in serum PFOA concentrations was associated with a ~70% increase in RCC risk (ORcontinuous 1.71, 95% CI 1.23–2.37; P = 0.002). Interestingly, PFAS concentrations also varied according to race: in multivariable analyses, adjusted geometric mean concentrations of PFOS, perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid were significantly higher in African American participants than in non-Hispanic white participants (P < 0.01). “Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical in the USA and worldwide,” concludes Hofmann. “Efforts to replicate these findings are needed, particularly in populations with racial and ethnic diversity. Notably, the incidence of RCC in the USA differs by race, with the highest rates among Black Americans; as in previous studies, we observed higher concentrations of certain PFAS among Black Americans in our study.” Annette Fenner Original article Shearer, J. J. et al. Serum concentrations of per- and polyfluoroalkyl sub stances and risk of renal cell carcinoma. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa143 (2020) www.nature.com/nrurol  (...truncated)