Association of Prostate-Specific Antigen Levels with Prostate Cancer Risk in a Multiethnic Population: Stability Over Time and Comparison with Polygenic Risk Score

Prostate-specific antigen (PSA) is the biomarker most commonly used for prostate cancer screening and multiple studies in the United States and Europe have shown that PSA levels in midlife are associated with increased risk of prostate cancer later in life (1–9). This association is likely the result of increasing PSA production in the prostate reflective of the development of cancer. Studies have also reported midlife PSA levels to be an indicator of disease aggressiveness (10–14). A nested case–control study in the Malmö Preventive cohort found that 44% of prostate cancer deaths occurred in men within the top 10th percentile of PSA levels measured in men 45 to 55 years of age, 25 to 30 years prior to death (15). PSA levels assessed in midlife, 9 years (median) before a prostate cancer diagnosis, were also associated with risk of overall and lethal prostate cancer in a primarily White population under 60 in the Physician's Health Study (16). A more recent study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial also found PSA levels measured 6 years (median) before a prostate cancer diagnosis in middle-ages men (55–60 years old) to be significantly associated with risk of overall and clinically significant prostate cancer (17). These studies in men of European ancestry suggest PSA may be a marker of very early prostate cancer development that may help to risk-stratify men earlier in life (18).

There is limited information on PSA levels and risk of prostate cancer in non-White populations and in men older than 60. In a small study among African American men 40 to 64 years of age in the Southern Community Cohort Study (SCCS) with median follow-up time of 9 years, men with PSA levels in the top decile had a >30-fold increase in risk of prostate cancer compared with those with ≤median PSA levels (19). In the current population-based study, we examined whether PSA levels in older adult men (mean age at blood draw: 68) measured up to 10+ years before a prostate cancer diagnosis were associated with prostate cancer among African American (AA), Latino (LA), Japanese (JA), Native Hawaiian (NH), and Non-Hispanic White (WH) men in the Multiethnic Cohort (MEC). To compare with previous studies, we in addition examined the association between midlife PSA and risk of prostate cancer in men ages 60 years or younger. We also compared the discriminative ability of PSA years before diagnosis to that of the multiancestry polygenic risk score (PRS) for prostate cancer (20).

The MEC is a large prospective multiethnic cohort established between 1993 and 1996 to investigate risk of cancer and other chronic conditions among individuals living in Hawaii and Los Angeles (21). Participants included self-reported AA, LA, JP, NH, and WH race/ethnicity groups who completed a detailed baseline questionnaire to obtain information on cancer risk factors and health conditions (22). On the third questionnaire (between 2003 and 2008), 72% of men reported having undergone PSA screening. Blood samples were collected between 1994 and 2006 from approximately 67,000 participants for nested case–control studies of cancer. Prostate cancer cases and information on Gleason score and stage were identified through linkage of the MEC to Surveillance, Epidemiology, and End Results (SEER) cancer registries in Hawaii and California. Cancer mortality was determined by routine linkages to state death files and to the National Death Index for deaths that occurred outside of Hawaii and California. Inclusion and exclusion criteria were as follow: After exclusion of prevalent prostate cancer cases, this study included 2,245 incident prostate cancer cases diagnosed after blood collection and 2,203 controls. The cases in the study are incident cases whereas controls are men who were selected because they did not have prostate cancer prior to being included in the study. Around 50% of men underwent PSA screening in the MEC. Although controls with undiagnosed disease may have been included, this would only lead to attenuation in the associations reported in this study. Controls included males matched to cases on race/ethnicity, age at blood draw (±5 years), location (Hawaii or Los Angeles), hours of fasting (±2 hours), year of collection (±0.5 years), and time of blood draw (±3 hours). The primary outcomes assessed were overall prostate cancer versus controls, 8+ versus ≤7 Gleason score disease, and localized versus nonlocalized disease. Subgroup analyses were also conducted for lethal prostate cancer, defined as metastatic prostate cancer or death from prostate cancer. All participants provided written informed consent, and study protocols were approved by the Institutional Review Boards overseeing research on human subjects at the University of Hawaii and the University of Southern California.

Immunoassay measurements of total PSA were performed using AutoDELFIA 1235 automatic immunoassay systems, which have been described previously (23). Total PSA values were measured using the dual label DELFIA ProStatus total PSA Assay calibrated in accordance with WHO standards. All measurements were performed blinded to case–control status.

Samples were processed in two batches, with 38 duplicate samples being processed in both batches. Measurements between batches for these 38 samples were highly correlated, and coefficients of variation within batches one and two were comparable, as detailed in a previous study (24).

The genotype data used in this project was derived from multiple GWAS studies of cancer and other phenotypes in the MEC. For all projects, Illumina Infinium arrays were used, with imputation conducted using Minimac4 and the 1000 Genomes (1000G) Project reference panel (Phase 3 v5). Both subject call rates and variant call rates were ≥0.95. Ethnic-specific frequencies were calculated and compared with corresponding ethnic groups in Phase3 1000G for quality control. Infoscore filtering was not implemented in an effort to include all 269 prostate cancer-associated variants (20), as poor imputation is only likely to introduce nondifferential bias. Average r² was 0.88 and only 2 SNPs (0.7%) had r² below 0.30. Principal components were calculated using EIGENSTRAT (25) with 20,202 independent common variants to adjust for potential confounding due to genetic ancestry.

PSA was log-transformed and geometric means were reported adjusted for age at blood draw (and race/ethnicity in the overall sample). In association analyses, age- and ethnicity-adjusted PSA was assessed using residuals from a linear model of log-transformed PSA with covariates for age at blood draw, race/ethnicity, and an interaction term between age at blood draw and race/ethnicity. PSA increases with age and differs between racial/ethnic groups. The interaction between age at blood draw and race/ethnicity was included to standardize subject's PSA by these factors. In this study, the age and ethnicity-adjusted residual PSA is referred to as simply “PSA.” PSA percentile cutoffs were determined using all controls or controls within race/ethnicity group. Unconditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) for the association between PSA levels and risk of prostate cancer phenotypes, adjusting for BMI at blood draw, laboratory batch, and the matching factors. Corresponding conditional logistic models formally accounting for the matching led to qualitatively similar effect estimates but were limited to a smaller sample size. Analyses were also conducted excluding cases diagnosed within 2, 5, and 10 years of blood draw to assess the temporal stability of the association between PSA and prostate cancer risk. We also conducted analyses in men ages 60 or younger to examine the relationship between midlife PSA and risk of prostate cancer.

We also evaluated the discriminative ability of PSA relative to a multi-ancestry PRS for prostate cancer that we previously reported to be strongly associated with prostate cancer risk (20). Of the 4,448 MEC participants, 3,110 had genotype data (24) that could be used to construct the PRS. A weighted PRS was calculated for each participant as the sum of the number of risk alleles carried by an individual, weighted by multi-ancestry variant-specific effects for 269 prostate cancer-associated variants, as described previously (20). Although participants in this analysis were included in the multi-ancestry prostate cancer GWAS, the prostate cancer PRS is unlikely to be noticeably impacted by overfitting because the number of subjects included in the multi-ancestry prostate cancer GWAS meta-analysis (234,253 subjects) was substantially larger compared with that of the current analysis (3,110 subjects). Moreover, we have previously shown that after accounting for the within sample bias using bias-corrected estimates, results were essentially unchanged (20). Because PRS distributions have been shown to differ by populations (20), residuals from a linear regression model of PRS adjusted for race/ethnicity were used in combined analyses including all populations. Principal components were calculated using 20,202 independent common variants to adjust for potential confounding by genetic ancestry (25). In a series of independent unconditional logistic regression models adjusting for the matching factors and the first 10 principal components, we evaluated the association between prostate cancer risk and (i) PRS, (ii) PSA, and (iii) both PRS and PSA, with cases stratified on the basis of time between blood draw and diagnosis (2+, 5+, and 10+ years). ORs are reported per SD increase in PRS and PSA to better compare the relative associations of each factor. Model AUCs were calculated to compare PSA, PRS, and PSA + PRS models’ ability to discriminate between prostate cancer outcomes and controls.

Lorenz curves were used to characterize the proportion of prostate cancer cases captured by various PSA or PRS cut points (12). For most analyses, we focus on reporting effect estimates and corresponding confidence intervals. We only rely on P values for assessment of effect heterogeneity between: Gleason ≤7 and Gleason 8+ prostate cancer; Gleason ≤6, Gleason 7, and Gleason 8+ prostate cancer; nonlocalized and localized prostate cancer; and prostate cancer outcomes across race/ethnicity groups. In this analysis, we consider each outcome as an independent hypothesis and consider statistical significance in two ways: (i) Two-sided P-values <0.05, treating every outcome and subgroup analysis as an independent hypothesis. (ii) Two-sided P-value < α, where α = |$\frac{{0.05}}{{{n}_{{\rm{subgroups}}}}}$| = |$\frac{{0.05}}{8}\ = 0.006 $|⁠, for treating each outcome as an independent hypothesis but correcting for multiple testing across eight subgroups (two PSA percentile subgroups × four time subgroups) within each outcome. Analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria, 2015).

The Multiethnic Cohort investigators and institutions affirm their intention to share the research data consistent with all relevant NIH resource/data sharing policies. Data requests should be submitted through MEC online data request system at https://www.uhcancercenter.org/for-researchers/mec-data-sharing.

The mean age at blood draw for cases was 68 (range: 47–86) and 69 (47–87) for controls (Table 1). Among cases, mean age at diagnosis was 73 years, with a mean timespan between blood draw and a prostate cancer diagnosis of 4.9 years (range: <1 year to 18 years), with 82%, 49%, and 11% having a timespan longer than 2, 5, and 10 years, respectively. In the multiethnic sample, the median PSA level was 1.21 ng/mL (range: 0.05–90.3 ng/mL; IQR: 0.70–2.30 ng/mL) in controls and 3.38 ng/mL (range: 0.11–250 ng/mL; IQR: 2.00–5.59 ng/mL) in cases (Table 1). Among both prostate cancer controls and cases, older age at blood draw was significantly associated with higher PSA level (P < 0.001 and P = 0.004, respectively). Age-adjusted geometric mean PSA was significantly different across race/ethnicity groups in cases (P < 0.001) but not in controls (P = 0.056). Among cases, compared with Whites, African Americans, and Latinos had higher PSA levels, whereas Native Hawaiians and Japanese had lower PSA levels. Among controls, Latinos had the same PSA level as Whites whereas African Americans, Japanese, and Native Hawaiians had lower levels compared with Whites (Table 1).

Compared with men with a PSA level at or below the median in the overall population, ORs (95% CI) for total prostate cancer in men with a PSA above the 50th and 90th percentiles were 10.05 (8.50–11.93) and 24.54 (19.75–30.67), respectively (Table 2). Significant effect heterogeneity (P < 0.05) was observed between Gleason ≤7 prostate cancer and Gleason 8+ prostate cancer for men with a PSA above the 50th and 90th percentiles: ORs for Gleason ≤7 prostate cancer were higher [11.89 (9.75–14.61) and 27.49 (21.53–35.39), respectively], whereas ORs for Gleason 8+ prostate cancer were lower [6.65 (5.07–8.85) and 17.04 (12.40–23.71), respectively; Table 2]. This trend was also observed when comparing risks for Gleason ≤6, Gleason 7, and Gleason 8+ tumors (Supplementary Table S1). After considering multiple tests across subgroups, significant effect heterogeneity (P < 0.006) is observed for PSA above the 50th percentile. ORs for localized prostate cancer were lower [10.26 (8.53–12.42) and 24.20 (19.21–30.68), respectively], compared with nonlocalized prostate cancer [11.63 (7.80–18.14) and 29.81 (18.94–48.78), respectively], although the differences were not statistically significant (Table 2).

The positive association between PSA and prostate cancer risk attenuated with time between the PSA measurement and prostate cancer diagnosis (Table 2). Excluding cases diagnosed within 2, 5, and 10 years of blood draw, compared with men with PSA below the median, men with PSA above the median had ORs for total prostate cancer (95% CI) of 9.12 (7.66–10.92), 6.65 (5.43–8.20), and 3.52 (2.50–5.03), respectively. Excluding cases diagnosed within 2, 5, and 10 years of blood draw, the magnitude of the associations were consistently and significantly (P_{heterogeneity} < 0.05) higher for Gleason ≤7 compared with Gleason 8+ prostate cancer (Table 2). After considering multiple tests across subgroups, significant effect heterogeneity (P < 0.006) is observed for PSA above the 50th percentile. The magnitude of associations were lower for localized compared with nonlocalized prostate cancer, although the differences were not statistically significant (Table 2). Overall, the magnitude of the associations were greater for all race/ethnicity groups compared with WH, although statistically significant effect heterogeneity was only observed for total prostate cancer and PSA above the median versus below the median measured 5+ years before a prostate cancer diagnosis when considering a single test (P < 0.05), but not after consideration of multiple tests (P < 0.006; Table 3; Supplementary Table S2).

As shown in Fig. 1 and Supplementary Table S3, 91% of all prostate cancer cases occurred among those with a PSA level above the median, whereas 42% of cases occurred among those with a PSA level in the top 10th percentile. Excluding cases diagnosed within 2, 5, and 10 years of blood draw, 90%, 86%, and 75% of all prostate cancer cases occurred among those with a PSA level above the median, respectively, whereas 36%, 26%, and 19% of cases occurred among those with a PSA level in the top 10th percentile, respectively. These percentages were higher for Gleason ≤7 prostate cancer (92%, 91%, and 88%) compared with Gleason 8+ prostate cancer (87%, 85%, 80%) among those with PSA above the median (Supplementary Table S3; Supplementary Figs. S1 and S2), whereas percentages were similar for localized (91%, 90%, 85%) and nonlocalized prostate cancer (92%, 92%, 89%; Supplementary Table S3; Supplementary Figs. S3 and S4). There were 171 lethal cases, with 141, 79, and 19 diagnosed more than 2, 5, and 10 years since blood draw, respectively. At 10+ years since blood draw, 68% of lethal cases occurred among men with a PSA above the median, whereas 16% occurred in men in the top 10th percentile. Percentages of total prostate cancer and different disease characteristics captured were similar across populations (Figs. 1; Supplementary Figs. S1 and S4; Supplementary Table S3).

For 436 cases and 342 controls ages 60 or younger at blood draw, mean age at blood draw was 57 (range: 47–60). Among cases, the average timespan between blood draw and a prostate cancer diagnosis was 6.3 years (range: <1 year to 18 years). In this younger group of men, OR for total prostate cancer were elevated compared with those estimated in the full sample, although no significant effect heterogeneity was observed (Supplementary Tables S4–S6). Compared with men with PSA below the median, men with PSA above the median had an OR (95% CI) of 16.22 (10.43–26.17), and ORs of 14.81 (9.51–23.91), 12.91 (7.97–21.83), and 7.44 (3.69–16.31) when excluding cases diagnosed within 2, 5, and 10 years of blood draw, respectively (Supplementary Table S4). As shown in Supplementary Fig. S5 and Supplementary Table S7 for men ages 60 or younger, 94% of all prostate cancer cases occurred among those with a PSA level above the median which reduced only slightly to 93%, 92%, and 85% when excluding cases diagnosed within 2, 5, and 10 years of blood draw. As observed in all men, the percentages were higher for Gleason ≤7 versus Gleason 8+ tumors (Supplementary Table S7).

Finally, we compared the performance of PSA measured 2, 5, and 10 years before diagnosis to a multi-ancestry prostate cancer PRS (20). The correlation (r) between the PRS and PSA decreased with time from PSA measurement to diagnosis. The correlation was 0.24 in the overall population, 0.10 in cases and 0.12 in controls. Excluding cases diagnosed within 2, 5, and 10 years of blood draw, the correlation between prostate cancer PRS was 0.22, 0.19, and 0.14, respectively in the overall population, and 0.08, 0.06, and 0.11, respectively in cases. As shown in Fig. 1, 42% of cases occurred among those in the top 10th percentile of the PSA distribution, with this number decreasing to 36%, 26%, and 19% when excluding cases diagnosed within 2, 5, and 10 years of blood draw, respectively, whereas 26% of cases occurred among those in the top 10th percentile of the PRS distribution. Although PSA is more informative closer to the time of diagnosis, at 10+ years, the magnitude of the association of PSA (OR per SD increase: 1.88; 95% CI, 1.45–2.46) was comparable with that of the PRS (OR per SD increase: 2.12; 95% CI, 1.55–2.93) in a model that mutually adjusted the effects of both PSA and PRS (Fig. 2). PRS and PSA measured 10+ years before diagnosis captured a similar percentage of cases across percentiles of PRS and PSA for all prostate cancer outcomes (e.g., Gleason ≤7 or 8+, localized, nonlocalized, and lethal disease; Supplementary Figs. S1 and S4), and the magnitudes of the associations of PSA were comparable with that of the PRS (Supplementary Fig. S6). In case–case comparisons of Gleason 8+ versus ≤7 prostate cancer and localized versus nonlocalized disease, no statistically significant difference was observed between PSA and PRS when excluding cases diagnosed within 2, 5, and 10 years of blood draw (Supplementary Fig. S7). Comparing model AUCs between PSA, PRS, and PSA+PRS similarly showed that whereas PSA's discriminative ability was better closer to the time of diagnosis, at 10+ years, the discriminative ability of PSA was comparable with that of PRS (Supplementary Table S8). AUCs for PSA+PRS were comparable with that of PSA across time. These observations were similar for all prostate cancer outcomes.

In this multiethnic study, we found that a PSA measurement taken 5 years on average before diagnosis was associated with prostate cancer risk. The association was observed to be consistent across racial/ethnic populations, was significantly stronger for men with low-grade versus high-grade disease but similar for advanced and lethal versus localized disease. We also found PSA to be less effective as a marker of risk with increased length of time since measurement, and at 10+ years before diagnosis, the magnitude of the association of PSA with prostate cancer risk was observed to be equivalent to that of the PRS.

Our findings in this multiethnic population with opportunistic screening are consistent with studies in U.S. White and African American men (16, 17, 19). In a nested case–control study in the PHS of primarily White men ages 40 to 59 years, with PSA measured a median of 9 years before prostate cancer diagnosis, ORs (95% CI) for total prostate cancer in men with a baseline PSA above the median and 75th percentile were 8.7 (5.5–13.9) and 14.1 (8.6–23.3), respectively, compared with men with PSA below the median (16). Among White men ages 60 or younger in our study, we observed comparable effect sizes for total prostate cancer of 7.9 (3.8–17.4) and 14.0 (6.2–34.6) with PSA above the median and 75th percentile, respectively, measured 6 years on average before prostate cancer diagnosis. We also observed similar effect sizes for total prostate cancer in the other racial/ethnic groups. In PHS, ORs (95% CI) for lethal prostate cancer in men with a baseline PSA above the median, and 90th percentile were 3.1 (1.6–6.1) and 7.4 (3.3–16.6), respectively (16). In our multiethnic study, with PSA measured at least 5 years before diagnosis, we observed similar ORs for lethal prostate cancer in men with a PSA above the median, and 90th percentiles [3.6 (2.1–6.5) and 7.5 (3.9–14.7), respectively]. In a small nested case–control study in the SCCS among African American men, ORs for prostate cancer in men with a baseline PSA above the median, and 90th percentile were 18.8 (9.5–42.3) and 71.5 (31.0–190), respectively (19), with similar effect sizes reported in a subset of men (n = 91) with aggressive prostate cancer. Our results are consistent with these previous U.S. studies that emphasized PSA being predictive of future lethal prostate cancer. Our findings are also in line with the consistent observation from these studies that PSA does not differentiate predicting indolent versus lethal prostate cancer.

Opportunistic PSA screening is a potential limitation in interpreting results of U.S.-based studies examining PSA as a predictive marker for prostate cancer and lethal disease. Screened men with higher PSA levels when measured may be at greater risk of eventually having a tumor that would have progressed but are more likely to have their cancer detected and treated. This results in fewer nonlocalized and lethal cases in this group of men compared with a nonscreened population. As a result, this would lead to an attenuation of the association of PSA levels years before diagnosis with overall prostate cancer and advanced stage disease (e.g., nonlocalized, metastatic, and lethal prostate cancer). This potential bias may explain the lack of significant differences in the PSA association by disease stage in our study and in the previous U.S.-based studies conducted following the introduction of PSA screening. However, we also found the magnitude of PSA associations to be significantly stronger for less aggressive Gleason ≤7 versus 8+ tumors, which does not support the underlying hypothesis that PSA is a marker for more aggressive disease. This unexpected result is less likely to be due to opportunistic screening as grade progression is less common (26). We expect that the results from this multiethnic study of older men (and from the analysis of men ages <60) undergoing opportunistic screening would be generalizable to men in the U.S. today.

As reported in previous studies (19, 27), we observed that PSA is less effective as a marker of prostate cancer risk with increased length of time since PSA measurement, with 90% of cases captured in the top PSA decile for cases diagnosed more than 2 years after blood draw, which was reduced to 75% for cases 10+ years since blood draw; these percentages were similar for the other prostate cancer endpoints and 86% and 68% for lethal prostate cancer, respectively. When limited to cases diagnosed 10+ years after a PSA measurement, we found the association of PSA (OR per SD increase = 1.9; 95% CI, 1.5–2.5) to be comparable with that of the PRS (OR per SD increase = 2.1; 95% CI, 1.6–2.9). Given the attenuated effect of PSA with time to diagnosis, the PRS assigned risk at birth is likely to be a comparable indicator of risk earlier in life until prostate cancer starts to develop and PSA levels rise. On the basis of our findings, PSA appears to only be more effective than PRS as an indicator of risk within 10 years of diagnosis, with both PRS and PSA having limited ability to differentiate risk of advanced versus localized disease.

In conclusion, in this multiethnic study population with opportunistic screening, PSA was significantly associated with prostate cancer risk, with the effectiveness of PSA for risk prediction significantly attenuated with time to prostate cancer diagnosis. Our findings among older men suggest that PSA is informative as a marker of risk within 10 years of diagnosis, whereas the PRS is comparable for risk stratification earlier in life. Although we did not find PSA to differentiate risk of advanced versus localized disease, only a small fraction of non-localized (23%) or lethal disease (32%) occurred in men with PSA levels below the median, diagnosed 10 or more years after blood draw. These suggest, as indicated by others (17), that a risk-stratified approach to screening is warranted (based on early life PSA and/or PRS), with men at low risk being screened less frequently than men at high risk, which would translate into fewer biopsies, associated complications, and overdiagnoses for men at lower risk of dying from prostate cancer.

H. Lilja reports grants from Memorial Sloan Kettering Cancer Center and Lund University during the conduct of the study; other support from OPKO Health, Diaprost AB, and Acousort AB and personal fees from Fujirebio Diagnostics Inc. outside the submitted work; also has a patent for Antibody, immunoassay and method for prostate cancer detection issued, licensed, and with royalties paid from Arctic Partners/OPKO Health, a patent for Methods and apparatuses For predicting risk Of prostate cancer and prostate gland volume, issued, licensed, and with royalties paid from Arctic Partners/OPKO Health, and a patent for Free PSA antibodies as diagnostics, prognostics and therapeutics for prostate cancer, issued, licensed, and with royalties paid from Diaprost AB/Radiopharmtheranostics. D.V. Conti reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors.

A. Chou: Conceptualization, data curation, software, formal analysis, investigation, visualization, methodology, writing–original draft, writing–review and editing. B.F. Darst: Conceptualization, data curation, investigation, methodology, writing–review and editing. L.R. Wilkens: Conceptualization, resources, data curation, investigation, methodology, writing–review and editing. L. Le Marchand: Conceptualization, resources, data curation, investigation, methodology, writing–review and editing. H. Lilja: Conceptualization, investigation, methodology, writing–review and editing. D.V. Conti: Conceptualization, resources, data curation, software, supervision, investigation, methodology, writing–review and editing. C.A. Haiman: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, methodology, writing–review and editing.

The Multiethnic Cohort Study (MEC) is supported by NIH/NCI grant U01 CA164973. This work was supported by the NCI at the NIH (grant nos. U01 CA164973 to C. Haiman and K99 CA246063 to B. Darst), the Prostate Cancer Foundation (grants 21YOUN11 to B. Darst and 20CHAS03 to C. Haiman), and the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B. Darst. H. Lilja was supported in part by the NIH/NCI with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to H. Scher (P50 CA092629), and by Grant Award from the Swedish Cancer Society to H. Lilja (Cancerfonden 20 1354 PjF).

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