Serum 25-hydroxyvitamin D levels predict cancer survival: a prospective cohort with measurements prior to and at the time of cancer diagnosis

Abstract

Purpose

Circulating 25-hydroxyvitamin D (25-OHD) levels have been inversely associated with cancer death, but the nature of this relationship is unclear. We investigated this association using repeated measurements of serum 25-OHD.

Patients and methods

Pre-diagnostic serum samples were collected in population health surveys in Norway (1973–2004). Participants who subsequently developed cancer (1984–2004) provided a second serum sample at the time of cancer diagnosis. Samples were stored in the Janus Serum Bank. Repeated samples existed from 202 breast cancers, 193 lung cancers, 124 lymphomas, and 37 colon cancers. Serum 25-OHD was measured via competitive radioimmunoassay. Cox regression models assessed associations between 25-OHD and cancer-specific death (case fatality) through 2012, given as hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

The median time between pre-diagnostic and diagnostic samples was 14.4 years. The median 25-OHD levels were 63.3 and 62.5 nmol/L, respectively. During follow-up, 313 cancer deaths occurred. Compared to low pre-diagnostic 25-OHD levels (<46 nmol/L), higher levels (≥46 nmol/L) had significantly lower HRs (39–54%) of case fatality. This result was also seen for the diagnostic samples. Donors who had both samples at high (≥62 nmol/L) levels had 59% lower HR of case fatality, compared to those for whom both samples were at low levels (<46 nmol/L). Furthermore, versus a decline in serum 25-OHD (median −22.4 nmol/L) from pre-diagnostic to diagnostic samples, a rise (median 22.3 nmol/L) was associated with lower case fatality (HR 0.57, 95% CI 0.43−0.75).

Conclusion

Our findings suggest a causal relationship between vitamin D and cancer case fatality.

Keywords:

• serum 25-OHD
• repeated measurement
• longitudinally
• cancer case fatality

Supplementary materials

Additional analyses were conducted to estimate hazard ratios (HR) of cancer case fatality according to clinical categories of 25-OHD, both for pre-diagnostic and diagnostic samples. The established limits for vitamin D levels are defined with respect to bone health, with cut-off at ≥50 nmol/L for sufficiency.¹ Laboratories use categories of vitamin D levels as follows: deficient <25 nmol/L, insufficient <50 nmol/L, sufficient 50–75 nmol/L and optimal >75 nmol/L.² Due to low numbers (only 9 in deficient), we collapsed the deficient and insufficient categories. Results from the adjusted model (Table S1) show that, compared to insufficient levels (<50 nmol/L), cases with sufficient (50–75 nmol/L) and optimal levels (>75 nmol/L) have significantly lower HRs of case fatality. The association was found for the pre-diagnostic and the diagnostic samples. The dose–response trend was significant (p_trend ≤0.001).

Table S1 Hazard ratios (HR) with 95% confidence interval (95% CI) of cancer case fatality according to clinically categories of pre-diagnostic (I) and diagnostic (II) 25-OHD levels

The 25-OHD levels in the Norwegian population vary by season due to seasonal variation in ultraviolet radiation. To account for this variability, the date of blood sampling was categorized as Winter (December–February), Spring (March–May), Summer (June–August), and Fall (September–November), which variable was included in the analysis model (Tables 2 and 3, adjusted model). In analyses based on combinations of the repeated serum samples, we used another approach to account for seasonal variation. The 25-OHD levels were season-standardized, using a seasonal variation factor that was defined as the ratio of the 25-OHD average to the monthly 25-OHD average. This ratio, which is similar to the ratio in the moving average method of de-trending time-series data,³ was used to smooth out the fluctuations in levels of 25-OHD that are due to season. Table S2 shows HRs of cancer case fatality by season-standardized 25-OHD levels categorized into the predefined 25-OHD categories, separately for the pre-diagnostic and the diagnostic serum samples. Results from the adjusted model show significantly lower HRs of case fatality for cases with serum levels in category 3 (62−81 nmol/L) and 4 (≥82 nmol/L), compared to cases in category 1 (<46 nmol/L). The association was found for pre-diagnostic and diagnostic samples, with a significant dose–response trend (p_trend 0.007 and <0.001, respectively).

Table S2 Hazard ratios (HR) with 95% confidence interval (95% CI) of cancer case fatality according to season-standardized 25-OHD levels in predefined categories of pre-diagnostic (I) and diagnostic (II) 25-OHD levels

Acknowledgments

We address sincere thanks to Janus Serum Bank, which made this study possible. The Norwegian Cancer Society is gratefully acknowledged for grant support, and we also address our thanks to the Hormone Laboratory at Aker, Oslo University Hospital, for the 25-OHD assessment.

Ethical approval

The study was approved by the National Committee for Research Ethics, South-East Health Authority and by the Janus Serum Bank board. All procedures performed in the study were in accordance with ethical standards of the institution and national research committee.

Abbreviations list

25-OHD, 25-Hydroxyvitamin D; HR, hazard ratio; CI, confidence interval; n, number; ICD-10, the World Health Organization’s International Classification of Diseases codes for cancer 10th edition; T, tertile; p_trend, p-value for trend; BMI, body mass index.

Author contributions

All authors contributed towards data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest in this work.