Lung Cancer Calcium Intake Pooling Project

We will apply for extramural NIH funding.

Lung cancer is the leading cause of cancer death in the world, and survival among lung cancer patients is generally poor; 5-year survival is estimated to be 9-15% (1). Bone metastasis is one of the major complications among these patients and is incurable with a median survival time of 4 months (2). Although tobacco smoking is the leading cause of lung cancer, up to 25% of lung cancer cases are non-smokers, and non-smoking-related risk factors are not well understood (3). In China, despite a very low prevalence of female smokers (2.4%) (4), lung cancer incidence is relatively high among these women (19.0 per 100,000 person-years) (1). In the Shanghai Women’s Health Study, we recently observed a strong inverse association between dietary calcium intake and lung cancer risk among non-smokers [hazard ratio (HR) = 0.66 and 95% confidence intervals (CI) = 0.48-0.91 comparing the highest quartile with the lowest] (5). This finding is supported by one previous study (6), but not two other studies (7, 8). None of these studies, however, had sufficient numbers of cases to evaluate this association among non-smokers. Our finding is also corroborated by in vitro and experimental studies that suggest a potential role for calcium in carcinogenesis, especially through cell signaling and cell cycle regulation (9).

Plasma calcium concentration is tightly regulated by parathyroid hormone (PTH) and vitamin D, through calcium absorption, deposition and resorption, and excretion. Increasing calcium and/or vitamin D intakes may affect bone turnover markers, but not necessarily circulating calcium concentrations (10, 11). Thus, measurement of biomarkers related to calcium metabolism is necessary to elucidate the role of calcium in chronic diseases.

In vitro studies suggest that osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) play important roles in bone turnover and were recently linked to immune system and tumor growth (12). PTH-related proteins, 1,25-dihydroxyvitamin D, and prostaglandins can induce the expression of RANKL for bone resorption (13, 14). OPG is a member of the tumor necrosis factor (TNF) receptor superfamily and inhibits bone resorption by binding to RANKL (14). RANKL is expressed in lung cancer cells (15) and experimental studies suggest that RANKL may serve as a major mediator for skeletal morbidity among cancer patients (14). Further, serum OPG concentrations have been positively associated with the risk of other chronic diseases, such as coronary events and carotid atherosclerosis (16, 17). Other bone turnover markers, including serum bone-specific alkaline phosphatase (BALP) for bone formation and N-terminal telopeptide cross-link of type I collagen (NTX) for bone resorption, have also been associated with the risk of disease progression among lung cancer cases (18, 19) and have been used clinically for monitoring skeletal-related complications (20). In comparison with controls, serum concentrations of BALP, RANKL and OPG and the ratio of RANKL to OPG were generally higher in lung cancer cases (21-23), particularly among the cases with bone metastasis (21). Additionally, in a cohort of osteoporotic men and women in Denmark, the risk of lung cancer was higher than the general population (24). Since these studies, except for the Danish cohort study, were conducted retrospectively and included a small number of participants, their findings need to be followed up in a large prospective study.

(List of references is included in a separate file.)

The overall goal of the proposed project is to evaluate the role of calcium intake and bone turnover in lung cancer among non-smokers.

1. To evaluate the association between dietary calcium intake and the risk of incident lung cancer among non-smokers.

2. To test whether bone turnover markers, including plasma or serum OPG, RANKL, and the ratio of RANKL to OPG, are associated with lung cancer risk among non-smokers.

3. To test whether these associations are modified by vitamin D status, age group, menopausal status, or hormone therapy use.

We propose to conduct a nested case-control study and select controls matched on age, gender, date of blood draw, and race/ethnicity. Multivariate conditional logistic regression will be used to calculate odds ratios and the 95% CIs for lung cancer risk. Calcium intake and bone turnover markers will be analyzed both continuously and categorically.

Lung cancer incidence among non-smokers is rare and a consortium approach is needed to ensure sufficient statistical power for testing the proposed aims.

50

Primary, incident lung cancer (ICD-9: 162)
Tumor stage and histology (if available)

Dietary calcium intake
Plasma or serum samples

Gender, age, race/ethnicity, place of residence, date of blood draw, family history of cancer and lung cancer, previous history of lung diseases or bone diseases (fractures, osteoporosis, etc), alcohol consumption, menopausal status, hormone therapy use, bisphosphonate use, body mass index, physical activity, dietary calcium intake, dietary magnesium intake, dietary phosphorus intake, use of calcium-containing supplements, use of multivitamin supplements, total caloric intake, passive smoking (if available) or cotinine level (if measured from other lung cancer projects), and 25-hydroxyvitamin D concentration (if available; if not available, it will be measured in the proposed project)

Yes

Either serum or plasma samples are required. No special processing is necessary.